Gene Literature Dashboard

<h4>Objective</h4>The temporomandibular joint (TMJ) is anatomically comprised of the mandibular condylar cartilage (CC) lined with fibrocartilaginous superficial zone and is crucial for eating and dental occlusion. TMJ osteoarthritis (OA) leads to pain, joint dysfunction and permanent loss of cartilage tissue. However, there are no drugs clinically available that ameliorate OA and little is known about global profiles of genes that contribute to TMJ OA. Furthermore, animal models that recapitulate the complexity of signalling pathways contributing to OA pathogenesis are crucial for designing novel biologics that thwart OA progression. We have previously developed a New Zealand white rabbit TMJ injury model that demonstrates CC degeneration. Here, we performed genome-wide profiling to identify new signalling pathways critical for cellular functions during OA pathology.<h4>Materials and methods</h4>Temporomandibular joint OA was surgically induced in New Zealand white rabbits. Three months following injury, we performed global gene expression profiling of the TMJ condyle. RNA samples from TMJ condyles were subjected to sequencing. After raw RNA-seq data were mapped to relevant genomes, differential expression was analysed with DESeq2. Gene ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis were conducted.<h4>Results/conclusions</h4>Our study revealed multiple pathways altered during TMJ OA induction including the Wnt, Notch and PI3K-Akt signalling pathways. We demonstrate an animal model that recapitulates the complexity of the cues and signals underlying TMJ OA pathogenesis, which is essential for developing and testing novel pharmacologic agents to treat OA.

No abstract available.

The involvement of necroptosis in the immunosuppressive tumor microenvironment has been established and has been shown to contribute to the growth of pancreatic ductal adenocarcinoma, indicating its role in promoting tumor development. However, the relationship between necroptosis and bladder urothelial carcinoma (BUC) has yet to be fully understood. To shed light on this issue, our study aimed to uncover the impact of necroptosis on immune cell infiltration and immunotherapy response in BUC patients. We conducted an analysis of 67 necroptosis genes to assess their expression and genomic changes across pan-cancer and identified 12 necroptosis genes that are prognostically relevant and associated with immune subtypes and tumor stemness in BUC. Using a public database of 1841 BUC samples, we then performed Unsupervised Cluster Analysis and discovered two distinct necroptotic phenotypes in BUC. These phenotypes showed significant differences in molecular subtypes, immune infiltration patterns, and gene mutation profiles. We confirmed this discovery in BUC through qPCR and WB experiments. To evaluate the impact of necroptosis on prognosis, chemotherapy sensitivity, and immunotherapy response (such as anti-PD-L1), we developed a principal component analysis model called NecroScore. Finally, we validated the effects of RIPK3 and MLKL through a nude mouse transplantation model for BUC. Our study has uncovered that necroptosis plays a role in shaping the tumor immune microenvironment in BUC. The high necroptosis phenotype (Cluster B) was characterized by a higher abundance of tumor immunosuppressive cells and more key biological processes driving tumor progression, while the low necroptosis group (Cluster A) had higher FGFR3 mutations. We found that the infiltration levels of immune cells, including CD8+ T cells, were significantly different between FGFR3 mutated and wild-type (WT) samples. Our results confirmed the reliability of NecroScore as a comprehensive assessment tool for evaluating the immunotherapeutic effect and prognosis of BUC patients, with high NecroScore values favoring basal-like differentiation and lower FGFR3 alterations. We also observed that high expression of MLKL had a significant inhibitory effect on tumor growth and increased neutrophil infiltration in vivo. In our study, we uncovered the regulation pattern of necroptosis in the tumor immune microenvironment of BUC. Additionally, we developed a scoring tool called NecroScore that can be utilized to predict the most suitable chemotherapy and immunotherapy strategy for bladder urothelial carcinoma patients. This tool can effectively guide the chemotherapy and immunotherapy regimens for patients with advanced BUC.

Protein profiling offers an effective approach to characterizing how far epidermis departs from normal in disease states. The present pilot investigation tested the hypothesis that protein expression in epidermal corneocytes is perturbed in the forehead of subjects exhibiting frontal fibrosing alopecia. To this end, samples were collected by tape stripping from subjects diagnosed with this condition and compared to those from asymptomatic control subjects and from those exhibiting androgenetic alopecia. Unlike the latter, which exhibited only 3 proteins significantly different from controls in expression level, forehead samples from frontal fibrosing alopecia subjects displayed 72 proteins significantly different from controls, nearly two-thirds having lower expression. The results demonstrate frontal fibrosing alopecia exhibits altered corneocyte protein expression in epidermis beyond the scalp, indicative of a systemic condition. They also provide a basis for quantitative measures of departure from normal by assaying forehead epidermis, useful in monitoring response to treatment while avoiding invasive biopsy.

The response of gamma delta (γδ) T cells in the acute versus chronic phases of the same infection is unclear. How γδ T cells function in acute <i>Mycobacterium tuberculosis</i> (Mtb) infection is well characterized, but their response during persistent Mtb infection is not well understood, even though most infections with Mtb manifest as a chronic, clinically asymptomatic state. Here, we analyze peripheral blood γδ T cells from a South African adolescent cohort and show that a unique CD8⁺ γδ T cell subset with features of "memory inflation" expands in chronic Mtb infection. These cells are hyporesponsive to T cell receptor (TCR)-mediated signaling but, like NK cells, can mount robust CD16-mediated cytotoxic responses. These CD8⁺ γδ T cells comprise a highly focused TCR repertoire, with clonotypes that are <i>Mycobacterium</i> specific but not phosphoantigen reactive. Using multiparametric single-cell pseudo-time trajectory analysis, we identified the differentiation paths that these CD8⁺ γδ T cells follow to develop into effectors in this infection state. Last, we found that circulating CD8⁺ γδ T cells also expand in other chronic inflammatory conditions, including cardiovascular disease and cancer, suggesting that persistent antigenic exposure may drive similar γδ T cell effector programs and differentiation fates.

<h4>Abstract</h4>The prevalence of obesity has increased worldwide in recent decades. Genetic factors are now known to play a substantial role in the predisposition to obesity and may contribute up to 70% of the risk for obesity. Technological advancements during the last decades have allowed the identification of many hundreds of genetic markers associated with obesity. However, the transformation of current genetic variant-obesity associations into biological knowledge has been proven challenging. Genomics and proteomics are complementary fields, as proteomics extends functional analyses. Integrating genomic and proteomic data can help to bridge a gap in knowledge regarding genetic variant-obesity associations and to identify new drug targets for the treatment of obesity. We provide an overview of the published papers on the integrated analysis of proteomic and genomic data in obesity and summarize four mainstream strategies: overlap, colocalization, Mendelian randomization, and proteome-wide association studies. The integrated analyses identified many obesity-associated proteins, such as leptin, follistatin, and adenylate cyclase 3. Despite great progress, integrative studies focusing on obesity are still limited. There is an increased demand for large prospective cohort studies to identify and validate findings, and further apply these findings to the prevention, intervention, and treatment of obesity. In addition, we also discuss several other potential integration methods.

Pediatric acute myeloid leukemia (AML) is an uncommon but aggressive hematological malignancy. The poor outcome is attributed to inadequate prognostic classification and limited treatment options. A thorough understanding on the genetic basis of pediatric AML is important for the development of effective approaches to improve outcomes. Here, by comprehensively profiling fusion genes as well as mutations and copy number changes of 141 myeloid-related genes in 147 pediatric AML patients with subsequent variant functional characterization, we unveil complex mutational patterns of biological relevance and disease mechanisms including MYC deregulation. Also, our findings highlight TP53 alterations as strong adverse prognostic markers in pediatric AML and suggest the core spindle checkpoint kinase BUB1B as a selective dependency in this aggressive subgroup. Collectively, our present study provides detailed genomic characterization revealing not only complexities and mechanistic insights into pediatric AML but also significant risk stratification and therapeutic strategies to tackle the disease.

<h4>Background</h4>Super-enhancers (SEs), driving high-level expression of genes with tumor-promoting functions, have been investigated recently. However, the roles of super-enhancer-associated lncRNAs (SE-lncRNAs) in tumors remain undetermined, especially in gliomas. We here established a SE-lncRNAs expression-based prognostic signature to choose the effective treatment of glioma and identify a novel therapeutic target.<h4>Methods</h4>Combined analysis of RNA sequencing (RNA-seq) data and ChIP sequencing (ChIP-seq) data of glioma patient-derived glioma stem cells (GSCs) screened SE-lncRNAs. Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA) datasets served to construct and validate SE-lncRNA prognostic signature. The immune profiles and potential immuno- and chemotherapies response prediction value of the signature were also explored. Moreover, we verified the epigenetic activation mechanism of LINC00945 via the ChIP assay, and its effect on glioma was determined by performing the functional assay and a mouse xenograft model.<h4>Results</h4>6 SE-lncRNAs were obtained and identified three subgroups of glioma patients with different prognostic and clinical features. A risk signature was further constructed and demonstrated to be an independent prognostic factor. The high-risk group exhibited an immunosuppressive microenvironment and was higher enrichment of M2 macrophage, regulatory T cells (Tregs), and Cancer-associated fibroblasts (CAFs). Patients in the high-risk group were better candidates for immunotherapy and chemotherapeutics. The SE of LINC00945 was further verified via ChIP assay. Mechanistically, BRD4 may mediate epigenetic activation of LINC00945. Additionally, overexpression of LINC00945 promoted glioma cell proliferation, EMT, migration, and invasion in vitro and xenograft tumor formation in vivo.<h4>Conclusion</h4>Our study constructed the first prognostic SE-lncRNA signature with the ability to optimize the choice of patients receiving immuno- and chemotherapies and provided a potential therapeutic target for glioma.

Loss of synapses is the most robust pathological correlate of Alzheimer's disease (AD)-associated cognitive deficits, although the underlying mechanism remains incompletely understood. Synaptic terminals have abundant mitochondria which play an indispensable role in synaptic function through ATP provision and calcium buffering. Mitochondrial dysfunction is an early and prominent feature in AD which could contribute to synaptic deficits. Here, using electron microscopy, we examined synapses with a focus on mitochondrial deficits in presynaptic axonal terminals and dendritic spines in cortical biopsy samples from clinically diagnosed AD and age-matched non-AD control patients. Synaptic vesicle density within the presynaptic axon terminals was significantly decreased in AD cases which appeared largely due to significantly decreased reserve pool, but there were significantly more presynaptic axons containing enlarged synaptic vesicles or dense core vesicles in AD. Importantly, there was reduced number of mitochondria along with significantly increased damaged mitochondria in the presynapse of AD which correlated with changes in SV density. Mitochondria in the post-synaptic dendritic spines were also enlarged and damaged in the AD biopsy samples. This study provided evidence of presynaptic vesicle loss as synaptic deficits in AD and suggested that mitochondrial dysfunction in both pre- and post-synaptic compartments contribute to synaptic deficits in AD.

Ligand activation of the aryl hydrocarbon receptor (AHR) accelerates keratinocyte differentiation and the formation of the epidermal permeability barrier. Several classes of lipids, including ceramides, are critical to the epidermal permeability barrier. In normal human epidermal keratinocytes, the AHR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin, increased RNA levels of ceramide metabolism and transport genes: uridine diphosphate glucose ceramide glucosyltransferase (UGCG), ABCA12, GBA1, and SMPD1. Levels of abundant skin ceramides were also increased by 2,3,7,8-tetrachlorodibenzo-p-dioxin. These included the metabolites synthesized by UGCG, glucosylceramides, and acyl glucosylceramides. Chromatin immunoprecipitation-sequence analysis and luciferase reporter assays identified UGCG as a direct AHR target. The AHR antagonist, GNF351, inhibited the 2,3,7,8-tetrachlorodibenzo-p-dioxin-mediated RNA and transcriptional increases. Tapinarof, an AHR ligand approved for the treatment of psoriasis, increased UGCG RNA, protein, and its lipid metabolites hexosylceramides as well as increased the RNA expression of ABCA12, GBA1, and SMPD1. In Ahr-null mice, Ugcg RNA and hexosylceramides were lower than those in the wild type. These results indicate that the AHR regulates the expression of UGCG, a ceramide-metabolizing enzyme required for ceramide trafficking, keratinocyte differentiation, and epidermal permeability barrier formation.

Cell-free (cf) extrachromosomal circular DNA (eccDNA) has a potential clinical application as a biomarker. Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with a complex immunological pathogenesis, associated with autoantibody synthesis. A previous study found that SLE patients with deoxyribonuclease 1-like 3 (DNASE1L3) deficiency exhibit changes in the frequency of short and long eccDNA in plasma compared to controls. Here, using the DifCir method for differential analysis of short-read sequenced purified eccDNA data based on the split-read signal of the eccDNA on circulomics data, we show that SLE patients with DNASE1L3 deficiency have a distinctive profile of eccDNA excised by gene regions compared to controls. Moreover, this profile is specific; cf-eccDNA from the top 93 genes is detected in all SLE with DNASE1L3 deficiency samples, and none in the control plasma. The top protein coding gene producing eccDNA-carrying gene fragments is the transcription factor <i>BARX2,</i> which is involved in skeletal muscle morphogenesis and connective tissue development. The top gene ontology terms are 'positive regulation of torc1 signaling' and 'chondrocyte development'. The top Harmonizome terms are 'lymphopenia', 'metabolic syndrome x', 'asthma', 'cardiovascular system disease', 'leukemia', and 'immune system disease'. Here, we show that gene associations of cf-eccDNA can serve as a biomarker in the autoimmune rheumatic diseases.

The temporal trends in haematological parameters and their associations with blood product transfusion requirements in patients supported with extracorporeal membrane oxygenation (ECMO) are poorly understood. We performed a retrospective data analysis to better understand the behaviour of haematological and coagulation parameters and their associations with transfusion requirements during ECMO.<h4>Methods</h4>Patient demographics, haematological and coagulation parameters, plasma haemoglobin and fibrinogen concentrations, platelet count, the international normalised ratio (INR), the activated partial thromboplastin time (APTT), and blood product transfusion data from 138 patients who received ECMO in a single high-volume centre were analysed.<h4>Results</h4>Ninety-two patients received venoarterial (VA) ECMO and 46 patients received venovenous (VV) ECMO. The median (IQR) duration of VA, and VV ECMO was 8 (5-13) days and 13 (8-23) days, respectively. There were significant reductions in haemoglobin, the platelet count, and the fibrinogen concentration upon initiation of ECMO. On average, over time, patients on VV ECMO had platelet counts 44 × 10⁹/L higher than those on VA ECMO (<i>p</i> ≤ 0.001). Fibrinogen and APTT did not vary significantly based on the mode of ECMO (<i>p</i> = 0.55 and <i>p</i> = 0.072, respectively). A platelet count < 50 × 10⁹/L or a fibrinogen level < 1.8 g/L was associated with 50% chance of PRBC transfusion, regardless of the ECMO type, and packed red blood cell (PRBC) transfusion was more common with VA ECMO. APTT was predictive of the transfusion requirement, and the decrement in APTT was discriminatory between VVECMO survivors and nonsurvivors.<h4>Conclusion</h4>ECMO support is associated with reductions in haemoglobin, platelet count, and fibrinogen. Patients supported with VA ECMO are more likely to receive a PRBC transfusion compared to those on VV ECMO. Thrombocytopaenia, hypofibrinogenaemia, and anticoagulation effect the likelihood of requiring PRBC transfusion. Further research is needed to define optimal blood management during ECMO, including appropriate transfusion triggers and the anticoagulation intensity.

Bone tissue engineering integrates biomaterials, cells, and bioactive agents to propose sophisticated treatment options over conventional choices. Scaffolds have central roles in this scenario, and precisely designed and fabricated structures with the highest similarity to bone tissue have shown promising outcomes. On the other hand, using nanotechnology and nanomaterials as the enabling options confers fascinating properties to the scaffolds, such as precisely tailoring the physicochemical features and better interactions with cells and surrounding tissues. Among different nanomaterials, polymeric nanofibers and carbon nanofibers have attracted significant attention due to their similarity to bone extracellular matrix (ECM) and high surface-to-volume ratio. Moreover, bone ECM is a biocomposite of collagen fibers and hydroxyapatite crystals; accordingly, researchers have tried to mimic this biocomposite using the mineralization of various polymeric and carbon nanofibers and have shown that the mineralized nanofibers are promising structures to augment the bone healing process in the tissue engineering scenario. In this paper, we reviewed the bone structure, bone defects/fracture healing process, and various structures/cells/growth factors applicable to bone tissue engineering applications. Then, we highlighted the mineralized polymeric and carbon nanofibers and their fabrication methods.

A series of electrospun polyvinyl alcohol (PVA) fiber membranes were crosslinked with citric acid (CA) at concentrations of 10, 20, and 30 wt.% (designated as CA10, CA20, and CA30). The effects of CA on the chemical structure, mechanical strength, swelling resistance, and cytotoxicity of the crosslinked PVA fibrous membranes were investigated. Infrared spectroscopy indicated the enhanced esterification of carboxyl and hydroxyl groups between CA and PVA. The modulus and strength of the electrospun PVA membrane increased due to the crosslinking between CA and PVA. The crosslinking of the PVA fiber matrix with CA increased the PVA binding point, thereby increasing the swelling resistance and modulus; however, the concentration of CA used was limited. Results showed that the water absorption of the PVA membranes decreased from 6.58 ± 0.04 g/g for CA10 to 3.56 ± 3.33 g/g for CA20 and 2.85 ± 0.40 g/g for CA30 with increasing CA. The water absorption remained unchanged after the membrane was soaked for a period of time, so no significant difference was found in the water absorption capacity of the same group after immersion from 1 h to 3 d. The tensile strength increased from 20.52 MPa of CA10 to 22.09 MPa of CA20. With an increased amount of CA used for crosslinking, the tensile strength and modulus of CA30 decreased to 11.48 and 13.94 MPa, respectively. Our study also showed that CA was not toxic to L929 cell viability when used for fiber crosslinking at less than 20 wt.% PVA, meaning it may be a good candidate as a support layer for guided tissue engineering.

