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Obesity-related liver disease remains a critical global health challenge, underscoring the need to elucidate the molecular mechanisms underlying hepatic inflammation and metabolic dysfunction, and to identify novel therapeutic targets. This study aimed to determine whether erythropoietin (EPO) modulates soluble epoxide hydrolase (sEH) and lipid mediator pathways to ameliorate hepatic inflammation and metabolic dysfunction in high-fat diet (HFD)-induced obese mice. Male C57BL/6 mice were fed HFD with or without EPO treatment, and metabolic phenotyping, including glucose tolerance testing and homeostasis model assessment of insulin resistance, was performed. Hepatic histology and quantitative real-time polymerase chain reaction were conducted, together with flow cytometry to assess macrophage polarization, western blotting for sEH, and targeted liquid chromatography-tandem mass spectrometry profiling of cytochrome P450 epoxygenase-derived epoxides. EPO treatment improved glucose metabolism, reduced hepatic steatosis, lowered Ccr2, Mcp1, and Tnfα expression, promoted a shift of hepatic macrophages toward an M2 (anti-inflammatory) phenotype, downregulated hepatic sEH protein levels, and increased both hepatic and plasma concentrations of epoxygenase-derived epoxides. These findings indicate that EPO suppresses hepatic sEH and favors pro-resolving lipid mediator signaling, suggesting a potential therapeutic avenue for obesity-related hepatic inflammation.

Hepatocellular carcinoma (HCC) represents an extremely complex and heterogeneous malignant tumor. Protein palmitoylation, a highly conserved and pivotal form of post-translational protein modification, is extensively implicated in cancer progression and exerts a regulatory role in immune responses. Nevertheless, the prognosis significance and therapeutic potential of palmitoylation-related genes (PRGs) in HCC remain incompletely explored. In the present study, we systematically analyzed multiple transcriptome cohort samples from the TCGA, ICGC and GEO databases, including the TCGA-LIHC, ICGC-LIRI, GSE16757, GSE54236, GSE14520, GSE45267 and GSE36376 cohorts. Subsequently, within the TCGA training cohort, a PRGsSig comprising three hub PRGs, namely HSP90AA1, CTHRC1, and PTDSS2, was constructed via machine learning algorithms. Then, the efficacy of this PRGsSig on prognosis prediction was assessed in the training and validation cohorts. Further analysis of immunotherapy response indicated that patients with low PRGsSig scores benefited more from treatment. Additionally, remarkable disparities were observed between patients in different signature score groups in terms of clinical characteristics, tumor mutation burden, tumor microenvironment, and potential drugs. Furthermore, among the three hub PRGs, PTDSS2 was significantly upregulated in HCC cells and its knockdown significantly inhibited the proliferation and metastasis of HCC cells. In conclusion, we established a robust PRGsSig that offers valuable insights for prognostic prediction and informs treatment strategies in HCC.

The chronic and refractory infected wounds of diabetes are primarily attributed to the persistent bacterial infection and the inhibition of wound healing caused by hypoxia. Hydrogel with intelligent drug delivery systems hold significant potential in the treatment of diabetic wounds. Herein, we have developed an glucose-responsive intelligent hydrogel named as CF-CPGaMPN, which incorporates polyvinylpyrrolidone-coated calcium peroxide (PVP@CaO₂) nanoparticles, catalase, and gallium-polyphenol (GaMPN) nanoparticles. The borate ester bonds in the CF-CPGaMPN hydrogel break under high glucose conditions, releasing GaMPN nanoparticles, thereby achieving glucose-triggered on-demand drug release. The CF-CPGaMPN hydrogel not only inhibits various microorganisms but also continuously releases oxygen, thereby promoting the healing of diabetic infection wounds. Furthermore, the multicellular ecosystem surrounding the CF-CPGaMPN hydrogel is also explored, and the diverse cellular heterogeneity is analyzed by single-cell RNA sequencing, highlighting the critical roles of Neutrophils, Fibroblasts, and Epidermal cells in diabetic infected wound. In addition, CF-CPGaMPN hydrogel inhibits the Neutrophil extracellular trap (NET) formation and alleviates the cellular hypoxic environment to improve diabetic wound healing. In conclusion, the CF-CPGaMPN hydrogel not only provides a promising drug release strategy for the healing of diabetic infected wounds, but also contributes to the rational design of customized hydrogels for biomedical use targeting different cellular functions.

Fragment-based Drug Discovery (FBDD) is a proven methodology for the discovery of new therapeutics. After the identification of small molecular fragments, subsequent steps are guided by the "Design, Make, Test" (DMT) cycle. During the "Design" phase, chemical modifications are proposed that generate Structure-Activity Relationship information, improve interaction profiles and physicochemical properties. In the "Make" phase, designs are synthesised into viable compounds, with an emphasis on feasibility, scalability and the incorporation of novel chemistries enabling broad chemical space sampling. Finally, the "Test" phase evaluates these compounds through a series of assays, identifying binders and enabling Structure-Activity Relationship models that guide subsequent designs. Within DMT cycles, fragment progression - the process of converting initial hits into more potent follow-up lead compounds - is an essential component, but has many challenges associated with it. Here, we review such challenges along with recent developments designed to mitigate them.

Selective neuronal vulnerability is a hallmark of Alzheimer's disease (AD), yet the molecular basis of resilience remains poorly understood. Using single-nucleus and spatial transcriptomics to compare neocortical regions affected early (prefrontal cortex, precuneus) or late (primary visual cortex) in AD, we identified a resilient excitatory population in layer 4 of the primary visual cortex expressing RORB, CUX2, and EYA4. Layer 4 neurons in association neocortex shared molecular signatures of resilience. Early-stage resilient neurons upregulated genes associated with synapse maintenance, synaptic plasticity, calcium homeostasis, and neuroprotection (GRIN2A, RORA, NRXN1, NLGN1, NCAM2, FGF14, NRG3, NEGR1, CSMD1). We identified KCNIP4, which encodes a voltage-gated potassium channel-interacting protein, as a key resilience factor consistently upregulated during early stages of AD pathology. AAV-mediated overexpression of Kcnip4 in male App^SAA mice reduced the expression of activity-dependent genes Arc and c-Fos, suggesting compensatory mechanisms against neuronal hyperexcitability. Our dataset provides a resource for investigating mechanisms underlying resilience to neurodegeneration.

Chronic obstructive pulmonary disease (COPD) is characterized by chronic airway inflammation and is closely linked to oxidative stress. This study aimed to identify and validate key oxidative stress-related genes and pathways involved in COPD using integrated bioinformatics and experimental approaches. Public COPD datasets were obtained from the Gene Expression Omnibus (GEO) database, and oxidative stress-related genes were retrieved from the GeneCards database. Differentially expressed genes (DEGs) were screened and analyzed for functional enrichment. Machine-learning algorithms, including Least Absolute Shrinkage and Selection Operator (LASSO) regression and Random Forest, were used to identify hub genes and evaluate diagnostic value by calculating the area under the receiver operating characteristic (ROC) curve (AUC). Single-cell RNA sequencing (scRNA-seq) data were analyzed to determine the distribution of hub genes across different cell types. Finally, a COPD combined oxidative stress cell model was established using human bronchial epithelial cells (BEAS-2B), and key gene expression was experimentally validated. We identified 76 overlapping genes associated with both COPD and oxidative stress, mainly enriched in necroptosis, JAK-STAT, MAPK, and related pathways. 12 hub genes were screened using machine-learning methods. Single-cell analysis showed that TPPP3 and VEGFA were predominantly expressed in epithelial cells. Experimental validation confirmed the bioinformatics predictions at the gene level. This study identified and validated 12 oxidative stress-related hub genes in COPD, highlighting TPPP3 and VEGFA as key genes enriched in epithelial cells and potentially involved in tissue remodeling. These findings not only provide insights for exploring new therapeutic strategies but may also serve as potential diagnostic biomarkers or candidate therapeutic targets for COPD.

Phelan-McDermid Syndrome (PMS), primarily linked to SHANK3 haploinsufficiency, presents with complex neurodevelopmental features, including developmental regression, whose underlying mechanisms are poorly understood. This study investigated the impact of SHANK3 disruption across multiple levels, from gene expression in patient-derived iPSC neurons to in vivo brain network activity. RNA-sequencing of iPSC-derived neurons from PMS patients with SHANK3 disruption only (n = 9) and controls (n = 7) revealed dysregulation in differential gene expression and co-expression modules linked to cell cycle, RNA metabolism, and metabolic pathways in SHANK3-mutated neurons. All modules were correlated with PMS regression and enriched for genes implicated in neurodevelopmental or neurodegenerative disorders, such as autism, ADHD, and Alzheimer's disease. At the cellular level, SHANK3-mutated cultures exhibited increased proliferation of neural progenitors and intermediate progenitor markers. Differentiated neurons showed reduced morphological complexity, specific changes in postsynaptic marker density and puncta size, and electrophysiological characteristics suggestive of neuronal hyperexcitability. Electroencephalography (EEG) in a PMS patient cohort (n = 20) compared to controls (n = 30) demonstrated hyperconnectivity and excessive high-frequency oscillations, suggesting altered neural network dynamics. In summary, the use of different analytical approaches suggested that SHANK3 haploinsufficiency disrupts neurodevelopmental trajectories and revealed that regression in PMS may share common genes and pathways with neurodegeneration. We also characterized molecular and neurophysiological markers that can be useful in therapeutic protocols for PMS.

<h4>Background</h4>Sheep have diversified into distinct breeds worldwide through both natural adaptation and human-driven selection, with hybridization serving as an effective strategy for rapid trait improvement. The Tianhua mutton sheep (TMS) is a novel breed derived from crossing South African Mutton Merino (SAMM) with Gansu alpine fine-wool sheep (GAFS). After nearly two decades of selective breeding, TMS has developed great meat quality traits and impressive cold tolerance at high altitudes. To study the genetic mechanism and provide new insights into phenotypic variation, we analyzed the genetic diversity, population structure, and selective signatures of TMS based on whole-genome sequencing of 55 TMS, 11 SAMM, and 197 public sheep genomes worldwide.<h4>Results</h4>Population genetic analysis revealed that TMS forms a distinct branch, with a pedigree composition showing an approximate 5:3 ratio of SAMM to GAFS lineages, consistent with the breeding design. Genetic diversity assessment showed that TMS exhibits higher genetic diversity and a lower inbreeding coefficient than commercial sheep from Africa, the Americas, and Europe, suggesting that TMS has considerable breeding potential to be tapped. Genome-wide scanning using the F_ST and XP-EHH methods was also performed to detect the signatures of selection in TMS, with significance thresholds set at Z(F_ST) >2.57 and XP-EHH >2.31. Functional annotation analysis revealed that the selected genes were related to meat quality traits, high-altitude adaptation, and disease resistance. Specifically, genes such as PLA2G10, SAMD12, CKMT2, ACOT12, and TNS3 are implicated in the processes related to fat metabolism. ZNF280D, RANBP3L, CSRP1, TNNI1, and AGBL4 are related to muscle growth and development. ABCB1 regulates energy metabolism via ATP transport to enhances low-oxygen adaptation, while NOTCH3, FBXO32, and LAMA1 regulate cardiopulmonary function and reduce pulmonary hypertension. Additionally, ATM, GALNTL6, and B4GALT5 may improve disease resistance and enhance environmental adaptability.<h4>Conclusion</h4>The results provide valuable insights for investigating the genetic mechanisms underlying TMS fine traits, enhancing TMS breeding, and developing mutton sheep suited to high-altitude and cold environments. Furthermore, it also indicates that hybrid breeding represents an effective strategy to provide a source of phenotypic variation for local adaptation and rapid acquisition of agronomically important traits.

<h4>Objective</h4>Disrupted neurofluid regulation may contribute to neurodegeneration in Huntington disease (HD). Because neurofluid pathways influence waste clearance, inflammation, and the distribution of central nervous system (CNS)-delivered therapeutics, understanding their dysfunction is increasingly important as targeted treatments emerge. We aimed to evaluate structural and physiological changes in two key neurofluid components, the choroid plexus (ChP), which produces cerebrospinal fluid (CSF), and the parasagittal dural (PSD) space, a major CSF outflow pathway, across the HD spectrum and in relation to CSF flow dynamics.<h4>Methods</h4>PSD and ChP volumes were assessed using a validated deep learning pipeline on 3-Tesla T₂-weighted and FLAIR MRI. CSF flow at the cerebral aqueduct was measured with phase contrast MRI, and ChP perfusion was quantified using pseudo-continuous arterial spin labeling MRI. Linear regression models assessed the relationships between PSD and ChP volume, CSF flow kinetics, ChP hemodynamics, disease severity, disease exposure, and disease presentation, adjusting for age, sex, and intracranial volume.<h4>Results</h4>80 HD participants and 65 age-matched healthy controls were included. HD showed significantly larger ChP and PSD volumes (p < 0.01) and reduced ChP perfusion (p < 0.01). Greater CAG repeat expansion correlated with larger PSD and ChP volume and lower ChP perfusion (p < 0.01). These alterations were associated with worse motor impairment (p < 0.01).<h4>Interpretation</h4>HD is associated with structural and functional alterations in neurofluid pathways. These findings suggest relevance for disease mechanisms and for optimizing CSF-based therapeutic delivery, highlighting the need for further mechanistic studies.

Induced-proximity therapeutics have emerged as a transformative paradigm in chemical biology and drug discovery, enabling selective control of cellular processes beyond conventional inhibitors. Between 2020 and 2025, major progress has been achieved across five modalities: proteolysis-targeting chimeras (PROTACs), molecular glues, lysosome-targeting chimeras (LYTACs), autophagy-targeting chimeras (AUTACs) and related tethering strategies, and ribonuclease-targeting chimeras (RIBOTACs). Each exploits endogenous degradation or regulatory pathways using chemically engineered bifunctional or monofunctional small molecules, thereby expanding the druggable proteome and transcriptome. This review provides a comparative analysis of their underlying organic chemistry, design principles, and mechanistic diversity. We highlight structure activity relationships, linker optimization, and chemical motifs that govern induced proximity and degradation efficiency. Advances in ligand discovery, modular synthetic methodologies, and strategies to improve pharmacokinetics and tissue selectivity are emphasized. Schematic diagrams illustrate key mechanistic steps, offering a visual framework for comparing similarities and differences across approaches. While prior reviews have focused on mechanistic and pharmacological aspects, our perspective emphasizes synthetic strategies, linker chemistry, SAR studies, and ligand optimization principles that underpin each degrader class. We examine how advances in synthetic design, modular assembly, and chemical reprogramming of ligases or receptors have broadened therapeutic potential. By critically assessing strengths, limitations, and chemical challenges across modalities, we propose a unifying organic chemistry perspective that distinguishes induced-proximity strategies from conventional small-molecule inhibition and outlines future opportunities in degrader design.

<h4>Purpose</h4>The relationship between Obstructive sleep apnea (OSA) and hypercoagulability remains unclear. To address this uncertainty, the present study combined observational and Mendelian randomization (MR) analyses to assess the associations of OSA and coagulation markers.<h4>Patients and methods</h4>We conducted an observational study of 790 patients with OSA, evaluating associations between OSA severity and coagulation markers, including activated partial thromboplastin time (APTT), prothrombin time (PT), and fibrinogen (Fib). Multivariate linear regression adjusted for age, gender, body mass index (BMI), and comorbidities. Additionally, we performed a large-scale Mendelian randomization analysis using two East Asian OSA genome-wide association study (GWAS) datasets (Million Veteran Program [MVP], n=6550; Taiwan Precision Medicine Initiative [TPMI], n=316351) as exposures, and East Asian coagulation GWAS data from BioBank Japan (BBJ) as outcomes (APTT: n=37767; Fib: n=18348; PT: n=58110). Multivariable MR (MVMR) with body mass index (BMI)(TPMI GWAS, n=191458) was performed to assess residual direct effects of OSA.<h4>Results</h4>Severe OSA showed higher Fib (<i>p</i>-value<0.01) and shorter PT (<i>p</i>-value<0.05) and APTT (<i>p</i>-value<0.05) than mild-moderate OSA. Multivariate regression analysis showed T90 (the percentage of time oxygen saturation is below 90%) and MSaO2 (mean oxygen saturation) were associated with Fib (β=-0.259; β=-0.224, <i>p</i>-value<0.001). While OSA severity is observationally associated with subclinical hypercoagulability, these significances vanished after adjusting for BMI and are not supported by genetic evidence since MR analyses provide no evidence for a moderate or clinically meaningful independent causal effect between genetic OSA liability and coagulation markers. MVMR confirmed no residual direct effect of OSA on coagulation after accounting for BMI.<h4>Conclusion</h4>Severe OSA is associated with subclinical hypercoagulability, but this relationship is confounded by BMI. Genetic evidence does not support a moderate or clinically meaningful causal role for OSA in coagulation dysfunction, urging a paradigm shift toward obesity management as the primary strategy to reduce thrombotic risk in OSA patients.

<h4>Background</h4>Recurrent implantation failure (RIF) remains clinically unresolved at this stage. Hydroxychloroquine, as an immunomodulator, is still lacking clinical evidence, but it is being used by increasing numbers of reproductive centers and physicians worldwide, so a well-designed randomized controlled trial (RCT) is urgently needed to elucidate whether hydroxychloroquine can improve pregnancy outcomes in patients with RIF.<h4>Methods and analysis</h4>In this study, we plan to recruit 686 volunteers who will undergo IVF/ICSI at 5 reproductive centers from 6 December 2022. Participants will be randomized to two parallel groups and treated with hydroxychloroquine sulfate tablets or placebo from the start of endometrial preparation to 14 days after frozen embryo transfer (if not pregnant) or to 12 weeks of pregnancy (if pregnant). The primary outcome is live birth rate, and the secondary outcomes include biochemical pregnancy rate, clinical pregnancy rate, embryo attachment rate, first trimester abortion rate and ongoing pregnancy rate, birth weight, pregnancy and perinatal complications, congenital anomaly, and other adverse events.<h4>Discussion</h4>This study aims to evaluate whether hydroxychloroquine (HCQ) improves pregnancy outcomes in patients with recurrent implantation failure (RIF). Secondary objectives include comparative analysis of gestational complications between the intervention and control groups.<h4>Trial registration</h4>ChiCTR2100047584 [Chinese Clinical Trial Registry (ChiCTR): registered on 20 June 2021]. LM2021267 [Ethics Committee of Peking University Third Hospital].

In the Learning Early About Peanut Allergy (LEAP) study, participants in the peanut consumption group, at 60 months of age, had higher levels of peanut-specific IgG4 (psIgG4), a biomarker of immune modulation, compared to those in the peanut-avoidance group. We investigated the genetic determinants of psIgG4 among participants who consumed peanuts. Using whole-genome sequencing data, we performed a genome-wide association study (GWAS) for psIgG4 in the LEAP peanut consumption group participants (N = 267). We generated a cumulative genetic score from the identified loci and evaluated its association with psIgG4 levels in LEAP. The association was then assessed for replication in two independent peanut oral immunotherapy (PnOIT) trials, IMPACT and POISED. We identified 45 variants that reached suggestive significance (p < 1 × 10^-5), mapping to 17 independent loci in the LEAP peanut consumption group; none of these variants were associated with the psIgG4 levels in the avoidance group, highlighting a potential gene-by-environment (GxE) interaction. One locus on chromosome 2 showed regulatory signatures for SEPT2, a gene involved in epithelial barrier function. The genetic score was significantly associated with psIgG4 among LEAP consumers (β = 0.433; p = 1.20 × 10^-58) in the discovery cohort and IMPACT PnOIT participants (β = 0.287; p = 0.02) in an independent testing cohort. No association was observed in older POISED PnOIT participants (β = -0.029; p = 0.79). Identification of the SEPT2 locus in participants protected from peanut allergy (PA) suggests involvement of epithelial barrier pathways in modulating immune responses. Findings across all three trials emphasise the importance of GxE interactions, specifically the interplay between genetics and oral peanut exposure. Taken together, the findings indicate that early, sustained peanut consumption, combined with genetic factors, promotes a protective immune response to peanut allergens. Trial Registration: LEAP: NCT00329784; IMPACT: NCT03345160; POISED, NCT02103270.

<h4>Purpose</h4>Colorectal-based brain metastasis formation is a rare and late event in colorectal cancer (CRC) patients and is associated with poor survival. Compared with other metastatic sites, the knowledge about copy number variation (CNV) in brain metastases is still very limited. To get more information about CNVs, we applied SNP array to analyze chromosomal regions with a higher density of SNP markers.<h4>Methods</h4>Genome-wide high resolution single nucleotide polymorphism (SNP) array (CytoScan™ HD) analyses were carried out in matched colorectal-based lung and brain metastases of two patients.<h4>Results</h4>Brain metastases harbored more CNVs (77 CNVs) than pulmonary metastases (24 CNVs). Not previously described specific CNVs were: gain of 1p36.33-p36.32, 4p16.3-p16.1, 6q27, 12q24.33, 16p13.3, as well as 16p12.1-p11.2 in lung metastases and gain of 1p36.33-p36.21, 5q11.1-q13.2, 21q22.2-q22.3, 22q11.21-q12.2, as well as 22q12.3-q13.33 in brain metastases. Furthermore, we found 20 copy-neutral loss of heterozygosity (cn-LOH) regions exclusively in brain metastases, of which 11 cn-LOH regions have not been previously described.<h4>Conclusion</h4>Brain metastases of CRC showed more cn-LOH regions than lung metastases. Potentially affected genes within these regions could influence signaling pathways (e.g., PI3K/AKT signaling) as well as transcriptional processes. Perspectively, increased awareness of specific genetic characteristics can potentially increase the chance of early diagnosis of brain metastases, which could contribute to improved treatment options.

Head and neck squamous cell carcinoma (HNSCC) exhibits significant survival disparities by ancestry. This review explores how genetic ancestry shapes the clinical and molecular features of HNSCC, providing insights into the molecular mechanisms underlying these disparities. We reveal the variation in gene expression, mutations, copy number alterations, and DNA methylation patterns between ancestral groups. These insights highlight the potential for more personalized, ancestry-informed therapies, advancing equity in cancer treatment.

The molecular circadian clock is a ubiquitous transcriptional-translational feedback loop that regulates CNS function, glial responses, and neurodegenerative pathology. The nuclear receptors REV-ERB-α (<i>Nr1d1</i>) and REV-ERB-β (<i>Nr1d2</i>) are components of the core circadian clock which regulate metabolism, neuroinflammatory responses, synaptic pruning, and protein aggregation, though the cell type-specific effects and relative compensatory effects of REV-ERB-α AND -β in the brain are unknown. To study the CNS functions of REV-ERBs, we developed mouse lines with global or astrocyte-specific, conditional knockout of both REV-ERB-α and -β. We demonstrate that inducible postnatal global deletion of both REV-ERB-α and -β unmasks extensive transcriptional changes in the brain in disease-relevant pathways such as protein catabolism, complement, and oxidative stress which are not observed with REV-ERB-α deletion alone, and drives spontaneous astrocyte reactivity. Astrocyte-specific deletion of REV-ERB-α/-β recapitulates this spontaneous astrocyte reactivity phenotype, indicating that REV-ERBs regulate astrocyte activation in a cell-autonomous manner downstream of the core circadian clock. Upstream transcription factor analysis revealed that REV-ERB-α/-β repress transcription of <i>Stat3</i>, and astrocytic deletion of REV-ERBs induced astrocytic STAT3 expression and downstream STAT3-mediated gene expression, providing a mechanistic link to the astrocyte reactivity shift. Dual REV-ERB deletion enhanced astrocyte alpha-synuclein uptake and protein degradation in vitro and mitigated alpha-synuclein spreading pathology in an in vivo model of Parkinson's Disease. This study reveals REV-ERBs as regulators of astrocyte function and implicates astrocyte REV-ERBs as potential therapeutic targets to prevent synucleinopathies and other neurodegenerative pathologies.

In magnetic resonance imaging (MRI), direct dipole-dipole interactions between paramagnetic metal centers and water molecules govern the <i>T</i>₁ relaxation of contrast agents. Metal chelates featuring multiple unpaired electrons have long dominated MRI contrast agents. Despite theoretically offering more paramagnetic centers per probe, nanoparticle-based contrast agents have struggled because of the insufficient direct dipolar interactions with water, impeding their clinical adoption. Here, we present an electrophilicity-engineered magnetic sensor (EEMS), which leverages high-electronegativity metal atoms to enhance the electrophilicity of paramagnetic centers in nanosensors, enabling direct electrophilic catalytic dipolar interactions (ECD) with water for enhanced MRI. EEMS demonstrates robust <i>T</i>₁ contrast with a longitudinal relaxivity of 23.2 per millimolar per second at 9 tesla, visualizing tumor cell clusters as small as 68.5 micrometer in vivo. ECD-MRI allows detecting and precise resection of axillary lymph nodes containing dormant tumor cell clusters, achieving 100% survival in mice 100 days postsurgery. EEMS-enhanced ECD-MRI presents a transformative imaging principle for noninvasive visualization of previously undetectable biological entities.

The human genome harbors millions of noncoding sequence variants. Genome-wide association studies (GWAS) have identified thousands of robust associations linking noncoding variants to human physiological traits and complex diseases. Integrative approaches, including expression quantitative trait locus mapping, epigenomic profiling, and precise genome editing in trait-relevant cell types, enable the identification of effector genes and underlying regulatory mechanisms, such as long-range chromatin interactions, that mediate the effects of noncoding variants. Investigations of blood pressure (BP)-associated noncoding sequence variants have uncovered previously unrecognized roles of genes in BP regulation, reinforced the human genetic relevance of established BP regulatory pathways, and elucidated specific regulatory mechanisms by which noncoding variants influence gene expression and BP. Studies of orthologous noncoding genomic regions in animal models corresponding to human genomic regions harboring BP-associated variants have demonstrated substantial effects on BP, suggesting that the phenotypic impact of noncoding sequence variants may be large within human subgroups. Continued expansion of functional studies of trait-associated noncoding sequence variants, together with advances in mapping molecular quantitative trait loci and epigenomic landscapes, will provide novel insights directly relevant to human biology and disease and essential for understanding humans as molecular systems.

Glioma, especially high-grade gliomas like glioblastoma, are aggressive and highly treatment-resistant brain tumors with poor prognosis. Despite advances in therapeutic strategies, the mechanisms driving glioma progression remain inadequately understood, with dysregulated apoptosis playing a central role in malignancy. RNA-binding proteins(RBPs) such as the poly(A)-binding protein family, including PABPC5, have gained attention due to their roles in regulating mRNA stability and translation. PABPC5’s role in glioma pathogenesis remains poorly characterized despite its identification as a key regulator of the mitochondria-associated programmed cell death index (mtPCDI) in low-grade glioma (LGG). This study thoroughly investigated the oncogenic functions of PABPC5. TCGA-GBM analysis revealed significant decreasing trend in PABPC5 expression with increasing glioma grade(G2 vs. G3:P < 0.05; G2vsG4: P < 0.0001;). However, immunohistochemistry and Western blotting demonstrated that PABPC5 protein levels were elevated in Grade 4 tumors compare to Grades 1–3. Notably, expression levels showed no correlation with overall survival (P = 0.92). Lentiviral infection of PABPC5 knockdown in glioblastoma cells (U87/U251) significantly suppressed malignant phenotypes while inducing pro-apoptotic molecular alterations: upregulated BAX and cleaved caspase−3 protein expression, enhanced ROS production, and reduced Bcl−2 and caspase−3 levels. In vivo validation showed that PABPC5 knocdown substantially inhibited subcutaneous tumor growth and increased apoptosis (TUNEL:3.164-fold increase,P < 0.001). Consistent with in vitro findings, immunofluorescence(IF)analysis of tumor tissues confirmed altered Bcl−2/cleaved-caspase−3 expression patterns and mitochondrial ultrastructural changes. This work establishes PABPC5 as a novel biomarker for glioma pathological grading and reveals its functional role in apoptosis regulation. These findings provide a mechanistic foundation for developing therapeutic strategies targeting apoptosis-resistant glioma.

GPR99 holds promise as a potential therapeutic target for inflammatory diseases. GPR99 exhibits marked basal activity when coupled with the G_q protein, its activation mechanism remains elusive. In this study, we determine the high-resolution structure of the human GPR99 in complex with the heterotrimeric miniG_q in the ligand-free state using cryo-electron microscopy (cryo-EM). Our structural analysis and functional experiments reveal that the second extracellular loop (ECL2) of GPR99 occupies the orthosteric binding pocket, thereby promoting receptor self-activation. Moreover, we observe structural water molecules forming an extended polar network that connects ECL2 and the binding pocket, intricately linking these elements to the receptor's functional activity. Structure-based mutagenesis experiments further validate the critical role of ECL2 in intracellular signal transduction of GPR99, offering a structural basis for exploring its function under physiological or pathological conditions. Additionally, these findings also provide a crucial theoretical framework for the design of drugs targeting GPR99.

Hereditary angioedema (HAE) with C1 inhibitor deficiency is a rare disease characterized by unpredictable episodes of tissue swelling (angioedema), which, in most cases, occur first under the age of 18 years, and entail a significant burden of disease not only for the patients but also for their families. Clinical symptoms of HAE are not specific, which may cause difficulties in differential diagnosis. Additionally, if not appropriately treated, HAE attacks can be life-threatening. The international HAE guidelines published so far have focused mainly on adults. A guideline that refers to the age-specific characteristics of pediatric patients, both in terms of diagnosis and management, was therefore needed. The International Steering Committee and Taskforce developed recommendations and provided evidence-based grading based on expert opinion and strength of evidence. Recommendations were presented to, discussed, and electronically voted by healthcare professionals during the 14th C1 Inhibitor Deficiency and Angioedema Workshop in Budapest, Hungary, 2025. This international guideline will ensure early diagnosis, standardized and up-to-date treatment, and promote the availability of effective therapies for all pediatric patients affected with this rare disease. It also draws attention to the importance of establishing HAE centers and registries, which solicit specialist care and research of the disease.

BackgroundBlood metabolites are crucial in various aspects of human health. However, current evidence regarding the role of circulating metabolites in various cardio-cerebrovascular diseases (CVDs) is limited. Mendelian randomisation (MR) can be used to provide information about these metabolites.ObjectivesOur primary aim was to investigate the causal relations between human blood metabolites and the risk of 10 CVDs.MethodsWe conducted a two-sample MR study. Data on 486 human blood metabolites were obtained from a genome-wide association study (GWAS) involving 7824 participants. Outcome data were sourced from the most recent large-scale GWAS meta-analysis by FinnGen (R9) on various CVDs. The inverse variance-weighted (IVW) model was used as the primary method for this analysis. Moreover, we performed sensitivity analyses, which included heterogeneity testing, horizontal pleiotropy testing and leave-one-out analysis, to evaluate the robustness and credibility of the findings.ResultsThis study identified 36 known metabolites potentially associated with 10 CVDs, and sensitivity analyses showed no significant heterogeneity or pleiotropy.ConclusionsOur study utilised systematic MR analyses and provides evidence for the causal relations between blood metabolites and CVDs. This sheds new light on the potential mechanisms underlying various CVDs and holds significant implications for screening, preventing and treating these conditions.

BACKGROUND: Transcriptomic profiling technologies have advanced the analysis of biological and toxicological responses. However, substantial differences in probe design, dynamic range, gene coverage, and preprocessing pipelines across platforms introduce artifacts that limit cross-study integration and hinder the reuse of historical datasets. We aim to develop computational methods for accurate cross-platform translation to maximize the value of legacy resources. RESULTS: We present TransPlatformer a deep learning framework for translating gene expression profiles across heterogeneous toxicogenomics platforms. TransPlatformer employs a novel attention-based architecture to map high-dimensional fold-change vectors from legacy microarray technologies to current platforms. Models are trained and evaluated using DrugMatrix, spanning three technological generations. We investigate mixed-tissue, single-tissue, and cross-tissue training paradigms and benchmark performance against multilayer perceptron and matrix-completion baselines. In mixed-tissue training, TransPlatformer achieves a greater than 50% reduction in mean absolute error (0.043 vs. 0.09) and nearly doubles Pearson correlation (≈ 0.71 vs. 0.37) relative to baseline methods. Importantly, TransPlatformer preserves rare but biologically meaningful over- and under-expressed signals, with mean absolute error below 0.22. Single-tissue models yield further improvements for well-represented organs, such as a 10% reduction in liver mean absolute error, while underscoring the need for data augmentation strategies in low-sample tissues.ra CONCLUSIONS: TransPlatformer provides an effective and scalable computational solution for cross-platform transcriptomic translation. By enabling biologically faithful harmonization of gene expression data, the proposed approach facilitates the reuse of legacy toxicogenomics datasets, enhances downstream biomarker discovery, and supports more reproducible predictive modeling in toxicology.

<h4>Background</h4>Patients with type 2 diabetes (T2D) are at an increased risk of developing acute myocardial infarction (AMI), yet the role of 5-hydroxymethylcytosines (5hmC) changes in T2D-associated cardiovascular events remains poorly understood. Despite therapeutic advances, patients with T2D who suffer an AMI continue to exhibit markedly elevated cardiovascular risk and poor prognosis, underscoring the need for improved detection and risk assessment.<h4>Methods</h4>We evaluated genome-wide 5hmC modifications in circulating cell-free DNA (cfDNA) for their value as noninvasive biomarkers for AMI in T2D. Genome-wide mapping of 5hmC in plasma cfDNA were obtained using the 5hmC-Seal technique from 225 participants, including 57 T2D patients with AMI (T2D + AMI), and 168 T2D patients without AMI (T2D + non-AMI). A weighted 5hmC-based model was developed to compute an epigenetic score for each individual, which was first derived from baseline cross-sectional data to discriminate between the patients from the two groups. Subsequently, the utility of the epigenetic score for predicting composite cardiovascular outcomes (CCO) was assessed prospectively within the same cohort using 5-year longitudinal follow-up data.<h4>Results</h4>255 differential 5hmC-gene bodies (P < 0.05) associated with T2D + AMI, involving pathways related to cardiac functions, such as heart process and heart contraction. A seven-feature weighted model based on 5hmC signatures was developed for distinguishing T2D + AMI from T2D + non-AMI, which achieved an area under the curve (AUC) of 99.2% (95% CI 98.1-100.0%) in training set and 95.6% (95% CI 89.8-100.0%) in testing set. Furthermore, we established and tested a 5hmC-derived weighted epigenetic score for predicting cardiovascular events in diabetic population (eSCORE-CARD) over a median follow-up of 5.3 years. Multivariate Cox regression analysis showed that the eSCORE-CARD values were significantly associated with an increased risk of CCO (HR = 4.25; 95% CI 1.41-12.80; P < 0.05). When combined with other established risk tools (SCORE2-Diabetes and SCORE2-OP), eSCORE-CARD demonstrated improved performance achieving an AUC of 76.4% (95% CI 65.9-86.8%), which holds promise for detection and prognosis of cardiovascular events in T2D.<h4>Conclusions</h4>Our work indicated specific 5hmC signatures implicated in AMI with T2D background, and provided the foundation for a comprehensive cardiovascular risk management tool for diabetic population.

Neurodegenerative disorders involve the gradual breakdown of neurons, leading to problems with thinking, movement, and mental health. More evidence is emerging about the important roles of non-coding RNAs (ncRNAs). CircRNAs are a type of ncRNA formed through back-splicing and are widely present in the mammalian brain. They play crucial roles in brain development and mainly regulate gene expression and post-transcriptional processes by acting as molecular sponges for miRNAs and RBPs. eRNAs are another class of ncRNAs. They are produced from enhancer regions of the genome and act as vital regulatory elements in gene expression. There is increasing evidence that abnormal levels of circRNAs and eRNAs can be found in many human diseases, including neurodegenerative conditions. This suggests they could have important clinical uses in these illnesses. The unique stability and disease-specific expression patterns of circRNAs and eRNAs in biofluids like blood and cerebrospinal fluid make them strong candidates for noninvasive biomarkers in neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis. Additionally, their roles in crucial pathological pathways open new opportunities for treatment. This includes strategies that target RNA, such as antisense oligonucleotides or miRNA sponges, to influence gene expression networks. This review gathers recent findings to propose that circRNAs and eRNAs might introduce a new layer of regulation in neurodegeneration, providing exciting possibilities for real-world applications.

Fibroblasts are a group of stromal cells that contribute to the scarring process in many neurological conditions in the central nervous system (CNS). Recently, single-cell sequencing efforts allowed an in-depth understanding of their cell origins and subpopulation profiles. Meanwhile, vascular leptomeningeal cells and the "type A pericytes" were also proposed as CNS fibroblast-like cells in the last decade by histological, functional and transcriptomic analysis. While these cells share overlapping features with CNS fibroblasts, the inconsistent use of nomenclature and partially overlapping cell-type markers is likely to cause confusion within the growing field of neurobiology. In this review, we will delineate the current knowledge of subtypes and functions of CNS fibroblasts, with special focus on the source of PVFs during development and the nomenclature origins of other similar cell types. We aim to provide comprehensive insights into these cells with similar functions or transcriptomic profiles.

X-linked recessive (XR) complete MCTS1 deficiency underlies Mendelian susceptibility to mycobacterial disease (MSMD) in patients with bacille Calmette-Guérin (BCG) disease. We investigated the genotypic and phenotypic landscape of four new unrelated families from four distinct countries. Three patients had adverse reactions to the BCG vaccine, whereas another patient was not vaccinated with BCG and had an infection with <i>Mycobacterium abscessus</i> at 16 years of age. Whole-exome sequencing of the probands revealed hemizygosity for rare germline <i>MCTS1</i> variants. In addition to a previously reported loss-of-expression (LOE) and loss-of-function (LOF) variant, we identified three new <i>MCTS1</i> variants. The p.L170* and E60Kfs5* variants are LOF, whereas p.W175* is hypomorphic when overexpressed. Thus, we report four new MSMD patients with complete or partial forms of XR MCTS1 deficiency, including three patients with newly discovered genotypes. A diagnosis of partial or complete XR MCTS1 deficiency should be considered in boys and men with MSMD displaying mycobacterial infection.