Owing to their antitumor and major histocompatibility complex (MHC)-independent capacities, γδ T cells have gained popularity in adoptive T-cell immunotherapy in recent years. However, many unknowns still exist regarding γδ T cells, and few clinical data have been collected. Therefore, this review aims to describe all the main features of the applications of γδ T cells and provide a systematic view of current γδ T-cell immunotherapy. Specifically, this review will focus on how γδ T cells performed in treating cancers in clinics, on the γδ T-cell clinical trials that have been conducted to date, and the role of γδ T cells in the pharmaceutical industry.

<h4>Introduction</h4>It is believed that ovarian cancer (OC) is the most deadly form of gynecological cancer despite its infrequent occurrence, which makes it one of the most salient public health concerns. Clinical and preclinical studies have revealed that intratumoral CD4+ T cells possess cytotoxic capabilities and were capable of directly killing cancer cells. This study aimed to identify the CD4+ conventional T cells-related genes (CD4TGs) with respect to the prognosis in OC.<h4>Methods</h4>We obtained the transcriptome and clinical data from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. CD4TGs were first identified from single-cell datasets, then univariate Cox regression was used to screen prognosis-related genes, LASSO was conducted to remove genes with coefficient zero, and multivariate Cox regression was used to calculate riskscore and to construct the CD4TGs risk signature. Kaplan-Meier analysis, univariate Cox regression, multivariate Cox regression, time-dependent receiver operating characteristics (ROC), decision curve analysis (DCA), nomogram, and calibration were made to verify and evaluate the risk signature. Gene set enrichment analyses (GSEA) in risk groups were conducted to explore the tightly correlated pathways with the risk group. The role of riskscore has been further explored in the tumor microenvironment (TME), immunotherapy, and chemotherapy. A risk signature with 11 CD4TGs in OC was finally established in the TCGA database and furtherly validated in several GEO cohorts.<h4>Results</h4>High riskscore was significantly associated with a poorer prognosis and proven to be an independent prognostic biomarker by multivariate Cox regression. The 1-, 3-, and 5-year ROC values, DCA curve, nomogram, and calibration results confirmed the excellent prediction power of this model. Compared with the reported risk models, our model showed better performance. The patients were grouped into high-risk and low-risk subgroups according to the riskscore by the median value. The low-risk group patients tended to exhibit a higher immune infiltration, immune-related gene expression and were more sensitive to immunotherapy and chemotherapy.<h4>Discussion</h4>Collectively, our findings of the prognostic value of CD4TGs in prognosis and immune response, provided valuable insights into the molecular mechanisms and clinical management of OC.

<h4>Introduction</h4>Mendelian susceptibility to mycobacterial disease (MSMD) is a rare inherited condition characterized by selective susceptibility to weakly virulent mycobacteria, such as substrains of the bacille Calmette-Guérin (BCG) vaccine and different environmental mycobacteria.<h4>Case presentation</h4>A 7-year-old Sudanese boy was referred to the immunology clinic with a suspected diagnosis of MSMD. This followed multiple presentations with disseminated tuberculosis and typhoid fever. Genetic testing surprisingly revealed pathogenic homozygous variants in <i>IL12RB1</i> Exon 9, c.913A>T (p. Lys305*) in both the patient and his father, with a completely healthy asymptomatic carrier mother who is not blood related to the patient's father.<h4>Conclusion</h4>It is challenging to diagnose MSMD, especially in developing countries where health systems are poor and have limited resources. Family history and genetic tests may help in early MSMD treatment and avoiding disease complications.

<b>Background:</b> Stroke and depression are the two most common causes of disability worldwide. Growing evidence suggests a bi-directional relationship between stroke and depression, whereas the molecular mechanisms underlying stroke and depression are not well understood. The objectives of this study were to identify hub genes and biological pathways related to the pathogenesis of ischemic stroke (IS) and major depressive disorder (MDD) and to evaluate the infiltration of immune cells in both disorders. <b>Methods:</b> Participants from the United States National Health and Nutritional Examination Survey (NHANES) 2005-2018 were included to evaluate the association between stroke and MDD. Two differentially expressed genes (DEGs) sets extracted from GSE98793 and GSE16561 datasets were intersected to generate common DEGs, which were further screened out in cytoHubba to identify hub genes. GO, KEGG, Metascape, GeneMANIA, NetworkAnalyst, and DGIdb were used for functional enrichment, pathway analysis, regulatory network analysis, and candidate drugs analysis. ssGSEA algorithm was used to analyze the immune infiltration. <b>Results:</b> Among the 29706 participants from NHANES 2005-2018, stroke was significantly associated with MDD (OR = 2.79,95% CI:2.26-3.43, <i>p</i> < 0.0001). A total of 41 common upregulated genes and eight common downregulated genes were finally identified between IS and MDD. Enrichment analysis revealed that the shared genes were mainly involved in immune response and immune-related pathways. A protein-protein interaction (PPI) was constructed, from which ten (CD163, AEG1, IRAK3, S100A12, HP, PGLYRP1, CEACAM8, MPO, LCN2, and DEFA4) were screened. In addition, gene-miRNAs, transcription factor-gene interactions, and protein-drug interactions coregulatory networks with hub genes were also identified. Finally, we observed that the innate immunity was activated while acquired immunity was suppressed in both disorders. <b>Conclusion:</b> We successfully identified the ten hub shared genes linking the IS and MDD and constructed the regulatory networks for them that could serve as novel targeted therapy for the comorbidities.

Astrocytes are central nervous system (CNS)-restricted glial cells involved in synaptic function and CNS blood flow regulation. Astrocyte extracellular vesicles (EVs) participate in neuronal regulation. EVs carry RNAs, either surface-bound or luminal, which can be transferred to recipient cells. We characterized the secreted EVs and RNA cargo of human astrocytes derived from an adult brain. EVs were isolated by serial centrifugation and characterized with nanoparticle tracking analysis (NTA), Exoview, and immuno-transmission electron microscopy (TEM). RNA from cells, EVs, and proteinase K/RNase-treated EVs was analyzed by miRNA-seq. Human adult astrocyte EVs ranged in sizes from 50 to 200 nm, with CD81 as the main tetraspanin marker and larger EVs positive for integrin β1. Comparison of the RNA between the cells and EVs identified RNA preferentially secreted in the EVs. In the case of miRNAs, enrichment analysis of their mRNA targets indicates that they are good candidates for mediating EV effects on recipient cells. The most abundant cellular miRNAs were also abundant in EVs, and the majority of their mRNA targets were found to be downregulated in mRNA-seq data, but the enrichment analysis lacked neuronal specificity. Proteinase K/RNase treatment of EV-enriched preparations identified RNAs secreted independently of EVs. Comparing the distribution of cellular and secreted RNA identifies the RNAs involved in intercellular communication via EVs.

Nosocomial infections caused by microbial biofilm formation on biomaterial surfaces such as urinary catheters are complicated by antibiotic resistance, representing a common problem in hospitalized patients. Therefore, we aimed to modify silicone catheters to resist microbial adherence and biofilm formation by the tested microorganisms. This study used a simple direct method to graft poly-acrylic acid onto silicone rubber films using gamma irradiation to endow the silicone surface with hydrophilic carboxylic acid functional groups. This modification allowed the silicone to immobilize ZnO nanoparticles (ZnO NPs) as an anti-biofilm. The modified silicone films were characterized by FT-IR, SEM, and TGA. The anti-adherence ability of the modified silicone films was evidenced by the inhibition of biofilm formation by otherwise strong biofilm-producing Gram-positive, Gram-negative, and yeast clinical isolates. The modified ZnO NPs grafted silicone showed good cytocompatibility with the human epithelial cell line. Moreover, studying the molecular basis of the inhibitory effect of the modified silicone surface on biofilm-associated genes in a selected Pseudomonas aeruginosa isolate showed that anti-adherence activity might be due to the significant downregulation of the expression of lasR, lasI, and lecB genes by 2, 2, and 3.3-fold, respectively. In conclusion, the modified silicone catheters were low-cost, offering broad-spectrum anti-biofilm activity with possible future applications in hospital settings.

Chromosomal imbalance is implicated in developmental delay (DD), congenital malformations (CM), and intellectual disability (ID), and, thus, precise identification of copy number variations (CNVs) is essential. We therefore aimed to investigate the genetic heterogeneity in Saudi children with DD/CM/ID. High-resolution array comparative genomic hybridization (array CGH) was used to detect disease-associated CNVs in 63 patients. Quantitative PCR was done to confirm the detected CNVs. Giemsa banding-based karyotyping was also performed. Array CGH identified chromosomal abnormalities in 24 patients; distinct pathogenic and/or variants of uncertain significance CNVs were found in 19 patients, and aneuploidy was found in 5 patients including 47,XXY (n = 2), 45,X (n = 2) and a patient with trisomy 18 who carried a balanced Robertsonian translocation. CNVs including 9p24p13, 16p13p11, 18p11 had gains/duplications and CNVs, including 3p23p14, 10q26, 11p15, 11q24q25, 13q21.1q32.1, 16p13.3p11.2, and 20q11.1q13.2, had losses/deletions only, while CNVs including 8q24, 11q12, 15q25q26, 16q21q23, and 22q11q13 were found with both gains or losses in different individuals. In contrast, standard karyotyping detected chromosomal abnormalities in ten patients. The diagnosis rate of array CGH (28%, 18/63 patients) was around two-fold higher than that of conventional karyotyping (15.87%, 10/63 patients). We herein report, for the first time, the extremely rare pathogenic CNVs in Saudi children with DD/CM/ID. The reported prevalence of CNVs in Saudi Arabia adds value to clinical cytogenetics.

A 50-year-old cohort from the Tampere adult population cardiovascular risk study having hypertension and their controls were examined retrospectively at the age of 35 years, and followed up prospectively up to the age of 65 years to determine whether an early hematocrit (HCR) measurement predicts later hypertension or cardiovascular complications. A total of 307 subjects having hypertension and 579 non-hypertensive controls were chosen from the 50-year-old cohort and regrouped according to HCR values obtained when they were 35 years old, one with HCT < 45 % (n = 581), and the other, with HCT ≥ 45 % (n = 305). Hypertension and coronary artery disease (CAD) by the age of 60 years were determined by self-report and the National Hospital Discharge Registry. Outcomes for death up to the age of 65 years were collected from the National Statistics Centre. HCT ≥ 45 % at the age of 35 years associated with hypertension (p = 0.041) and CAD (P = 0.047) by the age of 60 years. When the subjects were followed up to the age of 65 years, HCT ≥ 45 % associated with premature cardiovascular death (P = 0.029), and death by any cause (P = 0.004). These results were obtained after adjusting for BMI-class recorded at 50 years of age. However, when outcome was also adjusted by gender, current smoking, vocational education, and state of one's health, association of the ≥ 45 % group with CAD and death was abolished. The association with hypertension remained (P = 0.007). In conclusion, there was a significant association of HCT ≥ 45 % at early middle age with subsequent hypertension.

This paper reports a new concept of a film-shaped micropump array for biomedical perfusion. The detailed concept, design, fabrication process, and performance evaluation using prototypes are described. In this micropump array, an open circuit potential (OCP) is generated by a planar biofuel cell (BFC), which in turn generates electro-osmotic flows (EOFs) in multiple through-holes arranged perpendicular to the micropump plane. The micropump array is thin and wireless, so it can be cut like postage stamps, easily installed in any small location, and can act as a planar micropump in solutions containing the biofuels glucose and oxygen. Perfusion at local sites are difficult with conventional techniques using multiple separate components such as micropumps and energy sources. This micropump array is expected to be applied to the perfusion of biological fluids in small locations near or inside cultured cells, cultured tissues, living organisms, and so on.

Obesity is a global crisis leading to several metabolic disorders. Modernization and technology innovation has been easier for next generation sequencing using open-source online software galaxy, which allows the users to share their data and workflow mapping in an effortless manner. This study is to identify candidate genes for obesity by performing differential expression of genes. RNA-Seq analysis was performed for six different datasets retrieved from GEO database. 258 datasets from obese patients and 55 datasets from lean patients were analysed for differentially expressed genes (DEGs). DEGs analysis showed 1971 upregulated genes and 615 downregulated genes with log2FC count ≥ 2.5 and p-value < 0.05. The Gene enrichment analysis performed using Gene Ontology resource highlighted pathways associated to obesity such as cholesterol metabolism, Fat digestion and absorption and glycerolipid metabolism. Using string database protein-protein interactions network was built and the network clusters were visualized using Cytoscape software. The protein-protein interactions of the upregulated and downregulated genes were mapped to form a network, wherein PNLIP (Pancreatic lipase) and FTO (Fat mass and obesity associated protein) gene clusters were visualized as densely connected clusters in MCODE. PNLIP and FTO with its associated genes were identified as candidate genes for targeting obesity.

We study the effects of low short-term interest rates on the optimal portfolio allocation in Markowitz portfolios and Risk parity portfolios. We propose a measure of Portfolio Instabil-ity, gauging the amount of optimal portfolio shifts needed to respond to exogenous shocks to the expected risk and return of the risky portfolio assets. Portfolio Instability, i.e. the selling pressure on riskier asset holdings, is found to be stronger the lower the risk-free interest rate. Heightened portfolio instability in the presence of low rates is found to emerge through two channels both of which incentivise the build-up of large and leveraged risky asset shares during calm periods which need to be unwound in the event of higher market volatility: first, low rates (mechanically) augment the excess return to be gained by investing in riskier assets and second, they are found to dampen volatility of riskier assets in the portfolio. The inverse relationship between portfolio instability and the risk-free rates is found to increase the closer the risk-free rate approaches the effective lower bound. Counterfactual analyses of the behaviour of optimal multi-asset portfolios demonstrate that the sell-off in riskier asset classes during the Covid crisis in March 2020 was more severe than would have been in the presence of higher short-term interest rates.

Sarcopenia is a geriatric disease characterized by reduced muscle function and mass. The capacity to self-renew and myogenesis of satellite cells (SCs) declines with age, resulting in age-related sarcopenia. MicroRNAs (miRNAs) can regulate the proliferation and myogenesis of SCs. In this study, it is identified that miR-467a-3p and miR-874-5p could respectively mediate the stemness and myogenesis of SCs by performing bioinformatics analysis. AntagomiR-467a-3p (ant-467a) and antagomiR-874-5p (ant-874) improve the stemness and myogenesis of SCs, respectively. SC-targeting extracellular vesicles (EVs) are constructed by overexpressing TSG101 on the surface of EVs isolated from bone marrow mesenchymal stem cells. Ant-467a loaded EVs (EVs-467a) and ant-874 loaded EVs (EVs-874) are prepared by transferring ant-467a and ant-874 into SC-targeting EVs. EVs-467a and EVs-874 are more effective than ant-467a and ant-874 in promoting the stemness and myogenesis of SCs. Sequentially intermuscular injection of EVs-467a and EVs-874 significantly improve sarcopenia in ovariectomy mice. The effects of multiple injections of EVs-467a and EVs-874 in the treatment of sarcopenia could be achieved by using a hierarchically injectable hydrogel to sustainedly release EVs-467a and EVs-874 in vivo. The findings provide an EV-based SC-targeting antagomiRNAs controlled release strategy as a novel therapy against sarcopenia.

<h4>Background</h4>Cardiovascular disease (CVD) is the leading cause of death worldwide and considered one of the most environmentally driven diseases. The role of DNA methylation in response to the individual exposure for the development and progression of CVD is still poorly understood and a synthesis of the evidence is lacking.<h4>Results</h4>A systematic review of articles examining measurements of DNA cytosine methylation in CVD was conducted in accordance with PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines. The search yielded 5,563 articles from PubMed and CENTRAL databases. From 99 studies with a total of 87,827 individuals eligible for analysis, a database was created combining all CpG-, gene- and study-related information. It contains 74,580 unique CpG sites, of which 1452 CpG sites were mentioned in ≥ 2, and 441 CpG sites in ≥ 3 publications. Two sites were referenced in ≥ 6 publications: cg01656216 (near ZNF438) related to vascular disease and epigenetic age, and cg03636183 (near F2RL3) related to coronary heart disease, myocardial infarction, smoking and air pollution. Of 19,127 mapped genes, 5,807 were reported in ≥ 2 studies. Most frequently reported were TEAD1 (TEA Domain Transcription Factor 1) and PTPRN2 (Protein Tyrosine Phosphatase Receptor Type N2) in association with outcomes ranging from vascular to cardiac disease. Gene set enrichment analysis of 4,532 overlapping genes revealed enrichment for Gene Ontology molecular function "DNA-binding transcription activator activity" (q = 1.65 × 10^-11) and biological processes "skeletal system development" (q = 1.89 × 10^-23). Gene enrichment demonstrated that general CVD-related terms are shared, while "heart" and "vasculature" specific genes have more disease-specific terms as PR interval for "heart" or platelet distribution width for "vasculature." STRING analysis revealed significant protein-protein interactions between the products of the differentially methylated genes (p = 0.003) suggesting that dysregulation of the protein interaction network could contribute to CVD. Overlaps with curated gene sets from the Molecular Signatures Database showed enrichment of genes in hemostasis (p = 2.9 × 10^-6) and atherosclerosis (p = 4.9 × 10^-4).<h4>Conclusion</h4>This review highlights the current state of knowledge on significant relationship between DNA methylation and CVD in humans. An open-access database has been compiled of reported CpG methylation sites, genes and pathways that may play an important role in this relationship.