Chronic pain is currently being viewed as a major public health epidemic, especially as there is a higher rate of chronic pain amongst US adults than for other chronic diseases like diabetes, depression, and hypertension. A better understanding of the mechanisms driving chronic pain is needed to develop new and effective analgesics. Animal models have traditionally been valuable tools in pain research, but there have been many setbacks in translating preclinical findings into new therapeutics. This has brought a new sense of urgency for a better understanding of chronic pain pathophysiology in humans. To address this gap, a comprehensive and systematic study of human nociceptive pathways, integrating molecular, cellular, and systems-level data is critical for identifying clinically relevant targets and improving translational success in pain therapeutics. Fortunately, this mission has currently been aided by current advances in the next-generation sequencing coupled with the increased availability of nociceptive tissues from patients with chronic pain. As such, we and others have just begun initial studies examining the transcriptomic changes occurring in the dorsal root ganglia of subjects with chronic pain. Transcriptomic analyses of dorsal root ganglia have so far examined painful conditions including radicular/neuropathic pain, diabetic painful neuropathy, and rheumatoid arthritis. Here, we describe what has been learned from these transcriptomic studies so far, which shows that additional multiomics-driven research is needed to fully understand and target human nociceptive processes.

<b>Background/Objectives</b>: Diffuse large B-cell lymphoma (DLBCL) is an aggressive and heterogeneous malignancy, for which predicting clinical outcomes remains challenging. Although immune-checkpoint pathways are known to influence tumor biology, the impact of their germline variants on DLBCL susceptibility and prognosis has not been fully elucidated. <b>Methods</b>: Variants in PD-L1 gene <i>CD274</i> (rs4143815, rs822336), and miR-155 gene <i>MIR155HG</i> (rs767649, rs1893650), assessed by TaqMan assays in 99 DLBCL patients and 113 age- and sex-matched healthy controls, were associated with clinicopathological features, treatment response, overall survival (OS), relapse-free survival (RFS), and disease susceptibility. <b>Results</b>: The PD-L1 variant rs822336 was significantly associated with relapse status (<i>p</i> = 0.005) and RFS (<i>p</i> = 0.008), with the wild-type GG genotype showing the poorest RFS that remained independent in the multivariate Cox analysis (HR = 2.387, <i>p</i> = 0.003). Conversely, rs4143815 showed a nominal association with treatment resistance (<i>p</i> = 0.026), while patients carrying the GG genotype had worse OS (<i>p</i> = 0.006). In susceptibility analyses, miR-155 variant rs767649 showed a nominal association with DLBCL risk, with the rare AA genotype showing an increased risk of DLBCL (OR = 5.234, <i>p</i> = 0.045), which did not remain significant after Bonferroni correction. <b>Conclusions</b>: In a hypothesis-generating manner, these findings suggest that PD-L1 genetic variants may predominantly influence disease progression and outcomes, while miR-155 variation may contribute to DLBCL susceptibility. These findings highlight germline immunogenetic variants as stable, treatment-independent markers that may inform future studies on risk stratification and prognosis in DLBCL.

Pancreatic cancer (PC) is one of the most lethal malignancies worldwide, characterized by late diagnosis, aggressive progression, and limited responsiveness to current therapeutic strategies. Although extensive genomic analyses have identified key driver protein-coding genes (PCGs), therapeutic approaches targeting individual genes have shown limited clinical benefit. This limitation highlights the molecular complexity of PC, where tumor progression is governed by regulatory networks that extend beyond genetic alterations. Non-coding RNAs (ncRNAs), which constitute nearly 98% of the human genome, have emerged as regulators of gene expression in cancer. Among them, microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) regulate oncogenic processes, including aberrant signaling activation, tumor microenvironment remodeling, epithelial-mesenchymal transition, immune evasion, and resistance. Beyond their independent functions, lncRNAs, miRNAs, and mRNAs form an integrated regulatory network known as the lncRNA-miRNA-mRNA TRIAD, enabling control of gene expression. Such network-based regulation provides a framework for multi-target therapeutic strategies. Moreover, the rapid responsiveness and disease-specific expression patterns of ncRNAs suggest strong potential as diagnostic and prognostic biomarkers in PC, where early detection remains challenging. This review summarizes the regulatory roles of PCGs, miRNAs, and lncRNAs in PC and highlights the lncRNA-miRNA-mRNA TRIAD as a framework for understanding gene regulatory networks.

<h4>Background</h4>Anti-GD2 monoclonal antibody effectively treats high-risk neuroblastoma (HR-NB) by recruiting NK cells for antibody-dependent cellular cytotoxicity (ADCC). We recently developed a cell product containing mature, cytotoxic γδ T and NK cells (GADEKILL), and its potential use as a novel immunotherapy for HR-NB has been investigated.<h4>Methods</h4>The GADEKILL γδ T and NK cells were analyzed by flow cytometry for the expression of activating and inhibitory receptors and for cytotoxicity against NB, both with and without dinutuximab-β, at a 1:1 effector-to-target ratio. NB cell lines with high and low/absent GD2 expression, as well as patient-derived 3D tumor spheres, all GD2-expressing, were used as targets. Comparative analyses were performed between GADEKILL NK and purified NK cells obtained from the same donor leukapheresis. Furthermore, a panel of NB cell lines was tested for the expression of B7H6 (i.e., NKp30 ligand), Human influenza hemagglutinin-tag (HA-TAG) and calreticulin (i.e., NKp46 ligands), and butyrophilin (BTN)2A1 and BTN3A1/2/3 (i.e., TCRVδ2 ligands), and the impact on GADEKILL cytotoxicity was assessed.<h4>Results</h4>Compared to their purified counterparts, GADEKILL NK cells showed: (i) higher expression of NKp30 and NKp44 and lower expression of CD16 and NKG2D, (ii) greater cytotoxicity (CD107a⁺) against GD2^- NB cells, (iii) stronger induction of lysis in low GD2-expressing NB cells and patient-derived 3D tumor spheres, and (iv) comparable ADCC. In addition, both γδ T and NK cells degranulated and consistently induced lysis in a panel of NB cell lines and patient-derived 3D tumor spheres expressing B7H6, calreticulin, HA-TAG, BTN2A1, and BTN3A1/2/3 consistently. Finally, NB cell lysis positively correlated with B7H6 and BTN2A1, and B7H6-blocking experiments revealed a significant decrease in target cell lysis when cells highly expressing B7H6 were used as targets.<h4>Conclusions</h4>Our study demonstrated the potential antineuroblastoma activity of the GADEKILL, supporting its therapeutic use, particularly in the context of relapsed/refractory R/R HR-NB with low GD2 expression.

<h4>Background</h4>Acute pancreatitis (AP) ranges from mild to severe, and severe disease frequently causes multi-organ damage, with intestinal injury being a major complication. The mechanisms underlying SAP-induced intestinal injury remain unclear, particularly regarding spatial cellular reorganization and functional interactions.<h4>Methods</h4>This study constructed a severe acute pancreatitis (SAP) rat model and employed single-nucleus RNA sequencing (snRNA-seq) and spatial transcriptome sequencing (stRNA-seq) technologies to systematically analyze the dynamic changes in intestinal cellular composition, spatial distribution, and function during SAP-induced intestinal injury.<h4>Results</h4>snRNA-seq identified 18 major ileal cell populations spanning epithelial, immune, stem/TA, and stromal compartments. SAP was associated with compositional remodeling characterized by downward trends in Lgr5⁺/Olfm4⁺ stem cells, TA1, goblet cells, and Paneth cells, with a reciprocal increase in enterocytes, although most proportion changes did not reach statistical significance at the animal level. Spatial transcriptomics independently captured SAP-associated tissue remodeling, including a significant reduction in Paneth cells accompanied by increases in fat cells, macrophages, goblet cells, and TA2 cells. Across epithelial lineages, SAP induced a transcriptional shift toward immune interaction with up-regulation of antigen presentation-related genes (e.g., Cd74) and down-regulation of antimicrobial/barrier effectors (e.g., Defa24, Pla2g2a, Dmbt1), which was corroborated by spatial expression patterns and spatially variable gene programs enriched for host defense responses. Pseudotime analysis suggested a redistribution of epithelial states along the stem/TA-to-enterocyte continuum, with relative depletion of early states and expansion of enterocyte-dominant states in SAP. CellChat analysis revealed globally intensified intercellular communication and nominated FN1 as the pathway with the highest differential information flow, with Lgr5⁺ stem cells predicted as prominent FN1 senders targeting enterocytes and smooth muscle cells. SCENIC identified reduced activity and expression of Hmga2/Myb regulons in stem compartments, and immunofluorescence showed decreasing trends in Hmga2/Myb-positive Olfm4⁺ and Lgr5⁺ stem cells in SAP.<h4>Conclusions</h4>Integrated single-nucleus and spatial transcriptomics reveal that SAP is accompanied by spatially organized ileal remodeling, epithelial immune-interacting rewiring, and altered neighborhood architecture, together with an ECM-centered FN1 signaling axis and attenuated Hmga2/Myb-associated regulatory programs in stem compartments. These findings provide a spatially informed cellular framework and generate testable hypotheses for mechanisms underlying impaired epithelial regeneration during SAP-associated intestinal injury.

<h4>Objective</h4>This study evaluated the static cyclotorsion component (SCC) and dynamic cyclotorsion component (DCC) during femtosecond laser-assisted stromal <i>in situ</i> keratomileusis (FS-LASIK) and identified factors influencing these components.<h4>Methods</h4>This retrospective cross-sectional study included 196 patients (392 eyes) with refractive errors who underwent bilateral FS-LASIK. The cohort comprised 105 men and 91 women (mean age: 23.88 ± 6.90 years). An IntraLase femtosecond laser machine was used to create the corneal flap, whereas an AMARIS excimer laser machine was used to ablate the corneal stroma. Parameters related to SCC and DCC were collected using an eye tracker, which also calculated the registration success rate. Preoperative and intraoperative variables were analyzed.<h4>Results</h4>Static cyclotorsion was successfully registered in 80.6% of eyes, with corneal flap thickness [odds ratio (OR) = 0.903, <i>p</i> < 0.01] and laser cavity temperature (OR = 1.26, <i>p</i> = 0.047) identified as significant factors associated with registration failure. No significant correlation was found between absolute SCC and preoperative or intraoperative variables (all <i>p</i> > 0.05). For DCC, 98.7% of eyes were successfully registered, with a median amplitude of 1.00 degrees (0.78-1.30 degrees). Spearman's correlation analysis revealed significant correlations between age, equivalent spherical power, laser cavity temperature, actual ablation time, and DCC amplitude (all <i>p</i> < 0.05).<h4>Conclusion</h4>Thin corneal flap and elevated laser cavity temperature are risk factors associated with SCC registration failure. Age, equivalent spherical power, laser cavity temperature, and actual ablation time were correlated with dynamic cyclotorsion, highlighting the need for precise tracking in FS-LASIK.

A 7-year-old boy was admitted to the hospital for abdominal pain, vomiting, and edema. Examinations revealed microvascular hemolytic anemia, thrombocytopenia, acute kidney injury, and hypocomplementemia. He was diagnosed with atypical hemolytic uremic syndrome (aHUS), and treatment was initiated with a methylprednisolone pulse, followed by cyclophosphamide, mycophenolate mofetil, and fresh frozen plasma infusion, leading to remission. At the age of 12, he developed numbness in his fingers and pain in his toes while being febrile. At the age of 17, he presented with aggravated toe pain, renal impairment (creatinine concentration of 156 μmol/L; eGFR of 38.4 mL/min/1.73 m²), and remarkable left ventricular hypertrophy accompanied by obstruction of the left ventricular outflow tract. Screening for Fabry disease (FD) revealed a decrease in alpha-galactosidase A (<i>α</i>-GalA) activity <1.00 μmol/L/h, along with the identification of a variant of the α-GalA gene: c.611G > A (p.Trp204Ter). His father had a history of hypertrophic cardiomyopathy (HCM). Therefore, whole-exome sequencing of the pedigree was performed, and the results revealed an additional likely pathogenic MYH7 variant (c.1063G > A) (p.Ala355Thr). The final diagnoses included FD (classic), aHUS, and HCM (Fabry disease and MYH7 variants). Despite undergoing enzyme replacement therapy for FD, the patient's renal function progressed to chronic kidney disease (CKD) stage 5, and there was no improvement in cardiac hypertrophy after 2 years. This case highlights the diagnostic challenges and complex management of patients with multiple rare disorders and a compounded genetic background.

Mitophagy, a selective autophagic pathway that clears damaged or dysfunctional mitochondria, has emerged as a promising therapeutic approach. Mitophagy maintains a delicate balance between cell survival and death, while mounting evidence suggests that it predominantly promotes tumor cell survival under stress, particularly in responses to cancer therapy. Moreover, aberrant regulation of mitophagy results in cancer pathology with characteristic hallmarks, including remodeling of metabolic plasticity, maintenance of cancer stem cell characteristics, and immune regulation of the tumor microenvironment. This review synthesizes multifaceted roles of mitophagy in cancer biology, from tumor initiation and progression to therapy responses. It also summarizes molecular mechanisms underlying mitophagy. How cancer cells exploit mitophagy to survive therapy has been harnessed to develop therapeutic strategies. We elaborate the evolution of mitophagic therapy from small-molecule modulators to nanotechnology-based targeted delivery systems. Finally, we highlight the promise of targeting mitophagy in overcoming treatment resistance and improving clinical outcomes for patients.

<h4>Introduction</h4>The Warburg effect is a rare but often fatal condition in patients with malignancies. This phenomenon, known as type B lactic acidosis, is defined by lactatemia without tissue hypoxia or hypoperfusion, in contrast to type A lactic acidosis, which usually results from either or both.<h4>Case presentation</h4>A male patient in his seventies with a newly diagnosed diffuse large B-cell lymphoma is admitted to the intensive care unit due to severe metabolic derangements with hypoglycemia and lactatemia. Extensive investigations ruled out alternative etiologies, strongly suggesting the Warburg effects as the underlying mechanism. Despite hemodynamic instability, chemotherapy was initiated and resulted in initial clinical improvement.<h4>Conclusion</h4>We propose a stepwise approach to improve the management of patients with suspected type B lactic acidosis.

Wild jujube serves as an important source of natural antioxidants and holds significant economic value in the food and health industries. However, the core antioxidant components in its fruits and their mechanisms of action remain unclear, and the substantial variation in metabolite composition across different provenances severely hinders the development of functional wild jujube products. In this study, untargeted metabolomics combined with network pharmacology was employed to screen 87 potentially active components from the metabolic profile of wild jujube and to identify 41 core antioxidant targets. Among these, seven targets-TP53, AKT1, SRC, STAT3, JUN, EP300, and ESR1-were strongly correlated with antioxidant activity. On the basis of topological and Pearson correlation analyses, 26 key antioxidant compounds were screened from the metabolic profile of wild jujube. Finally, molecular docking revealed the most stable binding pairs: cymarin-ESR1 (-11.3 kcal/mol), procyanidin B1-SRC (-10.8 kcal/mol), and Licoisoflavone A-JUN (-9.9 kcal/mol). This study systematically elucidates the metabolic characteristics of wild jujube from different provenances, provides an in-depth investigation of its antioxidant active ingredients and their mechanisms of action, reveals the physiological functions of wild jujube, and establishes a theoretical foundation for the extraction of its bioactive compounds and the development of functional health foods.

<title>Abstract</title> <p> <bold>Background</bold> . Central respiratory chemoreceptors are not definitively identified, but the retrotrapezoid nucleus is the main center whose absence is characteristic of congenital central hypoventilation syndrome (CCHS). Intense chemosensory stimuli activate circuits that are wake- or attention-promoting, such as the raphe, which modulates chemoreflexes. The main objective of our study was to assess whether residual central CO ₂ chemosensitivity in CCHS is related to serotonin transporter gene polymorphisms (homozygous long (ll) variant versus variants with short form, ss or sl). Twenty-three children with CCHS and <italic>PHOX2B</italic> pathogenic variants had peripheral (controller gain measurement) and central CO ₂ chemosensitivity assessment (hyperoxic, hypercapnic test), resting end-tidal PCO ₂ (PETCO ₂ ) measurement and <italic>5-HTT</italic> polymorphism determination. <bold>Results</bold> . The percentages of the ll, ls, and ss genotypes were 5/23 (22%), 14/23 (61%) and 4/23 (17%), respectively, and were not influenced by <italic>Phox2b</italic> mutations. Both central (0.16 L/min/mmHg [0.02; 0.33] versus 0.21 [0.06; 0.41], P=0.551) and peripheral (0.47 L/min/mmHg [0.026; 0.71] versus 0.67 [0.24; 1.26], P=0.602) CO ₂ chemosensitivities were not significantly different when comparing the L group (n=5) and the S group (n=18), while their resting PETCO ₂ values were different; the L group presented a higher PETCO ₂ value than the S group did (49.3 mmHg [46.9; 53.0] versus 42.0 [36.7; 44.8], P=0.014). <bold>Conclusions</bold> . The CO ₂ chemosensitivity of children with CCHS was not related to <italic>5-HTT</italic> transporter polymorphisms, whereas the ll homozygous variant contributed to resting alveolar hypoventilation. </p>

Enhancers are distal cis-regulatory elements that orchestrate spatiotemporal gene expression patterns in response to developmental cues and environmental stimuli. Genetic and epigenetic alterations in enhancers are associated with the initiation and progression of human diseases, including cancers. Over the past few decades, accumulating evidence has revealed that a class of nascent RNA transcripts, known as enhancer RNAs (eRNAs), is broadly transcribed from active enhancers. These eRNA species contribute to complex and dynamic gene regulatory networks under both physiological and pathological conditions through diverse mechanisms. Notably, dysregulated eRNA expression has been reported across various cancer types and is often correlated with patient survival outcomes. Consequently, eRNAs are emerging as promising biomarkers and therapeutic targets for cancer treatment. This review provides a comprehensive summary of the current understanding of eRNAs and their mechanisms of action in gene regulation. We discuss the critical roles of eRNAs in both health and disease and highlight their diagnostic and prognostic value, as well as their therapeutic potential in cancer. Additionally, we review current strategies for targeting RNA transcripts, including eRNAs, and discuss the major challenges in developing eRNA-targeted therapies. Finally, we propose future directions for advancing eRNA-based interventions in the treatment of human diseases, including cancer.

Iron is an essential nutrient for almost all organisms. However, excess iron generates reactive oxygen species and causes tissue injuries. Iron is implicated in idiopathic pulmonary fibrosis (IPF). In this study, we examined iron accumulation in fibrotic lung fibroblasts and the underlying mechanisms. We hypothesize that the downregulation of Solute Carrier Family 40 Member 1 (SLC40A1) results in iron accumulation in lung fibroblasts of IPF patients. Using a Prussian Blue iron staining, we found that iron accumulated in the fibrotic region of the lungs from IPF patients and bleomycin- and asbestos-induced lung fibrosis mice. Iron was partially co-localized with the fibroblast marker vimentin in IPF lungs. By using publicly available single cell RNA sequencing datasets, we identified SLC40A1, the only known gene involved in iron export, as a downregulated gene in alveolar fibroblasts of IPF. The downregulation of SLC40A1 was confirmed in the lung fibroblasts isolated from IPF patients and bleomycin-treated mice. The treatment of human lung fibroblasts with transforming growth factor-β1 (TGF-β1), a major cytokine elevated in IPF, reduced SLC40A1 mRNA and protein expression. TGF-β1 downregulated SLC40A1 expression via SMAD3 as determined by chromatin immunoprecipitation and luciferase promoter reporter assays. Knockdown of SLC40A1 using lentiviral shRNAs or TGF-β1 treatment induced iron accumulation in human lung fibroblasts as determined by live cell ferrous dye staining using a SiRhoNox-1 probe. Knockdown of SLC40A1 enhanced the iron-induced lung fibroblast activation. In summary, we conclude that the downregulation of SLC40A1 caused by TGF-β1 induces iron accumulation in lung fibroblasts, resulting in fibroblast activation.

Glutamatergic neurons represent 40% of neurons in the human central nervous system. Glutamate accounts for approximately 90% of all excitatory neurotransmitters. Previous research reports the presence of glucagon-like peptide-1 (GLP-1) receptors on neurons that produce glutamate. Herein, we aim to evaluate whether GLP-1 receptor agonists' (GLP-1 RAs) modulate glutamatergic signaling and whether GLP-1 RAs' anti-obesity effects are mediated through the glutamatergic system. We conducted a systematic review of extant literature published on PubMed, Ovid and Scopus databases from inception to March, 2025. Identified studies were screened independently by two reviewers (S.W. and G.H.L.) using the Covidence platform. We sought to include in vitro, in vivo, and human clinical studies. A total of 31 studies were identified as meeting eligibility for an inclusion in this review. No human studies were identified. Across the included preclinical and pharmacologic studies, GLP-1 RAs were associated with increased glutamate release, NMDA/AMPA receptor activation and increased release of neurotrophic factors associated with neurogenesis, neurodifferentiation, and synaptic plasticity. In addition, GLP-1 RA-induced suppression of food intake was reported to be dependent on AMPA, but not NMDA, receptor signaling. The effect of GLP-1 RAs on feeding behavior is mediated via central glutamatergic signaling. A comprehensive mechanistic framework mediating GLP-1 RA activity implicates crosstalk between GLP-1 and ionotropic glutamate receptors. The aforementioned trends instantiate a need to evaluate the therapeutic efficacy of GLP-1 RAs for disparate neuropsychiatric disorders. Conducting target engagement studies of GLP-1 RAs with the glutamatergic system in humans is a future research vista.

Neurodegenerative diseases such as Huntington's Disease (HD) have a significant impact on healthcare accessibility and costs. A fatal genetic condition, characterized by the progressive loss of striatal neurons, HD is hindered by the lack of endogenous repair in the adult brain. Recent efforts toward protecting neural circuits through neurotrophic support using brain-derived neurotrophic factor (BDNF) have been suboptimal due to the protein's short half-life and limited diffusion. Addressing this, adeno-associated viral vectors (AAV) can be employed as a delivery tool to spatially transduce cells, enabling the localised production of BDNF with consequential neuron protection and/or plasticity, yet present their own constraints. To overcome these known challenges of AAV gene delivery, an injectable, physiologically stable hydrogel-mimic of the brain's extracellular matrix was fabricated to encapsulate the AAVs. This smart system both shielded and constrained the AAV; optimising transfection and therefore elevated and sustained BDNF presentation at the target site. Here, we achieved high neuroprotection using AAVDJ-BDNF delivered through a hydrogel formed via self-assembling peptide nanoscaffolds. These findings support the notion that the spatiotemporal release of BDNF to striatal neurons, facilitated by engineered biomaterial delivery systems, demonstrates tremendous promise by enhancing the efficacy of gene therapy targeted at slowing neurodegenerative disease progression.

Sorting Nexin 27 (SNX27), a key regulator of synaptic receptor trafficking and endosomal recycling, has been implicated in maintaining synaptic homeostasis and cognitive function. To date, variants in SNX27 have been reported in a small number of patients across three publications with severe neurodevelopmental phenotypes. However, the genetic and functional landscape of SNX27-related disorders remains poorly understood, and further evidence is needed to confirm its association with disease and to better delineate the associated phenotype. Two unrelated Pakistani families with a total of five affected individuals segregating a neurodevelopmental disorder were investigated via exome or genome sequencing. This revealed a novel homozygous frameshift variant in family I [NM_001330723.2: c.75dup; p. (Ser26Valfs*85)], predicted to be targeted by nonsense-mediated decay. In family II, a novel homozygous missense variant [NM_001330723.2: c.929 T>C; p. (Met310Thr)] was found within the FERM-like region of the SNX27 protein, which is critical for retromer complex interaction. Comparison of five cases described in this study with previously reported six cases reinforces the presence of consistent "core" clinical features-global developmental delay, intellectual disability, speech delay, behavioral abnormalities, seizures, and motor dysfunction in all assessed cases. Other features such as dental anomalies, failure to thrive, and dysmorphisms occurred variably in few. Affected individuals with predicted loss-of-function variants typically presented with a more severe phenotype. Thus, core features of SNX27-related neurodevelopmental disorders (NDDs) are intellectual disability, developmental, and speech delays. This study, alongside prior reports, augments the genetic and phenotypic spectrum of SNX27-associated NDDs. The novel frameshift variant p.(Ser26Valfs*85) is predicted to severely disrupt SNX27 function, causing profound neurodevelopmental impairment, whereas the missense p.(Met310Thr) in the FERM-like region is associated with a milder phenotype. Comparative analyses with previous reports reveal a spectrum from early lethality to long-term survival with intellectual disability in SNX27-linked families. These findings underscore the importance of SNX27 in neurodevelopment and further validate its link to a neurodevelopmental disorder.

Devil Facial Tumour Diseases (DFTD), threatening Tasmanian devils, consist of two distinct transmissible cancers, DFT1 and DFT2, with differing origins and geographic spread. We investigated the metabolic differences between DFT1 and DFT2, examining cell viability, metabolic outputs, and bulk gene expression. Using both DFT1 and DFT2 cell lines and biopsies, we found that glycolysis, oxidative phosphorylation, glutamate metabolism, and fatty acid synthesis are all essential for the survival of both tumour types. However, DFT2 exhibited higher rates of glycolysis and lactate generation compared to DFT1. This coincided with elevated ATP production, cholesterol biosynthesis, and ROS generation, as well as an increased reliance on fatty acid metabolism. Furthermore, DFT2 is less metabolically adaptable than DFT1, being unable to switch to oxidative phosphorylation as DFT1 can when required. These metabolic changes in DFT2, in conjunction with its higher growth rate, suggest a more aggressive cancer phenotype than DFT1. Our findings highlight distinct metabolic adaptations in DFT2 that may contribute to its competitive advantage.

Lung adenocarcinoma (LUAD) displays significant morphological and molecular heterogeneity both within and between tumors. This heterogeneity, coupled with the complexities of the tumor microenvironment (TME), notably influences LUAD progression and patient prognosis. Integrating mass-spectrometry-based proteomic data from human tumors with corresponding multi-omics data opens significant opportunities for comprehensive and systematic cancer proteogenomic analyses. In our study, we analyzed LUAD proteogenomic data from the Cancer Proteome Atlas Program (CPTAC) to conduct a systematic molecular classification by integrating multi-omics data (genomic, transcriptomic, and proteomic) using ten clustering algorithms. This approach successfully identified three distinct molecular subtypes with notable biological heterogeneity: metabolic pathway activation, cell cycle pathway activation, and immune modulation. The metabolic pathway activation subtype was characterized by significant upregulation of metabolic pathways, this subtype showed enhanced mRNA expression and protein abundance of genes related to fatty acid and bile acid metabolism (e.g., MLYCD, ACSM3, ACSL5, ACSS1, and MAOA). It also exhibited a notably higher frequency of EGFR mutations compared to other subtypes. The cell cycle pathway activation subtype was defined by the activation of cell cycle signaling pathways, this subtype demonstrated amplification of the PCNA gene and significantly increased mRNA and protein expression levels of key cell cycle-related genes, such as CCNB1 and CDK1. Importantly, a high mutation frequency, copy number deletions, and downregulation of the tumor suppressor gene STK11 were observed, leading to the inactivation of its tumor suppressor function. This subtype also showed potential sensitivity to various cell cycle inhibitors. The immune modulation subtype was characterized by high immune cell infiltration and low tumor purity. This subtype exhibited multi-omics activation of the Ras signaling pathway, including MET amplification, increased GRB2 expression, decreased PEBP1 expression, and RET activating mutations. These findings suggest that this subtype may benefit from a combination of immunotherapy and targeted therapy against the Ras signaling pathway. Based on the expression profiles of 300 subtype-specific marker genes, we validated the molecular characteristics and clinical relevance of these three subtypes in the TCGA-LUAD and GSE50081 cohorts. Moreover, to enhance clinical applicability, we developed a rapid and cost-effective multi-instance model based on pathological images combined with deep learning techniques. This deep learning model demonstrated excellent performance in multi-omics subtype predictions. In, conclusion, this study systematically elucidates the molecular heterogeneity of LUAD through a multi-omics integration strategy, establishes a clinically relevant molecular classification system, and provides a theoretical foundation for developing personalized treatment plans for LUAD.

<h4>Background</h4>To enhance early liver disease detection, a clinical pathway integrating reflex AST testing and automated AAR reporting was implemented. We aim to evaluate the long-term effectiveness of introducing reflex AST testing by assessing its impact after implementation in 2 regions of Wales.<h4>Methods</h4>We applied a quasi-experimental, Difference-in-Difference approach to evaluate the introduction of the reflex AST:ALT pathway in Wales (January 2010 to December 2023). Outcomes were the monthly incidence rate of (1) chronic liver disease (including cirrhosis) and (2) cirrhosis in the 2 intervention regions versus the control regions.<h4>Results</h4>In total, 78,917 individuals with liver disease were included in the study. A significant increase in cirrhosis diagnoses was observed in both regions (first region: incidence rate ratio=1.24, 95% CI: 1.15-1.34, p<0.001; second region: incidence rate ratio=1.16, 95% CI: 1.02-1.33, p=0.028). The incidence of composite chronic liver disease (including cirrhosis) increased transiently in the second region only (incidence rate ratio=1.35, 95% CI: 1.16-1.56, p<0.001).<h4>Conclusions</h4>In this long-term, population-level evaluation, reflex AST:ALT testing increased cirrhosis detection in both regions and produced a short-term rise in chronic liver disease (including cirrhosis) diagnoses one region, strengthening the evidence of the pathway's effect on cirrhosis detection. Further study is warranted to understand regional variation.

Understanding the pathophysiological substrates of schizophrenia is a major challenge for current neuropsychiatric research. As part of a set of multi-omics experiments, we performed an extensive case-control proteomics study on 192 post-mortem tissue sections from prefrontal cortex from 96 individuals, including 47 cases with schizophrenia and 49 healthy controls. Using two independently measured cortical datasets, we identified 387 proteins differentially expressed between schizophrenia cases and controls at a 5% FDR threshold. This significantly regulated set of proteins contains genes located in GWAS-identified schizophrenia loci and proteins identified by pQTL analysis. Gene ontology analysis using GOAT provided evidence for regulation of several major protein categories, emphasizing downregulation of mitochondrial oxidative respiration, ribosomes and the proteasome, upregulation of kinases and (small) GTPases. SynGO analysis supports the notion of synaptic dysfunction in schizophrenia, with major regulators of pre- and postsynaptic function compromised. Our findings highlight the complex molecular dysregulation in schizophrenia, with mitochondrial function downregulated versus signaling and trafficking upregulated, and synapse function disrupted; in combination with prior avenues of research, these finding support a role for energy deficits compromising highly ATP dependent neuronal function as a target for therapeutic interventions.

Via a solid-state reaction route, magnetic composites of chicken eggshell-derived β-tricalcium phosphate (β-TCP, referred to as TCP in the composite system) and zinc-nickel spinel ferrite (ZNF; Zn_xNi_1‒xFe₂O₄, x = 0.2, 0.4, 0.6, or 0.8) were successfully fabricated. Discs were prepared by uniaxial pressing of milled ZNF/TCP powders and sintered at 1200 °C. Cytocompatibility of all composites was confirmed by SEM observations of human osteoblasts (h-OBs) and MTT assays. At 4-wt% ZNF addition, the composites containing Zn_0.8Ni_0.2Fe₂O₄ (Z8NF) exhibited the greatest extent of early cell spreading and were selected for further investigation. For Z8NF/TCP composites containing 4-12 wt% Z8NF, the 8-12 wt% samples demonstrated the highest levels of cell colonization, while MTT assays suggested non-cytotoxic behavior, with cell viabilities comparable to β-TCP. High-temperature sintering induced partial transformation of β-TCP to β-calcium pyrophosphate (β-CPP), as evidenced by XRD and Rietveld refinement. Increasing Z8NF content promoted β-CPP formation and increased composite porosity, whereas densification and Vickers hardness decreased accordingly. Rietveld refinement further indicated that the detectable crystalline Z8NF phase persisted as a minor yet stable secondary phase ( < 2 wt%) and did not participate in Ca-P lattice substitution. For the 8-12 wt% composites, saturation magnetization decreased with increasing Z8NF because of higher porosity and dilution by the non-magnetic β-TCP/β-CPP matrix, while coercivity increased owing to enhanced effective magnetic anisotropy in the more porous microstructure. Overall, the Z8NF/TCP composites combined biodegradability, bioactivity, and tunable soft-magnetic properties, suggesting their potential for bone repair and bone tissue engineering applications.

Electrochemical gradients are essential to the functioning of cells and form across membranes using active transporters. Here we show in contrast that condensed biomolecular systems-often termed condensates-sustain pH gradients without any external energy input. By studying individual condensates on the micrometre scale using a microdroplet platform, we reveal dense-phase pH shifts towards conditions of minimal electrostatic repulsion. We demonstrate that protein condensates can drive substantial alkaline and acidic gradients, which are compositionally tunable and can extend to complex architectures sustaining multiple unique pH conditions simultaneously. Through in silico characterization of human proteomic condensate networks, we further highlight potential wide-ranging electrochemical properties emerging from condensation in nature, while correlating intracellular condensate pH gradients with complex biomolecular composition. Together, the emergent nature of condensation shapes distinct pH microenvironments, thereby creating a regulatory mechanism to modulate biochemical activity in living and artificial systems.

BACKGROUND: Steatotic liver disease (SLD) is commonly associated with higher burden of cardiometabolic risk factors (CMRFs). This study aimed to examine the associations between CMRF count, patterns and risk of cardiovascular disease. METHODS: We included 10,121 UK Biobank participants (39% women) with MRI-confirmed liver steatosis. Latent class analysis was used to derive CMRF patterns based on 5 CMRFs (obesity, diabetes, hypertension, high triglycerides and low HDL). Cox models were used to estimate associations between CMRF count and patterns with incidence and mortality of cardiovascular disease (CVD), and all-cause mortality. RESULTS: Approximately 95% of SLD participants had ≥ 2 CMRFs. During a median follow-up of 4.9 years, 268 CVD events and 212 deaths were recorded. Higher CMRF count was independently associated with elevated risk of CVD (HR per each additional CMRF: 1.23 (1.08, 1.40)), CVD mortality (1.47 (1.07, 2.02)), and all-cause mortality (1.25 (1.08, 1.44)). Three distinct CMRF patterns were identified, reflecting varying levels of CMRF burden and demographic characteristics. While certain patterns with high CMRF burden were associated with increased CVD risk, the associations were substantially attenuated after adjusting for CMRF count. CONCLUSIONS: CMRF burden is a key determinant of cardiovascular risk in people with SLD, but data-driven CMRF patterns do not improve risk prediction beyond simple counts. CMRF count remains a practical measure of cardiometabolic burden.

Anxiety disorder is one of the most prevalent psychiatric diseases, with stress being a high-risk factor that functions by inducing neuroinflammation, particularly through the release of tumor necrosis factor α (TNFα). Although stress-induced transcription of TNFα is well documented, whether it also controls the proteolytic maturation of membrane-anchored TNFα precursor (proTNFα) remains unknown. Here we showed that the astrocyte-derived extracellular protein Netrin-1 was highly expressed in the mouse medial prefrontal cortex (mPFC) and down-regulated by restraint stress. Conditional knockout (cKO) of astrocytic Netrin-1 in astrocytes, both in embryo and adult, increased susceptibility to stress-induced anxiety. Mechanistically, Netrin-1 interacted with A disintegrin and metalloprotease 17 (ADAM17) and blocked ADAM17-mediated shedding of TNFα from proTNFα. Consequently, Netrin-1 deficiency elevated soluble TNFα and altered microglial morphology. Pharmacological neutralization of TNFα with Infliximab normalized anxiety-like phenotypes in stressed Netrin-1 cKO mice. Collectively, our data identify Netrin-1 as a critical brake on TNFα release and position the Netrin-1–ADAM17 axis as a tractable therapeutic target for TNFα-driven neuropsychiatric disorders.

Ethiopia, located at the intersection of Africa and Eurasia, is a hub of human genetic diversity and cultural richness. Its proximity to the Middle East has historically positioned it as a vital trade corridor connecting Asia, Europe, and Africa. Located along both the “out of Africa” and “back to Africa” human migration routes, Ethiopia has become one of the most genetically, ethnically, culturally and linguistically diverse countries in the world. This diversity is further shaped by adaptations to a wide range of environments, from the peaks of the Semien Mountains (4550 m or 14,928 feet above sea level) to the arid Danakil depression (100 m or 328 feet below sea level), both of which harbor rich fauna and flora. Despite its strategic location and rich genetic diversity, Ethiopian populations remain underrepresented in global genomics research. This review: (1) highlights key examples of genetic adaptations that shape the Ethiopian gene pool, including positive selection for high- and low-altitude adaptation, lactase persistence, UV exposure, disease resistance, sour taste perception, and metabolism, and (2) calls for genetics studies that incorporate the unique genetic evolutionary history of the Ethiopian population, which can generate important scientific insights. In the era of precision medicine, it is essential to include genetically diverse populations, such as Ethiopia’s, to ensure the advancement of clinical medicine for everyone.

The conversion of low-concentration CO₂ streams into fuel is highly desirable for industrial applications, avoiding energy-intensive CO₂ capture and concentration. Here, we report a highly active molecular electrocatalyst, fac-[Mn(CO)₃(bis-MeNHC)(MeCN)]⁺ (1-MeCN⁺), which enables the direct electrochemical reduction of near-atmospheric CO₂ concentrations to CO with up to 100% Faradaic efficiency. Voltammetric analysis at varying CO₂ concentrations reveals a clear transition between distinct kinetic regimes, shifting from pure kinetic control to a regime dominated by CO₂ depletion. Kinetic analysis in the 5%-100% CO₂ range reveals a first-order dependence on substrate concentration. Infrared spectroelectrochemistry confirms that the electrogenerated anionic catalyst remains active under extremely diluted CO₂ conditions. Computational modeling further supports that the CO₂-to-CO conversion mediated by the doubly reduced species is kinetically accessible at atmospheric CO₂ levels. This work demonstrates molecular electrocatalysis even at CO₂ concentrations as low as 420 ppm (i.e. atmospheric CO₂ partial pressure).

Oligonucleotide therapeutics are a new class of drugs that enable robust and sustained modulation of gene expression. However, achieving efficient delivery of small interfering RNAs (siRNAs) to tumors is a challenge for therapy. Here, we demonstrate that fully chemically modified siRNAs conjugated with an albumin-binding dendrimer are efficiently delivered to both neoplastic and stromal/immune cells within primary triple negative breast cancer mammary tumors. siRNAs were designed to selectively target insulin receptor substrate 2 (IRS2), a signaling adapter of insulin and insulin-like growth factor (IGF) signaling that has been implicated in aggressive breast cancers. These siRNAs reduced IRS2 expression in tumor and stromal cells without causing hyperglycemia, resulting in reduced tumor growth that was associated with decreased vascularization and alterations in macrophage polarization and the expression of EMT proteins. This work demonstrates that siRNAs can be delivered to neoplastic and specific stromal populations in mammary tumors and that they can effectively and specifically silence a driver of aggressive breast cancer.

The hypothalamus contains multiple regions, including the ventromedial hypothalamus (VMH) and arcuate (ARC), which are responsible for sex-differentiated functions such as endocrine signaling, metabolism, and reproductive behaviors. While molecular, anatomic, and sex-differentiated features of the rodent hypothalamus are well established, much less is known about these regions in humans. Here, we provide a spatially resolved single-cell atlas of sex-differentially expressed (sex-DE) genes in the human ARC and VMH. We identify neuronal populations governing hypothalamus-specific functions, define their spatial distributions, and show enrichment of sex-DE in retinoid metabolism- and retinoid receptor-regulated genes. Within the ARC and VMH, we find correlated autosomal expression differences localized to ESR1/TAC3-expressing and corticotropin-releasing hormone receptor 2 (CRHR2)-expressing neurons and extensive sex-DE genes linked to sex-biased disorders, including autism, depression, and schizophrenia. Our molecular mapping of disease associations to hypothalamic cell types with established roles in sex-divergent physiology and behavior provides insights into the mechanistic bases of sex bias in neurodevelopmental and neuropsychiatric disorders.

Chronic hepatitis B virus (HBV) infection is a major global health problem. Currently, existing antiviral drugs are difficult to achieve a functional cure for chronic hepatitis B (CHB). Therefore, it is necessary to develop new antiviral targets, especially those that can directly target HBV covalently closed circular DNA (cccDNA) in hepatocytes. Here, we identified a conserved SOX6 binding site in the enhancer I (ENI) region of the HBV genome, and found that SOX6 promotes the replication of multiple genotypes HBV through its HMG domain. Mechanistically, SOX6 binds to the conserved binding site located in the HBV ENI region through its HMG domain, thereby promoting HBV replication by enhancing the transcriptional activity of ENI. Moreover, cisplatin and doxorubicin not only promote HBV replication but also promote SOX6 expression. Knocking down the expression of endogenous SOX6 or mutating the SOX6 binding site in the HBV ENI region significantly weakens the direct promoting effect of cisplatin and doxorubicin on HBV replication. In summary, SOX6 promotes HBV replication by enhancing the transcriptional activity of HBV ENI through its HMG domain, suggesting that it can serve as a potential target for regulating HBV cccDNA transcription. In addition, SOX6 participates in the direct promotion of HBV replication by cisplatin and doxorubicin, providing new insights into the molecular mechanisms of tumor chemotherapy related HBV reactivation (HBVr) and potential targets for the prevention of HBVr during tumor chemotherapy.

<h4>Background & aims</h4>Mast cells (MCs) play a critical role in the pathogenesis of inflammatory bowel diseases (IBD), encompassing ulcerative colitis and Crohn's disease. Nevertheless, their regulatory impact on intestine stem cells (ISCs) compartment remains poorly characterized. We aim to study the effect of MCs on ISC-mediated epithelial regeneration in IBD.<h4>Methods</h4>The bulk RNA sequencing data of intestine tissues from patients with IBD were collected from the Mount Sinai Crohn's and Colitis Registry to explore the direct and indirect correlation of MCs with ISCs, stemness, and related pathways. Subsequently, the results were verified by experiments such as dextran sulfate sodium (DSS)-induced colitis in MC-deficient rats and C57BL/6 mice, and co-culture of bone marrow-derived mast cells and small intestinal organoids.<h4>Results</h4>Bulk RNA sequencing data analysis demonstrated significant MC activation in inflamed mucosa of patients with IBD, showing negative correlations with transcriptional signatures of ISC, stemness markers, and Wnt pathway activity. Genetic ablation of MCs in rats conferred protection against DSS-induced epithelial damage, exhibiting enhanced Lgr5 expression and Wnt/lrp6/β-catenin signaling activation compared with wild-type rats. Pharmacological stabilization of MCs with cromolyn sodium or intervention with a carboxypeptidase A inhibitor during the recovery phase of DSS-induced colitis promoted epithelial restoration in mice, evidenced by improved crypt architecture and upregulation of ISC-associated genes and proteins. In vitro co-culture experiments demonstrated MC-mediated suppression of intestinal organoid growth and Wnt/lrp6/β-catenin signaling pathway, reversible through Lrp6 activation and carboxypeptidase A3 inhibition. Mediation analysis coupled with neutrophils detection revealed an additional indirect regulatory axis involving MC-driven neutrophil recruitment to inhibit ISC-mediated epithelial repair.<h4>Conclusions</h4>Our findings establish that MCs play a pivotal role in inhibiting ISC-mediated epithelial regeneration by suppressing Wnt/lrp6/β-catenin pathway in IBD, directly through carboxypeptidase A3 secretion and indirectly through neutrophils recruitment.

Cells counteract proteotoxic conditions by launching transcriptional stress responses. While synthesis of heat shock proteins (HSPs) upon acute stress is well characterized, how distinct proteotoxic conditions reshape the transcriptome remains poorly understood. Here, we analyse polyA+ RNA expression under heat shock, HSP90 inhibition, and polyglutamine (polyQ) aggregation. We find fundamentally distinct transcriptional responses to proteotoxic stressors and a systemic deficiency of mice under chronic stress to launch acute responses. While heat shock and HSP90 inhibition induce chaperones, polyQ aggregation increases expression of RNAs linked to transcription repression, chromatin remodeling, and autophagy. Analysing wild-type and Huntington's Disease (HD) mice reveals tissue-specific transcriptional adaptations to polyQ, including repressed cell-type specific functions and altered energy metabolism. Despite profound reprogramming, remarkably few genes exhibit consistently increased (Acy3, Abhd1, Tmc3) or decreased (Fos) RNA levels across HD brain regions. These results emphasize cellular background in disease manifestation and support energy metabolism and detoxifying enzymes as therapeutic targets in late-stage HD. Moreover, the systemic deficiency of chronically stressed mice to launch responses challenges strategies that rely on induced transcription. Altogether, we characterize transcription signatures to proteotoxic stresses, identify key trans-activators driving proteotoxic stress responses, provide an interactive gene-by-gene viewer of global changes, and delineate tissue-specific transcription programs in HD mice.

Skeletal muscle is essential for voluntary movement and exhibits a remarkable capacity for regeneration following injury. NFIX, a member of the Nuclear Factor I (NFI) family of transcription factors, plays a critical role in both skeletal muscle development and regeneration. Despite its emerging importance, the molecular basis of NFIX-mediated DNA recognition and transcriptional regulation in skeletal muscle remains poorly defined. Here, we demonstrate that NFIX promotes key cellular processes in skeletal muscle cells, as siRNA-mediated knockdown of NFIX significantly reduces cell proliferation, increases apoptosis, and impairs differentiation. Transcriptomic analysis revealed that NFIX regulates a network of genes involved in muscle metabolism, stress responses, and immune inflammatory responses. Biophysical characterization showed that NFIX exists as a monomer in solution and binds palindromic DNA with a 1:1 stoichiometry. A high-resolution crystal structure of the NFIX_DBD bound to palindromic DNA reveals a monomeric binding mode driven by base-specific recognition of the TGGCA motif. Mutations that disrupt key DNA-contacting residues abolished both DNA binding and transcriptional activation in luciferase reporter assays. Together, these findings define the molecular mechanism of NFIX-dependent gene regulation in skeletal muscle and establish a structural framework for its function, providing new insights into the potential therapeutic targeting of NFIX in muscle diseases.

Understanding patterns and mechanisms underlying local adaptation is becoming increasingly important for species conservation amid anthropogenically driven environmental change. Alpine systems are experiencing particularly intense pressure from environmental change resulting from increased rates of warming and corresponding loss of snow and ice. We integrate morphological and genetic analyses to identify traits important for local adaptation in one of the highest elevation breeding birds in North America, the Sierra Nevada Gray-crowned Rosy-Finch. We performed an in-depth analysis of how traits with known links to thermoregulation in birds such as wing length, bill size, and feather microstructure vary between two populations at sites with contrasting climate and environmental conditions. We identified loci underlying these traits using a genome-wide association study and further examined regions of the genome related to altitude adaptation and cold tolerance using F_ST outlier tests. Together, these results indicate that temperature, food availability, and alpine landscape features may impose multifaceted and potentially conflicting selective pressures on morphological traits important to adaptation in alpine birds. Overall, this work represents one of the first in-depth analyses of the genetic basis of adaptation in an alpine specialist songbird.

Tissue regeneration is orchestrated by both intracellular signaling programs and extracellular matrix remodeling. Glycosaminoglycans (GAGs) are essential sugar chains ubiquitously expressed throughout the body. Their spatiotemporal turnover is an important part of normal organ biology and essential to tissue repair following injury. Glycoscience is a hot topic and is its role in organ physiology is being increasingly unraveled due to both scientific and technological advances. The mechanistic understanding of GAG regulation and manipulation is multidisciplinary effort, spanning biology, chemistry, materials science and translational medicine. This review broadly examines how GAG biology is naturally regulated and precisely controlled in health and disease, including data analysis from a stem cell-based model of liver disease. Despite being limited in types, GAGs successfully regulate complex cell and tissue level biology. We also discuss preclinical and clinical applications of GAGs, with a focus on biomaterials for tissue engineering and precision drug delivery, stressing their importance in biomedical engineering and clinical therapy. In addition, we outline state-of-art detection techniques and molecular modeling tools for analyzing GAG quantity, structure and interactions with other molecules. This review provides a timely and comprehensive overview of GAG biology highlighting their role in tissue repair and engineering, and outlines future directions for their design and next-generation therapies.

Fiber-forming polymers are increasingly used to control blood coagulation, either by accelerating the onset of hemostasis or by limiting thrombogenic events in contact with blood. Despite rapid progress in materials engineering, a unified view linking the molecular mechanisms of the coagulation cascade with specific design strategies of procoagulant and anticoagulant polymeric fibers is still missing. In this review, we summarize current knowledge on how natural and synthetic polymers interact with plasma proteins, platelets, and coagulation factors, emphasizing the role of fiber morphology, surface chemistry, charge distribution, and functionalization. Particular attention was paid to systems based on natural polysaccharides (e.g., chitosan, alginate, and cellulose derivatives), as well as synthetic polymers (e.g., PLA, PCL, polyurethanes, and zwitterionic materials). Two possible courses of action were described: their bioactivity may activate the contact pathway and/or support platelet adhesion or their ability to minimize protein adsorption and inhibit thrombin generation. We discuss how metal-polymer coordination, surface immobilization of heparin or nitric oxide donors, and nanoscale texturing modulate coagulation kinetics in opposite directions. Finally, we highlight emerging fiber-based strategies for achieving either rapid hemostasis or long-term hemocompatibility and propose design principles enabling precise tuning of coagulation responses for wound dressings, vascular grafts, and blood-contacting devices. This general compendium of knowledge on blood-material interactions provides a foundation for further design of biomaterials based on fiber-forming polymers and the development of manufacturing processes.

<h4>Background</h4>Curcumin is a biologically active substance present in turmeric. It has recently been suggested for its protective potential against a wide variety of chemical-induced toxicities.<h4>Purpose</h4>This systematic review aims to summarize current evidence on the protective effects of curcumin against chemical-induced toxicity, with particular emphasis on its impact on the male reproductive system.<h4>Methods</h4>A literature search was conducted using the major databases PubMed®, Scopus®, Web of Science®, and ScienceDirect®, up to December 2024. This review encompassed studies assessing curcumin's protective role against chemical toxicity, both <i>in vitro</i> and <i>in vivo</i>. Extracted data included the type of chemical agent, dosage, curcumin formulation, and reported toxicity outcomes.<h4>Results and discussion</h4>A total of 31 studies were included in the present review based on the established inclusion criteria. The toxicants studied contained heavy metals (lead and cadmium), pesticides (e.g., Malathion), and industrial solvents (notably titanium dioxide nanoparticles). Curcumin has demonstrated significant protective effects through multiple mechanisms, including antioxidant activity, anti-inflammatory effects, and modulation of detoxification enzymes. Interestingly, curcumin supplementation was associated with reduced oxidative stress markers and improved histopathological findings across various animal models. The effective dose varied widely across studies, with most showing positive effects at doses between 50 mg/kg and 200 mg/kg.<h4>Conclusion</h4>The results of this systematic review suggest that curcumin holds promise for preventing various chemical-induced toxicities. Its diversified mechanisms of action show promise as a therapeutic agent for the relief of chemical toxicity. Nonetheless, additional studies are required to determine the most effective dosing strategies, examine bioavailability, and assess the safety of long-term use.

Skin malignancies, including melanoma and non-melanoma cancers, are the most common cancers worldwide, with increasing incidence and fatality rates. Malignant melanoma (MM) is a highly aggressive cancer with poor prognosis, and despite various therapies, it remains a serious threat due to factors like tumor recurrence, drug resistance, and lack of effective treatments. Non-coding RNAs (ncRNAs) transcripts have gained attention due to their critical roles in regulating proliferation, angiogenesis, immune regulation, invasion, metastasis, and treatment resistance. Exosomes, biologically active lipid-bilayer extracellular vesicles secreted by various cell types, are also involved in cancer by carrying multiple bioactive molecules, including ncRNAs. Investigating the noncoding components of the transcriptome and their exosomal counterparts opens up the possibility of discovering new therapeutic and diagnostic targets. This review discusses current studies on the involvement of ncRNAs and their exosomal counterparts in the pathogenesis, diagnosis, and treatment of human skin cancers, particularly melanoma.

<h4>Introduction</h4>The neurobiological basis of gray matter (GM) alterations in juvenile myoclonic epilepsy (JME) remains poorly understood. This study aimed to identify robust GM changes and their underlying molecular signatures.<h4>Methods</h4>We performed an updated coordinate-based meta-analysis of 15 voxel-based morphometry studies (394 JME patients, 448 healthy controls) and integrated the resulting GM alteration map with data from the Allen Human Brain Atlas and neurotransmitter atlases using advanced spatial correlation, gene enrichment, and network analysis approaches.<h4>Results</h4>Our analysis revealed a consistent pattern of GM decreases in the sensorimotor areas and increases in regions implicated in emotion and cognition. These structural changes were spatially correlated with a set of 926 genes enriched for pathways related to ion channel activity, synaptic function, neuronal processes, and cellular metabolism, which showed peak expression during neurodevelopmental periods coinciding with JME onset. Protein-protein interaction analysis identified hub genes from two key functional classes: transcriptional regulators linked to circadian rhythms, and cellular signaling molecules including established monogenic epilepsy genes. Furthermore, the GM map correlated significantly with the spatial distributions of the serotonin, dopamine, and acetylcholine neurotransmitter systems.<h4>Discussion</h4>While these associations are based on data from healthy donors and require further validation, our findings bridge the gap between macroscopic brain alterations and their underlying molecular architecture in JME. This provides an integrated model of its pathophysiology and highlights potential therapeutic avenues.

Sleep in <i>Drosophila melanogaster</i> is regulated by a complex and distributed network of neural circuits that are influenced by factors such as internal state, circadian timing, and prior experiences. While no single "sleep center" has been identified, key brain regions-including the central complex, the mushroom bodies, and other associative structures-such as ventral nerve cord (VNC) contribute to the modulation of sleep and wakefulness. The roles of these regions appear to be dynamic, context-dependent, and often overlapping, reflecting the multifaceted nature of sleep regulation. At the circuit level, mechanisms such as changes in neuronal firing patterns, neurotransmitter systems (e.g., octopamine, dopamine, GABA), and experience-dependent synaptic plasticity have been shown to regulate sleep-wake cycles. On a molecular scale, a variety of genes-including <i>shaker, fruitless</i>, and <i>GAT</i>-influence sleep regulation through distinct pathways, with perturbations in these genes resulting in significant alterations in sleep duration, architecture, and homeostatic regulation. Recent studies, particularly those utilizing <i>Drosophila</i> sleep mutants, have provided valuable insights into the genetic and circuit-level interactions that govern sleep homeostasis and its coordination with the circadian system. These findings underscore sleep as an emergent property of interacting neural and genetic networks, providing a robust model for understanding the mechanisms of sleep in more complex organisms. This review synthesizes the latest advancements in <i>Drosophila</i> sleep research, with a focus on neural structures and the genetic basis of sleep regulation.

Parkinson's disease (PD) is characterized by progressive degeneration of the nigrostriatal dopaminergic system and α-synuclein (α-syn) pathology, with disease progression driven by convergent mechanisms including neuroinflammation, mitochondrial injury, oxidative stress, and regulated cell-death programs such as ferroptosis. Fibroblast growth factors (FGFs) and fibroblast growth factor receptors (FGFRs) constitute a key signaling system in the central nervous system, influencing not only neuronal survival and glial states but also intersecting with networks governing redox homeostasis and iron metabolism. Accumulating evidence indicates that, beyond classical neurotrophic actions, FGF-FGFR signaling can modulate mitochondrial quality control, glial inflammatory activation, and lipid peroxidation-related processes, thereby reshaping cellular susceptibility to ferroptotic injury. This review summarizes current advances in understanding FGF signaling networks in Parkinson's disease, synthesizes their potential mechanistic links to the interplay among neuroinflammation, mitochondrial dysfunction, and redox imbalance as well as to ferroptosis regulation, and discusses the experimental basis and translational challenges of targeting the FGF pathway as a disease-modifying therapeutic strategy.

Organoids are excellent and reproducible <i>in vitro</i> models for studying physiological mechanisms and modeling diseases in endangered species. However, intestinal organoids of red pandas have not yet been established. This study reports a culture system of intestinal stem cell-derived organoids of red panda that can be passaged, cryopreserved, and resuscitated <i>in vitro</i>. The single-cell RNA sequencing and RNA sequencing analysis showed that red panda intestinal organoids retain tissue-specific cell types and functions. In order to verify the application potential of <i>Lactobacillus salivarius</i> P103 as a probiotic in red pandas, these organoids were used to establish a co-culture system with <i>L</i>. <i>salivarius</i> P103. The results showed that <i>L. salivarius</i> P103 could promote mucin secretion, reduce intestinal inflammation, and inhibit infection induced by <i>Klebsiella pneumoniae</i> 28. The establishment of red panda intestinal organoids provides a long-term, reproducible model system for studying host-microbe interaction mechanisms and decreasing dependence on animal models in wildlife research.

No abstract available.

BACKGROUND: X-linked juvenile retinoschisis (XLRS) is a hereditary retinal disorder caused by mutations in the RS1 gene that leads to the formation of cavities in the inner nuclear layer (INL) and progressive vision loss, characterized by a disproportionate reduction of the b-wave compared to the a-wave in electroretinography (ERG). While previous research has largely focused on photoreceptor degeneration in XLRS, the specific roles of other cell populations, particularly bipolar cells and microglia, in the early stages of the disease have remained less well understood. Thus, this study aimed to elucidate the early cellular and molecular mechanisms of retinal degeneration in XLRS, with a particular focus on the role of microglia and bipolar cells. METHODS: Retinal structure and function were assessed in CRISPR/Cas9 Rs1-exon2 knockout (Rs1−/y) mice at 8 and 24 weeks using histology, spectral-domain optical coherence tomography (SD-OCT), ERG, and optokinetic response. To analyze cell-specific changes, we performed TUNEL assay, immunofluorescence, flow cytometry, and single-cell RNA sequencing (scRNA-seq) with trajectory analysis. RESULTS: Rs1−/y mice successfully recapitulated classic XLRS features, including INL schisis, reduced b/a-wave ERG ratio, and early vision loss. TUNEL assay and histological analysis revealed that cell death initiated in the INL at 8 weeks and progressed to the outer nuclear layer (ONL), while microglia displayed a progressive transition from a ramified to an ameboid morphology. scRNA-seq demonstrated a significant loss of cone bipolar cells, especially OFF-cone subtypes, which preceded photoreceptor degeneration. Importantly, microglial activation and enhanced phagocytosis of OFF-cone bipolar cells were observed prior to photoreceptor loss. This phagocytic process was found to be mediated by phosphatidylserine and complement C3b, independent of caspase-3 pathways. CONCLUSIONS: Our findings demonstrate that bipolar cell degeneration, driven by microglial phagocytosis of stressed yet viable OFF-cone bipolar cells, is an early and critical pathological event in XLRS that precedes photoreceptor loss. This process involves "eat-me" signals and complement activation independent of classical apoptosis. These results provide a new perspective on XLRS pathogenesis and suggest that therapeutic strategies targeting bipolar cells and microglial activity could offer promising avenues for early intervention.

The cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase-stimulator of interferon genes (cGAS-STING) pathway is crucial for tumor immunity. However, activation of the cGAS-STING pathway alone is seldom sufficient to eliminate established tumors. Here, we report the engineering of zinc/manganese (Zn/Mn)-based metal-organic framework (MOF) nanoparticles, that is, AMP@Zn/Mn-MOF, comprising Zn/Mn-MOF nanoparticles as the carrier and the STING agonist c-di-AMP diammonium as the therapeutic drug for reinforcing antitumor immune responses. These therapeutic nanoplatforms can significantly activate the cGAS‒STING pathway and facilitate the innate immune response. Furthermore, the peroxidase (POD)-mimetic and glutathione oxidase (GSHox)-mimetic activities of AMP@Zn/Mn-MOF can significantly potentiate tumor cell death and effectively induce robust immunogenic cell death (ICD), thereby amplifying the cGAS-STING pathway. Moreover, AMP@Zn/Mn-MOF reprogrammed the immunosuppressive tumor microenvironment by promoting intratumoral lymphocyte infiltration, thereby significantly suppressing the growth of murine MC38 tumors in mice. Notably, AMP@Zn/Mn-MOF amplified the therapeutic effect of anti-programmed death ligand 1 (αPD-L1) blockade by triggering systemic antitumor responses, resulting in a notable abscopal effect to effectively inhibit distant tumors. In summary, AMP@Zn/Mn-MOF offers a nanoplatform with enhanced antitumor effectiveness through activation of the cGAS-STING pathway and ICD, suggesting that enhanced immune checkpoint blockade-based immunotherapy is promising for colon cancer treatment.

Recent research demonstrated activation of the innate immune system in ALS models. This pathway can be activated by cGAS-STING sensing of cytosolic DNA that accumulates as a result of chronic DNA damage and defective mitochondria, both of which was identified as pathology in FUS-ALS. Therefore, we analyzed innate immune pathways in FUS-ALS, which revealed upregulation of interferon-stimulated genes (ISGs) and activation of the TBK1-IRF3 pathway in FUS^mut iPSC-derived spinal motor neurons (sMNs). Accumulation of cytosolic dsRNA and its sensor RIG-I, but not MDA5, was found to be significantly upregulated in FUS^mut sMNs, which was abolished upon siRNA-mediated knockdown of RIG-I. RIG-I was highly expressed in FUS-ALS post-mortem α-MNs. IFN treatment of FUS^wt sMNs phenocopied the axonal degeneration of FUS^mut sMNs. Mitochondrial transcription, a known source of dsRNA, was found to be upregulated in compartmental axonal RNAseq analysis and its inhibition reduced ISGs in FUS-ALS sMNs. The JAK-STAT inhibitor ruxolitinib alleviated the upregulated ISG expression and reversed the axonal degeneration of sMNs. Finally, we analyzed ISG expression in peripheral blood from 18 FUS-ALS patients, eight of whom had a significantly elevated interferon signature. RIG-I-mediated innate immune activation in sMNs may be an interesting novel individualized biomarker-driven therapeutic target in (FUS-) ALS. A one-sentence summary of your paper: RIG-I-mediated innate immune activation is found in FUS-ALS spinal motor neurons caused by cytosolic dsRNA accumulation due to mitochondrial transcriptional activation and is amenable to JAK-STAT inhibition and might thus be an interesting novel individualized biomarker-driven therapeutic approach in (FUS-) ALS.

<h4>Introduction</h4>HFE genetic variants, especially C282Y homozygosity (C282Y+/+), can increase systemic iron and cause hemochromatosis, though expression varies. Excess iron can lead to liver disease and liver cancer, yet factors influencing liver iron beyond HFE genotype remain unclear. We investigated genetic/environmental factors influencing liver iron, including HFE genotype and hemochromatosis diagnosis.<h4>Methods</h4>We analyzed 37,287 European ancestry UK Biobank participants (mean age 64.1, SD: 7.6) with HFE genotypes and MRI-estimated liver iron concentrations (MRLIC). Linear regression assessed MRLIC associations with genetic and environmental factors, adjusting for age, sex, and genetic covariates.<h4>Results</h4>Mean MRLIC was highest in undiagnosed C282Y+/+ males and females (2.56 and 2.31 mg/g) versus diagnosed (1.23 and 1.51 mg/g, p=0.0001 and 0.0004). Other HFE genotypes had nominal increases versus those without HFE genetic variants. Higher MRLIC was associated with higher alcohol intake (β=0.11, 95% CI: 0.09-0.11, p=6.0×10-128; >30 vs. 1-14 units/wk), frequent red/processed meat consumption (β=0.08, 95% CI: 0.07-0.09, p=3.7×10-54; ≥3 times/week vs. none), high waist-height ratio (β=0.01, 95% CI: 0.006-0.02, p=6.4×10-5; although magnitude was weak) and genetically predicted transferrin saturation (β=0.22, 95% CI: 0.19-0.26, p=3.8×10-46). Lower MRLIC was associated with underweight body mass index (β=-0.06, 95% CI: -0.09 to -0.03, p=1.1×10-4) and proton pump inhibitor use (β=-0.03, 95% CI: -0.04 to -0.03, p=3.5×10-17).<h4>Conclusions</h4>Undiagnosed C282Y+/+ individuals had excess liver iron versus diagnosed, likely due to treatment. Genetic and environmental factors influence liver iron beyond C282Y+/+. Tailored lifestyle advice could benefit those at risk of hemochromatosis.

<h4>Objective</h4>To investigate the feasibility of susceptibility-weighted imaging (SWI) for the diagnosis of different stages of liver fibrosis, and to assess its diagnostic accuracy compared with the serum fibrosis index commonly used in clinical settings.<h4>Materials and methods</h4>This prospective study included 108 patients and 16 healthy volunteers. All patients underwent MRI with SWI and histopathological evaluation. Liver and bilateral erector spinae signal intensities were measured on SWI to calculate liver-to-muscle signal intensity ratios (SIR). Serological biomarkers were collected to calculate the aspartate aminotransferase-to-platelet ratio index (APRI) and fibrosis index based on four factors (FIB-4). Histological correlation analysis between the SIR and liver fibrosis/iron deposition was performed using Spearman's rank correlation analysis. The diagnostic accuracies of SIR, APRI, and FIB-4 for staging liver fibrosis were assessed, and their performances were compared using the DeLong test.<h4>Results</h4>Receiver operating characteristic (ROC) curve analysis showed good-to-excellent diagnostic performance of SIR for different stages of liver fibrosis. The areas under the curve (AUC) of SIR for the diagnosis of liver fibrosis stages S0 vs S1-S4, S0-S1 vs S2-S4, S0-S2 vs S3-S4, and S0-S3 vs S4 were 0.851, 0.868, 0.872, and 0.931. Delong's test showed that the SIR outperformed the APRI and FIB-4 in the diagnosis of liver fibrosis S0-S1 vs S2-S4, S0-S2 vs S3-S4, and S0-S3 vs S4 (p = 0.011-0.036).<h4>Conclusion</h4>SWI-based SIR outperforms the serum indicators APRI and FIB-4 in diagnosing liver fibrosis of S0-S1 vs S2-S4, S0-S2 vs S3-S4, and S0-S3 vs S4.<h4>Critical relevance statement</h4>SWI-based SIR offers a new perspective on non-invasive diagnostic methods to guide the clinical diagnosis of liver fibrosis, particularly in cases where biopsy is contraindicated or impractical.<h4>Key points</h4>Searching for a non-invasive method to accurately diagnose stages of liver fibrosis is necessary because of the limitations of histopathological evaluation. SWI offers a dependable and non-invasive diagnostic approach for evaluating different stages of liver fibrosis compared to serological biomarkers. SWI-based SIR provides a highly accurate, non-invasive alternative to serum biomarkers for detecting advanced liver fibrosis.

Alzheimer's disease (AD) risk is strongly influenced by genetic variants that converge on pathways regulating endosomal homeostasis. Among these, <i>BIN1</i> and <i>RIN3</i> have emerged as susceptibility genes, yet their functional relationship in AD remains largely unknown. Here, we investigated how BIN1 and RIN3 interaction regulates RAB5 activity and endosomal pathology. RIN3 has been shown to bind BIN1, and we previously reported that this interaction modulates amyloid-β (Aβ) precursor protein (APP) trafficking and Aβ generation in vitro. To extend these findings, we used <i>Rin3</i> constitutive knockout (<i>Rin3-CKO</i>) mice and CRISPR-Cas9-edited human induced pluripotent stem cell-derived neurons carrying either <i>BIN1</i> knockout or rare familial AD <i>RIN3</i> missense mutations within the BIN1-binding domain. We found that disruption of BIN1-RIN3 binding, through either genetic deletion or pathogenic RIN3 variants, resulted in RIN3-mediated RAB5 hyperactivation and enlargement of neuronal endosomes, a hallmark of early AD pathology. Transcriptomic profiling further revealed dysregulated expression of AD-related genes. Together, these findings establish BIN1 as a critical regulator of RIN3-driven RAB5 activation and neuronal endosomal homeostasis.

Polycystic ovary syndrome (PCOS) is a heterogeneous reproductive endocrine condition in women, with implications in fertility and long-term metabolic health. PCOS with hyperandrogen (HA-PCOS; hyperandrogenic PCOS) has been recently identified as one of the four subtypes of PCOS. Dyslipidemia is known to be associated with clinical hyperandrogenism in PCOS. Indeed, patients with HA-PCOS were found to have the highest incidence of dyslipidemia among patients with the other three subtypes of PCOS. In the present study, we identified genes involved in lipid-associated processes (namely, lipid biosynthetic process, lipid catabolic process, hyperlipidemia, hypolipidemia and lipid homeostasis) whose expression are changed in granulosa cells from HA-PCOS patients compared to those from non-PCOS women, in order to identify molecular factors contributing to the highest risk of dyslipidemia incidence observed in patients with hyperandrogenic PCOS. We found 27 lipid biology-associated genes (ACSM1, ACSM3, AGPAT4, AJUBA, ALDH1A2, CCDC3, LPL, P2RX1, PITPNM1, PRLR, PTGIS, SLC44A5, SPTSSB, ST8SIA5, IDH1, ITPKA, PPM1L, SPTLC2, ADRA2A, ASPG, IRS1, PLB1, IDH1, LCT, NUDT8, SMPDL3A and SYNE2) whose transcript levels are significantly downregulated or upregulated in granulosa cells of women with HA-PCOS compared to those in control women. The majority of these genes have not been previously studied in the context of PCOS, and are possible candidates for further research to better understand the contribution of high androgen levels to dyslipidemia in PCOS. Targeting of high androgen-induced dyslipidemia might be of high clinical importance in the treatment of women with HA-PCOS.

With the increasing availability of long-read sequencing data, high-quality human genome assemblies, and software for fully characterizing tandem repeats, genome-wide genotyping of tandem repeat loci on a population scale is becoming more feasible. Such efforts not only expand our knowledge of the tandem repeat landscape in the human genome but also enhance our ability to differentiate pathogenic tandem repeat mutations from benign polymorphisms. To this end, we analyze genome datasets from 272 individuals that employ long-read sequencing technologies. Here, we report a catalog of over 5 million tandem repeat loci, many of which are previously unannotated. Some of these loci are highly polymorphic, and many of them reside within protein-coding sequences.

Magnetically-actuated microswimmers are promising candidates for controlled cargo transport and microscale manipulation; however, achieving efficient, fuel-free propulsion with precisely defined anisotropic structures remains a significant fabrication challenge. We present a novel bio-hybrid helical microswimmer architecture that utilizes the bio-template of Spirulina platensis. This design incorporates anisotropic magnetite Janus nanoparticle (MJNP) heads made from hydrophilic chitosan and hydrophobic polycaprolactone (PCL). This architecture is created through a two-step dip-coating and anisotropic linking process, which ensures stability, magnetic responsiveness, and a defined structural asymmetry. To assess therapeutic potential, Doxorubicin (DOX) was loaded onto the MJNPs, and the biocompatibility of the microswimmers was confirmed in vitro. The microswimmers exhibited efficient corkscrew-like propulsion when exposed to rotating magnetic fields. By systematically tracking their trajectories in biofluids, we observed that increasing the number of helical turns significantly enhances both their forward velocity and translational diffusion. This directly correlates the length of the helices with the optimized conversion of rotational torque into translational motion. This study establishes a robust, bio-templated platform that provides valuable design insights for enhancing the functional versatility of helical microswimmers in advanced biomedical applications.

Indigenous cattle account for approximately 80% of Uganda's cattle population. These animals are well adapted to the country's ten agroecological zones and are mainly kept under pastoral and agropastoral systems. Unlike commercial breeds, they thrive on low-quality feeds, while tolerating major tropical diseases and parasites including tsetse flies, ticks, and vector-borne infections. Whole-genome sequence (WGS) analysis offers opportunities to uncover genomic regions underlying these adaptations and to trace the genetic footprints of long-term breeding decisions taken by cattle keepers. In this study, WGS data from 95 animals representing six indigenous cattle populations (Ankole, Karamojong, Nganda10, Nganda17, Nkedi, and Ntuku) were analyzed to identify genomic regions under putative selection. Two complementary approaches were applied: enumeration of the µ-statistic in RAiSD and runs of homozygosity (ROH) analysis. RAiSD identified population-level signals, while conserved ROH regions were defined using breed-specific SNP-incidence thresholds. The two methods identified 803 and 49 candidate genes respectively. The top genes identified included SLC37A1 (BTA1), CHCHD3 (BTA4), and RAB3GAP1 (BTA2) detected by RAiSD, and IL26 (BTA5), FBXL7 (BTA20), and HSPA9 (BTA7) contained in ROH. Furthermore, the regions harbored 107 novel genes (92 detected by RAiSD and 15 by ROH), corresponding to 255 quantitative trait loci. The identified genes under putative selection are associated with economically important traits including adaptation to tropical environments, resistance to parasites and diseases, and other farmer-preferred characteristics. These findings provide insights into the genetic basis of adaptation, selection and production in Ugandan indigenous cattle, supporting conservation and breeding strategies to enhance resilience and productivity.

Eukaryotic genome replication is surveyed by the S-phase checkpoint, which coordinates sequential origin activation to prevent the exhaustion of poorly defined, rate-limiting replisome components^1-3. Here we show that excessive origin firing saturates chromatin-bound proliferating cell nuclear antigen (PCNA)-a sliding clamp for DNA polymerase processivity and Okazaki fragment processing⁴-thereby restricting further PCNA loading and lagging-strand synthesis when checkpoint control is lost. PCNA-associated factor 15 (PAF15) emerges as a dosage-sensitive regulator of this process^5-9. During unperturbed S phase, the entire soluble PAF15 pool binds to chromatin, leaving no reserve to stabilize PCNA under conditions of excessive origin activation. PAF15 binds to PCNA specifically on the lagging strand through a high-affinity PIP motif and occupies the DNA-encircling channel, protecting the clamp and associated enzymes from premature unloading by the ATAD5-RFC complex. Conversely, overexpression of PAF15 or forced redistribution to the leading strand disrupts replisome progression and induces cell death. These detrimental effects are mitigated by Timeless-Claspin, which blocks PAF15-PCNA binding on the leading strand. E2F4-mediated repression fine-tunes PAF15 expression to ensure optimal dosage and strand specificity. These findings reveal a previously unrecognized replisome constraint: when PAF15-PCNA assemblies are exhausted, the S-phase checkpoint globally restricts origin activation, linking a strand-specific rate-limiting mechanism to global replication dynamics.

<h4>Background</h4>Sarcopenia and depression are both common and impactful conditions in older adults. However, there has been limited research on their relationship, particularly in older patients with type 2 diabetes (T2D).<h4>Objectives</h4>To investigate the association between sarcopenia and depressive symptoms among older Vietnamese adults with T2D.<h4>Methods</h4>From May to December 2024, 630 patients with T2D were recruited from the outpatient clinics of the National Geriatric Hospital in Vietnam, of whom 618 were included in the cross-sectional analysis. Sarcopenia was diagnosed based on the 2019 Asian Working Group for Sarcopenia criteria (AWGS 2019). Depressive symptoms were evaluated using the validated Vietnamese version of the 15-item Geriatric Depression Scale (GDS-15), with scores of 5 or higher indicating the presence of depressive symptoms. Demographic factors, lifestyle behaviours, diabetes-related indicators (HbA1c, duration, complications), and geriatric characteristics were also analysed as potential confounders. Logistic regression was used to assess the association between sarcopenia and depressive symptoms.<h4>Results</h4>Among the 618 participants (mean age 73.5 ± 7.1 years, 63.7% female), 34.5% were diagnosed with sarcopenia, and 25.9% exhibited depressive symptoms. Sarcopenia was significantly associated with depressive symptoms (AOR 1.73, 95% CI 1.09-2.72). Other significant predictors of depressive symptoms included female sex (AOR 2.32, 95% CI 1.08-4.98), older age (AOR 1.04, 95% CI 1.01-1.07), higher BMI (AOR 1.08, 95% CI 1.01-1.17), more comorbidities (AOR 1.23, 95% CI 1.07-1.42), chronic diabetic complications (AOR 1.79, 95% CI 1.12-2.85), and cognitive impairment (AOR 1.61, 95% CI 1.09-2.38).<h4>Conclusions</h4>This study reveals a significant association between sarcopenia and depressive symptoms in older adults with T2D, suggesting that comprehensive screening strategies may help in the early detection of coexisting physical and mental health problems in this vulnerable population.

<h4>Background</h4>Taurine is a powerful antioxidant necessary for mitochondrial function. Lactic acidosis is a complication encountered in the condition mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS), which can be successfully treated with supplemental taurine. Furthermore, taurine regulates the production of iron-dependent proteins such as ferritin that can act as chelating agents to sequester labile iron.<h4>Case presentation</h4>A 38-year-old Greek male with a β-zero thalassemia trait developed multiple severe symptoms soon after his first and only mRNA (Pfizer) SARS-CoV-2 vaccination that included hematological stress to be a candidate for blood transfusion. Amongst the hematological readings, the patient had lactate levels > 4 mmol/ml, indicating lactic acidosis, and ferritin levels > 820 ng/ml, representing hyperferritinemia. Moreover, the patient has organic acid and plasma metabolite levels in the urine that are indicative of mitochondrial dysfunction. Regular taurine intake (500 mg/day) for years helped the patient control lactate and ferritin levels and avoid more serious clinical decompensation.<h4>Conclusion</h4>Regular taurine intake helps to avoid lactic acidosis and reverse hyperferritinemia after mRNA SARS-CoV-2 vaccination in a patient with β-zero thalassemia trait with no obvious genetic trait linked to mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes. Taurine seemed to be protective for mitochondria.