The term 'autophagy' literally translates to 'self-eating' and alterations to autophagy have been identified as one of the several molecular changes that occur with aging in a variety of species. Autophagy and aging, have a complicated and multifaceted relationship that has recently come to light thanks to breakthroughs in our understanding of the various substrates of autophagy on tissue homoeostasis. Several studies have been conducted to reveal the relationship between autophagy and age-related diseases. The present review looks at a few new aspects of autophagy and speculates on how they might be connected to both aging and the onset and progression of disease. Additionally, we go over the most recent preclinical data supporting the use of autophagy modulators as age-related illnesses including cancer, cardiovascular and neurodegenerative diseases, and metabolic dysfunction. It is crucial to discover important targets in the autophagy pathway in order to create innovative therapies that effectively target autophagy. Natural products have pharmacological properties that can be therapeutically advantageous for the treatment of several diseases and they also serve as valuable sources of inspiration for the development of possible new small-molecule drugs. Indeed, recent scientific studies have shown that several natural products including alkaloids, terpenoids, steroids, and phenolics, have the ability to alter a number of important autophagic signalling pathways and exert therapeutic effects, thus, a wide range of potential targets in various stages of autophagy have been discovered. In this review, we summarised the naturally occurring active compounds that may control the autophagic signalling pathways.

Rotavirus is one of the main pathogens causing severe diarrhea in infants and young children < 5 years of age. The development of the next-generation rotavirus vaccine is of great significance for preventing rotavirus infection and reducing severe mortality. The current study aimed to develop and evaluate the immunogenicity of inactivated rotavirus vaccine (IRV) in rhesus monkeys. Monkeys received two or three IRV injections intramuscularly at a 4-week interval. Neutralizing antibodies, cellular immunity, PBMC gene expression profiling, and immune persistence were evaluated. Three-dose immunization of IRV induced a higher level of neutralizing, IgG and IgA antibodies compared to two-dose immunization. IRV induced IFN-γ secretion to mediate cellular immune responses, including robust pro-inflammatory and antiviral responses. Chemokine-mediated signaling pathways and immune response were broadly activated by IRV injection. The IRV-induced neutralizing antibodies resulting from two doses returned to baseline levels 20 weeks after full immunization, while those resulting from three doses returned to baseline levels 44 weeks after full immunization. Increasing immunization dose and injection number will help to improve IRV immunogenicity and neutralizing antibody persistence.

Many pathogens rely on their insect vectors for transmission. Such pathogens are under selection to improve vector competence for their transmission by employing various tissue or cellular responses of vectors. However, whether pathogens can actively cause hypoxia in vectors and exploit hypoxia responses to promote their vector competence is still unknown. Fast dispersal of pinewood nematode (PWN), the causal agent for the destructive pine wilt disease and subsequent infection of pine trees, is characterized by the high vector competence of pine sawyer beetles (<i>Monochamus</i> spp.), and a single beetle can harbor over 200,000 PWNs in its tracheal system. Here, we demonstrate that PWN loading activates hypoxia in tracheal system of the vector beetles. Both PWN loading and hypoxia enhanced tracheal elasticity and thickened the apical extracellular matrix (aECM) of the tracheal tubes while a notable upregulated expression of a resilin-like mucin protein Muc91C was observed at the aECM layer of PWN-loaded and hypoxic tracheal tubes. RNAi knockdown of <i>Muc91C</i> reduced tracheal elasticity and aECM thickness under hypoxia conditions and thus decreasing PWN loading. Our study suggests a crucial role of hypoxia-induced developmental responses in shaping vector tolerance to the pathogen and provides clues for potential molecular targets to control pathogen dissemination.

Proteolysis targeting chimeras (PROTACs) represent a new pharmacological modality to inactivate disease-causing proteins. PROTACs operate via recruiting E3 ubiquitin ligases, which enable the transfer of ubiquitin tags onto their target proteins, leading to proteasomal degradation. However, several E3 ligases are validated pharmacological targets themselves, of which inhibitor of apoptosis (IAP) proteins are considered druggable in cancer. Here, we report three series of heterobifunctional PROTACs, which consist of an IAP antagonist linked to either von Hippel-Lindau- or cereblon-recruiting ligands. Hijacking E3 ligases against each other led to potent, rapid, and preferential depletion of cellular IAPs. In addition, these compounds caused complete X-chromosome-linked IAP knockdown, which was rarely observed for monovalent and homobivalent IAP antagonists. In cellular assays, hit degrader <b>9</b> outperformed antagonists and showed potent inhibition of cancer cell viability. The hetero-PROTACs disclosed herein are valuable tools to facilitate studies of the biological roles of IAPs and will stimulate further efforts toward E3-targeting therapies.

<h4>Purpose</h4>A previous study by the International Berlin-Frankfurt-Münster Study Group (I-BFM-SG) on childhood <i>KMT2A</i>-rearranged (<i>KMT2A</i>-r) AML demonstrated the prognostic value of the fusion partner. This I-BFM-SG study investigated the value of flow cytometry-based measurable residual disease (flow-MRD) and evaluated the benefit of allogeneic stem-cell transplantation (allo-SCT) in first complete remission (CR1) in this disease.<h4>Methods</h4>A total of 1,130 children with <i>KMT2A</i>-r AML, diagnosed between January 2005 and December 2016, were assigned to high-risk (n = 402; 35.6%) or non-high-risk (n = 728; 64.4%) fusion partner-based groups. Flow-MRD levels at both end of induction 1 (EOI1) and 2 (EOI2) were available for 456 patients and were considered negative (<0.1%) or positive (≥0.1%). End points were 5-year event-free survival (EFS), cumulative incidence of relapse (CIR), and overall survival (OS).<h4>Results</h4>The high-risk group had inferior EFS (30.3% high risk <i>v</i> 54.0% non-high risk; <i>P</i> < .0001), CIR (59.7% <i>v</i> 35.2%; <i>P</i> < .0001), and OS (49.2% <i>v</i> 70.5%; <i>P</i> < .0001). EOI2 MRD negativity was associated with superior EFS (n = 413; 47.6% MRD negativity <i>v</i> n = 43; 16.3% MRD positivity; <i>P</i> < .0001) and OS (n = 413; 66.0% <i>v</i> n = 43; 27.9%; <i>P</i> < .0001), and showed a trend toward lower CIR (n = 392; 46.1% <i>v</i> n = 26; 65.4%; <i>P</i> = .016). Similar results were obtained for patients with EOI2 MRD negativity within both risk groups, except that within the non-high-risk group, CIR was comparable with that of patients with EOI2 MRD positivity. Allo-SCT in CR1 only reduced CIR (hazard ratio, 0.5 [95% CI, 0.4 to 0.8]; <i>P</i> = .00096) within the high-risk group but did not improve OS. In multivariable analyses, EOI2 MRD positivity and high-risk group were independently associated with inferior EFS, CIR, and OS.<h4>Conclusion</h4>EOI2 flow-MRD is an independent prognostic factor and should be included as risk stratification factor in childhood <i>KMT2A</i>-r AML. Treatment approaches other than allo-SCT in CR1 are needed to improve prognosis.

SINE-VNTR-Alu (SVA) retrotransposons arose and expanded in the genome of hominoid primates concurrent with the slowing of brain maturation. We report genes with intronic SVA transposons are enriched for neurodevelopmental disease and transcribed into long non-coding SVA-lncRNAs. Human-specific SVAs in microcephaly CDK5RAP2 and epilepsy SCN8A gene introns repress their expression via transcription factor ZNF91 to delay neuronal maturation. Deleting the SVA in CDK5RAP2 initiates multi-dimensional and in SCN8A selective sodium current neuronal maturation by upregulating these genes. SVA-lncRNA AK057321 forms RNA:DNA heteroduplexes with the genomic SVAs and upregulates these genes to initiate neuronal maturation. SVA-lncRNA AK057321 also promotes species-specific cortex and cerebellum-enriched expression upregulating human genes with intronic SVAs (e.g., HTT, CHAF1B and KCNJ6) but not mouse orthologs. The diversity of neuronal genes with intronic SVAs suggest this hominoid-specific SVA transposon-based gene regulatory mechanism may act at multiple steps to specialize and achieve neoteny of the human brain.

Excessive apoptosis of intestinal epithelial cell (IEC) is a crucial cause of disrupted epithelium homeostasis, leading to the pathogenesis of ulcerative colitis (UC). The regulation of Takeda G protein-coupled receptor-5 (TGR5) in IEC apoptosis and the underlying molecular mechanisms remained unclear, and the direct evidence from selective TGR5 agonists for the treatment of UC is also lacking. Here, we synthesized a potent and selective TGR5 agonist OM8 with high distribution in intestinal tract and investigated its effect on IEC apoptosis and UC treatment. We showed that OM8 potently activated hTGR5 and mTGR5 with EC₅₀ values of 202 ± 55 nM and 74 ± 17 nM, respectively. After oral administration, a large amount of OM8 was maintained in intestinal tract with very low absorption into the blood. In DSS-induced colitis mice, oral administration of OM8 alleviated colitis symptoms, pathological changes and impaired tight junction proteins expression. In addition to enhancing intestinal stem cell (ISC) proliferation and differentiation, OM8 administration significantly reduced the rate of apoptotic cells in colonic epithelium in colitis mice. The direct inhibition by OM8 on IEC apoptosis was further demonstrated in HT-29 and Caco-2 cells in vitro. In HT-29 cells, we demonstrated that silencing TGR5, inhibition of adenylate cyclase or protein kinase A (PKA) all blocked the suppression of JNK phosphorylation induced by OM8, thus abolished its antagonizing effect against TNF-α induced apoptosis, suggesting that the inhibition by OM8 on IEC apoptosis was mediated via activation of TGR5 and cAMP/PKA signaling pathway. Further studies showed that OM8 upregulated cellular FLICE-inhibitory protein (c-FLIP) expression in a TGR5-dependent manner in HT-29 cells. Knockdown of c-FLIP blocked the inhibition by OM8 on TNF-α induced JNK phosphorylation and apoptosis, suggesting that c-FLIP was indispensable for the suppression of OM8 on IEC apoptosis induced by OM8. In conclusion, our study demonstrated a new mechanism of TGR5 agonist on inhibiting IEC apoptosis via cAMP/PKA/c-FLIP/JNK signaling pathway in vitro, and highlighted the value of TGR5 agonist as a novel therapeutic strategy for the treatment of UC.

<h4>Purpose</h4>To explore the potential of AVPR2 in the immunotherapy of head and neck squamous cell carcinoma (HNSCC), thus providing insights into a novel antitumour strategy.<h4>Methods</h4>In this study, we performed a comprehensive analysis of the AVPR2 gene in HNSCC using public datasets from The Cancer Genome Atlas and Gene Expression Omnibus. We explored the potential molecular mechanism of HNSCC in clinical prognosis and tumour immunity from the aspects of gene expression, prognosis, immune subtypes, and immune infiltration.<h4>Results</h4>AVPR2 expression was significantly downregulated in primary HNSCC tissue compared with normal tissue. HNSCC patients with high AVPR2 expression had a better prognosis. Moreover, the results of GSEA showed that immune subtype surface AVPR2 is involved in immune modulation. Furthermore, significant strong correlations between AVPR2 expression and infiltrating immune cells existed in HNSCC, and marker genes of infiltrating immune cells were also significantly related to AVPR2 expression in HNSCC. These results suggest that AVPR2 expression can influence the infiltration of tumour immune cells. Finally, we found that only high levels of B-cell infiltration, rather than those of other immune cells, can predict a longer overall survival in patients with HNSCC. Future studies are needed to explore the role of AVPR2 and tumour-infiltrating B cells in HNSCC.<h4>Conclusions</h4>The AVPR2 gene may be a prognostic biomarker of HNSCC. Moreover, AVPR2 may play a role in HNSCC immune modulation, and the regulation of tumour-infiltrating B cells by AVPR2 may be a key link.

The aim of this paper was to investigate the effects of semaglutide on phosphorylated protein expression, and its neuroprotective mechanism in hippocampi of high-fat-diet-induced obese mice. In total, 16 obese mice were randomly divided into model group (H group) and semaglutide group (S group), with 8 mice in each group. In addition, a control group (C group) was set up comprising 8 C57BL/6J male normal mice. The Morris water maze assay was conducted to detect cognitive function changes in the mice, and to observe and compare body weight and expression levels of serological indicators between groups after the intervention. Phosphorylated proteomic analysis was performed to detect the hippocampal protein profile in mice. Proteins up-regulated twofold or down-regulated 0.5-fold in each group and with t-test p < 0.05 were defined as differentially phosphorylated proteins and were analyzed bioinformatically. The results showed that the high-fat diet-induced obese mice had reduced body weight, improved oxidative stress indexes, significantly increased the percentage of water maze trips and the number of platform crossings, and significantly shortened the water maze platform latency after semaglutide intervention. The phosphorylated proteomics results identified that 44 overlapping proteins among the three experimental groups. Most of the phosphorylated proteins identified were closely associated with pathways of neurodegeneration-multiple diseases. In addition, we identified Huntington, Neurofilament light chain, Neurofilament heavy chain as drug targets. This study demonstrates for the first time that semaglutide exerts neuroprotective effects by reducing HTT Ser1843, NEFH Ser 661 phosphorylation and increasing NEFL Ser 473 phosphorylation in hippocampal tissue of obese mice.

Chronic hepatitis B (CHB) often causes iron overload in the liver but rarely causes severe secondary hemochromatosis (SH). A 48-year-old man was infected with CHB via vertical transmission. For 21 years, nonstandard treatment with second-line hepatitis B antiviral drugs has been administered. Repeated abnormalities in the liver transaminase function and continuous low-level replication of the hepatitis B virus (HBV) have been detected. The skin had turned black 5 years back. Biochemical tests and imaging revealed the presence of hemochromatosis. A liver biopsy suggested severe iron overload. Two genetic tests ruled out hereditary hemochromatosis. The patient was diagnosed with SH and treated with 400 ml bloodletting once per week and an iron-chelating agent. After 12 weeks, liver function was normal, and the skin turned white. First, hepatitis B surface antigen (HBsAg) was lost, and HBV DNA was copied at low levels. The patient was diagnosed with an occult hepatitis B infection. HBV DNA was undetectable after 4 weeks of antiviral treatment with tenofovir. Upon reviewing the patient's medical history, hemochromatosis was believed to be related to CHB with chronic inflammatory damage and no complete virological response. Improvements in hemochromatosis may promote HBsAg disappearance.

Tumors shed cell-free DNA (cfDNA) into the plasma. "Liquid biopsies" are a diagnostic test to analyze cfDNA in order to detect minimal residual cancer, profile the genomic tumor landscape, and monitor cancers non-invasively over time. This technique may be useful in patients with head and neck squamous cell carcinoma (HNSCC) due to genetic tumor heterogeneity and limitations in imaging sensitivity. However, there are technical challenges that need to be overcome for the widespread use of liquid biopsy in the clinical management of these patients. In this review, we discuss our current understanding of HNSCC genetics and the role of cfDNA genomic analyses as an emerging precision diagnostic tool.

Cardiovascular complications combined with COVID-19 (SARS-CoV-2) lead to a poor prognosis in patients. The common pathogenesis of ischemic cardiomyopathy (ICM) and COVID-19 is still unclear. Here, we explored potential molecular mechanisms and biomarkers for ICM and COVID-19. Common differentially expressed genes (DEGs) of ICM (GSE5406) and COVID-19 (GSE164805) were identified using GEO2R. We performed enrichment and protein-protein interaction analyses and screened key genes. To confirm the diagnostic performance for these hub genes, we used external datasets (GSE116250 and GSE211979) and plotted ROC curves. Transcription factor and microRNA regulatory networks were constructed for the validated hub genes. Finally, drug prediction and molecular docking validation were performed using cMAP. We identified 81 common DEGs, many of which were enriched in terms of their relation to angiogenesis. Three DEGs were identified as key hub genes (<i>HSP90AA1</i>, <i>HSPA9</i>, and <i>SRSF1</i>) in the protein-protein interaction analysis. These hub genes had high diagnostic performance in the four datasets (AUC > 0.7). Mir-16-5p and KLF9 transcription factor co-regulated these hub genes. The drugs vindesine and ON-01910 showed good binding performance to the hub genes. We identified <i>HSP90AA1</i>, <i>HSPA9</i>, and <i>SRSF1</i> as markers for the co-pathogenesis of ICM and COVID-19, and showed that co-pathogenesis of ICM and COVID-19 may be related to angiogenesis. Vindesine and ON-01910 were predicted as potential therapeutic agents. Our findings will contribute to a deeper understanding of the comorbidity of ICM with COVID-19.

Mutations of <i>TSC1</i> and <i>TSC2</i> genes cause classical Tuberous Sclerosis Complex (TSC), a neurocutaneous disorder characterized by a tendency to develop hamartias, hamartomas, and other tumors. We herein report on a girl, now aged 5 years, who presented a previously unreported, distinct clinical phenotype consisting of primary microcephaly (head circumference = 40 cm, -5.6 standard deviations), brain anomalies including hypoplasia of the corpus callosum (with a residual draft of the genu), simplified parieto-temporal gyral pattern, colpocephaly with ectasia of the temporal ventricular horns, intellectual disability, and a general pattern of reduced growth (with weight and height < 3rd centiles). No classical features of TSC were recorded; the girl harbored a novel missense variant in <i>TSC1</i> (c.611G > A). We hypothesize that her clinical phenotype could be related to a "gain-of-function" of the <i>TSC1</i> protein product hamartin, causing an increase in the effects of the protein on inhibition of its intracellular targets (i.e., mTORC or RAC1 pathways), resulting in a distinct "inverse <i>TSC1</i>-hamartin" phenotype characterized by reduced growth of cells instead of the more classical predisposition to increased cell growth.

Ferroptosis, a novel type of regulated cell death mediated by iron-dependent lipid oxidation, was discovered a decade ago. Significant progress has been made in our knowledge of ferroptosis and immune dysfunction. This review covers recent advancements in the interaction of ferroptosis and the immune system, with an emphasis on autoimmune diseases. The critical regulators of ferroptosis are summarized in the context of reactive oxygen species biology, lipid metabolism, and iron homeostasis. The molecular crosstalk between ferroptosis and different immune cells is also highlighted. Future research is expected to yield new insights into the mechanisms governing ferroptosis and its potential therapeutic benefits in autoimmune diseases.