<h4>Background</h4>Cardiovascular disease is the leading cause of death worldwide, and its risk is closely linked to metabolic abnormalities. Through summary-data-based mendelian randomization and colocalization analysis, we investigate the causal relationships between plasma proteins, six cardiovascular diseases (atrial fibrillation, coronary artery disease, heart failure, venous thromboembolism, peripheral artery disease and stroke), and 19 metabolic traits (including anthropometric phenotypes, blood pressure, glycemic phenotypes, inflammatory phenotypes, kidney-related phenotypes, lipidemic phenotypes, and liver-related phenotypes).<h4>Results</h4>We identify 49 proteins genetically associated with cardiovascular diseases, validated across two proteomic platforms. Among them, 35 are also associated with one or more metabolic phenotypes, with six showing evidence of colocalization. These six candidate proteins are classified into three categories based on drug development status, with PCSK9 already successful in therapies for cardiovascular diseases and hypercholesterolemia. DUSP13B, LRIG1, APOH, INHBC, and GUSB also demonstrate high therapeutic potential. Further phenome-wide MR analysis indicates that INHBC, APOH and DUSP13B represent promising therapeutic targets for cardiovascular diseases characterized by metabolic disorders.<h4>Conclusions</h4>Overall, this study revealed causal plasma proteins underlying the onset of cardiovascular diseases and metabolic abnormalities, advancing the understanding of disease mechanisms and facilitating drug discovery.

BACKGROUND: Protein ubiquitination is a key post-translational modification that governs protein stability and cellular homeostasis. KLHDC3 is a substrate recognition receptor in the recently identified C-terminal degron-mediated DesCEND ubiquitination pathway. It selectively binds proteins with C-terminal RxxxG motifs, targeting them for degradation. While N-terminal degron pathways are well-characterized, the physiological roles of C-terminal degrons remain poorly understood. To explore KLHDC3’s function in a physiological context, we generated mice deficient in the Klhdc3 gene. RESULTS: Klhdc3-deficient mice exhibited sub-Mendelian birth rates and progressive postnatal lethality, with a median survival of 136 days and a maximum lifespan of approximately one year. Surviving mice showed early growth retardation followed by normalization of body mass, and later developed pronounced obesity, with some individuals reaching fat mass levels exceeding 50% of total body weight. Transcriptomic and proteomic analyses of Klhdc3−/− embryonic fibroblasts revealed significant changes in protein expression with minimal alterations in transcript levels, consistent with KLHDC3’s role in post-translational regulation. Among the upregulated proteins, HINT1 was identified as a novel KLHDC3 substrate containing a C-terminal degron motif. Protein stability assays and immunoblotting confirmed HINT1 as a candidate target of KLHDC3. CONCLUSIONS: This study establishes a physiological role for the DesCEND pathway in vivo and identifies KLHDC3 as a critical regulator of development, survival, and adiposity in mice. The identification of HINT1 as a putative KLHDC3 substrate expands our understanding of C-terminal degron-mediated protein regulation and suggests broader implications for developmental and metabolic processes.

Cancer pain is a complex issue of significant importance in daily clinical practice, requiring a multidimensional approach. Approximately 90% of cancer pain cases can be effectively managed through the appropriate and often combined use of pharmacological and non-pharmacological treatments. In addition to the analgesic drugs outlined in the WHO analgesic ladder, the concurrent use of adjuvant drugs may be considered, which are sometimes essential for effective cancer pain management. These treatments can be adjusted based on the presence of inflammatory processes and oxidative stress.<h4>Methodology</h4>This is an observational, descriptive, retrospective, real-world data study conducted in daily practice at the Country Medical Center in Bogotá, Colombia. It involved patients with any type of cancer diagnosis who were receiving chemotherapy, radiotherapy, oncological surgery, and/or hormonal therapy. From 2018 to 2023, protocols for intravenous high dose of sodium ascorbate were applied, resulting in a sample of 92 patients.<h4>Results</h4>The administration of sodium ascorbate at dose of 100 to 300 and 300 to 600 mg/kg/day showed statistically significant improvements in quality of life (<i>P</i> = .000). However, only the 300 to 600 mg/kg/day dose demonstrated a statistically significant reduction in pain (<i>P</i> = .0061).<h4>Conclusions</h4>It is possible that by controlling or reducing inflammation, pain sensation can be decreased, therefore high dose of an antioxidant such as sodium ascorbate may be an alternative to improve oxidative stress and inflammation as an adjuvant to analgesic prescription according to pain management guidelines for cancer patients.

<h4>Background & aims</h4>Dietary fat increases the risk of intestinal cancer, but the effect of the fatty acid composition on tumorigenesis is unclear. The aim of this study is to investigate the impact of diets with different fatty acids on carcinogenesis in the intestine.<h4>Methods</h4>Mice were fed a linoleic acid (LA)-rich or stearic acid (SA)-rich high-fat diet (HFD) from the age of 4 weeks. The Apc^Min/+ mice and an azoxymethane- and a dextran sulfate sodium-induced colorectal cancer (CRC) mouse model were used to examine the effects of different dietary fatty acids on CRC development. Fatty acid-binding protein 5 (FABP5) knockout mice and SBFI-26, an inhibitor of FABP5, were used to assess its contribution.<h4>Results</h4>We found that an SA-rich HFD more strongly accelerated tumorigenesis in murine CRC models than an LA-rich HFD, with fewer obesity phenotypes compared with LA-rich HFD-fed mice. Dietary SA more strongly promoted epithelial cell proliferation and Paneth cell differentiation than LA, whereas no differences in the numbers of leucine-rich repeat-containing G protein-coupled receptor 5⁺ and B lymphoma Mo-MLV insertion region 1 homolog⁺ intestinal stem cells were detected between the groups. In murine and human intestinal organoids, SA promoted crypt formation. We found that FABP5 was expressed in a small population of Ki67⁺ proliferative cells in crypts, and the number of Ki67⁺ FABP5⁺ cells was increased by SA-rich HFD feeding. FABP5 inhibition suppressed SA-induced epithelial cell proliferation, Paneth cell differentiation, and tumorigenesis.<h4>Conclusions</h4>Dietary SA can promote CRC via FABP5 without promoting obesity.

Osteoporosis (OP) is a common chronic disease that significantly increases the risk of bone fractures. Pharmacotherapy uses, among others, 17beta-estradiol (E2), which has been replaced in recent years by raloxifene hydrochloride (RLX). The need for long-term, high-dose therapy with these drugs is associated with serious adverse effects. The aim of this review is to analyze the current state of knowledge over the last 5 years (2020-2025) regarding the use of nanoparticles (NPs) in the delivery of E2 and RLX, with particular emphasis on their impact on bioavailability, pharmacokinetic profile, reduction in adverse effects, and improvement in the effectiveness of postmenopausal osteoporosis therapy. Preclinical studies show that combining E2 or RLX with various types of NPs reduces cytotoxicity, improves pharmacokinetic parameters, and enhances the therapeutic effects of drugs used in postmenopausal osteoporosis. These effects are mainly attributed to improved pharmacokinetics and controlled drug release, rather than confirmed active tissue targeting. However, these findings are based on preclinical models and require further validation in clinical studies. The analysis concludes that while NP systems significantly enhance the pharmacokinetic profile and safety of E2 and RLX in preclinical models, claims of true bone-specific targeting remain largely unsubstantiated, highlighting a key area for future research.

The incidence and mortality of hepatocellular carcinoma (HCC) are increasing worldwide, underscoring the need for novel therapeutic strategies. Synthetic 2-naphthyl 2-butanamido-2-deoxy-1-thio-β-d-glucopyranoside (<b>612</b>) is a selective inhibitor of β1,4-galactosyltransferase 1 (β4GalT1). In this study, we investigated the cytotoxic effects of <b>612</b> across multiple cancer cell lines, with a focus on HCC, and explored the underlying mechanisms. We demonstrate that <b>612</b> preferentially exhibits cytotoxicity toward cancer cells with elevated expression of β4GalT family members, while human umbilical vein endothelial cells and immortalized human embryonic kidney epithelial cells are comparatively less sensitive. Treatment with <b>612</b> suppresses cancer cell migration and invasion and induces pronounced endoplasmic reticulum and Golgi stress, accompanied by G2/M cell cycle arrest. Furthermore, <b>612</b> activates apoptosis through ER stress-associated pathways by downregulating the anti-apoptotic protein Bcl-2 and upregulating pro-apoptotic proteins Bax and Bak, along with activation of caspase-3, -8, and -9. Collectively, these findings identify <b>612</b> as a promising anti-cancer candidate targeting β4GalTs-overexpressing HCC cells and warrant further therapeutic development.

Mitochondria play a crucial role in metabolism and energy production by generating adenosine triphosphate (ATP) through oxidative phosphorylation. They also help maintain intracellular calcium levels, facilitate communication between the nucleus and cytoplasm, detoxify reactive oxygen species (ROS), and regulate apoptosis. Reversible acetylation of mitochondrial proteins is a key post-translational modification influencing these processes, with the NAD⁺-dependent deacetylase SIRT3 being a major regulator. While SIRT3 has been described as a tumor suppressor in some contexts and as a tumor promoter in others, its role appears to be tissue- and metabolism-specific. Here, we compared the proteomic and acetylomic responses of lung adenocarcinoma (A549) and breast adenocarcinoma (MCF7) cell lines to SIRT3 inhibition by 3-TYP. The two lines were selected based on distinct metabolic phenotypes and reported differences in basal SIRT3 abundance. Total proteome and mitochondrial-enriched fractions were analyzed separately for each cell line to avoid cross-line normalization bias. We identified 6457 proteins and 4199 acetylated peptides, revealing distinct pathway enrichments and acetylation changes after SIRT3 inhibition. A549 cells showed increased oxidative metabolism, while MCF7 cells exhibited metabolic reprogramming. These results indicate that the proteomic impact of SIRT3 modulation is strongly influenced by cellular metabolic context. All raw mass spectrometry data are publicly available in PXD063181.

<h4>Introduction</h4>Maternal obesity (pregravid body mass index >30 kg/m²), which has reached epidemic levels in the US, increases the incidence of cardiovascular disease and all cause premature death in the offspring. The placenta modulates fetal access to lipids and other nutrients and is considered a key player in fetal growth and maturation. However, the complex interplay between dysregulated metabolism in mothers with obesity and placental pathways mediating impacts on fetal development that predispose offspring to morbidities later in life, is poorly understood.<h4>Methods</h4>We used unbiased <i>Whole Genome Correlation Network Analysis</i> (WGCNA) in 39 full-term unlabored placentas from mothers affected by obesity to explore relationships between coding and non-coding placental transcripts with maternal and fetal metabolic variables.<h4>Results</h4>We identified positive correlations between members of the Rho network, a key inflammation regulator, with maternal leptin and cord blood free fatty acids (cbFFA). Furthermore, we identified negative correlations between epigenetic regulators and the lipid metabolism drivers <i>SMUG1</i> and <i>CDS1</i>, with cbFFA. A set of placental miRNAs showed positive correlations with cbFFA. Using mirTarRnaSeq, an R/Bioconductor package, we predicted interactions between placental coding genes and miRNA, which correlated negatively and positively with cbFFA, respectively. Several FFA-associated miRNAs (miR-23b cluster, -168, -138, -6825, -6845) have been previously associated with obesity in animal models and human cohorts.<h4>Discussion</h4>Further studies are required to investigate the role that the Rho network plays in placental inflammation and the link between miRNAs and the predisposition towards cardiovascular diseases in the offspring of obese mothers.

Individuals suffering from mental illness often report an abnormal family of origin. Previous family theories have primarily focused solely on family risk factors or treated family members equally and have largely overlooked the critical role of family of origin in offspring development. In this study, we proposed a <i>Family Dominant Hypothesis</i> to emphasize the critical role of family of origin in the lifelong mental health of offspring. The core concept is that family and environmental variables, encompassing both risk and protective factors, contribute to different mental health outcomes in offspring, with the family of origin playing a directly dominant and indirectly mediating role in child development. This theoretical hypothesis highlights the dominant and mediating role of family of origin, considering both risk and protective factors--including biological genetics, family conditions, parental mental wellness, the relationship between parents, parenting style, and the parent-child relationship--in child development. Potential neurobiological mechanisms underlying the influence of the family of origin were also explored. Meanwhile, potential family interventions targeting the identified risk factors were proposed. The Family Dominant Theory is proposed to draw attention from society, particularly families and young parents, to emphasize the importance to family of origin environment. A comprehensive understanding of family of origin can help establish a healthier family environment and promote lifelong mental health of offspring.

<h4>Background</h4>Autonomic dysregulation and cognitive decline often co-occur in aging, but most work uses only resting heart rate variability (HRV). Therefore, we examined whether global cognitive performance modulates dynamic HRV responses to a functional exercise test in community-dwelling older adults.<h4>Methods</h4>In this cross-sectional study, 104 adults aged 60-85 years from southern Chile completed a rest-exercise-recovery protocol using the 2-Min Step Test. Global cognition was assessed with the Addenbrooke's Cognitive Examination. Short-term HRV (time and frequency domains), parasympathetic (PNS) and sympathetic (SNS) indices, and Baevsky's Stress Index were derived from Polar H10 recordings at rest, during exercise, and recovery. Hierarchical Bayesian regression models characterized HRV trajectories as a function of cognitive performance, adjusting for body mass index.<h4>Results</h4>Higher cognitive scores were associated with a more favorable autonomic profile at rest, including higher standard deviation of normal-to-normal intervals, low frequency (LF), and very low frequency (VLF) and lower SNS and Stress Index values. During exercise, better cognition was linked to greater high frequency power and larger reductions in LF and VLF from rest to effort, indicating enhanced autonomic flexibility. Lower cognitive scores showed flatter LF/VLF trajectories and a sharper in-exercise decline in the PNS index. Higher body mass index was consistently related to reduced vagal modulation and higher sympathetic markers.<h4>Conclusion</h4>Older adults with better cognitive performance show healthier resting autonomic profiles and greater adaptability of cardiac autonomic regulation during a brief functional test. Blunted HRV trajectories in individuals with lower cognition may signal early neurophysiological vulnerability, and 2-Min Step Test-derived HRV responses may provide a non-invasive marker of cognitive health in aging.

<h4>Introduction</h4>Chronic obstructive pulmonary disease (COPD) is a heterogeneous inflammatory disorder characterized by persistent immune dysregulation and progressive structural deterioration of the lung. However, how COPD reshapes lung architecture, immune signaling, and cellular identity at a systems level remains incompletely understood.<h4>Methods</h4>We performed integrative, multi-dimensional transcriptomic analysis of human COPD lung datasets to evaluate alterations in immune signaling, regulated cell death pathways, fibrosis-associated programs, cell type-specific transcriptional identity, and immune checkpoint regulation. Genetic and cytokine-based perturbations targeting trained immunity pathways were analyzed to assess functional relevance.<h4>Results</h4>COPD induced broad transcriptional activation of cytokines, secretory and plasma membrane proteins, CD markers, innate immune genes, and trained immunity genes. Deficiency of SET7, a promoter of trained immunity, or overexpression of IL-37, an inhibitor of trained immunity, attenuated expression of COPD-upregulated immune genes. COPD also promoted tissue injury through coordinated upregulation of genes regulating multiple forms of regulated cell death, including autosis, autophagy, parthanatos, immunogenic cell death, mitochondrial permeability transition-associated death, lysosomal cell death, apoptosis, necroptosis, ferroptosis, mitotic cell death, and proliferation-associated cell death. In parallel, COPD enhanced epithelial-to-mesenchymal transition and fibrosis-related transcriptional programs. Transcriptomic identity was disrupted in 10 of 14 major human lung cell types, with evidence of pathological trans-differentiation marked by aberrant expression of over 50 cell type-specific marker genes. Alveolar macrophages exhibited extensive dysregulation of immune checkpoint ligand; notably, PVR (CD155) expression was reduced in severe emphysema, while experimental PVR overexpression suppressed pro-inflammatory gene expression in both alveolar and interstitial macrophages. Additionally, COPD impaired the suppressive capacity of CD4⁺Foxp3⁺ regulatory T cells through downregulation of key immunosuppressive genes, including those associated with FoxP3⁺, TIGIT⁺, and LPS-responsive Tregs. Shared immunosuppressive gene signatures were identified between PVR-overexpression-inducing CD4⁺ T cells and IL-10-mediated regulatory pathways in T cells and monocytes.<h4>Discussion</h4>Collectively, these findings demonstrate that COPD reprograms the lung toward an immune-like organ by promoting immune cell-like trans-differentiation of structural cells, activating diverse regulated cell death pathways, and altering immune checkpoint signaling. These mechanisms highlight potential therapeutic targets for immunomodulatory intervention in COPD.

<h4>Background</h4>Coagulation is an important physiological process for the body to cope with vascular injury, involving platelet activation, coagulation factor cascade reaction and fibrin formation. The role of the coagulation system in inflammatory and degenerative diseases has received increasing attention in recent years. However, its impact for osteoarthritis remains to be well investigated.<h4>Methods</h4>The GEO database provided us with microarray data that included osteoarthritis and normal samples. The Genecards database provided coagulation-related genes. Protein interaction network analysis, machine learning, and screening for differentially expressed genes were used to identify coagulation-related core genes relevant to osteoarthritis. Coagulation-related osteoarthritis subtypes were identified by clustering analysis. Enrichment analysis and immune infiltration analysis revealed the potential mechanism of coagulation-related genes promoting osteoarthritis progression. The screened core genes were further validated by chondrocyte experiments.<h4>Result</h4>We successfully screened the coagulation-related genes COL3A1 and MMP1 as core genes for osteoarthritis diagnosis. Both nomogram and diagnostic model constructed based on them have excellent diagnostic value, while OA samples can be classified into different subtypes. Immune infiltration study confirmed enrichment analysis's finding that COL3A1 could affect the course of osteoarthritis by controlling immunological pathways. Basic research confirms that overexpression of COL3A1 inhibits proliferation and viability of chondrocytes and promotes senescence and damage. We confirmed that COL3A1 is an intervention target for osteoarthritis.<h4>Conclusion</h4>Our study identifies osteoarthritis subtypes associated with coagulation and reveals the regulatory role of COL3A1 on chondrocytes in inflammatory environment. It offers fresh perspectives on osteoarthritis management.

<h4>Introduction</h4>Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a major global health threat. γδ T cells, critical innate immune responders, provide rapid anti-TB defenses and act as a bridge between innate and adaptive immunity. Studies have demonstrated that γδ T-cell activation by phosphoantigens is mediated by butyrophilin subfamily 3 member A1 (BTN3A1), leading to enhanced cytokine production and cytotoxicity. Mtb heat-resistant antigen (Mtb-HAg), extracted from Mtb H37Ra, specifically activates γδ T cells and induces cytokine secretion. However, the contribution of Mtb-HAg to γδ T cell-mediated cytotoxicity and its dependence on BTN3A1 remain unclear.<h4>Methods</h4>This study explored the regulatory mechanism of Mtb-HAg on the cytotoxic function of γδ T cells through RNA-Seq analysis and functional validation methods. The RNA-Seq analysis to profile the transcriptome of Mtb-HAg-activated γδ T cells.The expression of key cytotoxic factors was analyzed using ELISA, and the capacity of activated γδ T cells to inhibit intracellular Mtb growth was assessed using a co-culture assay with Mtb-infected macrophages. The specific role of BTN3A1 was investigated using a blocking antibody to assess its impact on activation markers, cytotoxic factor secretion, and mycobacterial killing efficiency.<h4>Results</h4>RNA-Seq analysis revealed that Mtb-HAg-activated γδ T cells are significantly enriched for genes associated with cytotoxic immune responses, with significant upregulation of key cytotoxic factors granzyme B (GzmB) and perforin (PFP), indicating that the cytotoxic function of these cells was activated at the transcriptional level. Subsequently, protein expression analysis revealed that the secretion of GzmB and PFP was increased in Mtb-HAg-activated γδ T cells. Meanwhile, intracellular Mtb growth inhibition assays demonstrated that activated γδ T cells lysed infected target cells and suppressed intracellular Mtb proliferation. We further found that BTN3A1 blockade significantly reduced the expression of CD69 and CD107a in γδ T cells, decreased the secretion of GzmB and PFP, and diminished the killing efficiency of γδ T cells against Mtb-infected macrophages.<h4>Conclusion</h4>Our findings demonstrated that Mtb-HAg enhances the cytolytic activity of γδ T cells and inhibits intracellular Mtb growth, with BTN3A1 playing a regulatory role in these processes.

The nervous system plays a profound role in human health and disease, particularly in regulating cancer development through immune system interactions. The enteric nervous system (ENS), often referred to as the "second brain," comprises millions of neurons and glial cells specialized for the gastrointestinal tract. This system is intimately involved in the growth, infiltration, and metastasis of gastrointestinal tumors. Furthermore, the ENS establishes a bidirectional communication network with the central nervous system via the vagus nerve and spinal afferent nerves, mediating interactions between gut microbiota, the immune system, and the nervous system. Emerging fields like "neuro-immuno-oncology" have introduced neuroimmunomodulatory drugs into clinical practice, but most research focuses on intestinal inflammation, leaving a gap in systematic understanding regarding gastrointestinal tumors. This review systematically summarizes the bidirectional regulatory mechanisms of neuro-immune interactions in gastrointestinal tumors and explores the interplay between nerves, immunity, and microbiota in the gastrointestinal tumor microenvironment. Its aim is to provide a new perspective for understanding the neuro-immune ecology of gastrointestinal tumors and to lay a theoretical foundation for developing cross-scale precision treatment strategies.

This work presents a concise and practical synthetic route to the biologically multifunctional avenanthramide C (Avn C, <b>1a</b>), one of the natural products derived from oats, utilizing three classical organic reactions. Condensation of diacetyl caffeoyl chloride (<b>5</b>) with methyl 5-hydroxyanthranilate (<b>6</b>) in tetrahydrofuran at 80 °C in the presence of pyridine, followed by saponification with 5.0 equiv of lithium hydroxide (3.0 M in H₂O) in a THF-H₂O (3:1 v/v) cosolvent system and subsequent acidification to approximately pH 2 using 6.0 M hydrochloric acid, successfully afforded <b>1a</b> as a pale brown solid in >82% yield and 99% purity. Furthermore, 14 structural analogs of <b>1a</b> were efficiently synthesized in 60-88% yields by applying the same synthetic strategy.

Deregulated Nlrp3 (NOD-like receptor pyrin 3) inflammasome activation is strongly associated with age-related blinding diseases, including cataract. Previously, we demonstrated that loss of peroxiredoxin6 (Prdx6) promotes reactive oxygen species (ROS) amplification and aberrant activation of Klf9 and Nlrp3 inflammasome activity-driven pyroptosis. In this study, using aging mouse(m)/human(h) lenses and lens epithelial cells (LECs), we reveal a critical link between Nlrp3 and thioredoxin (TRX)-interacting protein (TXNIP), which increases during aging and oxidative stress conditions. We found that aging lenses exhibiting opacity showed elevated ROS levels, increased TXNIP expression, along with upregulation of Nlrp3 inflammasome components, including caspase-1, ASC, IL-1β, IL-18, and gasderminD (GSDMD), with significantly reduced TRX1. mLECs overexpressing TXNIP were more susceptible to hydrogen peroxide (H₂O₂), Lipopolysaccharide (LPS), ultraviolet B (UVB)-induced oxidative stress, displaying increased ROS accumulation, reduced cell viability, and enhanced activation of Nlrp3 inflammasome and its downstream inflammatory mediators, hallmarks of pyroptotic cell death. Conversely, TXNIP knockdown suppressed Nlrp3 inflammasome activation, decreased ROS production, and significantly improved cell survival, indicating a protective effect against oxidative injury. <i>Ex vivo</i>, TAT-HA-Prdx6 delivery inhibited H₂O₂-induced Nlrp3 activation and preserved lens transparency, demonstrating its potent antioxidant and anti-inflammatory effects. Collectively, these findings identify TXNIP as a key regulator of Nlrp3 inflammasome signaling and thereby highlight the therapeutic potential of TXNIP silencing (ShTXNIP) or TAT-HA-Prdx6 delivery to halt Nlrp3-mediated pyroptosis during aging or oxidative stress conditions.

Hereditary hyperferritinemia-cataract syndrome (HHCS) is a rare autosomal dominant disorder caused by pathogenic variants in the iron-responsive element (IRE) of the 5' untranslated region (5'UTR) of the FTL gene, resulting in dysregulated ferritin synthesis independent of body iron stores. Because elevated serum ferritin is commonly interpreted as a surrogate marker of iron overload, HHCS is frequently misdiagnosed as hereditary hemochromatosis or secondary iron overload, leading to unnecessary investigations and potentially harmful therapeutic phlebotomies. We report the case of a 58-year-old male patient with longstanding unexplained hyperferritinemia, normal transferrin saturation, and a striking multigenerational family history of early-onset cataracts. Despite the absence of biochemical or radiological evidence of iron overload, the patient initially underwent therapeutic phlebotomy. Subsequent targeted sequencing of the FTL 5'UTR identified a heterozygous pathogenic c.-168G>A variant within the IRE, confirming the diagnosis of HHCS. This case highlights a critical diagnostic pitfall in hematology practice and emphasizes the importance of interpreting serum ferritin in conjunction with transferrin saturation, exclusion of secondary causes, and careful assessment of family history. Early recognition of HHCS and appropriate use of targeted genetic testing can prevent inappropriate iron-depleting therapies and improve patient management.

RNA interference (RNAi) has emerged as a key molecular tool in various commercially important decapod crustaceans, offering potential biotechnological applications in aquaculture. However, in the tropical rock lobster <i>Panulirus ornatus</i>, gene silencing through RNAi has proven difficult to achieve despite the availability of extensive omics data. This study investigates the RNAi response across life stages in <i>P. ornatus</i>, focusing on larvae and juveniles to determine when the species is most receptive to RNAi. Late-stage phyllosoma larvae and early juveniles were microinjected with dsRNA for the insulin-like growth factor binding protein encoding gene to determine silencing efficiency. Our results show that while juveniles exhibit an efficient systemic RNAi response with robust silencing across tissues, larvae display limited silencing capacity. A key finding is the differential expression of RNAi pathway components, including SID1, which facilitates dsRNA uptake in juveniles but is less active in larvae. Fluorescent microscopy revealed that dsRNA is rapidly sequestered and expelled by the antennal gland in larvae, potentially limiting RNAi efficacy. To further explore the mechanisms underlying RNAi in <i>P. ornatus</i>, RNA-seq analysis was conducted on pleopods collected across time points after dsRNA exposure in juvenile lobsters. Transcriptomic analysis identified significant upregulation of RNAi machinery, including Dicer-2, Argonaute-2, and SID1, which are critical for silencing. Additionally, several genes associated with antiviral responses were differentially expressed, suggesting broader involvement of RNAi in immune regulation. These findings highlight the potential to enhance RNAi strategies in <i>P. ornatus</i> juveniles, advancing the development of RNAi-based tools for disease resistance and productivity in aquaculture.<h4>Supplementary information</h4>The online version contains supplementary material available at 10.1007/s42995-025-00336-3.

<h4>Context</h4>Insulin action is critical for energy homeostasis and its dysfunction in muscle cells is associated with type 2 diabetes. Insulin receptor (INSR) internalization and cell-surface dynamics at rest and during insulin exposure are incompletely understood in muscle cells.<h4>Objective</h4>We aimed to characterized the INSR dynamics and interactions in muscle.<h4>Methods</h4>We applied inter-domain tagged INSR, microscopy, immunoprecipitation, mass spectrometry, and AlphaFold multimer to comprehensively profile INSR internalization and interactions with or without insulin stimulation.<h4>Results</h4>Using surface labeling and live-cell imaging, we observed robust basal internalization of INSR in C2C12 myoblasts, without an effect of added insulin. Mass spectrometry using INSR knockout cells as controls identified high-confidence binding partners, including proteins associated with internalization. We confirmed known interactors, including insulin-like growth factor 1 receptor, and also identified underappreciated INSR-binding factors, such as annexin A2. AlphaFold multimer analysis predicted potential INSR-binding sites of these proteins. Protein-protein interaction network mapping suggested links between INSR and caveolin-mediated endocytosis. INSR interacted with both caveolin and clathrin heavy chain (CLTC) in mouse skeletal muscle and C2C12 myoblasts. Whole-cell 2-dimensional super-resolution imaging revealed that high levels of insulin (20 nM) increased INSR colocalization with caveolin-1 (CAV1) but decreased its colocalization with CLTC. Single-particle tracking confirmed the colocalization of cell-surface INSR with both overexpressed CAV1-mRFP (monomeric red fluorescent protein) and CLTC-mRFP. INSR tracks that colocalized with CAV1 exhibited longer radii and lifetimes, regardless of insulin exposure, compared with noncolocalized tracks, whereas insulin further increased the lifetime of INSR/CLTC-colocalized tracks.<h4>Conclusion</h4>Overall, these data suggest that muscle cells utilize both CAV1- and CLTC-dependent pathways for INSR mobilization and internalization.

<title>Abstract</title> <p> Metastasis, a critical phase in cancer progression, involves the dissemination of malignant cells to distant organs, significantly driving mortality. The hypothesis that genetic and molecular signatures regulate metastatic site selection underpins this study. Transcriptomic analyses of four common metastatic patterns, colorectal cancer (CRC) to lung or liver, and pancreatic cancer (PC) to these organs, were performed using GEO microarray datasets (GSE71729, GSE41258). Differentially expressed genes (DEGs) were identified by comparing metastatic and primary tissue profiles, excluding broadly shared metastatic genes to isolate site specific markers, and analyzed via Cytoscape with the MCC algorithm to determine 10 hub genes per site. Liver metastases in both CRC and PC shared nine hub genes: <italic>ALB, APOH, AHSG, APOA2, FGA, SERPINC1, FGB, HPX</italic> , and <italic>APOA1</italic> , linked to cholesterol metabolism and coagulation, regulated by transcription factors (HNF4A, FOXA2, NR2F1), microRNAs (hsa-miR-124-3p, hsa-miR-182-5p), and lncRNAs (TUG1, NEAT1, XIST). Lung metastases across both cancers shared five hub genes: <italic>SFTPC, SFTPB, SCGE1A1, NKX2-1</italic> , and <italic>ABCA3</italic> , associated with ABC transporter and phagosome pathways, modulated by FOXA1, microRNAs (hsa-miR-15a-5p, hsa-miR-34a-5p, hsa-let-7b-5p), and lncRNAs (NEAT1, KCNQ1OT1). These consistent genetic and regulatory patterns provide strong evidence that genetic and molecular signatures determine metastatic site specificity, laying a foundation for targeted therapies. </p>

<h4>Abstract</h4>Pediatric health is the foundation for people's lifelong health. The co-evolution of host genetics and the gut microbiome fosters a symbiotic relationship that is important for pediatric growth and the pathogenesis of various diseases. However, a comprehensive overview of the human genetics-gut microbiome axis in pediatric diseases remains unavailable. This review summarizes the human genetic variants that are associated with pediatric diseases, affecting the nervous, respiratory, and immune systems, as well as those linked to preterm birth (PTB), as identified by genome-wide association studies (GWAS). As the gut microbiome plays a crucial role in pediatric health, we have systematically discussed microbial biomarkers associated with the onset and progression of pediatric diseases, with an emphasis on their clinical impact across four key axes: the gut-brain, gut-lung, gut-skin, and gut-immune axes. The GWAS on the gut microbiome revealed numerous genetic variants that intricately regulate its composition. These variants predispose individuals to gut microbiome dysbiosis, potentially initiating or exacerbating pediatric disease manifestations. Moreover, the underrepresentation of populations from low- and middle-income countries in existing microbiome-related data, coupled with technical challenges, limits our understanding of the association between microbiome and health. Finally, we emphasize the promising potential of elucidating and modulating host gene-gut microbiome interactions to offer novel insights for advancing precision pediatric medicine and developing innovative therapeutic strategies.

Ferroptosis is an iron-dependent form of programmed cell death governed by redox homeostasis. Although Ezrin, Radixin, and Moesin (ERM) proteins are established membrane-actin cytoskeleton linkers, their role in ferroptosis remains unexplored. Here, ERM proteins are identified as modulators of erastin-induced ferroptosis. In human fibrosarcoma HT-1080 cells, pharmacological inhibition of ERM phosphorylation, knockdown of individual ERM members, or overexpression of a phospho-deficient Ezrin mutant (T567A) consistently attenuated ferroptosis, whereas wild-type ERM overexpression enhances ferroptosis susceptibility. Mechanistically, ERM inhibition leads to F-actin depolymerization accompanied by a modest rise in reactive oxygen species (ROS). F-actin stabilization prevents this ROS surge and restores ferroptotic sensitivity, whereas its depolymerization mimics the protective effect of ERM inhibition. ROS elevation triggers KEAP1 degradation, stabilizing NRF2 and promoting its nuclear translocation. Activated nuclear NRF2 induces antioxidant genes, particularly HMOX1, a key effector of heme catabolism that enhances redox buffering and limits lipid peroxidation, ultimately conferring resistance to ferroptosis. The protective effects of ERM inhibition are further validated in ferroptosis-relevant ex vivo and in vivo models. Notably, other pro-oxidants similarly attenuate ferroptosis at appropriate concentrations. Together, these results establish ERM proteins as regulators of ferroptosis and reveal an underappreciated group of ferroptosis inhibitors that engage ROS-NRF2-mediated redox-adaptation.

Corticospinal neurons (CSN) centrally degenerate in amyotrophic lateral sclerosis (ALS), along with spinal motor neurons, and loss of voluntary motor function in spinal cord injury (SCI) results from damage to CSN axons. For functional regeneration of specifically affected neuronal circuitry <i>in vivo</i>, or for optimally informative disease modeling and/or therapeutic screening <i>in vitro</i>, it is important to reproduce the type or subtype of neurons involved. No such appropriate <i>in vitro</i> models exist with which to investigate CSN selective vulnerability and degeneration in ALS, or to investigate routes to regeneration of CSN circuitry for ALS or SCI, critically limiting the relevance of much research. Here, we identify that the HMG-domain transcription factor <i>Sox6</i> is expressed by a subset of NG2+ endogenous cortical progenitors in postnatal and adult cortex, and that <i>Sox6</i> suppresses a latent neurogenic program by repressing proneural <i>Neurog2</i> expression by progenitors. We FACS-purify these progenitors from postnatal mouse cortex and establish a culture system to investigate their potential for directed differentiation into CSN. We then employ a multi-component construct with complementary and differentiation-sharpening transcriptional controls (activating <i>Neurog2</i>, <i>Fezf2</i>, while antagonizing <i>Olig2</i> with <i>VP16:Olig2</i>). We generate corticospinal-like neurons from SOX6+/NG2+ cortical progenitors and find that these neurons differentiate with remarkable fidelity compared with corticospinal neurons in vivo. They possess appropriate morphological, molecular, transcriptomic, and electrophysiological characteristics, without characteristics of the alternate intracortical or other neuronal subtypes. We identify that these critical specifics of differentiation are not reproduced by commonly employed <i>Neurog2</i>-driven differentiation. Neurons induced by <i>Neurog2</i> instead exhibit aberrant multi-axon morphology and express molecular hallmarks of alternate cortical projection subtypes, often in mixed form. Together, this developmentally-based directed differentiation from cortical progenitors sets a precedent and foundation for <i>in vitro</i> mechanistic and therapeutic disease modeling, and toward regenerative neuronal repopulation and circuit repair.

Pathological cardiac hypertrophy is characterized by profound disruptions in protein turnover, a hallmark of maladaptive cardiac remodeling. This study aimed to elucidate the role and underlying molecular mechanisms of an FBP, F-box and leucine-rich repeat protein 4 (FBXL4), in pathological cardiac hypertrophy. Transcriptomic analysis of murine heart failure and human dilated cardiomyopathy samples revealed consistent downregulation of FBXL4. Similarly, FBXL4 expression was reduced in failing human hearts, hypertrophic mouse hearts, and angiotensin II (Ang II)-treated neonatal mouse cardiomyocytes (NMCMs). Inducible ablation of FBXL4 in cardiomyocytes resulted in HF with reduced cardiac function, an enlarged heart chamber, increased fibrosis, and myofibrillar disorganization and sarcomere remodeling. Conversely, cardiac-specific overexpression of FBXL4 attenuated pressure overload-induced hypertrophy. Mechanistically, FBXL4 interacts with PFN1 and promotes its K48-linked ubiquitination at lysine 70, leading to its proteasomal degradation and the preservation of sarcomeric integrity. Restoration of FBXL4 expression via AAV9 delivery ameliorated cardiac hypertrophy and dysfunction in FBXL4-iCKO mice, while AAV9-mediated PFN1 knockdown or pharmacological inhibition partially reversed these phenotypes. Furthermore, the transcription factor SP1 was found to repress FBXL4 expression during hypertrophy. FBXL4 deficiency also induced hypertrophic features in hiPSC-derived cardiomyocytes. Together, these findings establish FBXL4 as a key regulator of sarcomere integrity and cardiac function through ubiquitin-mediated degradation of PFN1.

Accumulating evidence implicates that disrupted ovarian neurovascular coupling is a vital driver for polycystic ovary syndrome. Electroacupuncture (EA), as a form of peripheral neuromodulation, offers a potential therapeutic avenue to restore this coupling and improve ovarian function. However, how neural regulation leads to vascular changes remains unclear. Conventional histological and imaging methods cannot capture either immediate or long-term effects of EA on neurovascular dynamics, as they are limited by the lack of real-time and continuous in vivo visualization. Here, core-shell lanthanide nanocrystals α-NaYbF₄:2%Er,2%Ce@NaYF₄ showed deep-tissue penetration in the second near-infrared long-wavelength region (NIR-II-L, 1500-1900 nm). Moreover, it could achieve real-time and high-resolution visualization of EA-induced structural and functional changes in the ovarian blood vessels. Our results showed that immediate EA (iEA) at specific parameters and acupoints transiently induced ovarian vasodilation, while cumulative EA (cEA) further strengthened sympathetic-vascular coupling, leading to sustained improvements in local perfusion and follicular development. Additionally, we validated that these effects were dependent on the neurovascular coupling mediator Netrin-1, an axon guidance molecule increasingly recognized for its role in arterial innervation and blood flow regulation in peripheral organs. This study elucidated parameter-specific mechanisms by which EA regulated ovarian function and proposed a visualizable strategy for in vivo analysis of neurovascular structural-functional remodeling.

Lymph node metastasis marks a critical transition in prostate cancer progression, yet causal molecular links between primary tumour immunity and metastatic capability remain unclear. We analysed 425 primary prostate cancer patients, integrating transcriptomic profiling with Mendelian randomisation to establish causal relationships between immune cell gene expression and lymph node metastasis. Differential expression analysis identified 131 significantly altered genes between N1 and N0 tumours. Functional enrichment revealed upregulated genes enriched in metal ion homeostasis, whilst downregulated genes involved viral defence and interferon signalling. Mendelian randomisation identified 11 significant causal associations, with 73% demonstrating protective effects. MT1F showed consistent protection across immune cell types, whilst CD38, GNMT, and SLC14A1 paradoxically increased risk despite upregulation in metastatic tumours. A 7-gene prognostic signature independently predicted progression-free survival across validation cohorts. Immune deconvolution analysis revealed high-risk tumours exhibited an immunosuppressive microenvironment with increased regulatory T cells and M2 macrophages, whilst individual signature genes paradoxically showed positive correlations with anti-tumour plasma cells. This study reveals the paradoxical nature of immune-related genes: promoting metastasis when expressed in cancer cells whilst providing protection when expressed in immune cells. Systematic immune suppression creates corrupted microenvironments where protective genes are co-opted for cancer survival. Effective immunotherapy strategies must account for this dual nature, necessitating multi-dimensional precision medicine approaches that target specific cellular compartments.

Cachexia is a debilitating syndrome characterized by progressive skeletal muscle wasting, commonly affecting patients with cancer, particularly those with pancreatic cancer. Despite its clinical significance, the molecular mechanisms underlying cancer cachexia remain poorly understood. In this study, we utilized single-nucleus RNA-seq (snRNA-seq) and bulk RNA-seq, complemented by biochemical and histological analyses, to investigate molecular alterations in the skeletal muscle of the KPC mouse model of pancreatic cancer cachexia. Our findings demonstrated that KPC tumor growth induced myofiber-specific changes in the expression of genes involved in proteolytic pathways, mitochondrial biogenesis, and angiogenesis. Notably, tumor progression enhanced the activity of specific transcription factors that regulate the mTORC1 signaling pathway, along with genes involved in translational initiation and ribosome biogenesis. Skeletal muscle-specific, inducible inhibition of mTORC1 activity further exacerbated muscle loss in tumor-bearing mice, highlighting its protective role in maintaining muscle mass. Additionally, we uncovered new intercellular signaling networks within the skeletal muscle microenvironment during pancreatic cancer-induced cachexia. Our study reveals previously unrecognized molecular mechanisms that regulate skeletal muscle homeostasis, and it identifies potential therapeutic targets for the treatment of pancreatic cancer-associated cachexia.

Genes of the Tumor Necrosis Factor Superfamily (TNFSF) encode proteins with critical roles in cell signaling in animals, particularly in immunity and development. The evolution of the TNF superfamily remains poorly understood. This study demonstrates that tunicates possess a much more complex TNF superfamily than previously assumed. Some species have a large number of TNFSF genes, up to 14, due to frequent, independent tandem duplications. Significantly, this number exceeds that observed in many vertebrates (e.g., all characterized cyclostomes, as well as some birds and reptiles). As in vertebrates, the TNF superfamily of tunicates is capable of rapid evolutionary change. All 24 model tunicate species analyzed have different sets of TNFSF genes and even closely related species often have quite distinct TNF superfamilies. A comparison of tunicate and vertebrate data suggests that four TNFSF genes were present in the last common ancestor of both lineages. One of these genes was subsequently lost while the other three underwent independent duplications in early tunicate evolution. Six TNFSF genes were likely present in the common ancestor of all tunicates except perhaps appendicularians, for which data remain inconclusive. These results are consistent with the current model of how the TNFSF vertebrate genes emerged and evolved, except that whole-genome duplications played a significant role in expanding the family in vertebrates but not in tunicates. Transcription data obtained from Ciona intestinalis type A (C. robusta) indicate that several distantly related TNFSF genes share similar patterns of expression during development and in adults. Gene expression data are compatible with TNFSF genes having multiple roles, some of them in the innate immune system. Their involvement in immune defense may explain the rapid changes in TNFSF gene number observed in both tunicates and vertebrates.

Corporate bankruptcy risk in China is increasingly driven by structural credit discrimination and a systemic financial mismatch. This study investigates the impact of cash holdings and financial constraints on corporate bankruptcy risk in China. We employ the Two-step system Generalized Method of Moments (GMM) to analyze an unbalanced panel of 32,081 annual observations from listed firms in China, spanning the period from 2010 to 2023. Our findings indicate that higher financial constraints increase bankruptcy risk, as a one-point rise in the SA index reduces the Z-score by 4.26 points, supporting Market Timing Theory. Conversely, cash holdings serve as a powerful protective buffer; a 1% increase in cash holdings raises the Z-score by 0.37 points, supporting the Precautionary Savings and Trade-off theories. Furthermore, our results highlight the buffer role of cash holdings for financially constrained firms, where higher cash reserves mitigate the adverse effects of financial constraints on bankruptcy risk. Our main findings remain robust after employing alternative bankruptcy risk proxies, firm size-based, and exchange subsamples. These findings provide valuable insights for financial managers and policymakers, highlighting the importance of effective liquidity management and credit accessibility in mitigating corporate distress in emerging markets.

Formulating cationic polyplexes (PP) with polyanions as ternary polyelectrolyte nanoparticles (TNP) offers a polymeric alternative to lipid nanoparticles (LNP) for targetable nucleic acid delivery. Although TNP <i>in vivo</i> transport is credited to their anionic surface charge, the relationships between polyanion chemistry and TNP structural stability, protein binding, and transfection are poorly understood compared to lipid-based systems. We hypothesized that carefully engineered hydrophobic polyanions could simultaneously endow TNPs with negative surface charge and enhanced extracellular stability critical to the future development of actively targeted formulations. We synthesized chemically diverse PEGylated polyanions to coat self-amplifying RNA (saRNA) PP, systematically studying how PEG architecture and polyanion chemistry modulate TNP structure and function. In both high-throughput stability assays and Small Angle Neutron Scattering structural studies, we found that PEG_5k-<i>bl</i>-polyanion_5k yields remarkably small particles with a pH-responsive core-shell structure. We identify a lead formulation (TNP5) with moderate hydrophobicity and charge density that balances extracellular stability and intracellular unpackaging for transfection. In agreement with spectroscopic characterization and <i>in vitro</i> cell studies, Molecular Dynamics simulations support the hypothesis that polyanions dictate TNP function from the inside-out by excluding water from the RNA core and by exposing functional groups that modulate protein binding. Our work correlates high throughput assays and detailed neutron scattering analysis to uncover mesoscale structural differences between two- and three-component polyelectrolyte delivery systems. These screening methods and the critical balances between polymer properties they uncover establish a framework for high throughput engineering of pH-responsive nanoparticle structure/function to navigate biological barriers to RNA delivery.

<h4>Background/aims</h4>Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide. Aberrant DNA methylation, which is primarily maintained by DNA methyltransferase 1 (DNMT1), has been linked to metabolic dysregulation; however, its contribution to MASLD pathogenesis remains poorly defined. This study aimed to elucidate the role of DNMT1-mediated methylation in transcriptional regulation during MASLD progression and to determine whether DNMT1 inhibition can reverse disease-associated epigenetic and transcriptional alterations.<h4>Methods</h4>We conducted integrated analyses of the liver transcriptome (n=131) and DNA methylome (n=106) of patients with biopsy-proven MASLD. We evaluated the effect of DNMT1 inhibition with 5-aza-4'-thio-2'-deoxycytidine (Aza-TdC) on a diet-induced MASLD mouse model. Multiomics approaches, including DNA methylome profiling, lipidomics, RNA sequencing, and chromatin immunoprecipitation sequencing, were applied to elucidate the role of DNMT1-mediated DNA methylation in regulating pathogenic gene expression.<h4>Results</h4>DNA methylome profiling revealed increased methylation variability associated with increased DNMT1 expression in MASLD patients. DNMT1 inhibition ameliorated dysregulated lipid metabolism by reducing hepatic triacylglycerol accumulation and inflammation. Aza-TdC treatment partially reversed MASLD-related hypermethylation of hepatocyte nuclear factor 4 alpha (HNF4α)- and peroxisome proliferator-activated receptor alpha (PPARα)-regulated genes, restoring their transcriptional activity. Notably, Aza-TdC reactivated the gluconeogenic enzyme-encoding gene phosphoenolpyruvate carboxykinase 1 (PCK1), which was hypermethylated and transcriptionally repressed in MASLD. Targeted DNA methylation of the PCK1 promoter using CRISPRoff confirmed the direct epigenetic regulation of PCK1 expression.<h4>Conclusions</h4>Targeting DNMT1 may mitigate lipid dysregulation and inflammation by reversing hypermethylation and restoring HNF4α- and PPARα-dependent gene transcription, highlighting DNMT1 as a potential therapeutic target for MASLD.

The endoplasmic reticulum (ER) is a central organelle for protein synthesis and folding, lipid metabolism and calcium signaling, etc. To maintain ER homeostasis, cells employ a specific autophagy process termed ER-phagy (reticulophagy), which depredates ER components via three forms: macro-ER-phagy (involving bulk ER sequestration), micro-ER-phagy (lysosome-direct), and ER-to-lysosome-associated degradation (ERLAD). The identification of specific ER-phagy receptors including FAM134A, FAM134B, FAM134C, TEX264, SEC62, RTN3L, CCPG1, ATL3, CALCOCO1 and others has significantly advanced our understanding of ER quality control mechanisms. In this review we summarize the current knowledge on ER-phagy receptors, and emerging evidence linking ER-phagy dysfunction to various disease pathologies including neurological disorders, cancer, metabolic diseases, cardiovascular diseases, infections and immune disorders. Recent evidence shows that ER-phagy receptors can form novel ER-derived structures, such as ER-tubular bodies (ER-TBs) consisted of ATL3 and RTN3L, which mediate Golgi-bypassing unconventional protein secretion under stress conditions, revealing non-degradative functions of these receptors beyond quality control. Targeting ER-phagy receptors may provide insights into potential therapeutic strategies for diseases associated with this fundamental cellular process.

Thymic stromal lymphopoietin (TSLP), initially described as a driver of type 2 helper T cell responses, can also act on dendritic cells (DCs) to promote the generation and accumulation of GATA3-expressing effector regulatory T (eT_reg) cells in the context of cutaneous melanoma. In this study, using an experimental mouse model with induced TSLP expression by epidermal keratinocytes combined with genetic tools, we find that TSLP drives GATA3⁺ eT_reg cells through a specific migratory DC population where the co-stimulatory molecule OX40L is required. By conducting transcriptomic identity, lineage-traced ontogeny, surface marker expression and functional studies, we identified and characterized this DC population. Our data demonstrated that TSLP acts on transitional dendritic cell-derived DC2 to promote GATA3⁺ eT_reg cells, thus uncovering a previously unrecognized tolerogenic axis in promoting immunosuppression, which is likely conserved in humans, across contexts of inflammation and cancer.

BACKGROUND: Hand grip strength is a crucial indicator of muscle strength and quality. Yet, there remain significant knowledge gaps in our understanding of the genetic factors that influence hand grip strength and its impact on digestive disorders. METHODS: This study employed data from the UK Biobank, comprising 405,394 individuals of European ancestry, who underwent assessments of both left- and right- hand grip strength at baseline. We calculated the relative hand grip strength (RHGS), defined as the average hand grip strength adjusted for body mass index (BMI). Subsequently, we performed genome-wide association study (GWAS) to identify RHGS-linked variants and genes. We evaluated RHGS’s impact on digestive disorders using linkage disequilibrium score regression (LDSC), Mendelian randomization (MR), Polygenic risk score (PRS), regression models, and interaction analyses. RESULTS: GWAS of 405,394 Europeans identified 1,111 independent SNPs across 226 autosomal loci and 407 genes associated with RHGS. TWAS with skeletal-muscle eQTLs prioritized genes, including L3MBTL3, CEP192 and NUCKS1, highly expressed in type I/II myocytes and mesenchymal cells. LDSC revealed significant negative genetic correlations between RHGS and abdominal hernia (rg = -0.121, p = 5.00 × 10⁻⁴), diaphragmatic hernia (rg = -0.155, p = 6.33 × 10⁻⁶) and diverticular intestine (rg = -0.141, p = 3.85 × 10⁻¹⁰). MR indicated that one-unit higher genetically predicted RHGS reduced odds of diaphragmatic hernia (OR = 0.45, 95% CI 0.25–0.82), diverticular intestine (OR = 0.42, 0.26–0.66), NAFLD (OR = 0.49, 0.29–0.83) and peptic ulcer (OR = 0.54, 0.31–0.97). Each standard-deviation increase in RHGS PRS was associated with lower risks of abdominal hernia (OR = 0.98), diaphragmatic hernia (OR = 0.96) and diverticular intestine (OR = 0.98) after full adjustment. Gene-environment analyses showed diabetes, hyperlipidemia and smoking attenuated the protective effects from elevated RHGS, whereas cardioprotective diet and higher fiber intake showed synergistic protection on abdominal hernia, diaphragmatic hernia and diverticular intestine. CONCLUSION: We identified multiple RHGS-associated loci enriched in skeletal muscle. Genetically high RHGS inversely correlated with risks of abdominal hernia, diaphragmatic hernia and diverticular intestine. RHGS polygenic risk score enables risk stratification, and its effects are modulated by diet and common comorbidities.

<h4>Background</h4>Brain development and plasticity depend on specific microRNA (miRNA) expression patterns across cell types and subcellular compartments. Nevertheless, comprehensive profiling of localized brain miRNAs is still limited by challenges in isolating individual cell types or compartments and in detection sensitivity.<h4>Results</h4>To overcome these limitations, we advanced HIV-1 Gag's ability to bind host miRNAs within Virus-like Particles to develop Synthetic Nano-Particles for Precise endogenous miRNA loading and export (SNaP). Our data establish SNaP's modularity and portability to clinically relevant neural cells, with particle yields matching benchmark packaging cells. The integration of SNaP with a cell-specific promoter enabled lineage-restricted miRNA export, while incorporating a dendritic localization signal improved the specificity of post-synaptic miRNA recovery over traditional synaptosomes. Additional engineering with a miRNA-binding module synergistically increased synaptic miRNA packaging in a sequence-independent manner.<h4>Conclusion</h4>Collectively, this work positions SNaP as a technological advancement supporting the high-resolution, spatially resolved profiling of miRNAs, adaptable to diverse polarized or heterogeneous culture systems.

The recombination-activating gene (RAG) complex initiates adaptive immunity by catalyzing V(D)J recombination to generate diverse antigen receptors. While the catalytic function of the RAG core is well defined, its regulatory interactions and physiological roles remain poorly understood due to limited knowledge of RAG-associated proteins. The RAG complex forms a heterotetramer of two RAG1 and RAG2 subunits, yet the individual contributions of each subunit remain unclear. Here, we use TurboID-mediated proximity labelling to map the human RAG interactome. By fusing TurboID to RAG1 or RAG2, we identify 88 RAG1- and 146 RAG2-associated proteins, with only 23 shared proteins, indicating distinct sets of proximal proteins. Although RAG1 and RAG2 are thought to exert their physiological functions by forming a complex, they display distinct potential interaction networks, suggesting subunit-specific functions and revealing their spatial proximity to each subunit. These findings uncover distinct RAG1 and RAG2 interaction landscapes and establish a framework for exploring broader RAG functions in immunity.

Severe vitamin B12 deficiency can clinically mimic Addison disease, with hyperpigmentation despite preserved adrenal function. We report a 34-year-old woman presenting with fatigue, an unintended weight loss of about 20 kg, and mucocutaneous hyperpigmentation raising concern for primary adrenal insufficiency. Examination showed pallor, mild scleral icterus, and elevated blood pressure. Laboratory testing demonstrated severe cobalamin deficiency with macrocytic anemia and biochemical evidence of intramedullary hemolysis, whereas morning cortisol and ACTH levels excluded adrenal failure. Intrinsic factor antibodies confirmed pernicious anemia. Notably, cancer antigen 15-3 was elevated at presentation but normalized after intramuscular vitamin B12 replacement, indicating a benign hematologic rather than oncologic etiology. Treatment triggered an appropriate reticulocyte response with subsequent hematologic recovery and gradual resolution of the hyperpigmentation. Pernicious anemia should be considered in the differential diagnosis of Addison-like pigmentation without adrenal insufficiency. Recognizing that tumor marker elevation may occur in severe megaloblastic anemia is essential to prevent unnecessary oncologic workup.

Paneth cells are secretory intestinal epithelial cells most abundant in the ileum that contribute to gut homeostasis and innate immunity through secretion of antimicrobial peptides and intestinal stem cell factors. Dysfunction of Paneth cells has been implicated in various gastrointestinal disorders. Although regulation of Paneth cell function by microbial signals has been well established, accumulating evidence highlights a pivotal role for cytokine networks in modulating Paneth cell activity. Cytokines such as Interferons (IFNs), Interleukin (IL)-9, IL-13, IL-17, IL-22, and tumor necrosis factor (TNF) influence diverse aspects of Paneth cell biology and, in turn, intestinal tissue homeostasis. In this review, we synthesize current knowledge of cytokine-mediated regulation of Paneth cells, explore the emerging role of Paneth cell phenotyping as predictive in intestinal disease outcomes, and conclude with key unanswered questions that define future research directions in the field.

Brain fingerprinting offers a promising method for delineating the unique functional architecture of individual brains using neuroimaging data. Here, we present a novel deep learning framework-Metric-BolT-for brain fingerprinting and use it to characterize distinct developmental trajectories during childhood and early adolescence. Based on longitudinal neuroimaging data, the extracted brain fingerprints achieved identification accuracies of 97.6% for two data runs acquired within a single session and 86.6% for runs spanning 4 years. Notably, the most discriminative brain fingerprints were driven by higher-order association cortices, particularly regions of the default-mode network. Moreover, we showed these fingerprints to correlate with cognitive abilities, such as fluid and crystallized intelligence, and to exhibit significant genetic associations, with stronger genomic relationships observed among individuals with more similar fingerprint patterns. Genes associated with brain fingerprinting tended to show upregulated expression in the frontal cortex, particularly in late childhood. Together, our study presents an innovative computational approach for brain functional fingerprinting and provides novel insights into individual variability in adolescent neurodevelopment.

No abstract available.

<b>Background:</b> Lung metastasis is a leading cause of breast cancer (BC)-related mortality, driven by the immunosuppressive traits of the metastatic tumor microenvironment. However, the mechanisms underlying cell-cell crosstalk in shaping immune evasion within the metastatic niche remain poorly defined. Neutrophil extracellular traps (NETs) and their associated proteins, such as cathelicidin, have emerged as key mediators of metastatic regulation in cancer. Here, we aimed to decipher the interaction between a neutrophil subset characterized by high expression of lymphocyte antigen 6 complex locus g (Ly6g^high) and cluster of differentiation 8-positive T lymphocytes (CD8⁺ T cells), mediated via cathelicidin embedded in NETs, as well as their synergistic mechanism and cooperative role in promoting lung metastasis of BC. <b>Methods:</b> We characterized neutrophil heterogeneity and functional dynamics by performing single-cell RNA sequencing and flow cytometry on lung tissues derived from murine models of BC lung metastasis. We utilized cathelicidin-related antimicrobial peptide (<i>Cramp</i>) knockout mice to dissect the role of cathelicidin in NETs. The spatial colocalization of apoptotic CD8⁺ T cells and NETs was analyzed using multiplex immunofluorescence, and the molecular interactions were probed by protein binding assays. <b>Results:</b> Neutrophils in the lung metastatic niche were classified into 2 subsets based on the Ly6g expression: Ly6g^high and Ly6g^low neutrophils. Ly6g^low neutrophils, which were recruited in the macrometastatic stage, exhibited myeloid-derived suppressor cell-like characteristics. Notably, Ly6g^high neutrophils induced CD8⁺ T cell apoptosis through NET formation, with apoptotic CD8⁺ T cells spatially clustered within NET-rich areas. Mechanistically, NET-derived cathelicidin (Cramp in mice) directly bound to mitochondrial adenine nucleotide translocator 1 (Ant1) in CD8⁺ T cells, triggering conformational changes and complex formation with voltage-dependent anion channel 1 (Vdac1). These events resulted in the opening of the mitochondrial permeability transition pore and loss of mitochondrial membrane potential. <b>Conclusions:</b> Our study demonstrates that Ly6g^high neutrophils play a critical role in immunosuppression and immune evasion through NET-induced apoptosis of CD8⁺ T cells. These findings underscore the importance of NETs and cathelicidin in BC lung metastasis, suggesting their potential as therapeutic targets in restoring antitumor immunity and in preventing metastatic progression.

Residual feed intake (RFI) is a key indicator of feed efficiency in poultry. Although regulatory links such as the hypothalamus-gut and gut-liver axes have been implicated, most studies remain restricted to single axes or fragmented analyses, and systematic multi-organ integration is lacking. Here, we measured feed efficiency in 1,000 Nonghua ducks and selected 12 individuals with divergent RFI for transcriptomic profiling of the hypothalamus, pituitary, liver, duodenum, jejunum, ileum, and cecum, combined with serum metabolomics. We identified 769 differentially expressed genes (DEGs), with the hypothalamus, liver, and cecum as major contributors, and 28 differential serum metabolites enriched in lipid and amino acid metabolism. Beyond tissue-specific functions, enrichment analysis highlighted several pathways that were repeatedly shared across central and peripheral tissues, including neuroactive ligand-receptor interaction, hormone signaling, steroid hormone biosynthesis, and insulin signaling, suggesting a coordinated regulation of feed efficiency between the brain, gut, and liver. To clarify their relevance, we integrated gene modules with metabolites and identified two candidate cross-organ association frameworks: the MEblack-6-Oxopiperidine-2-carboxylic acid (gut-liver) networks, enriched for liver genes CNTNAP1, SHC3, and RAB36, and cecal genes DCC and CCDC60. The MEblue-LysoPE(18:2(9Z,12Z)/0:0) (gut-brain) networks, enriched for cecal genes FABP6, KCNJ11, and the pituitary gene TRPA1, in which these genes and metabolites may contribute to RFI regulation. Together, these findings provide new insights into cross-organ molecular networks underlying feed efficiency in ducks and establish a valuable resource for future functional studies and breeding strategies.

<h4>Background</h4>Esophageal cancer (EC) is the eighth most prevalent malignancy worldwide and exhibits the sixth poorest prognosis. Esophageal squamous cell carcinoma (ESCC) is the predominant pathological subtype. Ferroptosis, an iron-dependent form of cell death, plays a critical role in cancer progression. Long non-coding RNAs (lncRNAs) have emerged as key regulators in the initiation and progression of EC. However, the role of lncRNAs in modulating ferroptosis within EC remains poorly understood. Therefore, this study aimed to identify key ferroptosis-related lncRNAs in ESCC and to investigate the role and mechanism of a specific lncRNA, long intergenic non-protein-coding RNA 92 (LINC00092).<h4>Methods</h4>Bioinformatics analysis was conducted to identify ferroptosis-related lncRNAs, transcription factors (TFs), and genes associated with ESCC. The expression, function, tumor microenvironment, immunotherapy, and downstream molecular pathways were also determined. The expression levels of LINC00092, MYC-associated zinc finger protein (MAZ), and NFE2 like bZIP transcription factor 2 (NFE2L2) were detected using quantitative real-time polymerase chain reaction (qRT-PCR), immunohistochemical analysis, and western blotting. Fluorescence in situ hybridization (FISH) was performed to determine the subcellular localization of LINC00092. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation, wound healing, Transwell, and flow cytometry apoptosis assays were performed to determine the phenotypes and functions of loss- and gain-of LINC00092. RNA immunoprecipitation (RIP) and luciferase reporter assays were used to evaluate interactions involving LINC00092. The expression of ferroptosis-related proteins was verified by western blotting.<h4>Results</h4>LINC00092 was found to be downregulated in ESCC datasets, cell lines, and tissue samples. Bioinformatics analysis revealed that LINC00092 was associated with ferroptosis and negatively correlated with NFE2L2 expression. Further investigations demonstrated that LINC00092 acted as a binder to the TF MAZ, modulating the expression of the ferroptosis-related gene <i>NFE2L2</i>. Overexpression of LINC00092 inhibited ESCC cell progression, whereas its downregulation promoted tumor progression. RIP and luciferase reporter assays confirmed that MAZ was a target of LINC00092, and <i>NFE2L2</i> was a downstream target of MAZ. Western blot analysis showed that LINC00092 enhanced ferroptosis in ESCC cells. The LINC00092/MAZ/NFE2L2 axis appeared to inhibit cancer progression by promoting ferroptosis through the regulation of <i>NFE2L2</i> and sequestration of the TF MAZ.<h4>Conclusions</h4>LINC00092 exerts tumor-suppressive effects in ESCC cells by inhibiting cancer progression through the LINC00092/MAZ/NFE2L2 axis and promoting ferroptosis. Therefore, LINC00092 may serve as a potential therapeutic target for ESCC.

CRISPR-Cas genome-editing technologies have emerged as powerful tools for precise DNA and RNA modulation, offering promising therapeutic strategies for neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). This review critically evaluates current CRISPR/Cas applications in neurodegeneration, with emphasis on mechanistic insights, therapeutic outcomes, and translational feasibility. Preclinical and early translational studies demonstrate that CRISPR-Cas platforms can correct pathogenic mutations, suppress toxic gene expression, and restore neuronal function. Advanced modalities, including base and prime editing, CRISPRi/a, and RNA-targeting Cas systems, improve precision and reduce genomic damage, which is particularly advantageous in post-mitotic neurons. Emerging CRISPR-based diagnostics (e.g., SHERLOCK and DETECTR), AI-assisted sgRNA design, and machine-learning approaches for predicting off-target effects further enhance the safety, stratification, and monitoring of CRISPR therapeutics. In parallel, patient-derived brain organoids and assembloids provide scalable human-relevant platforms for mechanistic studies and preclinical validation. Despite this progress, major challenges remain, including efficient delivery across the blood-brain barrier, immune responses, long-term safety, and ethical and regulatory considerations. Overall, CRISPR-Cas technologies hold strong potential as disease-modifying interventions for neurodegenerative disorders, provided that advances in delivery systems, artificial intelligence integration, and regulatory oversight continue to evolve toward clinical translation.

<h4>Background</h4>Lung cancer has a high incidence rate, and immunotherapy is only effective for a subset of patients. This study aimed to develop a signature associated with immunotherapy response to accurately predict the prognosis of non-small cell lung cancer (NSCLC) patients and assess immunotherapy efficacy. Such efforts are crucial to address the therapeutic challenges faced by patients with advanced lung cancer.<h4>Methods</h4>Using weighted gene co-expression network analysis (WGCNA), we identified genes correlated with immunotherapy response. These genes were subsequently integrated with the data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) to formulate prognostic signatures. A total of 101 machine learning algorithms were employed to construct these prognostic signatures. Following this, we conducted an in-depth analysis of the prognostic signatures and investigated their associations with patient prognosis, tumor microenvironment (TME), and the efficacy of chemotherapeutic agents, targeted therapies, and immunotherapy.<h4>Results</h4>The constructed signature demonstrated a significant disparity in prognosis between high-risk and low-risk NSCLC patient groups. The prognostic capability of this signature was rigorously validated across various clinical subgroups and TCGA cohorts, and it emerged as an independent prognostic factor through multivariable analysis. To augment the precision of prognostic predictions, we developed a nomogram. Notably, the immune checkpoint inhibitor response prediction scores (IPS) were elevated in the low-risk group, indicating a potential benefit of immunotherapy for these patients. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to determine the expression levels of key risk-associated genes in the tissue samples, leading to the identification of Acyl-CoA synthetase medium chain family member 5 (ACSM5) as a promising therapeutic target in NSCLC.<h4>Conclusions</h4>Our signature, which is linked to immunotherapy response, aids in predicting the prognosis and immunotherapy outcomes of NSCLC patients, thereby offering valuable insights for their clinical management.

Inflammatory bowel disease (IBD) is a chronic, immune-mediated intestinal disorder driven by dysregulated immune responses in genetically susceptible individuals. Despite recent advances in treatment, more than 30% of patients either fail to respond initially or lose response over time, underscoring the need for a deeper mechanistic understanding of immunogenetic pathways and the development of individualized therapeutic strategies. We first discuss how newly identified susceptibility genes (e.g., IL23R, NOD2, BDNF, SLC) and their polymorphisms influence immune cell function and epithelial barrier integrity. Single-cell technologies have further revealed novel cell subsets and interactions underlying disease heterogeneity. We then explore the clinical efficacy of classical and emerging targeted therapies, including cytokine-specific biologics, JAK inhibitors, and novel strategies aimed at restoring regulatory T-cell function or blocking integrin-mediated lymphocyte trafficking. Additionally, we highlight promising therapeutic approaches such as fecal microbiota transplantation, microbial metabolite-based interventions, and nanotherapeutics. We further discuss how genetic insights and immune biomarkers can facilitate treatment personalization and improve prognostic stratification. Ultimately, this review emphasizes the transition from broad immunosuppression to precision medicine and proposes integrated approaches-combining multiomics profiling, immune monitoring, and novel therapeutics-to achieve sustained remission and improve long-term outcomes in IBD patients.

<h4>Background</h4>The differentiation of naïve CD8⁺ T cells into effector cells upon activation is essential for eliminating intracellular pathogens and cancerous cells, although the underlying epigenetic mechanisms remain incompletely characterized.<h4>Methods</h4>Peripheral blood mononuclear cells (PBMCs) were obtained from healthy donors. naïve CD8⁺ T cells were purified and activated with α-CD3/CD28-conjugated microbeads for 0, 24, or 72 h <i>in vitro</i>. Flow cytometry was used to assess cytokine production and activation markers at each time point. Assay for transposase-accessible chromatin using sequencing (ATAC-seq) was performed to identify differentially accessible chromatin regions (DARs). RNA sequencing (RNA-seq) was performed to measure gene expression. Data from ATAC-seq and RNA-seq were integrated to examine the relationship between chromatin accessibility and gene expression. Enriched pathways for DARs and differentially expressed genes (DEGs) were determined by KEGG pathway and gene ontology (GO) enrichment analysis, and transcription factor (TF) binding patterns around these genes were visualized by footprint analysis.<h4>Results</h4>Upon activation, naïve CD8⁺ T cells showed increased production of IFN-γ, TNF, and IL-2, and elevated expression of CD69 and CD95. Integrated ATAC-seq and RNA-seq analysis identified 568 and 541 dual-upregulated genes (showing both increased chromatin accessibility and expression) at 24 and 72 h post-activation, respectively. These early-response genes were enriched in pathways including pyruvate metabolism and the DNA damage response. Footprint analysis predicted the ETS and bZIP TF families as key regulators driving this coordinated chromatin and transcriptional reprogramming. Furthermore, distinct chromatin remodeling patterns were observed in gene sets associated with memory, effector function, exhaustion, and metabolism, revealing that accessibility changes did not always directly correlate with transcriptional outcomes.<h4>Conclusion</h4>This study defines a core set of genes and TFs that critically regulate the initial activation of human naïve CD8⁺ T cells. These results provide a molecular roadmap for future efforts to engineer more potent and durable CD8⁺ T cell responses for adoptive cell therapy.

<h4>Background</h4>Metabolic disorders and neurocognitive diseases frequently co-occur, yet the specific mechanisms driving this comorbidity remain elusive. While epidemiological associations are well-documented, the causal links between these conditions are complex and incompletely understood, necessitating a systems-level investigation into their shared biological architecture.<h4>Methods</h4>This study integrates large-scale human genetics with experimental <i>in vivo</i> transcriptomics and computational chemistry to elucidate these shared pathways. Specifically, an AD-like murine model was used to experimentally prioritize a core network of 13 dysregulated genes within a pathologically relevant context.<h4>Results</h4>Network-informed Mendelian randomization identified bidirectional causalities, including a 14% elevated dementia risk from type 2 diabetes and protective effects of obesity against parental Alzheimer's disease (AD). The study identified a signature encompassing key lipid metabolism hubs <i>APOE, CLU</i>, and <i>LDLR</i>. This signature serves as a critical biological filter, anchoring human genetic associations by providing direct evidence of their dysregulation in a neurodegenerative environment. Subsequent chemical enrichment and molecular docking analyses indicated that these experimentally-prioritized targets are engaged by both therapeutic agents (e.g., valproic acid) and environmental toxins (e.g., benzo[a]pyrene).<h4>Conclusion</h4>This multi-modal investigation provides a robust framework that converges on a high-confidence, 13-gene signature of lipid dysregulation as a central mechanistic interface, offering a powerful set of prioritized targets for future functional validation and therapeutic development at the metabolic-neurocognitive nexus.

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease, marked by progressive degeneration of upper and lower motor neurons. Clinically, genetically, and pathologically heterogeneous, ALS poses a major challenge for disease modeling and therapeutic translation. Over the past two decades, induced pluripotent stem cells (iPSCs) have reshaped our understanding of ALS pathogenesis and emerged as a promising translational platform for therapy development. ALS modeling has further expanded with the advent of three-dimensional systems, including ALS-on-chip platforms and organoid models, which better capture cell-cell interactions and tissue-level phenotypes. Despite these advances, effective disease-modifying therapies remain elusive. Recent clinical trial setbacks highlight the need for improved trial design alongside robust, translational iPSC models that can better predict therapeutic response. Nonetheless, the outlook is promising as large iPSC patient cohorts, quantitative phenotyping combined with genetically informed patient stratification, and reverse translational research are beginning to close the gap between in vitro discovery and clinical testing. In this review, we summarize the major advances in iPSC technology and highlight key iPSC-based studies of sporadic ALS. We further discuss emerging examples of iPSC-informed therapeutic strategies and outline the challenges associated with translating iPSC-derived mechanistic insights and pharmacological findings into successful clinical therapies.

<b>Objectives</b>: To explore if MRI can monitor treatment and predict outcome in patients with human epidermal growth factor 2 (HER2)-negative breast cancer receiving neoadjuvant chemotherapy (NACT) with or without bevacizumab. <b>Methods</b>: Multiparametric MRI was performed at baseline and after 12 and 25 weeks of NACT. MRI assessment included tumour size, apparent diffusion coefficient (ADC) from diffusion-weighted imaging (DWI), and signal intensity-time curves and vascular volume transfer constant (K^TRANS) from dynamic contrast-enhanced MRI (DCE). The reference standards were pathological complete response (pCR) at the time of surgery, and 10-year recurrence-free survival. Receiver operating characteristics analyses were performed to assess the predictive value of the MRI parameters. MRI findings and outcomes were compared between the treatment groups. <b>Results</b>: Seventy women were included from November 2008 to July 2012, with a median age of 49.5 years and median tumour diameter of 47 mm. Fourteen patients (20.0%) achieved pCR, while eleven (15.7%) had recurrence during the 10-year follow-up. The treatment significantly reduced tumour size, increased ADC, decreased K^TRANS, and shifted the signal intensity-time curves towards more benign shapes. The DCE parameters changed significantly more in the bevacizumab group. In the bevacizumab group, baseline K^TRANS predicted pCR (Area under curve (AUC) = 0.73), but the difference in pCR-rates between the treatment groups was not significant (<i>p</i> = 0.07). Only tumour size and shrinkage at 12 weeks predicted pCR (AUC = 0.71-0.85) regardless of size measuring method. No MRI parameters predicted survival. <b>Conclusions</b>: All MRI parameters reflected treatment response, but no parameter predicted survival or benefit from adding bevacizumab to chemotherapy.

<h4>Purpose</h4>Despite existing signatures, there remains a lack of robust autophagy-based biomarkers validated across multi-omics datasets and independent clinical cohorts in ESCC. The aim of our study was to develop an autophagy-related prognostic model for ESCC.<h4>Methods</h4>Using transcriptomic data of ESCC from GEO/TCGA and autophagy-related genes (ARGs) from five autophagy-specific datasets, we identified the intersection between ARGs and tumor-normal differentially expressed genes (DEGs). We constructed a prognostic model using stepwise multivariate Cox regression based on these genes in GSE53625 (<i>n</i> = 179), validated in TCGA-ESCC (<i>n</i> = 94) through survival analysis and ROC curve, and analyzed the prognostic value of candidate genes in in-house ESCC samples.<h4>Results</h4>We successfully established a robust prognostic 4-ARGs model comprising <i>NBEA</i>, <i>CLOCK</i>, <i>NLRX1</i>, and <i>MAGEA3</i> (training: <i>p</i> < 0.0001, validation: <i>p</i> = 0.013). In the in-house ESCC cohort (<i>n</i> = 14), <i>NLRX1</i> was verified as a reliable prognostic factor for disease-free survival (<i>p</i> = 0.043). Significant correlations were observed between signatures and the immune microenvironment, and the model effectively predicted patients' responses to immunotherapy.<h4>Conclusion</h4>We developed a novel 4-ARGs prognostic model and identified <i>NLRX1</i> as a potential autophagy-dependent biomarker. These findings underscore its utility as a valuable tool for prognosis, risk stratification, and therapy guidance in ESCC.

<h4>Background</h4><i>KMT2A</i> rearrangements are a frequent genetic abnormality associated with Acute myeloid leukemia (AML), historically linked to varied prognoses and outcomes. The prognosis for patients with this rearrangement remains controversial, necessitating further research to stratify risk and guide treatment.<h4>Methods</h4>In this retrospective study, a total of 3468 adolescent and adult AML patients were screened, and 181 patients harboring <i>KMT2A</i> rearrangements were analyzed. We used FISH, RT-PCR, and next-generation sequencing, including transcriptome and targeted panels, for diagnosis and mutation profiling. All patients received intensive chemotherapy. We evaluated overall survival and event-free survival using Kaplan-Meier and Cox regression models, with HSCT analyzed as a time-dependent variable.<h4>Results</h4>The incidence of <i>KMT2A</i>-rearranged AML in our newly diagnosed cohort was 5.9%. Among the 181 patients included in the final analysis, 89 (49.2%) were male and 92 (50.8%) were female, with a median age of 33 years (range: 13-65). The distribution of fusion partners included <i>KMT2A</i>::<i>MLLT3</i> (<i>n</i> = 39), <i>KMT2A</i>::<i>AFDN</i> (<i>n</i> = 27), <i>KMT2A</i>::<i>MLLT10</i> (<i>n</i> = 25), <i>KMT2A</i>::<i>ELL</i> (<i>n</i> = 24), and others (<i>n</i> = 12). Seventy-four patients underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first complete remission (CR1). The median follow-up for survivors was 17.53 months (range 1.47-112.57), and the 3-year overall survival (OS) and event-free survival (EFS) for the entire cohort were 42.0% and 32.1%, respectively. Patients with <i>KMT2A</i>::<i>ELL</i> exhibited superior OS compared to other subtypes (3-year OS [ELL vs. non-ELL]: 59.8% vs. 39.3%, <i>p</i> = 0.023). Concomitant mutations did not significantly impact the prognosis of <i>KMT2A</i>-rearranged AML patients. In multivariate analysis, age and HSCT in CR1 were independently associated with OS and EFS (OS: HR = 1.022, <i>p</i> = 0.026 [age]; HR = 0.238, <i>p</i> < 0.001 [HSCT]; EFS: HR = 1.027, <i>p</i> = 0.002 [age]; HR = 0.155, <i>p</i> < 0.001 [HSCT]). Patients aged over 20 years were more likely to benefit from HSCT than those aged 20 years or younger (<i>p</i> < 0.001 [age > 20], <i>p</i> = 0.780 [age ≤ 20]).<h4>Conclusions</h4>Our study revealed the heterogeneous outcomes of <i>KMT2A</i>-rearranged AML patients and clarified the impact of HSCT across different age groups.