Libman-Sacks endocarditis accounts for 6-11 percent of systemic lupus erythematosus patients and is associated with varying degrees of valvular dysfunction, increased risk for stroke and transient ischemic attacks, and increased mortality. In previous studies, left-sided valvular Libman-Sacks vegetations were more frequently detected than right sided vegetations; reported cases of bilateral involvement is very rare. A comprehensive clinical assessment and the multimodality imaging is of utmost importance in the management of systemic lupus erythematosus. In this case report, we describe a 31-year-old female patient with uncontrolled systemic lupus erythematosus initially presented with gastrointestinal symptoms but eventually had a vegetation-like structure on the posterior leaflet of the mitral valve which was revealed during routine echocardiography. Two-dimensional/three-dimensional transthoracic and transesophageal echocardiography, cardiac magnetic resonance, and cardiac computed tomography further characterized the mitral valve vegetation and revealed an additional vegetation of the pulmonary valve. Echocardiography remains the cornerstone for the detection of Libman-Sacks vegetations. Cardiac MRI and cardiac CT are useful in characterizing lesion size and effects and may prove particularly helpful in the assessment of right-sided or multivalvular endocarditis. The presence of focal brain lesions on brain MRI prompted antithrombotic therapy.

<h4>Introduction</h4>Functional neuroimaging could provide abundant information of underling pathophysiological mechanisms of the clinical triad including motor, cognitive and psychiatric impairment in Huntington's Disease (HD).<h4>Methods</h4>We performed a voxel-based meta-analysis using anisotropic effect size-signed differential mapping (AES-SDM) method.<h4>Results</h4>6 studies (78 symptomatic HD, 102 premanifest HD and 131 healthy controls) were included in total. Altered resting-state brain activity was primarily detected in the bilateral medial part of superior frontal gyrus, bilateral anterior cingulate/paracingulate gyrus, left insula, left striatum, right cortico-spinal projections area, right inferior temporal gyrus area, right thalamus, right cerebellum and right gyrus rectus area. Premanifest and symptomatic HD patients showed different alterative pattern in the subgroup analyses.<h4>Discussion</h4>The robust and consistent abnormalities in the specific brain regions identified in the current study could help to understand the pathophysiology of HD and explore reliable neuroimaging biomarkers for monitoring disease progression, or even predicting the onset of premanifest HD patients.

<b>Background:</b> Soft tissue sarcoma (STS) is a highly malignant tumor with a dismal prognosis. Presently, the dysregulation of fatty acid metabolism has received increasing attention in tumor research, but fewer reports are relevant to STS. <b>Methods:</b> Based on fatty acid metabolism-related genes (FRGs), a novel risk score for STS was developed utilizing univariate analysis and least absolute shrinkage selection operator (LASSO) Cox regression analyses in the STS cohort, which were further validated using the external validation cohort from other databases. Furthermore, independent prognostic analysis, C-index, ROC curves, and nomogram were carried out to investigate the predictive performance of fatty acid-related risk scores. We also analysed the differences in enrichment pathways, the immune microenvironment, gene mutations, and immunotherapy response between the two distinct fatty acid score groups. Moreover, the real-time quantitative polymerase chain reaction (RT-qPCR) was used to further verify the expression of FRGs in STS. <b>Results:</b> A total of 153 FRGs were retrieved in our study. Next, a novel fatty acid metabolism-related risk score (FAS) was constructed based on 18 FRGs. The predictive performance of FAS was also verified in external cohorts. In addition, the independent analysis, C-index, ROC curve, and nomograph also revealed that FAS could serve as an independent prognostic factor for the STS patients. Meanwhile, our results demonstrated that the STS cohort in two distinct FAS groups had different copy number variations, immune cell infiltration, and immunotherapy responses. Finally, the <i>in vitro</i> validation results demonstrated that several FRGs included in the FAS exhibited abnormal expression in STS. <b>Conclusion:</b> Altogether, our work comprehensively and systematically clarifies fatty acid metabolism's potential roles and clinical significance in STS. The novel individualized score based on fatty acid metabolism may be provided as a potential marker and treatment strategy in STS.

With the development of social economics and the increase of working pressure, more and more women are suffering from long-term serious stress and showing symptoms of perimenopausal depression (PMD). The incidence rate of PMD is increasing, and the physical and mental health are seriously affected. However, due to the lack of accurate knowledge of pathophysiology, its diagnosis and treatment cannot be accurately executed. By consulting the relevant literature in recent years, this paper elaborates the neuroendocrine mechanism of perimenopausal depression from the aspects of epigenetic changes, monoamine neurotransmitter and receptor hypothesis, glial cell-induced neuroinflammation, estrogen receptor, interaction between HPA axis and HPG axis, and micro-organism-brain gut axis. The purpose is to probe into new ways of treatment of PMD by providing new knowledge about the neuroendocrine mechanism and treatment of PMD.

Short-chain fatty acids (SCFAs), such as butyrate, propionate, and acetate produced by the gut microbiota have been implicated in physiological responses (defense mechanisms, immune responses, and cell metabolism) in the human body. In several types of cancers, SCFAs, especially butyrate, suppress tumor growth and cancer cell metastasis via the regulation of the cell cycle, autophagy, cancer-related signaling pathways, and cancer cell metabolism. In addition, combination treatment with SCFAs and anticancer drugs exhibits synergistic effects, increasing anticancer treatment efficiency and attenuating anticancer drug resistance. Therefore, in this review, we point out the importance of SCFAs and the mechanisms underlying their effects in cancer treatment and suggest using SCFA-producing microbes and SCFAs to increase therapeutic efficacy in several types of cancers.

Solute carriers belong to the biggest group of transporters in the human genome, but more knowledge is needed to fully understand their function and possible role as therapeutic targets. SLC38A10, a poorly characterized solute carrier, is preliminary characterized here. By using a knockout mouse model, we studied the biological effects of SLC38A10 deficiency in vivo. We performed a transcriptomic analysis of the whole brain and found seven differentially expressed genes in SLC38A10-deficient mice (<i>Gm48159</i>, <i>Nr4a1</i>, <i>Tuba1c</i>, <i>Lrrc56</i>, <i>mt-Tp</i>, <i>Hbb-bt</i> and <i>Snord116/9</i>). By measuring amino acids in plasma, we found lower levels of threonine and histidine in knockout males, whereas no amino acid levels were affected in females, suggesting that SLC38A10^-/- might affect sexes differently. Using RT-qPCR, we investigated the effect of SLC38A10 deficiency on mRNA expression of other SLC38 members, <i>Mtor</i> and <i>Rps6kb1</i> in the brain, liver, lung, muscle, and kidney, but no differences were found. Relative telomere length measurement was also taken, as a marker for cellular age, but no differences were found between the genotypes. We conclude that SLC38A10 might be important for keeping amino acid homeostasis in plasma, at least in males, but no major effects were seen on transcriptomic expression or telomere length in the whole brain.

Introduction: Extracorporeal membrane oxygenation (ECMO) is associated with significant thrombotic complications necessitating anticoagulation, though optimal strategy remains unknown. We aimed to evaluate thrombotic and hemorrhagic complications with heparin versus bivalirudin use in veno-venous (V-V) ECMO.<br><br>Methods: We performed a retrospective cohort study of adult patients placed on V-V ECMO with intravenous anticoagulation with either heparin or bivalirudin. Time to thrombotic event (patient-sided thrombus or circuit membrane lung exchange) and major bleed were analyzed in addition to related outcomes.<br><br>Results: We identified 95 patients placed on V-V ECMO: 61 receiving heparin, 34 bivalirudin. The bivalirudin group were more likely to have severe COVID-19, higher BMI, and longer ECMO duration. Despite this, bivalirudin was associated with reduced risk of thrombotic event (HR 0.14, 95% CI 0.06-0.32, p<0.001) and a significant increase in average lifespan of the circuit membrane lung (16 vs 10 days, p=0.004). While there was no significant difference in major bleeding for the bivalirudin group, these patients required fewer transfusions of packed red blood cells and platelets per 100 ECMO days (means of 13 vs 39, p=0.004 and 5 vs 19, p=0.014, respectively). Lastly, there was significantly improved survival to ECMO decannulation with bivalirudin in univariate analysis (median OS 53 vs 26 days, p=0.015) and a trend towards improved survival after adjusting for influential factors (HR 0.43, 95% CI 0.15-1.24, p=0.120).<br><br>Conclusions: In this real-world analysis of bivalirudin versus heparin, bivalirudin is a viable option for V-V ECMO and associated with lower risk of thrombotic complications and fewer transfusion requirements.

<title>Abstract</title><p><bold>Background:</bold>Rheumatoid arthritis is a common inflammatory disease, with osteonecrosis of the femoral head being one of its common complications. However, the treatment of "osteonecrosis of the femoral head " is limited with insufficient drug development. The aim of this study is to explore molecular pathways and core genes associated with rheumatoid arthritis-induced osteonecrosis of the femoral head and investigate pharmacological targeting therapy for rheumatoid arthritis-induced osteonecrosis of the femoral head.<bold>Methods:</bold>In this analysis, intersection genes involved with both " rheumatoid arthritis " and "osteonecrosis of the femoral head " were identified using the Gene-Cards database, followed by functional analysis. The software programs STRING Online and Cytoscape were used to build protein-protein interaction (PPI) networks. Upon completion of the drug-gene interaction study, core genes and potential medicines were identified.<bold>Results:</bold>The Gene-Cards database discovered a total of 110 genes overlapped by "rheumatoid arthritis " and "osteonecrosis of the femoral head ". Following functional analysis, 108 important genes were selected. Subsequently, PPI analysis revealed 29 genes that may be targeted by 12 medicines and were candidates to treat rheumatoid arthritis-induced osteonecrosis of the femoral head.<bold>Conclusions:</bold>We used the Gene-Cards database and pathway analysis to identify highly related genes between " rheumatoid arthritis " and "osteonecrosis of the femoral head " and to explore potential therapeutic drugs. The following genes were investigated: HGF, MMP9, IL-1, EP300, SERPINC1, PLG, F5, and APOA1 are all involved in rheumatoid arthritis-induced osteonecrosis of the femoral head. It was found that fondaparinux, garcinol, canakinumab, and andecaliximab could be used as promising medications to treat rheumatoid arthritis-induced osteonecrosis of the femoral head.</p>

<b><i>Significance:</i></b> Reactive oxygen species (ROS) are essential in maintaining normal intestinal physiology. Inflammatory bowel disease (IBD) is a relapsing chronic inflammatory disease of the intestine that is a major risk factor for colorectal cancer (CRC). Excess ROS are widely implicated in intestinal inflammation and cancer. <b><i>Recent Advances:</i></b> Clinical data have shown that targeting ROS broadly does not yield improved outcomes in IBD and CRC. However, selectively limiting oxidative damage may improve the efficacy of ROS targeting. An accumulation of lipid ROS induces a novel oxidative cell death pathway known as ferroptosis. A growing body of evidence suggests that ferroptosis is relevant to both IBD and CRC. <b><i>Critical Issues:</i></b> We propose that inhibition of ferroptosis will improve disease severity in IBD, whereas activating ferroptosis will limit CRC progression. Data from preclinical models suggest that methods of modulating ferroptosis have been successful in attenuating IBD and CRC. <b><i>Future Directions:</i></b> The etiology of IBD and progression of IBD to CRC are still unclear. Further understanding of ferroptosis in intestinal diseases will provide novel therapies. Ferroptosis is highly linked to inflammation, cell metabolism, and is cell-type dependent. Further research in assessing the inflammatory and tumor microenvironment in the intestine may provide novel vulnerabilities that can be targeted. <i>Antioxid. Redox Signal.</i> 39, 551-568.

The use of 1,4-disubstituted 1,2,3-triazoles as trans-amide bond surrogates has become an important tool for the synthesis of metabolically stabilized peptidomimetics. These heterocyclic bioisosters are generally incorporated into the peptide backbone by applying a diazo-transfer reaction followed by CuAAC (click chemistry) with an α-amino alkyne. Even though the manual synthesis of backbone-modified triazolo-peptidomimetics has been reported by us and others, no procedure has yet been described for an automated synthesis using peptide synthesizers. In order to efficiently adapt these reactions to an automated setup, different conditions were explored, putting special emphasis on the required long-term stability of both the diazo-transfer reagent and the Cu(I) catalyst in solution. ISA·HCl is the reagent of choice to accomplish the diazo-transfer reaction; however, it was found instable in DMF, the most commonly used solvent for SPPS. Thus, an aqueous solution of ISA·HCl was used to prevent its degradation over time, and the composition in the final diazo-transfer reaction was adjusted to preserve suitable swelling conditions of the resins applied. The CuAAC reaction was performed without difficulties using [Cu (CH₃ CN)₄ ]PF₆ as a catalyst and TBTA as a stabilizer to prevent oxidation to Cu(II). The optimized automated two-step procedure was applied to the synthesis of structurally diverse triazolo-peptidomimetics to demonstrate the versatility of the developed methodology. Under the optimized conditions, five triazolo-peptidomimetics (8-5 amino acid residues) were synthesized efficiently using two different resins. Analysis of the crude products by HPLC-MS revealed moderate to good purities of the desired triazolo-peptidomimetics (70-85%). The synthesis time ranged between 9 and 12.5 h.

<h4>Background</h4>Diabetic nephropathy (DN) is a main cause of chronic renal failure. Despite decades of extensive study, the molecular mechanisms underlying diabetic tubulointerstitial injury remain unclear. We aim to identify key transcription factor genes involved in diabetic tubulointerstitial injury.<h4>Methods</h4>A microarray dataset (GSE30122) from Gene Expression Omnibus (GEO) was downloaded. A total of 38 transcription factor genes based on 166 differentially expressed genes (DEGs) were identified by UCSC_TFBS.<h4>Results</h4>The regulatory network showed connections between the top 10 transcription factors and their target DEGs. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of targeted DEGs indicated that extracellular space, extracellular exosome, cell surface and complement and coagulation cascades were most significantly enriched. Utilizing Nephroseq v5 online platform, the mRNA expression pattern analysis of transcription factor genes demonstrated that mRNA expression of CDC5, CEBPA, FAC1, HFH1, IRF1, NFE2 and TGIF1 increased in renal tubulointerstitium of DN patients compared with normal controls while that of CEBPB and FOXO4 decreased in renal tubulointerstitium of DN patients compared with normal controls. Correlation analysis between mRNA expression of transcription factor genes in renal tubulointerstitium and clinical features showed that AP1, BACH1, CDC5, FAC1, FOXD1, FOXJ2, FOXO1, FOXO4, HFH1, IRF1, POU3F2, SOX5, SOX9, RSRFC4, S8 and TGIF1 may be related to diabetic tubulointerstitial injury.<h4>Conclusions</h4>(1) CDC5, FAC1, FOXO4, HFH1, IRF1 and TGIF1 may be key transcription factor genes. (2)Transcription factors involved in diabetic tubulointerstitial injury may become prospective targets for diagnosis and treatment of DN.

<h4>Background</h4>RAD140 (Testalone) is a novel selective androgen receptor modulator with very limited data currently available on adverse effects related to this compound. The first-in-human phase 1 trial was recently published and did report a significant proportion of elevated aspartate aminotransferase, alanine transaminase, and total bilirubin among the test subjects. RAD140 may be associated with an idiosyncratic drug-induced liver injury. It is easily purchased online as a workout supplement. Given its ease of use from being an oral formulation, and not requiring a physician's prescription, its use among the young male population will likely rise. Clinicians should ask about the use of RAD140, and other workout supplements, in young men presenting with acute liver injury.<h4>Case presentation</h4>We present the case of a 26-year-old Caucasian male without any significant past medical history who presented with nausea, vomiting, severe right upper quadrant abdominal pain, and jaundice from acute liver injury. Extensive inpatient workup did not reveal a definite cause for his liver injury other than the use of a novel selective androgen receptor modulator called RAD140 (Testalone). He was treated with supportive care and discharged after short hospitalization. He was instructed to stop RAD140, which he reported compliance with, and on 2-month follow-up his liver function panel had normalized without recurrence of any symptoms.<h4>Conclusion</h4>Novel selective androgen receptor modulators such as RAD140 may be associated with idiosyncratic drug-induced liver injury. Workup of new liver injury in young and middle-aged males should involve asking about use of these novel compounds, for if missed and use continues, it can likely lead to fulminant liver failure or decompensated liver cirrhosis.

Programed cell death plays a key role in promoting human development and maintaining homeostasis. Ferroptosis is a recently identified pattern of programmed cell death that is closely associated with the onset and progression of neurodegenerative diseases. Ferroptosis is mainly caused by the intracellular accumulation of iron-dependent lipid peroxides. The cysteine/glutamate antibody Solute carrier family 7 member 11 (SLC7A11, also known as xCT) functions to import cysteine for glutathione biosynthesis and antioxidant defense. SLC7A11 has a significant impact on ferroptosis, and inhibition of SLC7A11 expression promotes ferroptosis. Moreover, SLC7A11 is also closely associated with neurodegenerative diseases. In this paper, we summarize the relationship between ferroptosis and neurodegenerative diseases and the role of SLC7A11 during this process. The various regulatory mechanisms of SLC7A11 are also discussed. In conclusion, we are looking forward to a theoretical basis for further understanding the occurrence and development of ferroptosis in SLC7A11 and neurodegenerative diseases, and to seek new clues for the treatment of neurodegenerative diseases.

<h4>Background</h4>Adherence to treatment, including inhaled therapies, is low in people with cystic fibrosis (CF). Although psychological interventions for improving adherence to inhaled therapies in people with CF have been developed, no previous published systematic review has evaluated the evidence for efficacy of these interventions.<h4>Objectives</h4>The primary objective of the review was to assess the efficacy of psychological interventions for improving adherence to inhaled therapies in people with cystic fibrosis (CF). The secondary objective was to establish the most effective components, or behaviour change techniques (BCTs), used in these interventions.<h4>Search methods</h4>We searched the Cochrane Cystic Fibrosis Trials Register, which is compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched databases (PubMed; PsycINFO; EBSCO; Scopus; OpenGrey), trials registries (World Health Organization International Clinical Trials Registry Platform; US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov), and the reference lists of relevant articles and reviews, with no restrictions on language, year or publication status. Date of search: 7 August 2022.<h4>Selection criteria</h4>We included randomised controlled trials (RCTs) comparing different types of psychological interventions for improving adherence to inhaled therapies in people with CF of any age, or comparing psychological interventions with usual care. We included quasi-RCTs if we could reasonably assume that the baseline characteristics were similar in both groups.<h4>Data collection and analysis</h4>Two review authors independently assessed trial eligibility and completed data extraction, risk of bias assessments, and BCT coding (using the BCT Taxonomy v1) for all included trials. We resolved any discrepancies by discussion, or by consultation with a third review author as necessary. We assessed the certainty of the evidence using GRADE.<h4>Main results</h4>We included 10 trials (1642 participants) in the review (children and adolescents in four trials; adults in five trials; and children and adults in one trial). Nine trials compared a psychological intervention with usual care; we could combine data from some of these in a number of quantitative analyses. One trial compared a psychological intervention with an active comparator (education plus problem-solving (EPS)). We identified five ongoing trials. Psychological interventions were generally multi-component and complex, containing an average of 9.6 BCTs (range 1 to 28). The two most commonly used BCTs included 'problem-solving' and 'instruction on how to perform the behaviour'. Interventions varied in their type, content and mode of delivery. They included a problem-solving intervention; a paper-based self-management workbook; a telehealth intervention; a group training programme; a digital intervention comprising medication reminders and lung function self-monitoring; a life-coaching intervention; a motivational interviewing (MI) intervention; a brief MI intervention (behaviour change counselling); and a digital intervention combined with behaviour change sessions. Intervention duration ranged from 10 weeks to 12 months. Assessment time points ranged from six to eight weeks up to 23 months. Psychological interventions compared with usual care We report data here for the 'over six months and up to 12 months' time point. We found that psychological interventions probably improve adherence to inhaled therapies (primary outcome) in people with CF compared with usual care (mean difference (MD) 9.5, 95% confidence interval (CI) 8.60 to 10.40; 1 study, 588 participants; moderate-certainty evidence). There was no evidence of a difference between groups in our second primary outcome, treatment-related adverse events: anxiety (MD 0.30, 95% CI -0.40 to 1.00; 1 study, 535 participants), or depression (MD -0.10, 95% CI -0.80 to 0.60; 1 study, 534 participants), although this was low-certainty evidence. For our secondary outcomes, there was no evidence of a difference between groups in terms of lung function (forced expiratory volume in one second (FEV₁) % predicted MD 1.40, 95% CI -0.20 to 3.00; 1 study, 556 participants; moderate-certainty evidence); number of pulmonary exacerbations (adjusted rate ratio 0.96, 95% CI 0.83 to 1.11; 1 study, 607 participants; moderate-certainty evidence); or respiratory symptoms (MD 0.70, 95% CI -2.40 to 3.80; 1 study, 534 participants; low-certainty evidence). However, psychological interventions may improve treatment burden (MD 3.90, 95% CI 1.20 to 6.60; 1 study, 539 participants; low-certainty evidence). The overall certainty of the evidence ranged from low to moderate across these outcomes. Reasons for downgrading included indirectness (current evidence included adults only whereas our review question was broader and focused on people of any age) and lack of blinding of outcome assessors. Psychological interventions compared with an active comparator For this comparison the overall certainty of evidence was very low, based on one trial (n = 128) comparing an MI intervention to EPS for 12 months. We are uncertain whether an MI intervention, compared with EPS, improves adherence to inhaled therapies, lung function, or quality of life in people with CF, or whether there is an effect on pulmonary exacerbations. The included trial for this comparison did not report on treatment-related adverse events (anxiety and depression). We downgraded all reported outcomes due to small participant numbers, indirectness (trials included only adults), and unclear risk of bias (e.g. selection and attrition bias).<h4>Authors' conclusions</h4>Due to the limited quantity of trials included in this review, as well as the clinical and methodological heterogeneity, it was not possible to identify an overall intervention effect using meta-analysis. Some moderate-certainty evidence suggests that psychological interventions (compared with usual care) probably improve adherence to inhaled therapies in people with CF, without increasing treatment-related adverse events, anxiety and depression (low-certainty evidence). In future review updates (with ongoing trial results included), we hope to be able to establish the most effective BCTs (or 'active ingredients') of interventions for improving adherence to inhaled therapies in people with CF. Wherever possible, investigators should make use of the most objective measures of adherence available (e.g. data-logging nebulisers) to accurately determine intervention effects. Outcome reporting needs to be improved to enable combining or separation of measures as appropriate. Likewise, trial reporting needs to include details of intervention content (e.g. BCTs used); duration; intensity; and fidelity. Large trials with a longer follow-up period (e.g. 12 months) are needed in children with CF. Additionally, more research is needed to determine how to support adherence in 'under-served' CF populations.

COVID-19 caused by the SARS-CoV-2 virus is widespread in all regions, and it disturbs host immune system functioning leading to extreme inflammatory reaction and hyperactivation of the immune response. Kabasura Kudineer (KSK) is preventive medicine against viral infections and a potent immune booster for inflammation-related diseases. We hypothesize that KSK and KSK similar plant compounds, might prevent or control the COVID-19 infection in the human body. 1,207 KSK and KSK similar compounds were listed and screened via the Swiss ADME tool and PAINS Remover; 303 compounds were filtered including active and similar drug compounds. The targets were retrieved from similar drugs of the active compounds of KSK. Finally, 573 genes were listed after several screening steps. Next, network analysis was performed to finalize the potential target gene: construction of protein-protein interaction of 573 genes using STRING, identifying top hub genes in Cytoscape plug-ins (MCODE and cytoHubba). These ten hub genes play a crucial role in the inflammatory response. Target-miRNA interaction was also constructed using the miRNet tool to interpret miRNAs of the target genes and their functions. Functional annotation was done via DAVID to gain a complete insight into the mechanism of the enriched pathways and other diseases related to the given target genes. In Molecular Docking analysis, IL10 attained top rank in Target-miRNA interaction and also the gene formed prominent exchanges with an excellent binding score (> = -8.0) against 19 compounds. Among them, Guggulsterone has an acute affinity score of -8.8 for IL10 and exhibits anti-inflammatory and immunomodulatory properties. Molecular Dynamics simulation study also performed for IL10 and the interacting ligand compounds using GROMACS. Finally, Guggulsterone will be recommended to enhance immunity against several inflammatory diseases, including COVID19.

The blueprints of developing organs are preset at the early stages of embryogenesis. Transcriptional and epigenetic mechanisms are proposed to preset developmental trajectories. However, we reveal that the competence for the future cardiac fate of human embryonic stem cells (hESCs) is preset in pluripotency by a specialized mRNA translation circuit controlled by RBPMS. RBPMS is recruited to active ribosomes in hESCs to control the translation of essential factors needed for cardiac commitment program, including Wingless/Integrated (WNT) signaling. Consequently, RBPMS loss specifically and severely impedes cardiac mesoderm specification, leading to patterning and morphogenetic defects in human cardiac organoids. Mechanistically, RBPMS specializes mRNA translation, selectively via 3'UTR binding and globally by promoting translation initiation. Accordingly, RBPMS loss causes translation initiation defects highlighted by aberrant retention of the EIF3 complex and depletion of EIF5A from mRNAs, thereby abrogating ribosome recruitment. We demonstrate how future fate trajectories are programmed during embryogenesis by specialized mRNA translation.

Cell state plasticity is carefully regulated in adult epithelia to prevent cancer. The aberrant expansion of the normally restricted capability for cell state plasticity in neoplasia is poorly defined. Using genetically engineered and carcinogen-induced mouse models of intestinal neoplasia, we observed that impaired differentiation is a conserved event preceding cancer development. Single-cell RNA sequencing (scRNA-seq) of premalignant lesions from mouse models and a patient with hereditary polyposis revealed that cancer initiates by adopting an aberrant transcriptional state characterized by regenerative activity, marked by <i>Ly6a</i> (Sca-1), and reactivation of fetal intestinal genes, including <i>Tacstd2</i> (Trop2). Genetic inactivation of Sox9 prevented adenoma formation, obstructed the emergence of regenerative and fetal programs, and restored multilineage differentiation by scRNA-seq. Expanded chromatin accessibility at regeneration and fetal genes upon Apc inactivation was reduced by concomitant Sox9 suppression. These studies indicate that aberrant cell state plasticity mediated by unabated regenerative activity and developmental reprogramming precedes cancer development.

Cartilage tissue exhibits early degenerative changes with onset of osteoarthritis (OA). Early diagnosis is critical as there is only a narrow time window during which therapeutic intervention can reverse disease progression. Computed tomography (CT) has been considered for cartilage imaging as a tool for early OA diagnosis by introducing radio-opaque contrast agents like ioxaglate (IOX) into the joint. IOX, however, is anionic and thus repelled by negatively charged cartilage glycosaminoglycans (GAGs) that hinders its intra-tissue penetration and partitioning, resulting in poor CT attenuation. This is further complicated by its short intra-tissue residence time owing to rapid clearance from joints, which necessitates high doses causing toxicity concerns. Here we engineer optimally charged cationic contrast agents based on cartilage negative fixed charge density by conjugating cartilage targeting a cationic peptide carrier (CPC) and multi-arm avidin nanoconstruct (mAv) to IOX, such that they can penetrate through the full thickness of cartilage within 6 h using electrostatic interactions and elicit similar CT signal with about 40× lower dose compared to anionic IOX. Their partitioning and distribution correlate strongly with spatial GAG distribution within healthy and early- to late-stage arthritic bovine cartilage tissues at 50-100× lower doses than other cationic contrast agents used in the current literature. The use of contrast agents at low concentrations also allowed for delineation of cartilage from subchondral bone as well as other soft tissues in rat tibial joints. These contrast agents are safe to use at current doses, making CT a viable imaging modality for early detection of OA and staging of its severity.

<h4>Background</h4>Long non-coding RNAs (lncRNAs) and messenger RNAs (mRNAs) play crucial roles in regulating various physiological and pathological processes. However, the role of lncRNAs and mRNAs in mediating the liver response during Toxocara canis infection remains incompletely understood.<h4>Methods</h4>In the present study, the expression profile of lncRNAs and mRNAs was investigated in the liver of Beagle dogs infected by T. canis using high-throughput RNA sequencing.<h4>Results</h4>Compared with the control groups, 876 differentially expressed (DE) lncRNAs and 288 DEmRNAs were identified at 12 h post-infection (hpi), 906 DElncRNAs and 261 DEmRNAs were identified at 24 hpi, and 876 DElncRNAs and 302 DEmRNAs were identified at 36 days post-infection (dpi). A total of 16 DEmRNAs (e.g. dpp4, crp and gnas) were commonly identified at the three infection stages. Enrichment and co-localization analyses identified several pathways involved in immune and inflammatory responses during T. canis infection. Some novel DElncRNAs, such as LNC_015756, LNC_011050 and LNC_011052, were also associated with immune and inflammatory responses. Also, LNC_005105 and LNC_005401 were associated with the secretion of anti-inflammatory cytokines, which may play a role in the healing of liver pathology at the late stage of infection.<h4>Conclusions</h4>Our data provided new insight into the regulatory roles of lncRNAs and mRNAs in the pathogenesis of T. canis and improved our understanding of the contribution of lncRNAs and mRNAs to the immune and inflammatory response of the liver during T. canis infection.

The serotonin transporter (5-HTT) plays a critical role in the regulation of serotonin neurotransmission. Mice genetically deficient in 5-HTT expression have been used to study the physiological functions of 5-HTT in the brain and have been proposed as a potential animal model for neuropsychiatric and neurodevelopmental disorders. Recent studies have provided evidence for a link between the gut-brain axis and mood disorders. However, the effects of 5-HTT deficiency on gut microbiota, brain function, and behavior remain to be fully characterized. Here we investigated the effects of 5-HTT deficiency on different types of behavior, the gut microbiome, and brain c-Fos expression as a marker of neuronal activation in response to the forced swim test for assessing depression-related behavior in male 5-HTT knockout mice. Behavioral analysis using a battery of 16 different tests showed that 5-HTT-/- mice exhibited markedly reduced locomotor activity, decreased pain sensitivity, reduced motor function, increased anxiety-like and depression-related behavior, altered social behavior in novel and familiar environments, normal working memory, enhanced spatial reference memory, and impaired fear memory compared to 5-HTT+/+ mice. 5-HTT+/- mice showed slightly reduced locomotor activity and impaired social behavior compared to 5-HTT+/+ mice. Analysis of 16S rRNA gene amplicons showed that 5-HTT-/- mice had altered gut microbiota abundances, such as a decrease in Allobaculum, Bifidobacterium, Clostridium sensu stricto, and Turicibacter, compared to 5-HTT+/+ mice. This study also showed that after exposure to the forced swim test, the number of c-Fos-positive cells was higher in the paraventricular thalamus and lateral hypothalamus and was lower in the prefrontal cortical regions, nucleus accumbens shell, dorsolateral septal nucleus, hippocampal regions, and ventromedial hypothalamus in 5-HTT-/- mice than in 5-HTT+/+ mice. These phenotypes of 5-HTT-/- mice partially recapitulate clinical observations in humans with major depressive disorder. The present findings indicate that 5-HTT-deficient mice serve as a good and valid animal model to study anxiety and depression with altered gut microbial composition and abnormal neuronal activity in the brain, highlighting the importance of 5-HTT in brain function and the mechanisms underlying the regulation of anxiety and depression.

Enhancer clusters overlapping disease-associated mutations in Pierre Robin sequence (PRS) patients regulate SOX9 expression at genomic distances over 1.25 Mb. We applied optical reconstruction of chromatin architecture (ORCA) imaging to trace 3D locus topology during PRS-enhancer activation. We observed pronounced changes in locus topology between cell types. Subsequent analysis of single-chromatin fiber traces revealed that these ensemble-average differences arise through changes in the frequency of commonly sampled topologies. We further identified two CTCF-bound elements, internal to the SOX9 topologically associating domain, which promote stripe formation, are positioned near the domain's 3D geometric center, and bridge enhancer-promoter contacts in a series of chromatin loops. Ablation of these elements results in diminished SOX9 expression and altered domain-wide contacts. Polymer models with uniform loading across the domain and frequent cohesin collisions recapitulate this multi-loop, centrally clustered geometry. Together, we provide mechanistic insights into architectural stripe formation and gene regulation over ultra-long genomic ranges.

<h4>Background</h4>Radix Astragali Mongolici, as a traditional Chinese medicine, is widely used in the treatment of qi deficiency, viral or bacterial infection, inflammation and cancer. Astragaloside IV (AST), a key active compound in Radix Astragali Mongolici, has been shown to reduce disease progression by inhibiting oxidative stress and inflammation. However, the specific target and mechanism of action of AST in improving oxidative stress are still unclear.<h4>Purpose</h4>This study aims to explore the target and mechanism of AST to improve oxidative stress, and to explain the biological process of oxidative stress.<h4>Methods</h4>AST functional probes were designed to capture target proteins and combined with protein spectrum to analyze target proteins. Small molecule and protein interaction technologies were used to verify the mode of action, while computer dynamics simulation technology was used to analyze the site of interaction with the target protein. The pharmacological activity of AST in improving oxidative stress was evaluated in a mouse model of acute lung injury induced by LPS. Additionally, pharmacological and serial molecular biological approaches were used to explore the underlying mechanism of action.<h4>Results</h4>AST inhibits PLA2 activity in PRDX6 by targeting the PLA2 catalytic triad pocket. This binding alters the conformation and structural stability of PRDX6 and interferes with the interaction between PRDX6 and RAC, hindering the activation of the RAC-GDI heterodimer. Inactivation of RAC prevents NOX2 maturation, attenuates superoxide anion production, and improves oxidative stress damage.<h4>Conclusion</h4>The findings of this research indicate that AST impedes PLA2 activity by acting on the catalytic triad of PRDX6. This, in turn, disrupts the interaction between PRDX6 and RAC, thereby hindering the maturation of NOX2 and diminishing the oxidative stress damage.

Melanocytes are essential for skin homeostasis and protection, and their loss or misfunction leads to a wide spectrum of diseases. Cell therapy utilizing autologous melanocytes has been used for years as an adjunct treatment for hypopigmentary disorders such as vitiligo. However, these approaches are hindered by the poor proliferative capacity of melanocytes obtained from skin biopsies. Recent advances in the field of human pluripotent stem cells have fueled the prospect of generating melanocytes. Here, we have developed a well-characterized method to produce a pure and homogenous population of functional and proliferative melanocytes. The genetic stability and potential transformation of melanocytes from pluripotent stem cells have been evaluated over time during the in vitro culture process. Thanks to transcriptomic analysis, the molecular signatures all along the differentiation protocol have been characterized, providing a solid basis for standardizing the protocol. Altogether, our results promise meaningful, broadly applicable, and longer-lasting advances for pigmentation disorders and open perspectives for innovative biotherapies for pigment disorders.

We have shown that all sub-retinal pigment epithelial (sub-RPE) deposits examined contain calcium phosphate minerals: hydroxyapatite (HAP), whitlockite (Wht), or both. These typically take the form of ca. 1 μm diameter spherules or >10 μm nodules and appear to be involved in the development and progression of age-related macular degeneration (AMD). Thus, these minerals may serve as useful biomarkers the for early detection and monitoring of sub-RPE changes in AMD. We demonstrated that HAP deposits could be imaged in vitro by fluorescence lifetime imaging microscopy (FLIM) in flat-mounted retinas using legacy tetracycline antibiotics as selective sensors for HAP. As the contrast on a FLIM image is based on the difference in fluorescence lifetime and not intensity of the tetracycline-stained HAP, distinguishing tissue autofluorescence from the background is significantly improved. The focus of the present pilot study was to assess whether vascular perfusion of the well tolerated and characterized chlortetracycline (widely used as an orally bioavailable antibiotic) can fluorescently label retinal HAP using human cadavers. We found that the tetracycline delivered through the peripheral circulation can indeed selectively label sub-RPE deposits opening the possibility for its use for ophthalmic monitoring of a range of diseases in which deposit formation is reported, such as AMD and Alzheimer disease (AD).