<h4>Background</h4>Malignant pleural mesothelioma (MPM) is an aggressive neoplasm, the major cause of which is asbestos exposure. Adjuvant radiotherapy after pleurectomy/decortication (P/D) aims at reducing locoregional recurrence but is limited by the risk of radiation pneumonitis (RP). In this study, we attempted to evaluate the predictive value of conventional and functional dosimetric parameters in assessing RP risk.<h4>Methods</h4>This retrospective study analyzed 68 patients with non-metastatic MPM treated with adjuvant radiotherapy after P/D. Dosimetric parameters, including V20, V5, and mean lung dose (MLD), were calculated for both total lung volume and functional lung volume (FLV), with emphysematous regions excluded based on CT imaging thresholds. Statistical analyses assessed correlations between these parameters and acute RP incidence.<h4>Results</h4>Acute RP developed in 42% of patients, and 28% had moderate-to-severe (Grade 2-3) events. V20 and FCL_V20 were significantly associated with the risk of RP (<i>p</i> = 0.017 and <i>p</i> = 0.028, respectively). Predictive accuracy for conventional V20 (AUC = 0.668) and Functional Contralateral Lung V20 (FCL_V20) (AUC = 0.655) showed moderate efficacy, without further significant improvement in using functional parameters. A V20 threshold > 1.8% predicted severe RP with high specificity (89.8%).<h4>Conclusions</h4>While functional lung delineation provides an alternative in dosimetry, conventional V20 is a robust predictor of RP. Optimization of dosimetric constraints, in an effort to reduce pulmonary toxicity in MPM patients, should be further combined with advanced radiotherapy techniques and biomarkers.

Red blood cells (RBCs) play a key role in vascular origin pathologies such as nephropathy, retinopathy, and neuropathy. Altered RBCs also occur in the case of hereditary spherocytosis, hemoglobinopathies, sickle cell disease, thalassemia and hemolytic anemia. The consequence of damage to the cell membrane and cytoskeleton are changes in RBC deformability, which play an important role in microcirculation. In turn, oxidative changes in hemoglobin lead to impaired oxygen transport to cells and tissues and, consequently, to ischemia and hypoxia. In this review, we discuss the structure of normal and pathological RBCs, including, more broadly, red blood cells occurring in type 2 diabetes. We present factors that play a major role in RBC damage in this pathology. Finally, we characterize the participation of hemoglobin and heme in the induction of oxidative damage to biological material, including RBCs.

Spinal cord injury (SCI) severely disrupts central nervous system (CNS) function by interrupting sensory and motor signal transmission, often resulting in permanent deficits due to the formation of a glial scar. Although the amniotic membrane (AM) is derived from the human placenta and is a promising biomaterial, its efficacy in treating SCI remains unexplored. This study investigates the therapeutic potential of AM fragments in a surgically induced acute SCI model in rats, focusing on preserving tissue integrity and modulating astrocyte distribution and reactivity. SCI was experimentally induced by a drop-weight mini-guillotine model in rats, which were subsequently allocated into three groups: Control (C), Injury (I), and Amniotic Membrane (AM), where a 4 cm² AM fragment was applied over the lesion. Animals were euthanized after 28 days for histological and immunohistochemical analysis of the T9-T10 region, specifically to assess Glial Fibrillary Acidic Protein (GFAP) expression and identify reactive astrocytes. The application of AM significantly preserved nervous tissue structure. The cystic cavity area in the AM group (9.00 ± 7.65) was drastically lower than in the Injury group (41.80 ± 11.30). Crucially, the AM fragments attenuated the progression of nervous tissue degeneration, limiting cavitation and glial scar formation while reducing astrocytic reactivity. These findings establish AM as a viable and effective scaffold for acute SCI treatment.

Neonatal arrhythmias, though relatively uncommon, can range from benign self-limiting conditions to life-threatening disorders requiring intensive management. Data on their clinical spectrum, management, and outcomes remain limited. This study aimed to evaluate the types, frequency, clinical characteristics, treatment strategies, and prognosis of neonatal arrhythmias in a tertiary pediatric cardiac center. We retrospectively reviewed neonates diagnosed with arrhythmia within the first 28 days of life at Basaksehir Cam and Sakura City Hospital between 1 January 2021 and 1 May 2025. Demographic data, electrocardiographic and echocardiographic findings, treatment modalities, recurrence, morbidity, and mortality were analyzed. Patients were categorized as having benign or non-benign arrhythmias. A total of 65 neonates (57% male, mean weight 3.2 kg) were included. Non-benign arrhythmias were more frequent (77%) compared to benign arrhythmias (23%). Supraventricular tachycardia (35%) was the most common non-benign arrhythmia, followed by long QT syndrome (10.7%) and complete atrioventricular block (9.2%). Antiarrhythmic therapy was required in 55% of patients. Pacemaker implantation was performed in seven infants with conduction disorders. Recurrence occurred in 3% of cases, exclusively among patients with supraventricular tachycardia. During a median follow-up of 12.8 months, no mortality was observed. Prenatal diagnosis and early management contribute to favorable outcomes, as reflected in the absence of mortality in this cohort. Larger, prospective studies are warranted to define optimal management strategies and treatment durations for neonatal arrhythmias.

Poorly differentiated gastric carcinoma (PGC) is aggressive, yet subtype-specific genomics are under-characterized. We queried AACR Project GENIE^® (cBioPortal v18.0-public; 12 August 2025) for PGC and analyzed somatic alterations from targeted panels (depth ≥ 100×; variant allele frequency ≥ 5%). Mutation and copy number frequencies were summarized, co-occurrence and exclusivity were tested, and primary versus metastatic tumors were compared using chi-square with Benjamini-Hochberg correction. The cohort included 189 tumors from 188 patients (71% primary; 25% metastatic), with primary and metastatic tumor samples being collected from different patients. Recurrently mutated genes were <i>TP53</i> (48.7%), <i>CDH1</i> (31.2%), <i>ARID1A</i> (21.2%), <i>KMT2C</i> (8.5%), and <i>POLD1</i> (7.4%); additional alterations involved <i>ERBB3</i>, <i>KMT2D</i>, <i>KEL</i>, <i>CDKN2A</i>, and <i>FAT1</i> (≈1-7%). Amplifications in <i>CCNE1</i> (8.2%) and <i>FGFR2</i> (7.6%) were common, alongside gains in <i>MET</i>, <i>MYC</i>, <i>KRAS</i>, and <i>ERBB2</i> and losses in <i>CDKN2A/CDKN2B</i>, <i>CDH1</i>, and <i>PTEN</i>. Significant co-occurrence was observed for <i>POLD1-KMT2D</i> (<i>p</i> < 0.001), <i>POLD1-ARID1A</i> (<i>p</i> < 0.001), and <i>ARID1A-KMT2D</i> (<i>p</i> < 0.001), while <i>TP53</i> was mutually exclusive with <i>ARID1A</i> (<i>p</i> = 0.029) and <i>CDH1</i> (<i>p</i> = 0.041). <i>CDH1</i> (48.9% vs. 29.6%; <i>p</i> = 0.021) and <i>MLH1</i> (8.5% vs. 1.5%; <i>p</i> = 0.040) were enriched in metastases, and <i>CCNE1</i> alterations showed female predominance (<i>p</i> = 2.83 × 10^-4). Several "primary-only" findings likely reflect small denominators and require replication. PGC demonstrates a mutational framework dominated by <i>TP53</i>, <i>CDH1</i>, <i>ARID1A</i>, and recurrent <i>CCNE1</i>/<i>FGFR2</i> amplifications, underscoring dysregulation of cell cycle and chromatin-remodeling pathways as key drivers. Co-occurrence of <i>POLD1</i>, <i>ARID1A</i>, and <i>KMT2D</i> suggests coordinated disruption of DNA repair and epigenetic regulation, whereas mutual exclusivity of <i>TP53</i>, <i>ARID1A</i>, and <i>CDH1</i> indicates distinct tumorigenic routes. Metastatic enrichment of <i>CDH1</i> and <i>MLH1</i> supports their roles in invasion and therapeutic resistance. Together, these findings highlight candidate biomarkers and actionable pathways warranting validation in larger, multi-omic cohorts to refine precision treatment strategies for this aggressive gastric cancer subtype.

<h4>Background</h4>Acute pulmonary embolism (PE) affects both hemodynamics and the clotting system, and changes in clotting protein activity may affect the effectiveness of anticoagulation. For example, PE may represent an acute, acquired antithrombin (AT)-deficient state, which may limit heparin effectiveness. However, the incidence and clinical effects of acquired AT deficiency after PE are not known.<h4>Objectives</h4>Our primary aim was to calculate the proportion of patients with PE and acquired AT deficiency, defined a priori as <80% functional activity. We also analyzed <90%, <100%, and <110% AT activity. Secondary aims were to identify clinical factors and outcomes associated with acquired AT deficiency.<h4>Methods</h4>We performed a prospective, observational study of patients diagnosed with acute PE without contraindications to heparin anticoagulation. We obtained blood within 24 hours after positive PE imaging and measured AT activity. Outcomes were culled from the medical record.<h4>Results</h4>We analyzed 200 patients. Mean age was 62 ± 16 years, and 120 (60%) were men. Fifty-four (27%) patients had <80%, 111 (56%) <90%, and 159 (80%) <100% AT activity. Low AT activity (<80%) was associated with longer hospital length of stay (<i>P</i> < .0001), intensive care unit admission (<i>P</i> = .0085), and adverse clinical outcomes (<i>P</i> = .0042), but not subtherapeutic anticoagulation.<h4>Conclusion</h4>Acquired AT deficiency is common after acute PE, occurring in at least one-quarter of all patients. Low AT levels are associated with adverse clinical outcomes, intensive care unit admission, and longer hospital length of stay, but whether this is related to subtherapeutic anticoagulation is not clear.

GPR52 is a promising therapeutic target for schizophrenia, capable of addressing positive, negative, and cognitive symptoms simultaneously. In this study, we designed and synthesized a series of <i>N</i>-arylindole GPR52 agonists by optimizing the "m6" linker configuration, hydrophilic head groups, and hydrophobic tails. Among them, three compounds (H11, H20, H26) exhibited good GPR52 potency and inhibition rates in the MK-801-induced hyperlocomotion model, with ED₅₀ values of 6.18-6.92 mg kg^-1. Structure-activity relationship studies revealed that balanced flexibility and hydroxyl group incorporation were critical for activity. Molecular docking confirmed stable binding interactions with GPR52's "bird's claw" pocket, while ADMET predictions supported favorable drug-like properties. These designed small molecules will facilitate the development of novel GPR52 agonists.

<h4>Background</h4>Alzheimer's disease (AD) is a common dementing disease associated with aging for which no specific etiology has been found.<h4>Objective</h4>Quantification and analysis of expression in a curated group of detoxification genes have not previously been reported in AD.<h4>Methods</h4>I compare AD and non-AD cohorts in a Gene Expression Omnibus (GEO) datasets study and a tissue RNA sequencing (RNA-seq) study. A list of 203 detoxification "genes of interest" (GOI) was created (see Methods and Supplemental Material).<h4>Results</h4>I identify 162 detoxification genes in one or both phases of the study with statistically significant differential detoxification gene expression comparing AD and non-AD samples. In addition, one dataset demonstrates a role of amyloid-β (Aβ) fibrils in regulating detoxification gene expression (phase 1, GSE227221); novel, long non-coding RNA (lncRNA) association with detoxification differential gene expression is also shown with marked upregulation in 6 MT2A groupings in the tissue study (Supplemental Table 22) and downregulation of GSS in GEO analysis (GSE159699 advyoung).<h4>Conclusions</h4>This research reports a novel finding of differential expression in multiple detoxification genes in AD compared with non-AD controls, supporting a new hypothesis: detoxification gene expression is related to etiology of AD, as shown by both decreased expression (GSS for example) and increased expression (MT2A for another example) of detoxification genes. Complexity of expression of detoxification genes is suggested by Aβ and lncRNA regulation of detoxification gene expression. Subsequent research to confirm and investigate implications of these findings and how they may relate to the etiology of AD is needed.

<h4>Purpose</h4>Inborn errors of immunity (IEIs) are a heterogeneous group of germline disorders whose recognition is increasing but which remain underdiagnosed and associated with significant pediatric morbidity and mortality. This review aims to systematize the main neuroimaging manifestations of IEIs, addressing how neuroradiologists can identify characteristic patterns to support earlier diagnosis and guide clinical management.<h4>Methods</h4>A narrative review of IEIs with neurological involvement was performed, focusing on reported primary and secondary neuroimaging features across major IEI categories. Imaging findings were correlated with underlying immune defects, typical clinical phenotypes, and their impact on diagnostic workup, risk assessment, and genetic counseling.<h4>Results</h4>IEIs demonstrate a broad neurological spectrum that extends beyond recurrent infections to encompass autoinflammatory, autoimmune, allergic, and malignant phenotypes with central nervous system involvement. Neuroimaging reveals both primary manifestations directly related to immune dysregulation and secondary features, allowing recognition of patterns in IEI subgroups that can provide crucial diagnostic clues in otherwise non-specific clinical scenarios.<h4>Conclusion</h4>Neurological involvement in IEIs is not uncommon and may be radiologically detectable, making imaging an important ancillary tool in their evaluation. Systematic recognition of primary and secondary neuroimaging features by neuroradiologists can raise suspicion for an underlying IEI, prompting appropriate immunologic and genetic work-up. Earlier diagnosis is crucial to enable timely implementation of preventive or targeted therapies, with the potential to improve long-term outcomes.

Ulcerative colitis (UC) is a multifactorial inflammatory bowel disease (IBD) with increasing incidence worldwide. Current treatments, including NSAIDs and corticosteroids, provide partial symptom relief but are associated with significant side effects, highlighting the need for novel therapies with improved safety profiles. Given the role of oxidative stress and inflammation in driving tissue damage during colitis, natural compounds with antioxidant and anti-inflammatory properties represent promising therapeutic candidates. Thinned apples (TA), an agricultural byproduct, were identified as a valuable source of polyphenols (TAP) with demonstrated anti-inflammatory and antioxidant activities in a cell-based inflammation model. This study evaluates TAP's therapeutic potential in a DNBS-induced colitis mouse model using label-free quantitative proteomics. Proteomic analysis revealed modulation of key pathways affected by TAP treatment, including: (i) activation of antioxidant defense mechanisms; (ii) reversal of DNBS-induced alterations, specifically ferroptosis and heme-toxicity; (iii) suppression of immune responses; and (iv) attenuation of ulcerative features, with downregulation of proteins involved in coagulation, inflammation, and angiogenesis. Overall, TAP showed significant therapeutic effects by targeting oxidative stress and inflammation, supporting its use as a polyphenol-rich extract in health products for UC. Moreover, repurposing TA as a bioactive extract offers an innovative strategy for industrial applications in therapeutic development.

The India EMBO lecture course 'RNA-protein complexes: from molecular assembly to physiological functions and disease' was held at The National Centre for Cell Science, Pune, India, from February 24 to 28, 2025. The major theme of the lecture series centred on the recent advances in RNA-protein interactions and their role in regulating complex assembly or condensation as well as cellular functions and plasticity. Additionally, the course highlighted the impact of dysregulated post-transcriptional processes in various diseases. Speakers from various biological disciplines presented their research on both the fundamental architecture of RNA and protein complexes and their contributions to higher-order cellular functions. The course also featured flash talks and poster presentations selected from abstract submissions, alongside special methodological workshops on omics and phase separation. This Meeting Review reflects on the event's key discussions, drawing attention to the overarching themes and main conclusions.

In vivo astrocyte-to-neuron (AtN) conversion suffers low efficiency due to pre-existing intrinsic barriers. However, it is unclear whether astrocytes have inducible barriers to reprogramming. Here, we identify Olig2, a basic helix-loop-helix (bHLH) transcription factor, as an inducible barrier to Ngn2-mediated AtN conversion. Olig2 is strongly upregulated in cortical astrocytes following the ectopic expression of bHLH neuronal reprogramming factors such as Ngn2, NeuroD1, and Ascl1, but is barely expressed in normal astrocytes. Knocking down Olig2 in Ngn2-transduced astrocytes reduces astrocyte-specific gene expression, enhances neurogenesis-related gene expression, and increases AtN conversion efficiency by approximately threefold. Further multi-omics analysis shows that astrocytic Olig2 directly binds to regulatory regions of pro-neurogenic genes, including Ngn2, inhibiting their expression and impeding the expression of neural progenitor genes. Collectively, our findings reveal Olig2 as an inducible barrier to AtN conversion, providing insights into the regulation of neuronal reprogramming.

Triple-negative breast cancer (TNBC) is a particularly aggressive subtype of breast cancer with a high risk of relapse and metastasis. Due to limited tumor immune infiltration in TNBC, the effectiveness of immunotherapy is constrained. In this study, analysis of human datasets (TCGA-BRCA and Kim cohorts) revealed that tumor necrosis factor superfamily member 9 (TNFSF9) and C-X-C motif chemokine ligand (CXCL9) expressions correlate with improved prognosis and enhanced immune cell infiltration. To exploit this, we engineered human umbilical cord mesenchymal stem cells (hUC-MSCs) to co-express TNFSF9 and CXCL9 (MSC-T9C9). In murine TNBC models, the engineered MSC-T9C9 recruits CD8⁺ T cells and natural killer (NK) cells to the tumor site, thereby increasing immune infiltration and remodeling the tumor immune microenvironment through activating CD8⁺ T cells and NK cells. This therapeutic strategy proved both effective and well-tolerated. Moreover, MSC-T9C9 enhanced the prognosis and therapeutic efficacy of anti-PD-1 immunotherapy in vivo. These findings demonstrate that the engineered MSC co-expressing chemokine CXCL9 and costimulatory ligand TNFSF9 effectively suppresses TNBC growth by reprogramming the intra-tumoral immune landscape, which offers a promising and safe immunotherapeutic strategy for TNBC treatment.

Paclitaxel has been a cornerstone of ovarian cancer chemotherapy for over two decades. However, its clinical application is constrained by poor solubility and non-specific delivery, resulting in systemic toxicity and inconsistent therapeutic outcomes. Nanotechnology-based drug delivery systems have emerged as a promising strategy to address these limitations. In this study, we employed elastin-like polypeptide (ELP) nanocarriers, precisely modified with the tumor-targeting AP1 peptide, to deliver paclitaxel in ovarian cancer. ELPs are biologically inspired, genetically engineered polymers that can form nano-sized structures with controlled physicochemical properties, facilitating passive tumor targeting. The integration of the AP1 peptide, which specifically binds to the IL-4 receptor overexpressed in numerous cancers, enables active targeting of these nanocarriers, complementing the passive delivery approach. This investigation focused on the synthesis and characterization of paclitaxel delivery vehicles based on modified (A60) and unmodified (E60) ELPs. Paclitaxel (PTX) was conjugated to ELPs via a thiol-maleimide Michael-addition strategy. Both ELP-PTX formulations formed stable, monodisperse micelles, with A60-PTX nanoparticles measuring 28 ± 2.8 nm and E60-PTX nanoparticles measuring 46.8 ± 6.6 nm, as determined by TEM. DLS analysis further confirmed the narrow size distribution, evidenced by a single, narrow peak in the size distribution profile, indicating near homogeneity of the micellar population. In vitro binding analysis in SKOV-3 and OVCAR-3 ovarian cancer cells demonstrated significantly enhanced targeting capability with A60, exhibiting ~ 8.6-fold and ~ 2.7-fold higher cell binding than E60, respectively. Consistently, A60-PTX demonstrated superior cytotoxicity, with ~ 2.6-fold and ~ 1.4-fold lower IC50 values than E60-PTX in SKOV-3 (47 nM vs. 120 nM) and OVCAR-3 (45 nM vs. 62 nM), respectively. The relevance of the active targeting was further validated in agarose-based 3D spheroid models of the two cell lines with A60-PTX demonstrating approximately ~ 3-fold (SKOV-3) and ~ 2.5-fold (OVCAR-3) higher cytotoxicity compared to E60-PTX. Overall, this study highlights the potential of AP1-functionalized ELP nanocarriers to enhance the precision and therapeutic efficacy of paclitaxel delivery, offering a promising strategy for targeted ovarian cancer therapy.

<h4>Background</h4>Sex differences are evident in anxiety and depression, and women more frequently present with comorbid anxiety and depression alongside gastrointestinal disturbances. This pattern suggests contributions from sex-specific biological mechanisms and gut-brain communication. Negr1, a molecule regulating neuronal growth and connectivity, has been linked to depression-relevant behaviors in animal models. However, its mechanisms and potential sex-specific effects remain unclear.<h4>Methods</h4>Behavioral tests were used to assess phenotypes related to depression, anxiety, and learning in male and female wild-type (WT) and Negr1^-/- mice, and molecular assays were performed to evaluate endoplasmic reticulum (ER) stress and apoptosis in the brain, liver, and colon. Behavioral test data were analyzed using a three-way mixed repeated-measures analysis of variance (RM-ANOVA), and molecular data were analyzed using two-way or three-way ANOVA.<h4>Result</h4>Negr1^-/- mice exhibited sex-dependent phenotypes in both central and peripheral systems. Baseline analyses revealed increased intestinal permeability in Negr1^-/- mice and sex-specific patterns of brain-derived neurotrophic factor (Bdnf) mRNA expression across multiple time points. Behaviorally, Negr1^-/- mice showed increased anxiety-like behavior, decreased social interaction, and impaired spatial learning in the Morris water maze, regardless of sex. Female Negr1^-/- mice displayed impaired fear learning and increased depression-like behavior, while male Negr1^-/- mice exhibited heightened anxiety-like responses. At the molecular level, ER stress marker spliced X-box binding protein 1 (Xbp1s) mRNA was upregulated in peripheral tissues of males but downregulated in females. Apoptosis analysis revealed enhanced caspase-3 activation in peripheral tissues of female Negr1^-/- mice, while males showed no significant changes. Brain tissue showed no significant apoptotic alterations in either sex.<h4>Conclusions</h4>This study demonstrates that, in Negr1^-/- mice, both sexes show general behavioral alterations. However, female Negr1^-/- mice exhibit greater vulnerability to fear learning impairments and depression-like behavior, whereas males Negr1^-/- mice show heightened anxiety responses. These behavioral differences were associated with opposing ER stress responses and differential apoptotic signaling between the sexes in peripheral tissues. Our findings highlight the importance of considering sex as a biological variable in depression research and suggest that Negr1 plays a crucial role in the sex-specific pathophysiology of psychiatric disorders through complex mechanisms spanning central and peripheral systems.

Traditional Chinese Medicine (TCM) is a valuable medical treasure trove that not only demonstrated unique advantages in treating complex and refractory diseases but also left behind a rich legacy of ancient texts and valuable evidence-based medical data based on its human experience for future generations. Nevertheless, the extensive data within TCM has been plagued by challenges, including inadequate data standardization, inconsistent data quality, limited data structuring, and obstacles in interdisciplinary integration. Recent advancements in artificial intelligence (AI) techniques have markedly improved the efficiency and effectiveness with which multimodal data in TCM, including machine learning (ML), deep learning (DL), knowledge graphs (KG), and natural language processing (NLP), particularly large language models (LLMs). These advancements have facilitated more precise data analysis, enhanced clinical decision-making, and improved research outcomes in TCM, such as target discovery, virtual screening of natural products (NPs), symptom differentiation and auxiliary prescription. This article presents a comprehensive review of the progress in applying AI across four dimensions: multiscale data in TCM, TCM research and development, TCM diagnosis and treatment, and LLMs. In summary, the application of AI technology in the modernization of TCM is expected to motivate researchers to achieve a deeper understanding of state-of-the-art applications in data-driven TCM complex systems, fundamental scientific research, and precision medicine, thereby bringing more opportunities and innovations for the modernization of TCM.

Noise-induced hearing loss (NIHL) is a common cause of acquired sensorineural hearing loss. Excessive endoplasmic reticulum (ER) stress-induced apoptosis of cochlear hair cells contributes to NIHL. ER autophagy (ER-phagy) is a critical pathway for maintaining ER homeostasis and cell survival. DDRGK1 (DDRGK domain containing 1) is a crucial receptor in ER-phagy, essential for the removal of injured ER components. This work investigates the involvement of DDRGK1-mediated ER-phagy in NIHL, which has remained unclear. ER-phagy flux is inhibited in HEI-OC1 cells treated with hydrogen peroxide. Noise exposure reduces XIAP (X-linked inhibitor of apoptosis protein) and DDRGK1 protein levels in these cells. Moreover, XIAP binds to DDRGK1, increasing the stability of DDRGK1 and activating ER-phagy. Notably, in noise-exposed CBA/CaJ mice, gastrodin, a traditional Chinese medicine ingredient, reduces noise-induced loss of cochlear hair cells, ribbon synaptic damage, and hearing loss by promoting XIAP expression, thereby increasing DDRGK1 protein levels and activating ER-phagy. These findings highlight XIAP-DDRGK1-mediated ER-phagy as a novel therapeutic target for NIHL treatment.

<h4>Background</h4>Mosquitoes (Diptera: Culicidae) are among the most important disease vectors worldwide. Several species exhibit high levels of anthropophily and are frequently found in human dwellings and forest fragments near urban areas.<h4>Objectives</h4>In this integrative study combining mosquito collection, viral detection, and ecological analyses, the assemblage of diurnal mosquitoes was investigated across three distinct environments - intradomiciles, and two distinct urban forest fragments (UFFs) - during a dengue outbreak in the city of Salinas, Minas Gerais, Brazil.<h4>Methods</h4>Sampled mosquitoes were tested for the presence of dengue, Zika, and chikungunya viruses through real-time quantitative polymerase chain reaction (RT-qPCR).<h4>Findings</h4>A total of 722 mosquitoes were collected, representing seven genera and 12 species. The most abundant species were Culex quinquefasciatus (270/722, 37.4%), Aedes aegypti (205/722, 28.4%), Ae. albopictus (112/722, 15.5%), and Ae. scapularis (110/722, 15.2%). Five of 81 pools tested positive for dengue virus serotype 1 (DENV-1) RNA, all belonging to Ae. aegypti species. Phylogenetic analyses of the nearly complete genome of DENV-1 revealed clustering with strains sampled in 2023 from São Paulo State. Mosquito richness and composition differed between environments (houses and urban forests), whereas abundance was similar across all environments.<h4>Main conclusions</h4>Important vector species were detected, including Ae. aegypti, Ae. albopictus, Cx. quinquefasciatus, Ae. scapularis, Sabethes albiprivus, and Coquillettidia venezuelensis, associated with the transmission of dengue, oropouche, mayaro, yellow fever, and Venezuelan equine encephalitis viruses. Entomological and virological investigations in urban and peri-urban environments are crucial, as these areas provide shelter and refuge for anthropophilic and opportunistic mosquito species. Our findings underscore a high potential for mosquito-borne disease spillover in these areas.

Oral squamous cell carcinoma (OSCC) is a prevalent and aggressive malignancy with a persistently high mortality rate, largely attributable to therapy resistance and tumor recurrence. This review comprehensively explores the critical interplay between epigenetic dysregulation and the tumor microenvironment (TME) in driving OSCC progression. We detail how key epigenetic mechanisms, including DNA methylation, histone modifications, and non-coding RNAs (ncRNAs), intrinsically transform cancer cells and actively orchestrate pro-tumorigenic TME. These alterations substantially contribute to resistance against conventional therapies. Furthermore, we discuss the therapeutic potential of targeting these pathways using epigenetic drugs (epi-drugs), such as DNA methyltransferase (DNMT) inhibitors and histone deacetylase (HDAC) inhibitors, as well as engineered extracellular vesicles (EVs). The primary objective of this review is to synthesize current knowledge on the epigenetic-TME axis, thereby providing a mechanistic foundation for developing novel therapeutic strategies. We emphasize that rational combinations of epigenetic-targeting agents with conventional treatments or immunotherapy hold significant promise for overcoming drug resistance and improving clinical outcomes in OSCC patients.

The cerebellum is critically involved in both motor coordination and affective regulation, and growing evidence suggests that cerebellar dysfunction contributes to neuropsychiatric disorders. While much attention has focused on synaptic signaling and calcium homeostasis, the role of potassium channels in cerebellar function remains relatively understudied. Here, we investigated the role of the potassium channel ROMK (renal outer medulla K⁺ channel) in cerebellar signaling and behavior using cre/loxP gene knockout in Pcp2cre-expressing cells. Surprisingly, ROMK expression was detected in a distinct cell population within the cerebellar granule layer, rather than in Purkinje cells, yet this expression was effectively targeted by Pcp2cre-mediated recombination. Mutant mice showed normal Purkinje cell density and soma size, but increased dendrite diameter. At the molecular level, we observed downregulation of cerebellar subtype-specific genes and potassium channel subunits, along with changes in markers of translational signaling. Increased presence of GFAP-positive cells further suggested underlying neuronal stress in the ROMK-deficient cerebellum. Behaviorally, ROMK-deficient mice exhibited clear impairments in motor coordination and heightened anxiety-like behavior in the elevated plus maze (EPM). Our findings link ROMK loss to molecular and cellular remodeling in the cerebellum and support the idea that ROMK contributes to neural circuits that regulate complex behaviors, providing a framework for further studies in this direction.

Breast cancer continues to be the most frequently diagnosed cancer among women worldwide and remains a leading cause of cancer-related mortality. Despite advances in imaging and biopsy-based approaches, current diagnostic methods are invasive, costly, and often insufficient to capture the molecular heterogeneity of tumors. Extracellular vesicles (EVs) have emerged as promising non-invasive biomarkers owing to their role in intercellular communication and their enrichment with tumor-specific cargo. This study conducted a systematic review and meta-analysis of published literature to investigate proteomic alterations in EVs derived from breast cancer samples. From an initial 1097 records screened, four eligible studies were identified, reporting 628 differentially expressed proteins, of which 38 were consistently observed across multiple datasets. Functional enrichment analyses revealed predominant localization of these proteins to vesicle-associated compartments and significant involvement in biological processes related to cell growth, immune regulation, and tumor progression. Pathway analysis further highlighted integrin-mediated interactions, platelet activation, and hemostasis pathways as key molecular mechanisms represented within breast cancer EVs. Overall, the findings reveal a distinct EV proteomic signature in breast cancer that could support early detection and patient monitoring through minimally invasive testing. Future large-scale and standardized studies are needed to validate these candidate proteins and advance EV proteomics toward clinical application in breast cancer management.

The triad association among type 2 diabetes mellitus (T2DM), metabolic associated fatty liver disease (MAFLD), and incretin secretion dysfunction, including GLP-1 (glucagon-like peptide-1) secretion dysfunction, maintains a critical cardiovascular risk and liver-related mortality. The aim of this study is to establish interactions between the GLP-1 plasma levels and metabolic syndrome clusters and adipokines profile (leptin, adiponectin, resistin) and proinflammatory cytokines (TNFα, IL-6, IL1β, IL-17) in diabetic subjects with or without MAFLD. The data revealed that insulin resistance (HOMA-IR) is present in all groups. MAFLD is more common in men than in women. The average FLI score in group IV was ≥70, confirming the diagnosis of MAFLD. The disorder of GLP-1 secretion is more pronounced in women than in men. HOMA-IR is negatively associated with plasma GLP-1 depletion in the MAFLD, T2DM, and MAFLD + T2DM groups. Adiponectin levels are decreased in all groups, as for GLP-1. In contrast, leptin, resistin, TNFα, IL-6, IL-1β, and IL-17 levels show an inverse correlation with GLP-1. GLP-1 accurately reflects metabolic and inflammatory status in subjects with MAFLD, T2DM, and diabetes-steatosis. The applied multivariate linear regression model confirms a highly significant association between MAFLD and GLP-1. It appears that plasma GLP-1 can be considered as biomarker in MAFLD and T2DM related to sex-gender disparities. Longitudinal studies are required to confirm these data.

Synthetic lethality has proven to be a tactical paradigm to design synergistic anticancer drug combinations. In this context, we leveraged BRCA2 and PARP as a synthetic lethal target pair to consolidate the use of small molecule inhibitors of RAD51-BRCA2 protein-protein interaction as inducers of the BRCAness phenotype that sensitizes <i>BRCA2</i>-functional cancer cells to PARP inhibitors. Starting from compound <b>1</b>, a phenyl furan-carboxyquinoline, we developed a series of analogues, leading to derivative <b>19</b>. This compound effectively inhibits RAD51-BRCA2 interaction, impairs homologous recombination, and synergizes with olaparib in BxPC-3 pancreatic cancer cells, inducing synthetic lethality in both 2D and 3D spheroids. Additionally, <b>19</b> showed efficacy in human pancreatic cancer cells and no toxicity in normal pancreatic cells, positioning it as an early tool compound and a starting point for further optimization.

Coagulation is a physiological process necessary to achieve homeostasis. Many pathologies lead to spontaneous activation of the coagulation pathways and increase the risk of venous thrombosis (e.g., atrial fibrillation, orthopaedic surgery, cancer). Therefore, a lot of patients need anticoagulant drugs as preventive or curative treatment. In general, older molecules (unfractionated heparin, low-molecular-weight heparins, vitamin K antagonists) have good efficacy. Still, their adverse reactions, increased risk of bleeding, or difficult administration led to low adherence to treatment and had even limited their use. Recently, new molecules were authorised to improve patient adherence to treatment, mainly formulated for oral administration (e.g., dabigatran, rivaroxaban, apixaban, etc.). This therapeutic approach has a low risk of bleeding and does not require special monitoring by laboratory tests. Also, new anticoagulants for patients with heparin-induced thrombocytopenia (e.g., argatroban, lepirudin, bivalirudin, etc.) were obtained. Moreover, reversal agents for the new anticoagulant molecules used in overdoses or in situations where immediate cessation of the anticoagulant effect is required (e.g., emergency surgery) were studied, some of them being authorised on the pharmaceutical market. This narrative review aims to provide a pharmacological and therapeutic overview of anticoagulant drugs, underlining their implementation and limitations.

Huntington's disease (HD) is a rare autosomal dominant neurodegenerative disorder caused by expansion of the cytosine-adenine-guanine (CAG) trinucleotide repeat in the huntingtin (HTT) gene. Although the disease typically presents in mid-adulthood, symptom onset after the age of 60, defined as late-onset Huntington's disease (LoHD), remains uncommon and may pose diagnostic challenges. We report the case of an 80-year-old man admitted for evaluation of progressive unintentional weight loss, whose clinical assessment revealed generalized chorea and progressive cognitive decline. Genetic testing identified an expanded CAG allele with 39 repeats, confirming the diagnosis of LoHD. Neuroimaging revealed ischemic leukoencephalopathy consistent with cerebral small vessel disease (CSVD), contributing to diagnostic complexity. This case highlights the importance of considering Huntington's disease in the differential diagnosis of late-onset chorea and cognitive impairment, even in the absence of a known family history.

Acute graft-versus-host disease (aGVHD) of the gastrointestinal tract is a frequent and often fatal complication of allogeneic hematopoietic stem cell transplantation. Suppressor of Cytokine Signaling 1 (SOCS1) is a key regulator of T cell pathogenicity, yet its role in aGVHD remains unclear. Using T cell-specific Socs1 knockout models, we show that Socs1 loss intrinsically drives pro-inflammatory T cell differentiation independent of antigen stimulation, with the strongest effects observed in CD8⁺ T cells. Mechanistically, Socs1 deficiency activates a STAT1/2-dependent transcriptional program, inducing Ccl5 expression, monocyte recruitment, and M1-like macrophage polarization in peripheral lymphoid organs at steady state. After transplantation, Socs1-deficient T cells display enhanced infiltration into intestinal crypts, accompanied by increased CD8⁺ T cell effector function, monocyte accumulation, and inflammatory macrophage polarization in target tissues. These changes promote tissue injury and impair regeneration, resulting in lethal aGVHD. Importantly, JAK1/2 inhibition with ruxolitinib reverses these pathogenic effects. Clinically, high SOCS1 expression in donor-derived CD8⁺ T cells correlates with reduced aGVHD incidence. Together, our findings identify SOCS1 as a predictive biomarker and a potential therapeutic target for personalized aGVHD prophylaxis.

Endometriosis is a chronic estrogen-dependent disorder affecting up to 10% of women of reproductive age, and the absence of reliable noninvasive diagnostic tools contributes to delayed diagnosis and disease progression. To identify potential biomarkers, we profiled miRNA expression in serum, saliva, and vaginal mucus from 20 women (10 with endometriosis and 10 controls) using next-generation sequencing. Differentially expressed miRNAs were identified, and their predicted targets underwent Gene Ontology and KEGG pathway enrichment analyses. Serum proteomics by data-independent acquisition LC–MS/MS was integrated with miRNA data to construct potential miRNA–protein interaction networks. Distinct miRNA profiles were observed across the three bodily fluids, with serum showing the most abundant miRNAs and saliva the lowest. Thirteen, three, and six differentially expressed miRNAs were detected in serum, saliva, and vaginal mucus, respectively. Enrichment analysis implicated apoptosis, Wnt signaling, autophagy, and cellular senescence. Integrated analysis revealed 59 upregulated serum proteins targeted by dysregulated miRNAs, including WNK2, CD44, USP15, GNAI3, HUWE1, and NRAS. ROC analysis suggested that serum miR-200a-3p and miR-200b-3p, may have potential utility as noninvasive biomarkers for the diagnosis and monitoring of endometriosis, pending further validation.