Microgravity (µ<i>g</i>) has a massive impact on the health of space explorers. Microgravity changes the proliferation, differentiation, and growth of cells. As crewed spaceflights into deep space are being planned along with the commercialization of space travelling, researchers have focused on gene regulation in cells and organisms exposed to real (r-) and simulated (s-) µ<i>g</i>. In particular, cancer and metastasis research benefits from the findings obtained under µ<i>g</i> conditions. Gene regulation is a key factor in a cell or an organism's ability to sustain life and respond to environmental changes. It is a universal process to control the amount, location, and timing in which genes are expressed. In this review, we provide an overview of µ<i>g</i>-induced changes in the numerous mechanisms involved in gene regulation, including regulatory proteins, microRNAs, and the chemical modification of DNA. In particular, we discuss the current knowledge about the impact of microgravity on gene regulation in different types of bacteria, protists, fungi, animals, humans, and cells with a focus on the brain, eye, endothelium, immune system, cartilage, muscle, bone, and various cancers as well as recent findings in plants. Importantly, the obtained data clearly imply that µ<i>g</i> experiments can support translational medicine on Earth.

Understanding the molecular mechanisms involved in adaptation to alternate diets has become a significant concern, as increasing amounts of fishmeal (FM) protein in aquafeeds are being substituted with plant protein. Thus, the goal of this study was to assess growth performance, quality, and liver function of juvenile <i>Sillago sihama</i> (<i>S. sihama</i>) through growth indices, whole-body composition, histology of the liver, and RNA-sequencing (RNA-seq), after they were fed a formulated diet with 64% low-gossypol cottonseed meal (LCSM) for 56 days, compared to those fed a traditional FM-based diet. Indicators of growth, including final body weight (FBW), weight gain rate (WGR), specific growth rate (SGR), protein efficiency ratio (PER), and condition factor (CF), were considerably lower in the 64% LCSM (R64) group than in the FM diet group. In the R64 diet, the whole crude lipid was significantly lower than in the FM diet. The hematoxylin-eosin section showed that dietary high levels of LCSM resulted in diffuse lipid vacuolation in the liver of <i>S. sihama</i>. According to a liver transcriptome analysis, high LCSM intake in the diet significantly impacted lipid synthesis and catabolism, elevated pathways for cholesterol synthesis, blocked several amino acid metabolic pathways, and adversely affected hepatic gluconeogenesis and glycolysis. The findings of this study indicate that feeding high levels of LCSM in <i>S. sihama</i> is harmful to the growth of the organism and can harm the liver's structural integrity, as well as obstruct the normal metabolism of amino acids, lipids, and carbohydrates. Therefore, it is not recommended to substitute LCSM for high levels of FM in the diet of <i>S. sihama</i>.

Major depressive disorder (MDD) is a psychiatric disorder with increasing prevalence worldwide. It is a leading cause of disability and suicide, severely affecting physical and mental health. However, the study of depression remains at an exploratory stage in terms of diagnostics and treatment due to the complexity of its pathogenesis. MicroRNAs are endogenous short-stranded non-coding RNAs capable of binding to the 3'untranslated region of mRNAs. Because of their ability to repress translation process of genes and are found at high levels in brain tissues, investigation of their role in depression has gradually increased recently. This article summarizes recent research progress on the relationship between microRNAs and depression. The microRNAs play a regulatory role in the pathophysiology of depression, involving dysregulation of monoamines, abnormalities in neuroplasticity and neurogenesis, hyperactivity of the HPA axis, and dysregulation of inflammatory responses. These microRNAs might provide new clue for the diagnosis and treatment of MDD, and the development of antidepressant drugs.

Neurodegenerative diseases (NDs) are chronic conditions that result in progressive damage to the nervous system, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic lateral sclerosis (ALS). Age is a major risk factor for NDs. Telomere shortening is a biological marker of cellular aging, and telomerase reverse transcriptase (TERT) has been shown to slow down this process by maintaining telomere length. The blood-brain barrier (BBB) makes the brain a unique immune organ, and while the number of T cells present in the central nervous system is limited, they play an important role in NDs. Research suggests that NDs can be influenced by modulating peripheral T cell immune responses, and that TERT may play a significant role in T cell senescence and NDs. This review focuses on the current state of research on TERT in NDs and explores the potential connections between TERT, T cells, and NDs. Further studies on aging and telomeres may provide valuable insights for developing therapeutic strategies for age-related diseases.

Autophagy is an evolutionarily conserved cellular process capable of degrading various biological molecules and organelles <i>via</i> the lysosomal pathway. Ferroptosis is a type of oxidative stress-dependent regulated cell death associated with the iron accumulation and lipid peroxidation. The crosslinks between ferroptosis and autophagy have been focused on since the dependence of ferroptosis on autophagy was discovered. Although the research and theories on the relationship between autophagy and ferroptosis remain scattered and fragmented, the crosslinks between these two forms of regulated cell death are closely related to the treatment of various diseases. Thereof, asthma as a chronic inflammatory disease has a tight connection with the occurrence of ferroptosis and autophagy since the crosslinked signal pathways may be the crucial regulators or exactly regulated by cells and secretion in the immune system. In addition, non-immune cells associated with asthma are also closely related to autophagy and ferroptosis. Further studies of cross-linking asthma inflammation with crosslinked signaling pathways may provide us with several key molecules that regulate asthma through specific regulators. The crosslinks between autophagy and ferroptosis provide us with a new perspective to interpret and understand the manifestations of asthma, potential drug discovery targets, and new therapeutic options to effectively intervene in the imbalance caused by abnormal inflammation in asthma. Herein, we introduce the main molecular mechanisms of ferroptosis, autophagy, and asthma, describe the role of crosslinks between ferroptosis and autophagy in asthma based on their common regulatory cells or molecules, and discuss potential drug discovery targets and therapeutic applications in the context of immunomodulatory and symptom alleviation.

Pancreatic cancer is one of the most malignant tumors with increased incidence rate. The effect of surgery combined with chemoradiotherapy on survival of patients is unsatisfactory. New treatment strategy such as immunotherapy need to be investigated. The accumulation of desmoplastic stroma, infiltration of immunosuppressive cells including myeloid derived suppressor cells (MDSCs), tumor associated macrophages (TAMs), cancer-associated fibroblasts (CAFs), and regulatory T cells (Tregs), as well as tumor associated cytokine such as TGF-β, IL-10, IL-35, CCL5 and CXCL12 construct an immunosuppressive microenvironment of pancreatic cancer, which presents challenges for immunotherapy. In this review article, we explore the roles and mechanism of immunosuppressive cells and lymphocytes in establishing an immunosuppressive tumor microenvironment in pancreatic cancer. In addition, immunotherapy strategies for pancreatic cancer based on tumor microenvironment including immune checkpoint inhibitors, targeting extracellular matrix (ECM), interfering with stromal cells or cytokines in TME, cancer vaccines and extracellular vesicles (EVs) are also discussed. It is necessary to identify an approach of immunotherapy in combination with other modalities to produce a synergistic effect with increased response rates in pancreatic cancer therapy.

<b>Background:</b> Recently, various combination therapies for tumors have garnered popularity because of their synergistic effects in improving therapeutic efficacy and reducing side effects. However, incomplete intracellular drug release and a single method of combining drugs are inadequate to achieve the desired therapeutic effect. <b>Methods:</b> A reactive oxygen species (ROS)-sensitive co-delivery micelle (Ce6@PTP/DP). It was a photosensitizer and a ROS-sensitive paclitaxel (PTX) prodrug for synergistic chemo-photodynamic therapy. Micelles size and surface potential were measured. In vitro drug release, cytotoxicity and apoptosis were investigated. <b>Results:</b> Ce6@PTP/DP prodrug micelles exhibited good colloidal stability and biocompatibility, high PTX and Ce6 loading contents of 21.7% and 7.38%, respectively. Upon light irradiation, Ce6@PTP/DP micelles endocytosed by tumor cells can generate sufficient ROS, not only leading to photodynamic therapy and the inhibition of tumor cell proliferation, but also triggering locoregional PTX release by cleaving the thioketal (TK) bridged bond between PTX and methoxyl poly (ethylene glycol). Furthermore, compared with single drug-loaded micelles, the light-triggered Ce6@PTP/DP micelles exhibited self-amplified drug release and significantly greater inhibition of HeLa cell growth. <b>Conclusion:</b> The results support that PTX and Ce6 in Ce6@PTP/DP micelles exhibited synergistic effects on cell-growth inhibition. Thus, Ce6@PTP/DP micelles represent an alternative for realizing synergistic chemo-photodynamic therapy.

Aberrant aggregation of the transactive response DNA-binding protein (TDP-43) is associated with several lethal neurodegenerative diseases, including amyotrophic lateral sclerosis and frontotemporal dementia. Cytoplasmic neuronal inclusions of TDP-43 are enriched in various fragments of the low-complexity C-terminal domain and are associated with different neurotoxicity. Here we dissect the structural basis of TDP-43 polymorphism using magic-angle spinning solid-state NMR spectroscopy in combination with electron microscopy and Fourier-transform infrared spectroscopy. We demonstrate that various low-complexity C-terminal fragments, namely TDP-13 (TDP-43_300-414), TDP-11 (TDP-43_300-399), and TDP-10 (TDP-43_314-414), adopt distinct polymorphic structures in their amyloid fibrillar state. Our work demonstrates that the removal of less than 10% of the low-complexity sequence at N- and C-termini generates amyloid fibrils with comparable macroscopic features but different local structural arrangement. It highlights that the assembly mechanism of TDP-43, in addition to the aggregation of the hydrophobic region, is also driven by complex interactions involving low-complexity aggregation-prone segments that are a potential source of structural polymorphism.

As our society ages inexorably, geroscience and research focusing on healthy aging is becoming increasingly urgent. Macroautophagy (referred to as autophagy), a highly conserved process of cellular clearance and rejuvenation has attracted much attention due to its universal role in organismal life and death. Growing evidence points to autophagy process as being one of the key players in the determination of lifespan and health. Autophagy inducing interventions show significant improvement in organismal lifespan demonstrated in several experimental models. In line with this, preclinical models of age-related neurodegenerative diseases demonstrate pathology modulating effect of autophagy induction, implicating its potential to treat such disorders. In humans this specific process seems to be more complex. Recent clinical trials of drugs targeting autophagy point out some beneficial effects for clinical use, although with limited effectiveness, while others fail to show any significant improvement. We propose that using more human-relevant preclinical models for testing drug efficacy would significantly improve clinical trial outcomes. Lastly, the review discusses the available cellular reprogramming techniques used to model neuronal autophagy and neurodegeneration while exploring the existing evidence of autophagy's role in aging and pathogenesis in human-derived <i>in vitro</i> models such as embryonic stem cells (ESCs), induced pluripotent stem cell derived neurons (iPSC-neurons) or induced neurons (iNs).

Human factor-related accidents account for an increasing portion of the total accidents through the advancing level of system automation. Human reliability becomes the key issue in human-machine systems especially for safety-relevant tasks and operations. Rasmussen's SRK (skill-rule-knowledge) model is well known in the field of human factors. Likewise, it is well known that skill-based behaviors have the highest human reliability, while knowledge-based behaviors are associated with the lowest reliability scores. Although numerous studies exist on human error probability (HEP), correspondingly typically attributed directly or indirectly to these three levels of behavior, a coherent, consistent representation, especially using data sources, has not been available. In this contribution, the quantification of human behavior levels with Rasmussen's SRK model is given based on three databases for the first time. Effects of time pressure and training on human reliability switching are also analyzed based on related publications. To determine the HEP of these three levels, three databases, technique for human error rate prediction (THERP), Savannah river site human reliability analysis (SRS-HRA) and nuclear action reliability assessment (NARA), from human reliability analysis (HRA) methods are used. The procedure contains identifying the tasks including the operator involved and the assumptions the analysts made and classifying the tasks into suitable cognitive behavior mode (CBM). In this case, the relationship between SRK levels and HEP is mapped. The effects of the two in automation context very relevant performance shaping factors (PSFs), time pressure and training/knowledge degradation, on human behavior levels switching are analyzed and the explanations of the SRK switching are presented. In this case, a more general structure is established to illustrate the dynamic behavior of levels switching with six directions under different conditions. From the results we conclude that skill, rule, and knowledge behavior levels are continuous in terms of HEP and therefore allow a new inside into this key aspect of human factor quantification. Based on this analysis the consequences of daily automation in the context of autonomous transport systems in combination with human qualification and reliability degrading are from this specific and in the current automation discussion very intensively discussed. The presented discussion linking SRK levels and HEP gives a new perspective on the foreseeable consequences of further automation in application areas with increasing automation of everyday tasks (like using a highly automated vehicle).

Reduced glutathione (GSH) is the most abundant non-protein endogenous thiol. It is a ubiquitous molecule produced in most organs, but its synthesis is predominantly in the liver, the tissue in charge of storing and distributing it. GSH is involved in the detoxification of free radicals, peroxides and xenobiotics (drugs, pollutants, carcinogens, etc.), protects biological membranes from lipid peroxidation, and is an important regulator of cell homeostasis, since it participates in signaling redox, regulation of the synthesis and degradation of proteins (S-glutathionylation), signal transduction, various apoptotic processes, gene expression, cell proliferation, DNA and RNA synthesis, etc. GSH transport is a vital step in cellular homeostasis supported by the liver through providing extrahepatic organs (such as the kidney, lung, intestine, and brain, among others) with the said antioxidant. The wide range of functions within the cell in which glutathione is involved shows that glutathione's role in cellular homeostasis goes beyond being a simple antioxidant agent; therefore, the importance of this tripeptide needs to be reassessed from a broader metabolic perspective.

Bile acids (BAs) are amphiphilic steroidal molecules generated from cholesterol in the liver and facilitate the digestion and absorption of fat-soluble substances in the gut. Some BAs in the intestine are modified by the gut microbiota. Because BAs are modified in a variety of ways by different types of bacteria present in the gut microbiota, changes in the gut microbiota can affect the metabolism of BAs in the host. Although most BAs absorbed from the gut are transferred to the liver, some are transferred to the systemic circulation. Furthermore, BAs have also been detected in the brain and are thought to migrate into the brain through the systemic circulation. Although BAs are known to affect a variety of physiological functions by acting as ligands for various nuclear and cell-surface receptors, BAs have also been found to act on mitochondria and autophagy in the cell. This review focuses on the BAs modified by the gut microbiota and their roles in intracellular organelles and neurodegenerative diseases.

Bats have received increasing attention because of some unique biological features they possess. TRIM is a large family of proteins that participate in diverse cellular functions, such as antiviral immunity, DNA damage repair, tumor suppression, and aging. These functional areas appear to be highly consistent with the special characteristics of bats, such as tolerance to viruses and DNA damage generated in flight, low cancer incidence, and longevity. However, there is still a lack of systematic study of the TRIM family in bats. Here, we explored the TRIM family of bats using the genomes of 16 representative species. The results showed that the bat TRIM family contains 70 members, with 24 under positive selection and 7 duplicated. Additional transcriptomic analysis revealed the tissue-specific expressions of <i>TRIM9</i>, <i>46</i>, <i>54</i>, <i>55</i>, <i>63</i>, and <i>72</i>. Additionally, following interferon or viral stimulation, <i>TRIM</i> orthologs associated with antiviral immunity reported in humans were also upregulated in bat cells. The present study systematically analyzed the composition, evolution, and expression of bat <i>TRIM</i> genes. It may provide a theoretical basis for studies of bat TRIM in the fields of antiviral immunity, longevity, and tolerance to DNA damage.

Over 150 000 Americans are diagnosed with colorectal cancer (CRC) every year, and annually over 50 000 individuals will die from CRC, necessitating improvements in screening, prognostication, disease management, and therapeutic options. Tumor metastasis is the primary factor related to the risk of recurrence and mortality. Yet, screening for nodal and distant metastasis is costly, and invasive and incomplete resection may hamper adequate assessment. Signatures of the tumor-immune microenvironment (TIME) at the primary site can provide valuable insights into the aggressiveness of the tumor and the effectiveness of various treatment options. Spatially resolved transcriptomics technologies offer an unprecedented characterization of TIME through high multiplexing, yet their scope is constrained by cost. Meanwhile, it has long been suspected that histological, cytological, and macroarchitectural tissue characteristics correlate well with molecular information (e.g., gene expression). Thus, a method for predicting transcriptomics data through inference of RNA patterns from whole slide images (WSI) is a key step in studying metastasis at scale. In this work, we collected tissue from 4 stage-III (pT3) matched colorectal cancer patients for spatial transcriptomics profiling. The Visium spatial transcriptomics (ST) assay was used to measure transcript abundance for 17 943 genes at up to 5000 55-micron (i.e., 1-10 cells) spots per patient sampled in a honeycomb pattern, co-registered with hematoxylin and eosin (H&E) stained WSI. The Visium ST assay can measure expression at these spots through tissue permeabilization of mRNAs, which are captured through spatially (i.e., x-y positional coordinates) barcoded, gene specific oligo probes. WSI subimages were extracted around each co-registered Visium spot and were used to predict the expression at these spots using machine learning models. We prototyped and compared several convolutional, transformer, and graph convolutional neural networks to predict spatial RNA patterns at the Visium spots under the hypothesis that the transformer- and graph-based approaches better capture relevant spatial tissue architecture. We further analyzed the model's ability to recapitulate spatial autocorrelation statistics using SPARK and SpatialDE. Overall, the results indicate that the transformer- and graph-based approaches were unable to outperform the convolutional neural network architecture, though they exhibited optimal performance for relevant disease-associated genes. Initial findings suggest that different neural networks that operate on different scales are relevant for capturing distinct disease pathways (e.g., epithelial to mesenchymal transition). We add further evidence that deep learning models can accurately predict gene expression in whole slide images and comment on understudied factors which may increase its external applicability (e.g., tissue context). Our preliminary work will motivate further investigation of inference for molecular patterns from whole slide images as metastasis predictors and in other applications.