Patients with metabolic dysfunction-associated steatotic liver disease (MASLD) are at high risk of atherogenic dyslipidemia and cardiovascular events, which are considered the most important cause of death in these patients. The aim of this study was to investigate the association between atherogenic indices with adiposity and to compare the atherogenic status between obese and non-obese MASLD patients. In this cross-sectional study, 452 participants with Fibroscan-proven MASLD were included. Atherogenic indices, insulin resistance and sensitivity indicators were calculated for all patients. Atherogenic risk of participants were compared based on their body mass index (BMI). Pearson correlation analysis and linear regression were applied to analyze the relationship between BMI and cardiovascular risk factors. Atherogenic indices were higher in overweight and obese MASLD patients than non-obese ones. Insulin resistance progressively increased in proportion to the BMI, while insulin sensitivity decreased (P < 0.001). Obesity, but not overweight, was associated with a significant increase in atherogenic indices in patients (P < 0.05). BMI was positively correlated with insulin resistance indicators (P < 0.001), triglyceride glucose index (r = 0.121, P = 0.010) and atherogenic index of plasma (r = 0.096, P = 0.042). It can be concluded that obesity, by exacerbating insulin resistance and atherogenic status, predispose patients with MASLD to an increased risk of developing cardiovascular diseases.

Arsenic (As), an environmental toxicant commonly found in groundwater, exerts its toxic effects primarily through oxidative stress. Selenium (Se) plays a crucial role in counteracting oxidative stress by promoting the synthesis of Se-containing antioxidant enzymes, such as glutathione peroxidases (GPx). To elucidate the impact of As on cellular Se metabolism, we investigated the effects of inorganic arsenic on cultured cells (HT-1080, Jurkat, and SH-SY5Y). Our findings indicate that As(III) disrupts Se metabolism and inhibits Se-induced GPx expression. By comparing different Se sources (selenoprotein P, selenocysteine, and selenite), we determined that As(III) primarily interferes with Se metabolism downstream of selenite, an inorganic form of Se. Notably, exposure to As(III) reduced Se incorporation into RNA, suggesting inhibition of Sec-tRNA^Sec synthesis, a critical step in selenoprotein biosynthesis. Additionally, As(III) increased cellular susceptibility to ferroptosis, a form of oxidative stress-driven lipid peroxidation-mediated cell death primarily regulated by GPx4. Supporting this, genetic deletion of PRDX6, a recently identified regulator of cellular Se metabolism, further suppressed selenoprotein expression and exacerbated As(III)-induced ferroptosis. These findings provide new insights into the toxicological mechanisms of As compounds, highlighting their role in disrupting Se metabolism and potentially mitigating the side effects associated with arsenic-based anticancer therapies.

B-cell non-Hodgkin lymphoma (NHL) is the most common hematopoietic malignancy in the United States, with a notably higher incidence and aggressiveness observed in individuals infected with human immunodeficiency virus (HIV), leading to AIDS-associated NHL (AIDS-NHL). The transferrin receptor 1 (TfR1/CD71), a type II transmembrane homodimeric protein, is overexpressed on several cancers, including NHL, providing a meaningful therapeutic target. Our group developed an anti-TfR1 IgG3-avidin fusion protein, ch128.1Av, designed to deliver biotinylated therapeutic agents into cancer cells through receptor-mediated endocytosis. When coupled with biotinylated saporin 6 (b-SO6), a plant-derived protein synthesis inhibitor, the resulting ch128.1Av/b-SO6 immunotoxin is highly effective at killing malignant cells. However, toxicity to normal cells limits its systemic administration. To overcome this problem, we developed a proimmunotoxin nanodrug, named "n(ch128.1Av/b-SO6)-CXCL13". This strategy involves encapsulating individual immunotoxins within a thin zwitterionic polymer shell, which is stabilized by peptide crosslinkers that only respond to metalloproteinase-2 (MMP-2), a tumor microenvironment-specific enzyme. The nanodrug is further conjugated with a B-cell targeting chemokine CXCL13. This design allows the proimmunotoxin to circulate safely, specifically accumulate and release encapsulated ch128.1Av/b-SO6 intratumorally in response to MMP-2. This approach not only minimizes off-target toxicity but also enhances tissue penetration by enabling choline analogues on proimmunotoxin nanodrugs to bind choline transporters expressed on tumor cells or the blood-brain barrier. Importantly, n(ch128.1Av/b-SO6)-CXCL13 demonstrated antitumor efficacy in an AIDS-associated NHL xenograft mouse model. Taken together, our results suggest that n(ch128.1Av/b-SO6)-CXCL13, or similar proimmunotoxin strategies, represents a promising therapeutic avenue for AIDS-NHL and potentially other malignancies.

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease, driven by hyperglycemia-induced mitochondrial apoptosis in renal tubular epithelial cells. Death-associated protein kinase 1 (DAPK1) is a key mediator of cell death, but its regulation in DKD remains unclear. Here, we investigated the mechanisms underlying DAPK1 upregulation and its role in mitochondrial apoptosis under high glucose (HG) conditions in HK-2 cells and db/db mouse models. In db/db mice, renal DAPK1 protein levels were elevated, while KLHL20 levels were reduced, correlating with glomerular and tubular injury. In HK-2 cells, HG (33 mM, 48 h) significantly increased DAPK1 mRNA and protein levels while prolonging its half-life. Mechanistically, HG transcriptionally suppressed KLHL20, an E3 ubiquitin ligase adaptor that targets DAPK1 for proteasomal degradation. Co-immunoprecipitation confirmed KLHL20-DAPK1 interaction and showed reduced DAPK1 ubiquitination under HG. Overexpression of KLHL20 restored DAPK1 ubiquitination and reduced its protein levels without affecting mRNA, confirming post-translational regulation. Functionally, DAPK1 knockdown attenuated HG-induced mitochondrial apoptosis. KLHL20 overexpression similarly protected against HG-induced apoptosis, but this effect was abrogated by DAPK1 co-overexpression, establishing DAPK1 as a critical downstream effector. These findings reveal a novel KLHL20-DAPK1 axis where HG stabilizes DAPK1 by downregulating KLHL20, promoting mitochondrial apoptosis in renal tubular cells. Targeting this pathway may offer therapeutic strategies for DKD.

Erythropoiesis is a tightly regulated developmental process that requires the switch from fetal hemoglobin (HbF) to adult hemoglobin (HbA). In β-hemoglobinpathies such as SCD and β-thalassemia, disease severity is influenced by the fetal-to-adult hemoglobin switch because persistence or induction of HbF will ameliorate the clinical manifestations. miRNAs play an essential role in regulating this switch by modulating the expression levels of key transcription factors, such as BCL11A, KLF1, and MYB, which repress γ-globin expression. Multiple miRNAs have been identified as potential modulators of the hemoglobin switch, including miR-144, miR-486, miR-26b, and miR-15a. The molecular interactions between miRNA and γ-to β-globin switch have the potential for new therapeutic interventions that aim to reactivate HbF expression to ameliorate β-hemoglobinopathies such as SCD and β-thalassemia. In this review, the latest advancements in miRNA-mediated regulation of Hb switching and nanoparticle-based strategies for miRNA delivery are explored.

Traumatic brain injury (TBI) can cause severe neurological damage. Ferroptosis, a recently discovered form of iron-regulated cell death, is closely associated with TBI. Cannabidiol (CBD) has been demonstrated to exhibit neuroprotective effects. However, the antiferroptotic role of CBD in TBI remains unclear. Investigating whether CBD inhibits ferroptosis after brain injury and its underlying mechanisms is of great significance. We find that ferroptosis can be induced in rats after TBI, and CBD significantly inhibits ferroptosis in TBI rats both <i>in vivo</i> and <i>in vitro</i>. MicroRNAs (miRNAs) are highly expressed in the brain. Differentially expressed miRNAs and mRNAs after TBI are detected by RNA sequencing, and miR-320-3p, Negr1, and the ERK/MEK pathway are screened out due to their strong correlations. The results show that CBD inhibits miR-320-3p expression, increases Negr1 expression, and suppresses the ERK/MEK pathway both <i>in vivo</i> and <i>in vitro</i>. Mechanistically, transfection with miR-320-3p mimics or siNegr1 inhibits the intervention effect of CBD on ferroptosis and the ERK/MEK pathway. Additionally, <i>Negr1</i> gene silencing reverses the effect of the miR-320-3p inhibitor on ferroptosis factors in PC12 cells, which suggests that miR-320-3p can target <i>Negr1</i>. In conclusion, our findings indicate that CBD can inhibit TBI-induced ferroptosis through the miR-320-3p/Negr1/ERK signaling axis.

Gliomas, including astrocytoma, oligodendrogliomas, and glioblastomas, represent the most common type of primary malignant brain tumors in adults and a significant burden in pediatric neuro-oncology. Despite being traditionally diagnosed according to histopathological features, the classification of gliomas has evolved significantly with the integration of molecular biomarkers, now essential components of the World Health Organization Central Nervous System 5 (WHO CNS5) classification. This review synthesizes key established and emerging molecular markers that define glioma subtypes and impact diagnosis, prognosis, and therapeutic decisions. Core biomarkers include IDH1/2 mutations, which are hallmarks of lower-grade gliomas and confer improved prognosis; 1p/19q codeletion, pathognomonic for oligodendrogliomas; and TERT promoter mutations, often associated with poor outcomes. Additional markers such as TP53, ATRX, and H3K27M mutations provide crucial subtype and grade-specific information, particularly in astrocytic and diffuse midline gliomas. Novel alterations, including BRAF V600E, EGFRvIII, and MET, NTRK, or ALK gene fusions, are increasingly recognized for their therapeutic relevance in targeted treatment approaches. Epigenetic profiling, including DNA methylation signatures, has further refined glioma taxonomy and classification. Emerging markers such as MYCN/MYC amplifications, PIK3CA/PTEN pathway alterations, and ZFTA::RELA fusions, although more prominent in other CNS tumors, may offer insights into tumor biology or therapeutic resistance in gliomas. This review provides an updated evidence-based overview of classical and novel biomarkers, highlighting their biological roles and clinical implications, and guiding future directions for precision neuro-oncology.

Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disease whose incidence increases with age. According to the gene-time-environment hypothesis, ALS onset occurs through the interaction between genes and environmental exposures during ageing, which may involve a continuous accumulation process. Alternatively, the multistep pathogenic hypothesis, based on the Armitage-Doll multistep model from cancer research, posits that a discrete number of specific sequential "hits" are necessary to trigger ALS. Here we analyzed three large population-based epidemiological datasets of ALS to formally test whether the ALS age-incidence curve is better described by a power law, as predicted by the Armitage-Doll model, or by an exponential function, which is generally associated to continuous accumulation of damage and is incompatible with the Armitage-Doll model. We obtained moderate-to-extreme Bayesian evidence in favor of the exponential function compared to the power law. Cancer data were instead better aligned, as expected, with the power law. These results suggest that the multistep pathogenesis hypothesis based on the Armitage-Doll model cannot be extended from cancer to ALS, because it is incompatible with the epidemiological data. This calls for a re-consideration of the current understanding of ALS pathogenesis. Our work also warns against extending the Armitage-Doll multistep model from cancer to other aging-related diseases solely based on age-incidence curves.

Aurora kinase A/AURKA is a serine/threonine kinase frequently overexpressed in cancer. Recent discoveries pointed to subcellular pools of AURKA, including at mitochondria. There, AURKA induces organelle clearance by mitophagy together with the autophagy mediator LC3, and its receptor PHB2.Here, we show that the natural product capsaicin modifies the AURKA/PHB2 interaction. We synthesize 16 capsaicin analogs, and Förster's Resonance Energy Transfer/Fluorescence Lifetime Imaging Microscopy (FRET/FLIM) in breast cancer cells reveals that compounds 12 and 13 increase the AURKA/PHB2 interaction. Molecular docking shows that they bind to the inhibitory pocket of PHB2 and to the AURKA active site. We demonstrate that compound 13 specifically inhibits mitophagy while leaving AURKA activation unaltered at centrosomes. Our results demonstrate that compound 13 is a PHB ligand acting on the AURKA/PHB2 interaction. Thanks to its specificity, it may lead to the development of anticancer drugs targeting the mitochondrial functions of AURKA.

BACKGROUND: Melioidosis is endemic in Southeast Asia and northern Australia and can resemble various conditions. Soft tissue involvement is usually limited to localised cellulitis or superficial abscesses. Our case presented with diffuse cellulitis and deep intramuscular abscesses of the thoracoabdominal wall—an exceedingly rare manifestation mimicking necrotising soft tissue infection, a surgical emergency. Reporting such cases is essential to prevent misdiagnosis and unnecessary surgery in endemic settings. CASE PRESENTATION: A man in his sixties from southern Vietnam with previously undiagnosed diabetes mellitus presented with right upper quadrant and flank pain, high fever, and hypotension. Laboratory tests showed leukocytosis and elevated inflammatory markers. Ultrasound revealed gallstones and a positive Murphy’s sign. He was diagnosed with acute calculous cholecystitis and septic shock, and promptly started on intravenous meropenem before emergency laparoscopic cholecystectomy. However, his back pain progressively intensified after admission and became severe and disproportionate to examination findings. Within 30 hours, he developed rapidly spreading erythema over the flank, back, buttock, and thigh. Necrotising soft tissue infection (NSTI) was suspected, with a Laboratory Risk Indicator for Necrotising Fasciitis (LRINEC) score of 7. Despite concern, he remained haemodynamically stable and inflammatory markers declined. MRI revealed diffuse cellulitis and multiple intramuscular abscesses involving thoracoabdominal and thigh muscles, including a large abscess in the right posterior thoracoabdominal wall. Blood cultures grew Burkholderia pseudomallei, confirming melioidosis. Meropenem was continued for four weeks, and oral trimethoprim–sulfamethoxazole was introduced. No surgical drainage was required. By day 6, pain and erythema improved. Follow-up MRI on day 10 showed reduced abscess size and improved cellulitis. At two-week follow-up, the patient remained asymptomatic, bedside ultrasound confirmed resolution, and he continued oral therapy to complete the three-month course. CONCLUSIONS: This case underscores the importance of considering melioidosis in patients from endemic areas presenting with rapidly progressive soft tissue infections that mimic necrotising soft tissue infection. Early recognition and a structured diagnostic approach can help distinguish non-necrotising forms and avoid unnecessary surgery. CLINICAL TRIAL: Not applicable.

BACKGROUND: Metabolic reprogramming of glutamine plays a pivotal role in the progression of clear cell renal cell carcinoma (ccRCC). Although inhibition of glutamine metabolism has been shown to suppress ccRCC progression, its effect on tumor immune evasion remains poorly understood. METHODS: Bioinformatic analysis and glutamine deprivation assays were performed to investigate the association between glutamine metabolism and clinical outcomes in ccRCC, as well as its effect on tumor cell proliferation. Western blot, flow cytometry, MTT, ELISA, RNA-Seq, immunohistochemistry, and multiplex immunofluorescence were used to evaluate the antitumor effects of the glutamine antagonist DON/DRP-104 and the glutaminase inhibitor CB-839 both in vitro and in vivo, along with their impacts on PD-L1 expression in tumor cells and CD8⁺T cell function. RNA-Seq, Western blot, flow cytometry, and immunofluorescence were further employed to explore the mechanisms by which DON/DRP-104 and CB-839 regulate PD-L1 expression. Finally, in vivo experiments were performed to evaluate the antitumor effects of DRP-104 or CB-839 in combination with an anti-PD-L1 antibody in renal cancer. RESULTS: We demonstrate that pharmacological inhibition of glutamine metabolism with DON/DRP-104 or CB-839 effectively suppressed tumor cell viability in vitro by inhibiting proliferation and inducing apoptosis, and delayed tumor progression in vivo. However, this metabolic inhibition paradoxically impaired CD8+T cell function. Further investigation revealed that inhibition of glutamine metabolism upregulated PD-L1 expression on tumor cells via a reactive oxygen species (ROS)-dependent EGFR/ERK1/2/c-Jun signaling pathway. Consequently, combining DRP-104 or CB-839 with anti-PD-L1 therapy enhanced the efficacy of immune checkpoint inhibitors (ICIs) in mouse models. CONCLUSION: While inhibition of glutamine metabolism blocks renal cancer growth, it concurrently impairs CD8⁺T cell function by upregulating PD-L1 expression on tumor cells via a ROS-dependent EGFR/ERK1/2/c-Jun pathway. Combining DRP-104 or CB-839 with ICIs restores CD8⁺T cell function and improves antitumor immunity.

<h4>Background</h4>Impaired cerebrospinal fluid (CSF) dynamics may affect brain health in older adults and contribute to age-related changes in brain structure. Disproportionately enlarged subarachnoid-space hydrocephalus (DESH) is a neuroimaging finding associated with impaired CSF dynamics. However, the association between frailty-a condition characterised by increased vulnerability in late life-and DESH-related CSF space volumes remains poorly understood. Therefore, in this study, we aimed to investigate this association.<h4>Methods</h4>This cross-sectional study was conducted using data from 1,395 community-dwelling Japanese adults aged ≥ 65 years without dementia. Frailty was assessed using the Japanese version of the Fried criteria, comprising slowness, weakness, low activity, shrinking, and exhaustion. Volumes of regions of interest (ROIs) were measured by magnetic resonance imaging, and DESH-related regions (ventricular system [VS], Sylvian fissures [SF], and the subarachnoid space at the high convexity and midline [SHM]) were quantified using voxel-based morphometry.<h4>Results</h4>Ordinal logistic regression analysis was conducted with frailty status (robust [reference], prefrail, or frail) as the dependent variable and each ROI volume as independent variables. The results showed positive associations of VS volume (odds ratio [OR] 1.21; 95% confidence interval [CI] 1.06-1.37) and SF volume (OR 1.81, 95% CI 1.09-3.02) with frailty, whereas SHM volume was negatively associated (OR 0.84, 95% CI 0.72-0.97). Logistic regression analyses of each frailty component and ROIs showed that slowness (slow gait speed) was consistently associated with all three DESH-related regions (false-discovery rate-adjusted q < 0.05).<h4>Conclusions</h4>DESH-related CSF space volumes, reflecting impaired CSF dynamics, were significantly associated with frailty in community-dwelling older adults. These findings highlight the potential role of CSF dynamics as a neural mechanism underlying frailty and suggest a novel target for preventive strategies.

BACKGROUND: Treatment failure due to drug resistance has always been a “roadblock” to cancer cure. For a long time, drug resistance research has focused on the nature of the cancer cells themselves; however, more and more studies have found the non-negligible significance of the tumor microenvironment (TME) in cancer malignant progression and therapeutic resistance. Within the TME, cancer-associated fibroblasts (CAFs) represent the most prevalent and highly plastic cells, exerting profound influence on tumor progression. METHODS: We integrate recent literature and synthesize evidence from both preclinical and clinical studies to elucidate the potential mechanisms by which CAFs contribute to therapeutic resistance and to summarize up-to-date research developments in nanotherapeutic strategies targeting CAFs. RESULTS: Emerging findings demonstrate that CAFs substantially contribute to drug resistance by secreting various soluble factors and metabolites, remodeling the extracellular matrix (ECM), and regulating immune responses and cell death. Nanotherapeutic strategies show considerable promise in improving treatment efficacy, while further research is required to facilitate their clinical translation. CONCLUSIONS: CAFs act as key orchestrators of the drug-resistant TME, positioning them as compelling targets for next-generation anticancer strategies. Moreover, advancing progress in nano-strategies targeting CAFs holds substantial promise for improving clinical outcomes in cancer therapy.

Understanding manganese (Mn) neurotoxicity requires experimental models that realistically reflect human exposure scenarios. A key limitation of current in vitro paradigms is the reliance on acute, high-concentration exposures, which may not accurately capture the molecular consequences of long-term Mn accumulation. To address this, this study compared transcriptomic responses to acute (6-hour) and chronic (40-day) Mn exposures in SH-SY5Y cells, using Mn concentrations spanning near-physiological to sub-cytotoxic ranges. The 6-hour exposure design replicates a widely applied acute duration in the literature, while the 40-day duration was selected to mimic prolonged, low-level Mn burden reported in epidemiological and occupational studies. Bulk RNA sequencing revealed that chronic Mn exposure induced distinct and more extensive transcriptional alterations compared to acute exposure, independent of concentration. Pathway enrichment analyses indicated that cellular functions selectively perturbed under chronic conditions are highly relevant to neurodegenerative risks and aligns with independent Parkinson's disease transcriptomic datasets. These pathways include axonal guidance signaling, amyloid fiber formation, extracellular matrix organization, and synaptic functioning. In contrast, acute exposures primarily disturbed intracellular ion homeostasis maintenance mechanisms. Protein kinase A signaling and metallothionein-mediated metal-binding pathway were the only two pathways that were shared between both applied durations exposed at Mn concentrations with reported adverse outcomes. Transcriptomic alterations in this study highlighted the contribution of mechanisms related to normal Mn-dependent cellular functions in the development of its neurotoxicity. Furthermore, these results emphasized that exposure duration is a critical determinant to be considered when evaluating long-term Mn overload-induced neurodegeneration via in vitro platforms.

<i>Background and Objectives</i>: Pancreatic ductal adenocarcinoma (PDAC) is among the most aggressive, heterogeneous, and lethal human malignancies, underscoring the urgent need for novel, targeted therapeutic strategies for neo(adjuvant) individualized treatment. The epidermal growth factor receptor family (ErbB) is directly involved in abnormal cell proliferation and tumor growth. The overexpression and amplification of HER2 and HER3 have emerged as key molecular events in pancreatic ductal adenocarcinoma. The aim of this study was to evaluate these membrane receptors' overexpression in relation to pTNM staging, perineural and lymphovascular invasion, and tumor volume in order to obtain the immunohistochemical profile and enhance the development of a targeted and personalized therapy. <i>Materials and Methods</i>: An observational analytical cohort study included patients with histopathologically naïve, confirmed PDAC who underwent cephalic pancreatoduodenectomy at a national high-volume referral center between 2017 and 2022. Archived surgical specimens were retrieved and examined using a tissue microarray technique in two separate pathology departments by two independent pathologists. <i>Results</i>: HER2 positivity was found in 25 cases, of which 84% had lymphatic invasion, 50% had vascular invasion, and 84% had perineural invasion. Patients with HER3 positivity had lymphatic invasion (82.5%), perineural invasion (79.4%), and vascular invasion (38.1%). Combined HER2 and HER3 positivity was present in 19 cases, and these patients had 84.2% perineural invasion. <i>Conclusions</i>: HER2 and HER3 overexpression often coexisted with pathological features, such as perineural invasion, in cases of combined HER2 and HER3 positivity. These findings support the involvement of the ErbB receptor family in pancreatic carcinogenesis and suggest their potential as targets for future (neo)adjuvant therapeutic strategies.

<h4>Background</h4>Placenta accreta spectrum (PAS) is a life-threatening condition often managed by cesarean hysterectomy, resulting in numerous negative impacts on women's health. Most PAS cases do not involve parametrial invasion and may not require aggressive or complex surgical approaches. However, no simplified uterus-sparing technique exists for this subgroup. Therefore, we developed a novel surgical approach, "Simple Conservative surgical Approach for Placenta Accreta Spectrum - SCAPAS," tailored for PAS without parametrial invasion. SCAPAS included eight main steps.<h4>Objectives</h4>To evaluate the efficacy and safety of SCAPAS in conservative surgical management of women with PAS without parametrial invasion.<h4>Study design</h4>This prospective study was conducted from January 2022 to June 2023 at Hanoi Obstetrics and Gynecology Hospital. Sixty-three women with PAS without suspected parametrial invasion, according to the prenatal ultrasound staging system for PAS disorder, underwent elective cesarean delivery using the SCAPAS technique at ≥35 weeks of gestation. Maternal and fetal outcomes were collected. Successful cases were defined as those achieved uterine conservation following SCAPAS without any life-threatening complications.<h4>Results</h4>Of the 63 cases, 74.6% were patients under 35, and 66.7% had a history of two or more cesarean sections. The majority of women were diagnosed with PAS2 (69.8%). The success rate of SCAPAS was 85.7%. Success rates for placenta accreta, increta, and percreta were 100%, 82.4%, and 81.8%, respectively. The overall median intraoperative blood loss was 1200 mL (range 400-2500 mL), and the median duration of surgery was 80 minutes (range 35-124 minutes), with a mean interval from skin incision to fetal delivery was 30 minutes. Bladder injury and mild wound infections occurred in 6.3% (4/63) and 4.8% (3/63) cases, respectively. No patient required re-laparotomy. Total 20.6% of newborns had an Apgar score of less than 7 at 1 minute, but all recovered after 5 minutes.<h4>Conclusions</h4>SCAPAS is a simple, safe, and effective surgical approach for conservative management of PAS without suspected parametrial invasion. Further studies are needed to develop a preoperative classification based on location, area, and degree of invasion to improve outcomes in PAS patients.

Mitochondrial pyruvate carrier (MPC) inhibition was found protective in models of neurodegenerative diseases, such as Alzheimer’s and Parkinson’s. However, little is known about MPC as a potential therapeutic target in Huntington’s disease (HD), a neurodegenerative disorder with dysregulation of the pro-survival pathway integrated stress response (ISR). Here, we investigate if MPC inhibition modulates the ISR and mitigates mutant huntingtin (mut-Htt) proteotoxicity in a cellular HD model. We treated cells expressing N-terminal fragments of wild-type- (wt-) or mut-Htt with two MPC inhibitors (mitoglitazone and UK5099) or solvent control. Metabolism was assessed analysing resazurin reduction, oxygen consumption, extracellular acidification, and ATP levels. ISR activation and huntingtin proteostasis were assessed using western-blot and filter-trap assays. Mut-Htt-expressing cells showed decreased resazurin reduction and ATP levels, and increased eIF2 α phosphorylation, indicating metabolic stress and ISR activation. MPC inhibitors (100 µM) increased resazurin reduction and decreased respiration. The latter was rescued by the membrane-permeant methyl pyruvate, which bypasses MPC inhibition. In wt-Htt-expressing cells, MPC inhibitors increased levels of ATP and ISR markers, suggesting metabolic adaptation and ISR activation. In mut-Htt-expressing cells, MPC inhibitors preserved ATP levels and attenuated mut-Htt-induced eIF2 α phosphorylation but without changing soluble or aggregated mut-Htt levels. This work showed that MPC inhibition differentially modulates the ISR: it activates ISR in control cells and attenuates overactive ISR in mut-Htt-expressing cells. However, MPC inhibition did not impact the proteostasis of N-terminal fragment mut-Htt. Further studies are essential to explore MPC inhibition in less severe full-length mut-Htt-expressing models to better understand its therapeutic potential in HD.

RNA-RNA interactions (RRIs) are fundamental to gene regulation and RNA processing, yet their molecular determinants remain unclear. In this work, we analyze several large-scale RRI datasets and identify low-complexity repeats (LCRs), including simple tandem repeats, as key drivers of RRIs. Our findings reveal that LCRs enable thermodynamically stable interactions with multiple partners, positioning them as key hubs in RNA-RNA interaction networks. These RRIs appear to be important for several aspects of RNA metabolism. Sequencing-based analysis of the lncRNA Lhx1os interactors validates the importance of LCRs in shaping contacts potentially involved in neuronal development. Recognizing the pivotal role of sequence determinants, we develop RIME, a deep learning model that predicts RRIs by leveraging embeddings from a nucleic acid language model. RIME outperforms traditional thermodynamics-based tools, successfully captures the role of LCRs and prioritizes high-confidence interactions, including those established by lncRNAs. RIME is freely available at https://tools.tartaglialab.com/rna_rna .

Acute Respiratory Distress Syndrome (ARDS) is a severe and heterogeneous critical illness characterized by systemic inflammation, lung injury, and profound hypoxemia. To investigate the temporal evolution of molecular features underlying ARDS heterogeneity, we applied advanced proteomics and redox proteomics to matched plasma and bronchoalveolar lavage (BAL) fluid samples collected longitudinally from 16 intensive care unit (ICU) ARDS patients during hospitalization. Exploratory, data-driven hierarchical clustering (Ward method) identified three distinct molecular patterns across patients represented as Groups A, B, and C. This framework was associated with illness severity at study enrollment (Group A profiling patients with more severe illness at enrollment), demonstrated temporal stability across sampling timepoints, and revealed molecular features associated with clinical improvement during hospitalization. Key pathways distinguishing the molecular patterns and consistent with prior findings included the production and detoxification of reactive oxygen species (ROS), Liver X receptor–Retinoid X receptor (LXR/RXR) activation and 24-dehydrocholesterol reductase (DHCR24) signaling, interleukin-12 (IL-12) signaling and production in macrophages, and neutrophil degranulation. Although plasma proteomic profiles were generally consistent with findings in BAL fluid, BAL fluid data were more mechanistically informative and enabled clearer and more consistent interrogation of ARDS molecular heterogeneity. The results highlight the potential value of lung–focused, temporal studies to improve patient stratification and guide future therapeutic strategies. However, the modest cohort size and exploratory nature of this study necessitate cautious interpretation of pathway-level inferences. Future longitudinal studies in larger, independent ARDS cohorts will be required to validate these molecular groups and assess their clinical relevance.

The management of nasopharyngeal carcinoma (NPC), a malignancy with pronounced geographic prevalence in Southeast Asia, is undergoing a paradigm shift toward precision medicine driven by innovations in early detection and minimally invasive therapy. Breakthroughs in Epstein‑Barr virus (EBV)‑based screening, such as CRISPR‑associated protein 12a (Cas12a) amplification‑free assays, P85 antibody profiling and T‑cell receptor sequencing, now achieve 97.9% sensitivity and 99.3% specificity, enabling ultra‑early risk prediction 6‑12 months before clinical diagnosis. These advances synergise with multimodal imaging techniques such as narrow‑band imaging and I‑scan virtual chromoendoscopy, which detect sub‑5 mm lesions with 90% sensitivity, revolutionizing screening protocols. Therapeutically, endoscopic nasopharyngectomy (ENPG) exemplifies precision oncology, achieving ≥90% negative resection margins and a 92.1% 5‑year survival rate in early‑stage NPC while preserving key functions (such as swallowing and hearing) and reducing radiotherapy‑related morbidity. Yet, it should be regarded as an indication‑bounded option for carefully selected T1‑T2 disease in experienced centers and does not constitute a universal substitute for radiotherapy. Persistent challenges, including tumor heterogeneity, limited access to advanced technologies in resource‑constrained regions and restrictive ENPG eligibility, underscore the need for artificial intelligence‑driven multi‑omics risk models, portable diagnostic tools and multinational trials to validate long‑term outcomes. By integrating surgical‑immune synergy (such as neoadjuvant programmed cell death protein 1 inhibitors) and equitable implementation strategies, NPC care is transitioning from empirical approaches to a precision framework targeting >80% early diagnosis and >90% functional preservation, offering a roadmap to mitigate the global burden of this regionally concentrated cancer.

Platinum-acridine hybrid agents (PAs) represent a mechanistically unique class of DNA-targeted anticancer compounds with superior potency compared to cisplatin, but systemic toxicity has limited their clinical utility. To address this, we have developed platinum(IV) prodrugs of PAs for controlled reductive activation in tumor tissues. Short-chain fatty acid (SCFA) containing derivatives demonstrated nanomolar cytotoxicity in cancer cells expressing human multidrug and toxin extrusion protein 1 (hMATE1), consistent with rapid transporter-dependent uptake. Long-chain fatty acid (LCFA)-modified derivatives were less potent than the SCFA-based prodrugs in hMATE1^high NCI-H460 (lung) and HepG2 (liver) cancer cells. Conversely, the LCFA derivatives, which target human serum albumin (HSA) and utilize the blood protein for cellular entry, showed an order of magnitude higher activity than the SCFA derivatives in hMATE1^low HCT116 colon cancer cells. Together, these prodrug strategies hold promise of extending treatment with PAs to hMATE1-deficient cancers and improving the therapeutic window of the hybrid agents.

<h4>Background and purpose</h4>Dominant PURA variants (encoding purine-rich element-binding protein A) cause a neurodevelopmental disorder with hypotonia, cognitive impairment, and variable neuromuscular symptoms. Clinical presentations and response to pyridostigmine, moreover, highlighted neuromuscular junction (NMJ) involvement. However, NMJ architecture, underlying molecular mechanisms, and potential minimally invasive biomarkers in PURA syndrome remain poorly characterized. This study aimed to profile PURA-related disease using integrated clinical, histological, ultrastructural, transcriptional, and protein analyses of skeletal muscle and blood.<h4>Methods</h4>Ten genetically confirmed patients underwent detailed phenotyping with emphasis on congenital myasthenic syndrome (CMS)-like features. Quadriceps biopsy from one patient was analyzed by histology, immunohistochemistry, and electron microscopy. Protein profiling of muscle, serum, and extracellular vesicles (EVs) was performed by ELISA and mass spectrometry, with validation by qPCR.<h4>Results</h4>In line with the recognized classification of PURA syndrome as a CMS subtype, our patients exhibited hypotonia, ptosis, ocular weakness, and myopathic facies, reflecting impaired neuromuscular transmission. Subtle vesicle accumulation and minor NMJ alterations suggest possible neuromuscular involvement in PURA syndrome. Muscle proteomics showed reduced PURA protein and dysregulation of transcriptional regulation, vesicle transport, extracellular matrix remodeling, and complement activation. qPCR confirmed POSTN and PHGDH upregulation among others. Serum analyses demonstrated elevated TSP4, identifying a promising candidate blood biomarker for PURA-associated NMJ dysfunction. EV proteomics revealed dysregulated immunoglobulins, complement components, and novel candidates including NOTCH2, TARSH, and PON1.<h4>Conclusions</h4>Pathogenic PURA variants may impair NMJ structure and vesicle homeostasis, potentially linking molecular and ultrastructural defects with clinical myasthenic features and pyridostigmine responsiveness. Proteomic analysis of skeletal muscle provides initial molecular insights into the consequences of dominant PURA variants in muscle tissue. The identification of TSP4 and extracellular vesicle-associated proteins as potential minimally invasive biomarkers provides a framework for biochemical monitoring of PURA syndrome.

Intervertebral disc degeneration (IDD) represents a significant health concern affecting a large portion of the population and leads to chronic pain and disability. Despite the prevalence of this condition, the underlying biological mechanisms and potential biomarkers for early diagnosis remain inadequately understood. Advances in proteomics have opened new avenues for identifying blood biomarkers that can facilitate better diagnostic and therapeutic strategies. The primary aim of this study was to identify and validate specific plasma proteins associated with varying grades of IDD. This case-control study compared plasma samples from patients with grade II (<i>n</i> = 10) and grade V (<i>n</i> = 10) IDD to assess differential protein expression. Proteomic analysis was conducted via the SomaScan Assay to screen and identify candidate proteins. Six differential proteins─COL6α3, REG1β, ATF5, CAP1, MAGEA4, and LILRB3─were identified with the highest fold changes and recognized as biomarkers. Subsequent validation of these biomarkers was performed using enzyme-linked immunosorbent assay (ELISA) technology in a validation cohort of 50 patients. A final six-protein combined model achieved an optimal predictive efficacy (AUC = 0.8700). This study provides several noninvasive and rapid plasma biomarkers for the early diagnosis of IDD.

The vascular endothelial glycocalyx is a major regulator of endothelium function, serving as a vital mechanotransducer and barrier. Shear stress due to blood flow exerted on the apical endothelial cell (EC) and glycocalyx have been the primary focus of the field due to their direct interaction. Recently, it has been demonstrated that the basal glycocalyx, exposed to the basement membrane, is sensitive to apical fluid shear stress and necessary for promoting mechanotransduction pathways key in the EC response to blood flow. Here, we demonstrate the fluid shear stress-dependent modulation of the basal endothelial glycocalyx, showing a notably different expression pattern and overall increased expression compared to the apical glycocalyx. Our findings, coupled with prior evidence linking the basal GCX to cytoskeletal dynamics, underscore its potential role in vascular barrier integrity and mechanotransduction.

Neurosyphilis (NS), caused by <i>Treponema pallidum</i>, results in irreversible neurological damage. This study elucidated NS pathogenesis via cerebrospinal fluid (CSF) proteomic analysis comparing NS, suspected neurosyphilis (spNS), and non-neurosyphilis (nNS) controls by using liquid chromatography-tandem mass spectrometry (LC-MS/MS), public data set PXD033034, and ELISA validation. Of 1261 quantified proteins in the CSF, 234 were differentially expressed in NS, with 189 downregulated and enriched in lysosomal, axon guidance, and neurodegeneration pathways. Three previously identified CSF biomarkers of neurosyphilis, i.e., SEMA7A, SERPINA3, and ITIH4, were replicated. Key proteins in the lysosome pathway, including PSAP, CTSL, NPC2, and DNASE2, were significantly downregulated in the CSF of NS patients, and spNS patients presented a high CSF IgG index (spNS-hi-IgG-i). We also identified EPHA4, a key protein in the axon guidance pathway, as significantly downregulated in the CSF of NS patients. A positive correlation between PSAP and EPHA4 suggested a potential impact of lysosomal function on axonostasis in NS. ROC analysis revealed PSAP and DNASE2 as potential biomarkers for assessing neurodegeneration in NS and spNS-hi-IgG-i. These findings suggest that disruptions in lysosomal and axonal processes may contribute to neurodegeneration in NS, and the identified biomarkers hold potential as diagnostic indicators and therapeutic targets.

<h4>Introduction</h4>The Women First (WF) Preconception Maternal Nutrition trial found greater benefits of small-quantity lipid-based nutrient supplements (SQ-LNS) for intrauterine growth among anaemic versus non-anaemic women at preconception. We investigated whether the benefits of SQ-LNS in improving markers of intrauterine growth occurred evenly across the mild to moderate spectrum of pre-pregnancy anaemia.<h4>Methods</h4>We analysed WF data (n=2443 maternal-newborn dyads) from Pakistan, India, Guatemala and the Democratic Republic of Congo. Women received SQ-LNS either ≥3 months preconception through pregnancy (Arm 1); starting in the late first trimester (Arm 2); or not at all (Arm 3: control), with all supplementations discontinued at delivery. The outcomes were infant weight, length and head circumference measured within 48 hours of birth, expressed as Z-scores. For each site, adjusted mean differences in the Z-scores were computed across six pre-pregnancy haemoglobin (Hb) categories (80-89, 90-99, 100-109, 110-119, 120-129, and ≥130 g/L) and pooled using meta-analysis.<h4>Results</h4>The effect of SQ-LNS on birth weight, length and head circumference varied by pre-pregnancy Hb categories. No significant differences in pooled mean Z-scores were observed for any Hb category >110 g/L, and no differences were found for Arm 1 vs Arm 2 across any Hb categories. For women with Hb 90-99 g/L pooled mean differences (95% CI) in the Z-scores for length (0.60 (0.03 to 1.23)), weight (0.50 (0.11 to 0.89)) and head circumference (0.26 (0.02 to 0.51)) were greatest for Arm 1 versus Arm 3. For women with Hb 100-109 g/L in Arm 1 versus Arm 3, pooled mean difference (95% CI) in birth weight Z-scores was significantly greater (0.33 (0.24 to 0.42)). Arm 2 vs Arm 3 women with Hb 90-99 g/L had greater birth weight Z-scores (0.14 (0.05 to 0.22)).<h4>Conclusion</h4>The findings highlight the importance of identifying women preconception for whom nutrition interventions may have the greatest impact on fetal growth.