Neoadjuvant chemotherapy is an alternative treatment modality for tumors. Methotrexate (MTX) has been often used as a neoadjuvant chemotherapy reagent for osteosarcoma surgery. However, the large dosage, high toxicity, strong drug resistance, and poor improvement of bone erosion restricted the utilization of methotrexate. Here, we developed a targeted drug delivery system using nanosized hydroxyapatite particles (nHA) as the cores. MTX was conjugated to polyethylene glycol (PEG) through the pH-sensitive ester linkage and acted as both the folate receptor-targeting ligand and the anti-cancer drug due to the similarity to the structure of folic acid. Meanwhile, nHA could increase the concentration of calcium ions after being uptake by cells, thus inducing mitochondrial apoptosis and improving the efficacy of medical treatment. In vitro drug release studies of MTX-PEG-nHA in phosphate buffered saline at different pH values (5, 6.4 and 7.4) indicated that the system showed a pH-dependent release feature because of the dissolution of ester bonds and nHA under acidic conditions. Furthermore, the treatment on osteosarcoma cells (143B, MG63, and HOS) by using MTX-PEG-nHA was demonstrated to exhibit higher therapeutic efficacy. Therefore, the developed platform possesses the great potential for osteosarcoma therapy.

Calcific aortic valve stenosis (CAVS) is a widespread valvular heart disease affecting people in aging societies, primarily characterized by fibrosis, inflammation, and progressive calcification, leading to valve orifice stenosis. Understanding the factors associated with CAVS onset and progression is crucial to develop effective future pharmaceutical therapies. In CAVS, native extracellular matrix proteins modifications, play a significant role in calcification in vitro and in vivo. This work aimed to review the evidence on the alterations of structural native extracellular matrix proteins involved in calcification development during CAVS and highlight its link to deregulated biomechanical function.

A percutaneous osseointegrated device becomes deeply ingrown by endosteal bone and traverses the overlying soft tissues of the residual limb, providing a direct link to the bone-anchored artificial limb. Continuous wound healing around these devices can result in the formation of sinus tracts as "down-growing" epithelial cells are unable to recognize and adhere to the "nonbiological" implant surface. Such sinus tracts provide paths for bacterial colonization and deep infection. In order to limit adverse outcomes and provide a robust seal, it was hypothesized that by coating the titanium surface of the percutaneous post with the mineral component of dental enamel, down-growing epidermal cells might recognize the coating as "biological" and adhere to this nonliving surface. To test this hypothesis, sintered partially and fully fluoridated hydroxyapatite (HA) was chosen as coatings. Using an established surgical protocol, fluorapatite (FA), hydroxyfluorapatite (FHA), HA-coated percutaneous posts, and titanium controls were surgically placed under the dorsal skin in 20 CD hairless rats. The animals were sacrificed at four weeks, and implants and surrounding tissues were harvested and subjected to further analyses. Downgrowth and granulation tissue area data showed statistically significant reductions around the FA-coated devices. Moreover, compared to the control group, the FA- and HA-coated groups showed downregulation of mRNA for EGFr, EGF, and FGF-10. Interestingly, the FA-coated group had upregulation of TGF-<i>α</i>. These data suggest that FA could become an ideal coating material for preventing downgrowth, assuming the long-term stability of these coated surfaces can be verified in a clinically relevant animal model.

<h4>Background</h4> Depression is a common psychiatric illness and global public health problem. However, our limited understanding of the biological basis of depression has hindered the development of novel treatments and interventions. <h4>Methods</h4> To identify new candidate genes for therapeutic development, we examined single-nucleus RNA sequencing (snucRNAseq) data from the dorsolateral prefrontal cortex (N=424) in relation to ante-mortem depressive symptoms. To complement these direct analyses, we also used genome- wide association study (GWAS) results for depression (N=500,199) along with genetic tools for inferring the expression of 22,159 genes in 7 cell types and 55 cell subtypes to perform transcriptome-wide association studies (TWAS) of depression followed by Mendelian randomization (MR). <h4>Results</h4> Our single-nucleus TWAS analysis identified 71 causal genes in depression that have a role in specific neocortical cell subtypes; 59 of 71 genes were novel compared to previous studies. Depression TWAS genes showed a cell type specific pattern, with the greatest enrichment being in both excitatory and inhibitory neurons as well as astrocytes. Gene expression in different neuron subtypes have different directions of effect on depression risk. Compared to lower genetically correlated traits (e.g. body mass index) with depression, higher correlated traits (e.g., neuroticism) have more common TWAS genes with depression. In parallel, we performed differential gene expression analysis in relation to depression in 55 cortical cell subtypes, and we found that genes such as ANKRD36 , MADD , TAOK3 , SCAI and CHUK are associated with depression in specific cell subtypes. <h4>Conclusions</h4> These two sets of analyses illustrate the utility of large snucRNAseq data to uncover both genes whose expression is altered in specific cell subtypes in the context of depression and to enhance the interpretation of well-powered GWAS so that we can prioritize specific susceptibility genes for further analysis and therapeutic development.

Subtyping of acute myeloid leukaemia (AML) is predominantly based on recurrent genetic abnormalities, but recent literature indicates that transcriptomic phenotyping holds immense potential to further refine AML classification. Here we integrated five AML transcriptomic datasets with corresponding genetic information to provide an overview (n=1224) of the transcriptomic AML landscape. Consensus clustering identified 17 robust patient clusters which improved identification of CEBPA -mutated patients with favourable outcomes, and uncovered transcriptomic subtypes for KMT2A rearrangements (2), NPM1 mutations (5), and AML with myelodysplasia-related changes (AML-MRC) (5). Transcriptomic subtypes of KMT2A , NPM1 and AML-MRC showed distinct mutational profiles, cell type differentiation arrests and immune properties, suggesting differences in underlying disease biology. Moreover, our transcriptomic clusters show differences in ex-vivo drug responses, even when corrected for differentiation arrest and superiorly capture differences in drug response compared to genetic classification. In conclusion, our findings underscore the importance of transcriptomics in AML subtyping and offer a basis for future research and personalised treatment strategies. Our transcriptomic compendium is publicly available and we supply an R package to project clusters to new transcriptomic studies.

<h4> ABSTRACT </h4> Iron-mediated cell death (ferroptosis) is a proposed mechanism of Alzheimer’s disease (AD) pathology. While iron is essential for basic biological functions, its reactivity generates oxidants which contribute to cell damage and death. To further resolve mechanisms of iron-mediated toxicity in AD, we analyzed postmortem human brain and ApoEFAD mice. AD brains had decreased antioxidant enzymes, including those mediated by glutathione (GSH). Subcellular analyses of AD brains showed greater oxidative damage and lower antioxidant enzymes in lipid rafts, the site of amyloid processing, than in the non-raft membrane fraction. ApoE4 carriers had lower lipid raft yield with greater membrane oxidation. The hypothesized role of iron to AD pathology was tested in ApoEFAD mice by iron chelation with deferoxamine, which decreased fibrillar amyloid and lipid peroxidation, together with increased GSH-mediated antioxidants. These novel molecular pathways in iron mediated damage during AD. <h4>Graphical Abstract</h4> Hypothesis: AD brain lipid peroxidation is driven by increased brain iron and decreased antioxidant defenses. Schema shows proteins that mediate iron metabolism in relation to lipid peroxidation (HNE) and antioxidant defenses in prefrontal cortex. AD-associated increase (red), decrease (blue), or no change (grey), relative to cognitively normal elderly controls. Aβ; amyloid beta, ALDH2; alcohol dehydrogenase, APP; amyloid precursor protein, DMT1; divalent metal transporter 1; FPN, ferroportin; FSP1, ferroptosis suppressor protein 1, which requires the quinol cycle to attenuate lipid peroxidation; FTH1, ferritin heavy chain; FTL; ferritin light chain; GCLC, glutathione cysteine ligase catalytic subunit; GCLM, glutathione cysteine ligase modulator; GPx4, glutathione peroxidase 4; GSH, glutathione; GSSG, glutathione disulfide; GSTA4, glutathione S-transferase A4; HMOX; heme oxygenase; IRP, iron regulatory protein; LAT1, large neutral amino acid transporter 1; LOOH, Lipid hydroperoxides; Nrf2, Nuclear factor erythroid 2-related factor 2; Prdx6, peroxiredoxin 6; TF, transferrin, TfR; Transferrin receptor; xCT, cysteine-glutamate antiporter.

<h4>Background</h4>Diagnosis of Parkinson's disease (PD) is associated with a vast number of challenges. This study aimed to assess the overlap of PD patients' transcriptomes in the substantia nigra (SN) with peripheral blood mononuclear cells (PBMCs) to discover potential biomarkers for diagnosis.<h4>Methods</h4>GEO data were used to select genes with significant changes in expression level in the SN region and eligible studies. Also, transcriptome data related to blood of PD patients with other neurodegenerative diseases (ND) was considered. Differential expression genes between PD and control were evaluated in the SN and blood, and RT-qPCR was applied to validate the findings.<h4>Results</h4>At the expression level, no significant similarity in long non-coding RNA was found between the patients' SN and blood. While in silico results revealed 16 common mRNAs in SN and blood with significant expression levels. Among all overexpressed mRNAs, HSPA1A/B expression level had the highest expression difference between control and PD samples. Moreover, DGKH had the highest score of down-regulated genes in both blood and SN. The NOTCH pathway had the highest score pathway among up-regulated pathways, and the expression levels of NOTCH2, H4C8, and H2BC21 associated with this pathway had the most ability to separate the control and PD populations. Furthermore, RT-qPCR results revealed that HSPA1A/B, NOTCH2, and H4C8 were overexpressed in PD PBMCs, while DGKH expression levels were lower compared to controls.<h4>Conclusion</h4>Our findings indicate that expression levels of HSPA1A/B, DGKH, and NOTCH2 could be applied as candidate biomarkers to diagnose PD patients in the SN region and PBMCs.

<h4>Background</h4>Hyalinizing trabecular tumor is a rare follicular cell-derived thyroid neoplasm that is considered to be a borderline tumor with malignant potential rather than a benign tumor. The detection of RET/PTC rearrangements and nuclear cytologic features suggests a relationship between hyalinizing trabecular tumor and papillary thyroid carcinoma. Some recent observations of pathogenic genetic alterations in hyalinizing trabecular tumor have indicated that hyalinizing trabecular tumor is not related to papillary thyroid carcinoma, and should be considered an independent entity. Here we present a case of papillary thyroid carcinoma with hyalinizing trabecular tumor-like features and discuss its interesting aspects and diagnostic issues from a histopathological perspective.<h4>Case presentation</h4>A 19-year-old Japanese woman with an enlarged thyroid gland was admitted to our hospital. Based on fine-needle aspiration cytology, the enlarged nodule was suspected to be a follicular lesion or follicular tumor. A nodular lesion approximately 3 cm in diameter was detected in the left lobe of the thyroid gland. Histological analysis revealed that the tumor cells were mainly arranged in follicles. Solid nests with occasional trabecular arrangements and papillary structures were intermingled, and the tumor cells showed ground-glass nuclei and occasional nuclear grooving. Petaloid and block-like periodic-acid-Schiff and periodic-acid-methenamine-positive basement membrane components were observed in the interstitium of the solid portions of the tumor. Incomplete membranous immunoreactivity of MIB-1 (Ki-67 (cell prolferation marker)) was also observed in the cells within the solid areas. Moreover, this tumor displayed extracapsular invasion and metastasis to the perithyroidal lymph nodes, suggesting that it may be a malignant tumor. However, BRAF^V600E mutation, RET/PTC rearrangements, and PAX8/GLIS 1 and PAX8/GLIS 3 rearrangements were not detected.<h4>Conclusion</h4>We diagnosed the tumor as a papillary thyroid carcinoma with characteristic features of hyalinizing trabecular tumor. Importantly, this case may indicate a possible relationship between papillary thyroid carcinoma and hyalinizing trabecular tumor, although specific genetic alterations could not be detected. We also discuss the preoperative diagnostic difficulties with fine-needle aspiration cytology and the unusual pathological findings in this case.

<i>Candida auris</i> is a multidrug-resistant fungus known to be a global public health problem. The skin-based transmission, together with the marked resistance to drugs, resulted in its rapid spread to all continents. The aim of this study was to identify an essential oil (EO) active in the fight against <i>C. auris</i>. A total of 15 EOs were tested against 10 clinical strains of <i>C. auris</i>. <i>Cinnamomum zeylanicum</i> EO (CZ-EO) was the most effective (MIC90 and MFC90 equal to 0.06% vol/vol). Three fractions obtained from CZ-EO, and the cinnamaldehyde (CIN), the major chemical compound, were tested to identify the principal compound effectives against <i>C. auris</i>. All CIN-containing samples showed anti-fungal activity. To study the synergy with fluconazole, CZ-EO, its active fraction (FR2), and CIN were tested in checkerboard tests. Results show that CZ-EO and FR2, but not CIN, synergize with fluconazole. Furthermore, only the copresence of CZ-EO or FR2 synergize with fluconazole at therapeutic concentrations of the drug (0.45 ± 0.32 μg/mL and 0.64 ± 0.67 μg/mL, respectively), while CIN only shows additive activity. <i>In vivo</i> studies conducted on <i>Galleria mellonella</i> larvae show the absence of toxicity of CZ-EO up to concentrations of 16% vol/vol, and the ability of CZ-EO to reactivate the efficacy of fluconazole when formulated at synergic concentrations. Finally, biochemical tests were made to study the mechanism of action of CZ-EO. These studies show that in the presence of both fluconazole and CZ-EO, the activity of fungal ATPases decreases and, at the same time, the amount of intracellular drug increases. <b>IMPORTANCE</b> This study highlights how small doses of CZ-EO are able to inhibit the secretion of fluconazole and promote its accumulation in the fungal cell. In this manner, the drug is able to exert its pharmacological effects bypassing the resistance of the yeast. If further studies will confirm this synergy, it will be possible to develop new therapeutic formulations active in the fight against <i>C. auris</i> resistances.

"γc" cytokines are a family whose receptors share a "common-gamma-chain" signaling moiety, and play central roles in differentiation, homeostasis, and communications of all immunocyte lineages. As a resource to better understand their range and specificity of action, we profiled by RNAseq the immediate-early responses to the main γc cytokines across all immunocyte lineages. The results reveal an unprecedented landscape: broader, with extensive overlap between cytokines (one cytokine doing in one cell what another does elsewhere) and essentially no effects unique to any one cytokine. Responses include a major downregulation component and a broad Myc-controlled resetting of biosynthetic and metabolic pathways. Various mechanisms appear involved: fast transcriptional activation, chromatin remodeling, and mRNA destabilization. Other surprises were uncovered: IL2 effects in mast cells, shifts between follicular and marginal zone B cells, paradoxical and cell-specific cross-talk between interferon and γc signatures, or an NKT-like program induced by IL21 in CD8+ T cells.

α₄β₁ integrin is a cell adhesion receptor deeply involved in the migration and accumulation of leukocytes. Therefore, integrin antagonists that inhibit leukocytes recruitment are currently regarded as a therapeutic opportunity for the treatment of inflammatory disorder, including leukocyte-related autoimmune diseases. Recently, it has been suggested that integrin agonists capable to prevent the release of adherent leukocytes might serve as therapeutic agents as well. However, very few α₄β₁ integrin agonists have been discovered so far, thus precluding the investigation of their potential therapeutic efficacy. In this perspective, we synthesized cyclopeptides containing the LDV recognition motif found in the native ligand fibronectin. This approach led to the discovery of potent agonists capable to increase the adhesion of α₄ integrin-expressing cells. Conformational and quantum mechanics computations predicted distinct ligand-receptor interactions for antagonists or agonists, plausibly referable to receptor inhibition or activation.

<h4>Objective</h4>APC (adenomatous polyposis coli) gene mutation is a central initialization in colon cancer tumorigenesis. However, the connection between APC gene mutation and immunotherapy efficacy for colon cancer remains unknown. This study aimed to explore the impact of APC mutation on immunotherapy efficacy for colon cancer.<h4>Methods</h4>Colon cancer data from The Cancer Genome Atlas (TCGA) and Memorial Sloan Kettering Cancer Center (MSKCC) were used for the combined analysis. Survival analysis was performed to evaluate the association between APC mutation and immunotherapy efficacy in colon cancer patients. The expressions of immune check point molecules, tumor mutation burden (TMB), CpG methylation level, tumor purity (TP), microsatellite instability (MSI) status and tumor-infiltrating lymphocyte (TIL) in the two APC status were compared to evaluate the associations between APC mutation and immunotherapy efficacy indicators. Gene set enrichment analysis (GSEA) was performed to identify signaling pathways related to APC mutation.<h4>Results</h4>APC was the most frequently mutated gene in colon cancer. The survival analysis demonstrated that APC mutation was correlated with a worse immunotherapy outcome. APC mutation was associated with lower TMB, lower expression of immune check point molecules (PD-1/PD-L1/PD-L2), higher TP, lower MSI-High proportion and less CD8 + T cells and follicular helper T cells infiltration. GSEA indicated that APC mutation up-regulated mismatch repair pathway, which may play a negative role in evoking an antitumor immune response.<h4>Conclusion</h4>APC mutation is associated with worse immunotherapy outcome and inhibition of antitumor immunity. It can be used as a negative biomarker to predict immunotherapy response.