The formation of catenanes through dynamic covalent reaction of self-assembling precursors in one pot offers a powerful route to complex interlocked architectures, yet the mechanistic insight remains underexplored. Here, we elucidate the nucleation-elongation mechanism in the one-pot synthesis of topologically distinct catenanes, using dimeric (DCC) and trimeric cage-catenanes (TCC) as model systems. Unlike conventional supramolecular polymerization, catenation exhibits topology-dependent pathways: DCC formation is driven by the strong templating effect of its monomeric unit MC-1, while TCC assembly proceeds with several pathways in parallel, via cooperative binding of partially catenated intermediates. Kinetic profiling of the catenation reveals sigmoidal growth with distinct induction periods, where longer induction period correlates with more challenging nucleation. Seeded growth experiments demonstrate that preformed nuclei (e.g., MC-1 for DCC) bypass kinetic barriers, remarkably reducing its induction period, akin to seeded supramolecular polymerization. Our work bridges the gap between supramolecular polymerization and mechanical bonding for interlocked structures, offering a hint for the rational synthesis of structures with sophisticated topology.

The biological mechanisms that sustain the vast blood production required for healthy life remain incompletely understood. To search for cell intrinsic regulators of hematopoiesis, we perform a genome-wide in vivo hematopoietic stem and progenitor cell (HSPC)-based CRISPR knockout screen. We discover SAGA complex members, including Tada2b and Taf5l, as key regulators of hematopoiesis. Loss of Tada2b or Taf5l strongly inhibits hematopoiesis in vivo, causing a buildup of immature hematopoietic cells in the bone marrow. The SAGA complex deposits histone H3 lysine 9 acetylation (H3K9ac) and removes histone H2B ubiquitination (H2Bub). Loss of Tada2b leads to a reduction in H3K9ac levels and altered H2Bub enrichment in HSPCs, implicating disruption of SAGA complex activity. This is associated with upregulation of interferon pathway genes, reduced mitochondrial activity, and increased megakaryocyte progenitor cell commitment. Loss of these factors also enhances the cell outgrowth and the interferon pathway in an in vivo human myelodysplastic syndrome cell line model. In summary, this study identifies the SAGA complex as an important regulator of hematopoiesis.

Chronic obstructive pulmonary disease (COPD) is clinically and molecularly heterogeneous. To investigate COPD heterogeneity, we profiled lung tissue by single-nucleus RNA sequencing from 141 study participants (1,516,727 nuclei) and identified shifts in cell composition and emergent cell states that correlated with lung function, emphysema and composite symptom scores. Epithelial regenerative states peaked in early COPD and declined thereafter, whereas inflamed nonimmune cells and profibrotic/remodeling states, together with select immune populations, expanded with disease progression. Clustering study participants by the proportion of pathologic cells coupled with spatial transcriptomics identified distinct patterns of cellular co-occurrence within spatially localized niches. Proteomic analyses identified plasma biomarkers of cell states and their impact on the extracellular matrix. Mediation and cell communication analyses revealed cell-autonomous and intercellular communication networks associated with disease. These data define the cellular landscape of COPD heterogeneity, revealing molecular drivers and biomarkers that could inform therapeutic strategies.

BACKGROUND: The clinical association between female reproductive disorders, such as endometriosis, polycystic ovary syndrome(PCOS), uterine leiomyoma, and female infertility and psychiatric disorders, such as major depressive disorder(MDD), schizophrenia, and anxiety disorders has been widely reported. However, the genetic mechanisms underlying their comorbidity remain unclear. This study aimed to elucidate the genetic links between these disease categories through comprehensive genomic analyses. METHODS: We analyzed genome-wide association study data from the Psychiatric Genomics Consortium and FinnGen database. Genetic correlations were estimated using linkage disequilibrium score regression and high-definition likelihood methods. Cross-trait meta-analyses through Multi-Trait Analysis of Genome-Wide Association Studies and Cross-Phenotype Association Analysis identified pleiotropic loci, followed by Fine-mapping with the ANNOVAR tool. Gene-based analyses integrated summary-data-based Mendelian randomization, multi-marker analysis of genomic annotation, and genome-wide complex trait analysis-fast gene-based association test approaches. Bidirectional Mendelian randomization assessed causal relationships using several complementary methods. RESULTS: We identified significant genetic correlations between endometriosis and Attention-Deficit/Hyperactivity Disorder, Bipolar disorder(BD), and MDD, as well as between infertility/PCOS and MDD. Cross-trait analyses pinpointed five shared loci, with fine-mapping supporting their role as credible causal variants. Gene annotation implicated specific candidate genes, including ARL14EP for the endometriosis-BD link, which was further validated across SMR, MAGMA, and GCTAfastBAT analyses. Mendelian randomization demonstrated a causal effect of MDD on the risk of both endometriosis and infertility.

<h4>Background</h4>Pneumonia risk is influenced by demographics, chronic disease burden, lifestyle, and environmental factors. Despite previous genetic studies, the impact of host genetics on pneumonia, particularly within specific patient groups, remains unclear.<h4>Methods</h4>We conducted genome-wide meta-analyses of pneumonia using data from FinnGen and Estonian biobank, analysing both the general population and patient subgroups based on age at first pneumonia diagnosis, recurrent pneumonia, and asthma status. Additionally, we investigated genetic correlations and causal relationships between pneumonia and other traits.<h4>Findings</h4>Our study included a total of 110,881 pneumonia cases and 509,253 controls, with subgroup analyses focussing on children (9534 cases, 509,253 controls), working-age adults (53,203 cases, 509,253 controls), elderly individuals (48,144 cases, 509,253 controls), patients with recurrent pneumonia (10,151 cases, 509,253 controls), and patients with asthma (23,943 cases, 54,456 controls). We identified 12 loci including 4 replicated (PTGER4, HLA, MUC5AC, CHRNA5) and 8 novel associations (PTPN22, CRP, CHRNA2, EML6, RP11-541P9.3, TNFSF15, CTD-2028E8.2, HNF1A). Subgroup analysis of children (HLA region), working age adults (CRP, HLA region, MUC5AC), the elderly (CRP, MUC5B, RP11-532E4.3, CHRNA5), recurrent pneumonia (CRP, EML6, RP11-541P9.3, CHRNA2, MUC5AC, CHRNA5) and patients with asthma (CRP) demonstrated significant differences in genetic associations. Loci associated with pneumonia harbour genes mainly related to acute inflammation, T cell development, antigen presentation and lung health. Further, downstream analyses suggest that well-known pneumonia risk factors, such as obesity and smoking, may be causal.<h4>Interpretation</h4>Genetics of immunology seem crucial to the development of pneumonia in early life, adulthood, and among patients with asthma, while genetics of nicotine dependency and lung health are more pronounced among the elderly and those suffering from recurrent pneumonia.<h4>Funding</h4>A complete list of sources of funding is provided in the Acknowledgements section.

Plant peptides have emerged as key regulators of plant growth, development, immunity, and environmental adaptation. Early studies in crops demonstrate the potential application of certain peptides, such as systemin and plant elicitor peptides, to enhance disease resistance. Based on their structure and function, plant peptides are typically classified into canonical peptides, non-canonical peptides, and non-ribosomal peptides. Advances in peptidogenomics and mass spectrometry enable genome-wide discovery of numerous endogenous peptides, including those translated from untranslated regions and non-coding RNAs, greatly expanding the known plant peptidome. This review provides a comprehensive overview of plant peptides, including their classification, biosynthesis, and functional mechanisms in regulating diverse biological processes. Importantly, it systematically summarizes the historical development and recent advances in strategies for plant peptide identification. Despite substantial progress, peptide discovery and functional annotation remain challenging. We therefore propose that integrating high-throughput technologies, functional genomics, and synthetic biology will be essential for unlocking the full potential of plant peptides in crop improvement and cross-disciplinary innovation.

Increasing evidence shows that RNA-binding proteins play crucial roles in modulating the blood-tumor barrier (BTB) permeability in glioblastoma (GB). In this study, we identified elevated expression of Musashi RNA-binding protein 2 (MSI2) and Long intergenic nonprotein coding RNA 667 (LINC00667) in glioma co-cultured endothelial cells. MSI2 enhanced the stability of LINC00667, and its knockdown elevated the BTB permeability. In contrast, transcription factor interferon regulatory factor 6 (IRF6) exhibited reduced expression in glioma co-cultured endothelial cells, and its over-expression elevated the BTB permeability. Mechanistically, LINC00667 facilitated IRF6 mRNA degradation through Staufen1-mediated mRNA decay pathway. IRF6 inhibited the transcriptions of key tight junction associated proteins (ZO-1, occludin, and claudin-5) through promoter binding. That is, MSI2 knockdown down-regulated the expression of LINC00667, thereby diminishing its ability to degrade IRF6 through the Staufen1-mediated mRNA decay pathway. This led to IRF6 accumulation, which transcriptionally suppressed ZO-1, occludin and claudin-5 expression, ultimately increasing BTB permeability. Furthermore, both individual and combined modulation of MSI2 knockdown, LINC00667 knockdown and IRF6 over-expression enhanced BTB permeability to doxorubicin, thereby increasing the apoptosis rate of GB cells. Collectively, the MSI2/LINC00667/IRF6 pathway plays an important role in modulating BTB permeability, offering potential targets for new molecular therapies in GB.

The human methyltransferases mixed lineage leukemia 4 and 3 (MLL4 and MLL3) play pivotal roles in the regulation of epigenetic and transcriptional programs. Here, we report the identification and characterization of a tryptophan-phenylalanine binding motif recognized by MLL4 and MLL3. Binding of the sixth PHD finger of MLL4 and the seventh PHD finger of MLL3 to the tryptophan-phenylalanine motif derived from a set of human proteins was detected in a proteomic peptide-phage screening of intrinsically disordered regions of the human proteome and confirmed in NMR and MST assays. Mutational, genetic and binding interface analyses reveal the molecular mechanism underlying the direct interaction of MLL4 and MLL3 with the motif. A high correlation of expression of MLL4/MLL3 and the motif containing proteins in several tumor types suggests shared roles in oncogenic transcriptional programs. In conclusion, our findings highlight a potential relationship between the MLL4/MLL3 methyltransferases and diverse motif-containing epigenetic coregulators.

Hydroxyapatite (HAp)/reduced graphene oxide (rGO)/yttrium oxide (Y₂O₃) composites were prepared by ethanol-assisted wet blending (colloidal dispersion), followed by drying and heat treatment, and systematically characterized. This study investigates the structural, optical, and functional enhancement in hydroxyapatite (HAp) after the incorporation of reduced graphene oxide (rGO) and yttrium oxide (Y₂O₃), aiming to develop multifunctional bioceramics for dual applications in bone regeneration. HAp/rGO/Y₂O₃ composites were prepared by ethanol-assisted wet blending (colloidal dispersion), followed by drying and heat treatment, and systematically characterized. XRD analysis confirmed the phase purity of the composites and revealed reduced crystallite sizes upon doping, while FT-IR spectroscopy validated the presence of functional groups linked with phosphate, hydroxyl, and rGO/Y₂O₃ interactions. SEM investigation displayed dense, homogeneous morphologies with reduced particle sizes (∼380 nm), which are favorable for biomedical integration. UV/visible spectroscopy showed a significant narrowing of the optical bandgap from 5.42 eV in pure HAp to 4.73 eV in HAp/rGO/Y₂O₃ composites. This bandgap reduction was attributed to the π-conjugation of rGO and defect states introduced by Y₂O₃, thereby enhancing light absorption and rendering the composites promising candidates for photothermal and oxidative cancer therapies. The combined effect of rGO's electron transport and Y₂O₃'s reactive oxygen species (ROS) generation potential is expected to induce synergistic anticancer activity while preserving osteoconductivity. The tested AA3 formula demonstrated a promising level of biofilm reduction rates against Gram-positive bacteria, <i>e.g. Streptococcus pneumoniae</i> (97.27% ± 5.36%), <i>Staphylococcus epidermidis</i> (95.89% ± 2.85%), <i>Staphylococcus aureus</i> (94.77% ± 1.24%), and <i>Bacillus cereus</i> (92.90% ± 0.95%). Additionally, its minimum inhibitory dosage (MIC) against Gram-positive bacteria ranged from 80 to 100 µg mL^-1, with a bactericidal effect (MBC) at 120 µg mL^-1. <i>In vitro</i> cytotoxicity studies on <i>Vero</i> cells demonstrated the safety of our tested materials and composites. The MTT assay showed that HAP, Y₂O₃, rGO and their different composites (AA1 and AA3-AA5) exhibited CC₅₀ values above 100 µg mL^-1. By contrast, the CC₅₀ value of the AA2 composite was detected at 8.5 µg L^-1. Consequently, our composites have the potential to be used in biomedical applications. Overall, our results suggest that HAp/rGO/Y₂O₃ nanocomposites exhibit improved physicochemical and optical properties and hold substantial promise as dual-functional materials for integrated bone healing and localized cancer treatment platforms.

In this study, a series of collagen-hydroxyapatite (Col-HAp) composite scaffolds in the presence and absence of hexagonal boron nitride (h-BN) were fabricated using a controlled lyophilization technique to fabricate a functional biomaterial for drug delivery application. The lyophilization technique creates an interconnected porous network. The incorporation of h-BN in the Col-HAp/h-BN (1 : 2 : 1) scaffold prominently improved the mechanical strength of the scaffold, reaching 10.27 MPa as compared to the non-loaded h-BN scaffold, thereby enhancing its durability and structural stability. The loading of h-BN also displays a significant increase in surface area (47.27 m² g^-1), gaining abundant active sites for drug encapsulation. Circular dichroism (CD) spectroscopy confirmed the conformational behaviour of the collagen's secondary structure, indicating that in the presence of hydroxyapatite it preserved the native conformation and biological functionality. The Col-HAp/h-BN (1 : 2 : 1) scaffold revealed efficient ciprofloxacin (CIP) loading with a rate constant of 0.0719 h^-1 which follows the first order kinetics, while the release process followed a second order kinetic model with a rate constant of 3.24 h^-1, exhibiting a diffusion-based mechanism controlled by the scaffold's architecture. Enzymatic degradation assessment under a collagenase enzyme established that the Col-HAp/h-BN (1 : 2 : 1) scaffold underwent a gradual and sustained degradation pattern, as compared to other scaffolds, signifying that the incorporation of h-BN improved structural resistance and sustained biodegradability. In addition, biocompatibility studies revealed excellent cell viability, confirming the non-toxic and cytocompatibility nature of the scaffolds, validating the scaffold's safety for biological applications.

Self-assembling nanocomposites (SANCs) represent a valuable and innovative drug delivery system that facilitates site-specific and stimulus-controlled drug administration. These composites have the capability to self-assemble into stimulus-responsive nanostructures, enabling the effective delivery of a wide range of therapeutic agents, from small molecules to biologics, to specific target sites. This advancement addresses crucial challenges in treating diseases like cancer and chronic inflammatory conditions. In this review, we briefly outline the advantages of SANCs in enhancing bioavailability, reducing systemic toxicity, and maintaining stability under physiological conditions. However, several significant obstacles remain, including challenges related to scalability, stability, storage, biocompatibility, and regulatory approvals that have not been met to obtain clinical applications. Furthermore, we explore the stimuli-responsive and biohybrid materials, as well as the integration of SANCs with artificial intelligence and nanotechnology to create intelligent drug delivery systems. Encouraging contributions for papers that emphasize the role of SANCs in personalized medicine, this review underscores the potential of these nanosystems in developing tailored, patient-specific treatment approaches. By establishing robust policy frameworks and fostering strategic partnerships, SANCs have the potential to usher in a new era of tailored solutions for delivering medications effectively, thereby advancing the field of modern medicine.

The Brazilian Society of Surgical Oncology and the Brazilian Society of Head and Neck Surgery developed a technical consensus on hierarchical coding in thyroid surgery, considering the role of the Brazilian Hierarchical Classification of Medical Procedures in determining appropriate codes. A panel of 40 specialists - recognized academic and clinical leaders from across Brazil - assessed the applicability of procedure codes for common thyroid surgeries and prepared the current consensus. Deliberations were conducted via electronic voting among 37 participants, and consensus was defined as agreement by at least 80%. Scenarios included total thyroidectomy for benign and malignant disease and resection of substernal goiter. The analysis covered codes for laryngeal nerve exploration, neurophysiological monitoring, carotid artery branch ligation, biopsy, parathyroid reimplantation, lymphadenectomy, and neck dissection. Consensus supported the use of the following codes: nerve exploration (83.3%), neurophysiological monitoring (97.3%), biopsy and parathyroid reimplantation (89.2%), cervical lymphadenectomy (89.2%), and unilateral or bilateral neck dissections (97.3% and 94.6%, respectively). No consensus was reached on including carotid artery branch ligation or adding a partial thyroidectomy code for unilateral substernal goiter; therefore, these codes were not validated. The current consensus provides clear, objective guidance on hierarchical coding for thyroid surgery based on technical, scientific, and ethical criteria. It is intended to support attending physicians and auditors by promoting consistency, transparency, and reduced conflict in clinical and administrative settings.

Serotonin is thought to regulate emotional learning and memory, but there remains much to be explored regarding its causal role in cued fear conditioning and extinction (CFC-E). Recent <i>in vivo</i> recording of dorsal raphe nucleus serotonin neuronal activity during CFC-E paradigm showed that the time course of serotonin level includes both rapid responses to conditioned and unconditioned stimuli and a slowly accumulating component that spans inter-trial intervals and reverses during extinction. By reviewing the studies that directly link the fear expression during CFC-E to the acute or chronic perturbations of serotonin dynamics at the organism level or within specific brain areas via pharmacological, genetic, and projection-specific manipulations, we argue that theoretical models defining the causal role of serotonin must incorporate continuous-time serotonin dynamics.

Elective Genomic Testing (EGT) can identify individuals at risk for actionable conditions that would not come to clinical attention following current testing guidelines. We describe the results of a checkup unit from a leading Spanish University hospital (Clínica Universidad de Navarra, Spain) that has incorporated EGT to their regular clinical practice. Medical anamnesis, biochemistry, low-intensity whole body scan and EGT with interpretation of over 560 genes related to actionable adult-onset diseases (Veritas Intercontinental, Spain) was performed in 400 participants, including medical consultation before and after the checkup. Clinically relevant variants were identified in 79/400 participants (19.8%). Thirteen individuals (3.3%) presented with clinical variants included in the American College of Medical Genetics and Genomics secondary finding list (ACMG SF list); 69.2% of these variants showed potential association with personal or family history (PFH). The study presents the results of the first hospital integrating EGT into the checkup unit.

Cardiac amyloidosis (CA) represents an increasingly recognized but historically underdiagnosed cause of restrictive cardiomyopathy and heart failure. CA is now understood to be more prevalent, particularly in older adults, as advancements in imaging and biomarker technologies have improved detection. The disease results from the misfolding of precursor proteins, primarily immunoglobulin light chains (in light chain (AL) amyloidosis) or transthyretin (in transthyretin (ATTR) amyloidosis), into insoluble fibrils that deposit in myocardial tissue. These deposits cause structural and functional cardiac impairment through both physical infiltration and cytotoxic mechanisms, leading to diastolic dysfunction, arrhythmias, and progressive heart failure. Understanding the molecular basis of amyloid formation and deposition has revealed subtype-specific mechanisms of toxicity and tissue tropism, highlighting the central role of protein instability, proteolytic cleavage, and oxidative stress in disease progression. Furthermore, increasing awareness of phenotypic variability and sex- or ethnicity-based diagnostic disparities has called for earlier recognition and differentiation of CA subtypes. Diagnostic precision is enhanced by a multimodal approach incorporating histopathology, biomarker staging, and advanced imaging techniques such as echocardiography, cardiac magnetic resonance, and nuclear scintigraphy. This review addresses our contemporary understanding of the molecular mechanisms, pathophysiologic cascade, and diagnostic evolution of AL and ATTR CA, emphasizing clinical progress. By delineating the biological mechanisms and tools for early identification, this paper aims to strengthen the framework for diagnosing and managing a disease that was once overlooked but is now at the forefront of modern cardiovascular medicine.

<h4>Background</h4>Immunotherapy targeting immune checkpoint proteins (ICPs) has transformed cancer care, yet current treatments focus on a narrow set of inhibitory ICPs and benefit only a subset of patients. The co-stimulatory pair OX40-OX40L, implicated in inflammation and autoimmunity, also plays roles in cancer immunity. We previously showed that high OX40L mRNA expression in melanoma correlates with favorable prognosis and improved responses to PD-1 blockade. However, the protein-level expression and functions of OX40L in melanoma remain poorly defined.<h4>Methods</h4>Formalin-fixed paraffin-embedded primary tumor samples from 30 patients with stage II-III melanoma were analyzed by multiplex immunofluorescence combined with quantitative image analysis. OX40L and OX40 expression were evaluated alongside immune cell phenotyping markers. Regulatory T cells (Tregs) isolated from human peripheral blood were examined by flow cytometry and RT-qPCR. Associations with recurrence were assessed in depth-matched subsets (n=22) using Kaplan-Meier analysis.<h4>Results</h4>OX40L was detected across tumor, immune, and stromal compartments, with marked intertumoral heterogeneity. OX40⁺ cells were less frequent but were often found in spatial proximity to OX40L⁺ cells. OX40L was infrequently detected in melanoma cancer cells, and was more prevalent in antigen-presenting cells, CD4⁺/CD8⁺ T cells, and regulatory T cells. Strikingly, intratumoral Tregs expressed OX40L more frequently than OX40 or other ICPs, whereas blood-derived Tregs showed the opposite pattern, with OX40 predominating over OX40L. Disease recurrence following resection of the primary tumor was associated with lower proportions of OX40L-expressing myeloid cells, providing preliminary evidence for a potential link between myeloid OX40L expression and recurrence risk.<h4>Conclusions</h4>OX40L protein expression is a heterogeneous but prominent feature of the melanoma microenvironment, with cell type-specific expression patterns that include regulatory T cells. An exploratory association was seen between myeloid OX40L expression and clinical outcome, warranting further investigation.

Family members of the SET domain family (SETD) of histone lysine methyltransferases (HKMTs) act as principal epigenetic regulators, modulating chromatin structure, transcription pathways, and immune responses. SETDs catalyze lysine methylation on histone and non-histone substrates, as well as non-histone proteins (e.g., p53, NF-κB). These biochemical modifications support gene activity requisite for directing immune cells, modulating cytokine cascades, and inflammatory responses. For SETD family members, systemic dysregulation has become the principal mechanistic fulcrum within the orchestration of major autoimmune and inflammatory syndromes, comprising rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), psoriasis, atherosclerosis and type 2 diabetes, and, to a lesser extent, multiple sclerosis (MS) and inflammatory bowel disease (IBD). SETD1A and SETD1B catalyze H3K4 methylation and regulate the chromatin states governing the proliferation of T-lymphocytes. SETD2 spatially regulates H3K36 trimethylation with the augmentation of DNA regulatory steps and cytokine signaling. SETD6 and SETD7, and other components, enhance the NF-κB signaling involving innate immune response and regulation of chromatin structure. Experimentally validated mutations transform transcript re-equilibration and catalysis of benign enzymes. These alterations disturb immune consistency and endorse predetermined inflammatory responses, and weaken self-tolerance. In the post-genomic era, integrated therapeutic approaches are emerging from potent SETD modulators, small inhibitors, epigenetic scissors, and multi-omics techniques. Overall, this review demonstrates the emerging domain of immuno-epigenetics, SETD enzymes, and the strategic value they could serve as therapeutic targets and biomarkers.

<h4>Introduction</h4>Osteoarthritis (OA) is a degenerative joint disease marked by chronic inflammation, extracellular matrix degradation, and dysregulated cell death. The roles of apoptosis-, autophagy-, and ferroptosis-related genes in OA pathogenesis remain unclear.<h4>Methods</h4>Integrated bioinformatics analyses were conducted on public GEO datasets to identify apoptosis-autophagy-ferroptosis-related genes (AAFRGs). TLR3 and GLUL were identified using LASSO, random forest, and SVM-RFE algorithms. Immune infiltration analysis, immunohistochemistry, and functional assays in human chondrocytes were performed, and ACLT-induced rat OA models were used for <i>in vivo</i> validation.<h4>Results</h4>TLR3 was upregulated and associated with pro-inflammatory immune cells, while GLUL was downregulated and correlated with anti-inflammatory signatures. TLR3 knockdown reduced inflammation, apoptosis, and aberrant mineralization, partially restoring extracellular matrix integrity. GLUL overexpression promoted cellular homeostasis. In rats, TLR3 inhibition and PRP treatment decreased pro-inflammatory cytokines (IL-1β, TNF-α), reduced matrix-degrading enzymes (MMP3, MMP13), and restored GLUL and IL-10 levels.<h4>Discussion/conclusion</h4>TLR3 and GLUL orchestrate inflammatory responses and homeostatic imbalance in OA, representing potential biomarkers and therapeutic targets for diagnosis and intervention.

Gadolinium-doped hydroxyapatite nanoparticles (HapGd NPs) have emerged as promising multifunctional platforms for biomedical applications due to their unique combination of biocompatibility, structural tunability, and magnetic responsiveness. In this work, HapGd nanoparticles were synthesized using a microwave-assisted method and subsequently functionalized with curcumin and folic acid to enhance therapeutic efficiency and selective targeting. The synthesized nanostructures were characterized using various techniques, including X-ray diffraction (XRD), transmission electron microscopy (TEM), Fourier-transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), vibrating sample magnetometry (VSM), and relaxometry. Structural analyses revealed successful incorporation of Gd³⁺ ions into the Hap lattice, resulting in reduced unit cell volume and slight lattice distortion, while preserving the apatite crystalline framework. Surface functionalization with curcumin and folic acid was confirmed through spectroscopic characterization, demonstrating effective molecular attachment. Nuclear Magnetic Resonance (NMR) relaxation measurements indicated that Gd doping endowed paramagnetic behavior suitable for contrast enhancement in magnetic resonance imaging (MRI). Relaxometry studies revealed a strong linear correlation between 1/T₁ and the Gd³⁺ concentration, especially in the functionalized samples, with performance comparable to the commercial contrast agent Omniscan™. The developed HapGd-based nanoplatform exhibits integrated diagnostic and therapeutic potential, providing a foundation for future research in biomedical applications.

Soil extracellular enzyme activity reflects microbial resource acquisition and metabolic efficiency. However, applying enzyme stoichiometry to explore microbial metabolic limitations and carbon use efficiency (CUE) in rhizosphere and bulk soils under saline conditions remains limited. In this study, rhizosphere and bulk soils of <i>Tamarix austromongolica</i> were sampled along a salinity gradient in the Yellow River Delta to assess microbial metabolic limitation and CUE. Results showed that increasing salinity intensified microbial metabolic limitations and markedly reduced CUE, identifying salinity as the dominant factor constraining microbial efficiency. Rhizosphere soils consistently exhibited phosphorus limitation, whereas bulk soils shifted from balanced N-P limitation to pronounced N limitation with increasing salinity. Despite stronger microbial C limitation, CUE remained significantly higher in the rhizosphere than in the bulk soils, suggesting that continuous carbon inputs and enhanced enzyme activity partially mitigated salinity-induced stress. These findings highlight the complex interplay between salinity stress and rhizosphere effects in regulating microbial nutrient acquisition and carbon metabolism. Overall, this study demonstrates the utility of enzyme stoichiometry for evaluating microbial functional adaptation in saline habitats and provides insights that may contribute to the theoretical basis for vegetation restoration in saline-alkali ecosystems.

Neurodegeneration is closely linked to neuroinflammation and is frequently accompanied by comorbidities with inflammatory features. Tripartite motif (TRIM) proteins are known to play an important role in innate immunity and inflammatory signaling in various tissues and organs of the body, including the central nervous system. Among the main cell types of the brain, TRIMs' functions in microglia are largely associated with the regulation of intracellular inflammatory signaling, while in neurons they mainly relate to cell survival and oxidative stress. Data concerning TRIMs' activity in astrocytes remain limited. Many TRIM proteins exert similar pro- or anti-inflammatory effects in neuroinflammation and in other inflammatory disorders in the body, although for some members their roles are reported to be opposite, contradictory, or insufficiently characterized, highlighting the need for further research. The aim of this review was to summarize published data on the common mechanisms of TRIMs' actions as modulators of inflammation, and compare available reports in the context of neuroinflammation and peripheral inflammatory pathologies. We suggested that such an analysis may be valuable for guiding future research-both by identifying existing gaps in knowledge and by supporting the rational selection of specific TRIM proteins for investigation as therapeutic targets, with careful consideration of their systemic effects.

Feline infectious peritonitis (FIP) is a major disease of cats which, unless promptly diagnosed and treated, is invariably fatal. Although it has long been recognised that the condition is the result of an aberrant immune response to infection with feline coronavirus, there remain significant gaps in our understanding of its pathogenesis. Consequently, diagnosis is complex and relies on the combined interpretation of numerous clinical signs and laboratory biomarkers, many of which are non-specific. In the case of effusive FIP, a commonly encountered acute form of the disease where body cavity effusions develop; the interpretation of fluid analysis results is key to diagnosing the condition. We hypothesised that machine learning could be applied to fluid analysis test data in order to help diagnose effusive FIP. Thus, historical test records from a veterinary laboratory dataset of 718 suspected cases of effusive disease were identified, representing 336 cases of FIP and 382 cases that were determined not to be FIP. This dataset was used to train an ensemble model to predict disease status based on clinical observations and laboratory features. Our model predicts the correct disease state with an accuracy of 96.51%, an area under the receiver operator curve of 96.48%, a sensitivity of 98.85% and a specificity of 94.12%. This study demonstrates that machine learning can be successfully applied to the interpretation of fluid analysis results to accurately detect cases of effusive FIP. Thus, this method has the potential to be utilised in a veterinary diagnostic laboratory setting to standardise and improve service provision.

<i>Helicobacter pylori</i> is a prevalent gastric pathogen that establishes chronic infection and contributes to gastritis, peptic ulcer disease, and gastric cancer. Its persistence depends on immune evasion strategies that promote sustained low-grade inflammation in the gastric mucosa. Nucleotide-binding oligomerization domain-like receptors (NLRs) are cytosolic pattern recognition receptors that play key roles in innate immune responses against <i>H. pylori</i>. Nod1 and Nod2 detect bacterial peptidoglycan delivered via the type IV secretion system or outer membrane vesicles, activating NF-κB, MAPK, and interferon signaling pathways that regulate inflammatory cytokine production, epithelial barrier function, autophagy, and antimicrobial defense. The NLRP3 inflammasome mediates the maturation of IL-1β and IL-18 primarily in myeloid cells, thereby shaping inflammatory and immunoregulatory responses during infection. In contrast, NLRC4 functions in a context-dependent manner in epithelial cells and is largely dispensable for myeloid IL-1β production. Emerging evidence also implicates noncanonical NLRs, including NLRP6, NLRP9, NLRP12, NLRX1, and NLRC5, in regulating inflammation, epithelial homeostasis, and gastric tumorigenesis. In addition, genetic polymorphisms in NLR genes influence host susceptibility to <i>H. pylori</i>-associated diseases. This review highlights the interplay between NLR signaling, bacterial virulence, and host immunity and identifies potential therapeutic targets.

Although immunotherapy has revolutionized cancer treatment, antitumor immunological responses remain limited by insufficient tumor immunogenicity and immunosuppressive tumor microenvironment. Herein, pyroptosis induction is integrated into a photosensitizer to potentiate tumor immunogenicity. In this part, artesunate is disclosed to increase GSDME and modified to synthesize its ROS-cleavable prodrug, which is then installed into the self-assembled photosensitizer, resulting in a novel oil-in-water nanoplatform (BDP-pATS). The cytotoxicity, pyroptosis feature and potentiated GSDME induced by BDP-pATS are well confirmed. Subsequently, a novel acid-activatable adenosine-A2AR inhibitor is synthesized and further installed into the aforementioned platform to obtain BDP-pATS-aA2Ai, manipulating immunometabolic strategy to counterbalance the enhanced adenosine caused by pyroptosis. Such a photo-controlled and acid-activatable nanoprodrug enhances cytotoxic T cell functions while restrains regulatory T cell activities, leading to potent effects toward primary and abscopal tumor inhibition. In addition, BDP-pATS-aA2Ai also manifests desirable performance on pulmonary metastasis and tumor recurrence mouse model. To the best of our knowledge, this study presents the first concept of blocking adenosine-A2AR pathway during pyroptosis occurrence. Collectively, this work strategically combines immunometabolic interception, pyroptosis induction, photodynamic therapy and epigenetic regulation, emphasizing the significance of comprehensive therapy, which should open up a new viewpoint for cancer immunotherapy.

<h4>SUMMARY</h4> Therapeutic resistance limits the efficacy of histone deacetylase (HDAC) inhibitors and immune checkpoint therapies in cancer. While HDAC inhibitors can induce ferroptosis, tumor cells often evade this cell death via antioxidant defenses. Here we identify peroxiredoxin 6 (PRDX6) as a critical modulator of resistance to HDAC inhibitor largazole by suppressing ferroptosis through its phospholipase A2 activity and maintaining GPX4 expression. Using genome-wide CRISPR activation screening, biochemical assays, and syngeneic tumor models, we show that PRDX6 depletion enhances largazole-induced lipid peroxidation, ferroptotic stress, and reshapes the tumor microenvironment to promote T-cell infiltration and inflammatory cytokine release. Importantly, combining PRDX6 knockdown with HDAC inhibition potentiates anti-PD-L1 immunotherapy efficacy and prolongs survival in vivo . These findings reveal PRDX6 as a redox gatekeeper linking ferroptosis resistance to immune evasion and suggest that co-targeting PRDX6 and HDAC pathways may improve responses to cancer immunotherapy.

The cerebral cortex comprises diverse excitatory and inhibitory neuron subtypes, each with distinct laminar positions and connectivity patterns. Yet, the molecular logic underlying their precise wiring remains poorly understood. To identify ligand-receptor (LR) interactions involved in cortical circuit assembly, we tracked gene expression dynamics in mice across major neuronal populations at 17 developmental stages using single-cell transcriptomics. This generated a comprehensive atlas of LR-mediated communication between excitatory and inhibitory neuron subtypes, capturing known and novel interactions. Notably, we identified NEOGENIN-1 as the principal receptor for CBLN4 during the perinatal period, mediating synapse formation between somatostatin-expressing interneurons and glutamatergic neurons. We also identified members of the cadherin superfamily as candidate regulators of perisomatic inhibition from parvalbumin-expressing basket cells onto deep and superficial excitatory neurons, exerting opposing effects on synapse formation. These findings suggest a context-dependent role for cadherins in synaptic specificity and underscore the power of single-cell transcriptomics for decoding the molecular mechanisms of cortical wiring.

In South Greenland, public concerns have linked "black livers" in sheep to presumed environmental pollution from the Kvanefjeld mining exploration project. Elevated concentrations of metals and radionuclides in the area reflect natural geochemistry and weathering processes, not pollution from exploration activities. However, in response, we conducted a preliminary case-control study to diagnose the condition, investigate links between liver discoloration and environmental concentrations of metals and radionuclides, and to estimate the annual effective dose to the public from polonium-210 (²¹⁰Po) ingestion via sheep and lamb liver consumption. We also evaluated the prevalence of acquired melanosis, grazing and herd effects, and their association with carcass quality and disease markers. Histological analysis confirmed acquired melanosis in affected liver samples. No statistically significant differences in concentrations of chemical elements or radionuclides (including ²¹⁰Po and ²¹⁰Pb) were found between case and control groups, across age groups, grazing areas, or farms. Except for the most exposed children (10% percentile), the estimated annual effective dose to adults and children from ²¹⁰Po ingestion in black and healthy livers remained below the world average of 120 µSv due to the ingestion of naturally occurring radionuclides. The overall prevalence of ovine acquired melanosis based on a large sample size was 10.59%, with herd prevalence ranging from 0% to 51.79%. Age-specific prevalence was 10.38% in lambs and 13.40% in adult sheep. Acquired melanosis was negatively correlated with fat and muscle content in carcasses. The consumption of sheep livers from South Greenland does not appear to pose a toxicological or radiological risk.

<h4>Background</h4>Pulmonary hypertension (PH) due to left heart disease (group 2 PH) is associated with a worse prognosis than isolated heart failure. Both pulmonary arterial hypertension (group 1 PH) and group 2 PH are involved in pulmonary artery (PA) remodeling, which is potentially driven by shared molecular mechanisms. The aim of this study was to investigate the underlying processes contributing to PA remodeling in group 2 PH.<h4>Methods</h4>To mimic the response to a left-sided pressure load, pulmonary arterial smooth muscle cells (PASMCs) were subjected to mechanical stretch. RNA sequencing of PAs from patients with group 2 PH was performed using the Gene Expression Omnibus database. Mice with transverse aortic constriction and spontaneously hypertensive rats were used as group 2 PH models, and they were treated with adeno-associated virus via intratracheal instillation.<h4>Results</h4>RNA sequencing of PASMCs after the stretch stress identified 1585 genes specifically upregulated in PASMCs from patients with group 1 PH. Further PA and plasma analyses from patients with group 2 PH, integrated with group 1 PH findings, identified enhancement of TGF-β (transforming growth factor-beta) signaling by the INHBA (inhibin subunit beta A) as a key feature. Metabolomics revealed that stretch-induced mitochondrial dysfunction in PASMCs caused lactic acidosis via enhancement of PDK1 (pyruvate dehydrogenase kinase 1) and c-MYC, leading to increased INHBA expression. Mice with transverse aortic constriction exhibited increased INHBA expression, decreased PDH (pyruvate dehydrogenase) expression, and acidic alterations in PAs. Targeted silencing of INHBA or PDK1 using adeno-associated virus in mice with transverse aortic constriction attenuated PA remodeling, improved right ventricular function, and reduced PH.<h4>Conclusions</h4>Integrated RNA sequencing and metabolomics with stretched PASMCs and animal models identified mitochondrial dysfunction and subsequent acidic alterations as stimulators of increased INHBA expression and TGF-β signaling. These mechanisms contributed to PA remodeling in group 2 PH and provided potential therapeutic strategies.