Chemotherapy-induced diarrhea causes dehydration, debilitation, infection, and even death, but there are currently no Food and Drug Administration (FDA)-approved drugs for treatment of chemotherapy-induced diarrhea. It is generally believed that the timely regulation of intestinal stem cell (ISC) fate may provide a meaningful solution for intestinal injuries. However, the lineage plasticity of ISCs during and after chemotherapy remains poorly understood. Here, we demonstrated that palbociclib, a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, regulated the fate of active or quiescent ISCs, provided multilineage protection from the toxicity of several different chemotherapeutics, and accelerated gastrointestinal epithelium recovery. Consistent with in vivo results, we determined that palbociclib enhanced intestinal organoid and ex vivo tissue survival after chemotherapy. Lineage tracing studies have shown that palbociclib protects active ISCs marked by Lgr5 and Olfm4 during chemotherapy and unexpectedly activates quiescent ISCs marked by Bmi1 to immediately participate in crypt regeneration after chemotherapy. Furthermore, palbociclib does not decrease the efficacy of cytotoxic chemotherapy in tumor grafts. The experimental evidence suggests that the combination of CDK4/6 inhibitors with chemotherapy could reduce damage to the gastrointestinal epithelium in patients. © 2023 The Pathological Society of Great Britain and Ireland.

Vγ9Vδ2 T cells play critical roles in microbial immunity by detecting target cells exposed to pathogen-derived phosphoantigens (P-Ags). Target cell expression of BTN3A1, the "P-Ag sensor," and BTN2A1, a direct ligand for T cell receptor (TCR) Vγ9, is essential for this process; however, the molecular mechanisms involved are unclear. Here, we characterize BTN2A1 interactions with Vγ9Vδ2 TCR and BTN3A1. Nuclear magnetic resonance (NMR), modeling, and mutagenesis establish a BTN2A1-immunoglobulin V (IgV)/BTN3A1-IgV structural model compatible with their cell-surface association in cis. However, TCR and BTN3A1-IgV binding to BTN2A1-IgV is mutually exclusive, owing to binding site proximity and overlap. Moreover, mutagenesis indicates that the BTN2A1-IgV/BTN3A1-IgV interaction is non-essential for recognition but instead identifies a molecular surface on BTN3A1-IgV essential to P-Ag sensing. These results establish a critical role for BTN3A-IgV in P-Ag sensing, in mediating direct or indirect interactions with the γδ-TCR. They support a composite-ligand model whereby intracellular P-Ag detection coordinates weak extracellular germline TCR/BTN2A1 and clonotypically influenced TCR/BTN3A-mediated interactions to initiate Vγ9Vδ2 TCR triggering.

<h4>Background</h4>Episodic ataxia (EA), characterized by recurrent attacks of cerebellar dysfunction, is the manifestation of a group of rare autosomal dominant inherited disorders. EA1 and EA2 are most frequently encountered, caused by mutations in <i>KCNA1</i> and <i>CACNA1A</i>. EA3-8 are reported in rare families. Advances in genetic testing have broadened the <i>KCNA1</i> and <i>CACNA1A</i> phenotypes, and detected EA as an unusual presentation of several other genetic disorders. Additionally, there are various secondary causes of EA and mimicking disorders. Together, these can pose diagnostic challenges for neurologists.<h4>Methods</h4>A systematic literature review was performed in October 2022 for 'episodic ataxia' and 'paroxysmal ataxia', restricted to publications in the last 10 years to focus on recent clinical advances. Clinical, genetic, and treatment characteristics were summarized.<h4>Results</h4>EA1 and EA2 phenotypes have further broadened. In particular, EA2 may be accompanied by other paroxysmal disorders of childhood with chronic neuropsychiatric features. New treatments for EA2 include dalfampridine and fampridine, in addition to 4-aminopyridine and acetazolamide. There are recent proposals for EA9-10. EA may also be caused by gene mutations associated with chronic ataxias (<i>SCA-14, SCA-27, SCA-42, AOA2, CAPOS</i>), epilepsy syndromes (<i>KCNA2, SCN2A, PRRT2</i>), GLUT-1, mitochondrial disorders (<i>PDHA1, PDHX, ACO2</i>), metabolic disorders (Maple syrup urine disease, Hartnup disease, type I citrullinemia, thiamine and biotin metabolism defects), and others. Secondary causes of EA are more commonly encountered than primary EA (vascular, inflammatory, toxic-metabolic). EA can be misdiagnosed as migraine, peripheral vestibular disorders, anxiety, and functional symptoms. Primary and secondary EA are frequently treatable which should prompt a search for the cause.<h4>Discussion</h4>EA may be overlooked or misdiagnosed for a variety of reasons, including phenotype-genotype variability and clinical overlap between primary and secondary causes. EA is highly treatable, so it is important to consider in the differential diagnosis of paroxysmal disorders. Classical EA1 and EA2 phenotypes prompt single gene test and treatment pathways. For atypical phenotypes, next generation genetic testing can aid diagnosis and guide treatment. Updated classification systems for EA are discussed which may assist diagnosis and management.

To improve the availability of inorganic phosphorus (P) in soil, we investigated the role of three macromolecular organic acids (MOAs), including fulvic acid (FA), polyaspartic acid (PA), and tannic acid (TA), in reducing the fixation of inorganic P fertilizer in the soil. AlPO₄, FePO₄, and Ca₈H₂(PO₄)₆·5H₂O crystals were chosen as insoluble phosphate representatives in the soil to simulate the solubilization process of inorganic P by MOAs. The microstructural and physicochemical properties of AlPO₄, FePO₄, and Ca₈H₂(PO₄)₆·5H₂O were determined by scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FT-IR), and X-ray photoelectron spectroscopy (XPS) before and after treatment of MOAs. In addition, the amounts of leached P and fixed inorganic P in Inceptisols and Alfisols affected by MOAs combined with superphosphate (SP) fertilizer were determined by soil leaching experiments. The presence of the three MOAs significantly increased the concentration of leached P and reduced the contents of insoluble inorganic phosphate formed with iron, aluminum, and calcium fixed in the soil, in which PA combined with SP had the most significant effect. Furthermore, the less inorganic P fixation in the combination treatment of MOAs and SP resulted in a greater wheat yield and P uptake. Therefore, MOAs could be a synergistic material for increasing P fertilizer utilization.

Differentiated epithelial cells reside in the homeostatic microenvironment of the native organ stroma. The stroma supports their normal function, their G₀ differentiated state, and their expansion/contraction through the various stages of the life cycle and physiologic functions of the host. When malignant transformation begins, the microenvironment tries to suppress and eliminate the transformed cells, while cancer cells, in turn, try to resist these suppressive efforts. The tumor microenvironment encompasses a large variety of cell types recruited by the tumor to perform different functions, among which fibroblasts are the most abundant. The dynamics of the mutual relationship change as the sides undertake an epic battle for control of the other. In the process, the cancer "wounds" the microenvironment through a variety of mechanisms and attracts distant mesenchymal stem cells to change their function from one attempting to suppress the cancer, to one that supports its growth, survival, and metastasis. Analogous reciprocal interactions occur as well between disseminated cancer cells and the metastatic microenvironment, where the microenvironment attempts to eliminate cancer cells or suppress their proliferation. However, the altered microenvironmental cells acquire novel characteristics that support malignant progression. Investigations have attempted to use these traits as targets of novel therapeutic approaches.

Glioblastoma (GBM) continues to be the most devastating primary brain malignancy. Despite significant advancements in understanding basic GBM biology and enormous efforts in developing new therapeutic approaches, the prognosis for most GBM patients remains poor with a median survival time of 15 months. Recently, the interplay between the <i>SOX</i> (SRY-related HMG-box) genes and lncRNAs (long non-coding RNAs) has become the focus of GBM research. Both classes of molecules have an aberrant expression in GBM and play essential roles in tumor initiation, progression, therapy resistance, and recurrence. In GBM, <i>SOX</i> and lncRNAs crosstalk through numerous functional axes, some of which are part of the complex transcriptional and epigenetic regulatory mechanisms. This review provides a systematic summary of current literature data on the complex interplay between <i>SOX</i> genes and lncRNAs and represents an effort to underscore the effects of SOX/lncRNA crosstalk on the malignant properties of GBM cells. Furthermore, we highlight the significance of this crosstalk in searching for new biomarkers and therapeutic approaches in GBM treatment.

Adequate dietary iron (Fe) intake is crucial for preventing Fe-deficient anemia, a recognized global public health concern which is important in Armenia. This study aimed to analyze the intake of Fe, both heme (from animal tissues) and non-heme (more prevalent, but less efficiently absorbed), as well as the Fe dietary sources, among adults in a representative national sample in Armenia. The study was conducted on 1400 individuals aged 18-80 and above, who were enrolled from all regions of Armenia. The Fe intake was assessed through a 24 h dietary recall survey, while Fe occurrence was determined through atomic absorption spectrophotometry (AAS). The results showed a high proportion of adults with a Fe intake lower than the average requirements set by EFSA (65%, 80% and 85% of males, total females and females at fertile age, respectively). Main Fe sources were bread, fruits and vegetables; heme Fe accounted only for <5% of total Fe intake. Compared to males, females had a lower intake of all forms of Fe (<i>p</i> < 0.05). Significant differences were observed in the intake of different forms of Fe between regions (<i>p</i> < 0.05), while the age-group 36-55 years had higher intakes of total Fe. Our data call for comprehensive nutritional security strategies in order to reduce iron deficiency in Armenia, that represents a public health concern.

Liver fibrosis is a repair response to injury caused by various chronic stimuli that continually act on the liver. Among them, the activation of hepatic stellate cells (HSCs) and their transformation into a myofibroblast phenotype is a key event leading to liver fibrosis, however the mechanism has not yet been elucidated. The molecular basis of HSC activation involves changes in the regulation of gene expression without changes in the genome sequence, namely, <i>via</i> epigenetic regulation. DNA methylation is a key focus of epigenetic research, as it affects the expression of fibrosis-related, metabolism-related, and tumor suppressor genes. Increasing studies have shown that DNA methylation is closely related to several physiological and pathological processes including HSC activation and liver fibrosis. This review aimed to discuss the mechanism of DNA methylation in the pathogenesis of liver fibrosis, explore DNA methylation inhibitors as potential therapies for liver fibrosis, and provide new insights on the prevention and clinical treatment of liver fibrosis.

<h4>Background</h4>The relationship between cuproptosis and HCC is still in the exploratory stage. Long noncoding RNAs (lncRNAs) have recently been linked to the progression of hepatocellular carcinoma (HCC). However, the clinical significance of lncRNAs associated with cuproptosis remains unclear.<h4>Methods</h4>Based on The Cancer Genome Atlas (TCGA) liver hepatocellular carcinoma (LIHC) dataset, we identified characteristic prognostic lncRNAs by univariate, LASSO, and multifactorial regression analysis, and constructed a prognostic signature of cuproptosis-related lncRNAs in HCC. The role of lncRNAs were identified through CCK-8, clone formation in Huh-7 cells with high expression of FDX1. Prognostic potential of the characteristic lncRNAs was evaluated in each of the two cohorts created by randomly dividing the TCGA cohort into a training cohort and a test cohort in a 1:1 ratio. Immune profiles in defined subgroups of cuproptosis-related lncRNA features as well as drug sensitivity were analyzed.<h4>Results</h4>We constructed a multigene signature based on four characteristic prognostic lncRNAs (AL590705.3, LINC02870, KDM4A-AS1, MKLN1-AS). These four lncRNAs participated in the development of cuproptosis. HCC patients were classified into high-risk and low-risk groups based on the median value of the risk score. The receiver operating characteristic curve area under the curve values for 1-, 3-, and 5-year survival were 0.773, 0.728, and 0.647, respectively, for the training cohort, and 0.764, 0.671, and 0.662, respectively, for the test cohort. Univariate and multifactorial regression analyses indicated that this prognostic feature was an independent prognostic factor for HCC. Principal component analysis plots clearly distinguished between low- and high-risk patients in terms of their probability of survival. Furthermore, gene set enrichment analysis showed that a variety of processes associated with tumor proliferation and progression were enriched in the high-risk group compared with the low-risk group. Moreover, there were significant differences in the expression of immune cell subpopulations, immune checkpoint genes, and potential drug screening, which provided distinct therapeutic recommendations for individuals with various risks.<h4>Conclusions</h4>We constructed a novel cuproptosis-associated lncRNA signature with a significant predictive value for the prognosis of patients with HCC. Cuproptosis-associated lncRNAs are associated with the tumor immune microenvironment of HCC and even the efficacy of tumor immunotherapy.

<h4>Introduction</h4>Papillary thyroid carcinoma is a type of thyroid cancer that exhibits significant variability in prognosis. Extensive research indicates that the impaired signaling of 1,25(OH)2D3-VDR may be a crucial factor in the development and progression of PTC.<h4>Methods</h4>To investigate this further, Integrated analysis mRNA expression information from The Cancer Genome Atlas and GEO, we compared gene expression in cancer and normal tissues and identified differentially expressed genes (DEGs). Through this analysis, we identified DEGs and calculated risk estimates for seven genetic markers.<h4>Results</h4>Subsequently, we constructed predictive models using LASSO-Cox regression to test the predictive value of these markers. Our results revealed that 64 calcium metabolism-related genes showed significant differences between tumor and normal tissues. Ten of the identified DEGs were significantly associated with overall survival, indicating their potential role in disease progression. Using the average risk score for the seven genetic markers, we divided patients into high- and low-risk groups. We found that patients in the low-risk group had significantly better overall survival than those in the high-risk group, highlighting the importance of these genetic markers in predicting prognosis. Further analysis using Cox regression demonstrated that the risk levels had independent predictive power. Additionally, we conducted functional analysis of the identified genetic markers, which showed significant differences in immune status between the two patient groups. We also investigated the effect of these calcium metabolism-related genes on thyroid cancer biological functions, immune microenvironment, and drug resistance.<h4>Discussion</h4>Our findings provide evidence of a novel genetic signature associated with calcium metabolism, which can predict prognosis in patients with PTC. These results may have significant implications for the development of new diagnostic and therapeutic approaches to improve outcomes for PTC patients.

The incidence of brain metastases (BrM) has become a growing concern recently. It is a common and often fatal manifestation in the brain during the end-stage of many extracranial primary tumors. Increasing BrM diagnoses can be attributed to improvements in primary tumor treatments, which have extended patients' lifetime, and allowed for earlier and more efficient detection of brain lesions. Currently, therapies for BrM encompass systemic chemotherapy, targeted therapy, and immunotherapy. Systemic chemotherapy regimens are controversial due to their associated side effects and limited efficacy. Targeted and immunotherapies have garnered significant attention in the medical field: they target specific molecular sites and modulate specific cellular components. However, multiple difficulties such as drug resistance and low permeability of the blood-brain barrier (BBB) remain significant challenges. Thus, there is an urgent need for novel therapies. Brain microenvironments consist of cellular components including immune cells, neurons, endothelial cells as well as molecular components like metal ions, nutrient molecules. Recent research indicates that malignant tumor cells can manipulate the brain microenvironment to change the anti-tumoral to a pro-tumoral microenvironment, both before, during, and after BrM. This review compares the characteristics of the brain microenvironment in BrM with those in other sites or primary tumors. Furthermore, it evaluates the preclinical and clinical studies of microenvironment-targeted therapies for BrM. These therapies, due to their diversity, are expected to overcome drug resistance or low permeability of the BBB with low side effects and high specificity. This will ultimately lead to improved outcomes for patients with secondary brain tumors.

The enteric nervous system (ENS) continues to dazzle scientists with its ability to integrate signals, from the outside as well as from the host, to accurately regulate digestive functions. Composed of neurons and enteric glial cells, the ENS interplays with numerous neighboring cells through the reception and/or the production of several types of mediators. In particular, ENS can produce and release n-6 oxylipins. These lipid mediators, derived from arachidonic acid, play a major role in inflammatory and allergic processes, but can also regulate immune and nervous system functions. As such, the study of these n-6 oxylipins on the digestive functions, their cross talk with the ENS and their implication in pathophysiological processes is in full expansion and will be discussed in this review.

Recently, there has been increasing interest in developing biocompatible inhalable nanoparticle formulations, as they have enormous potential for treating and diagnosing lung disease. In this respect, here, we have studied superparamagnetic iron-doped calcium phosphate (in the form of hydroxyapatite) nanoparticles (FeCaP NPs) which were previously proved to be excellent materials for magnetic resonance imaging, drug delivery and hyperthermia-related applications. We have established that FeCaP NPs are not cytotoxic towards human lung alveolar epithelial type 1 (AT1) cells even at high doses, thus proving their safety for inhalation administration. Then, D-mannitol spray-dried microparticles embedding FeCaP NPs have been formulated, obtaining respirable dry powders. These microparticles were designed to achieve the best aerodynamic particle size distribution which is a critical condition for successful inhalation and deposition. The nanoparticle-in-microparticle approach resulted in the protection of FeCaP NPs, allowing their release upon microparticle dissolution, with dimensions and surface charge close to the original values. This work demonstrates the use of spray drying to provide an inhalable dry powder platform for the lung delivery of safe FeCaP NPs for magnetically driven applications.

<h4>Background</h4>Biodegradable hydrogel scaffold is one of the crucial characteristics that determine the success of pulp regeneration. The degradation should be suitable for the growth of new tissue establishment. The aim of this study is to synthesize and compare the novel biodegradable hydrogel scaffold based on hydroxyapatite (HAp) eggshell, collagen, and epigallocatechin-3-gallate (HAp-Col-EGCG) with different HAp concentrations <i>in vitro</i>.<h4>Materials and methods</h4>This study is original research. HAp-Col-EGCG hydrogel scaffolds were prepared using 1:1, 1:2, and 1:4 ratios of collagen and HAp with 10 μmol/L EGCG. The samples were freeze-dried and immersed in phosphate buffer saline containing lysozyme enzyme. The dried samples were weighed to determine the percentage of biodegradation value (<i>P</i> < 0.05).<h4>Results</h4>The result showed HAp-Col-EGCG was biodegradable but it has not been concluded that it can be completely eliminated. The data were analyzed by one-way analysis of variance and it indicated significant differences in percentage values.<h4>Conclusion</h4>Hydrogel scaffold based on HAp-Col-EGCG can be degraded and have the potential to be used as a biodegradable scaffold in supporting tissue regeneration.

Early-onset osteoporosis (EOOP) has been associated with several genes, including <i>LRP5</i>, coding for a coreceptor in the Wnt pathway. Variants in <i>LRP5</i> were also described in osteoporosis pseudoglioma syndrome, combining severe osteoporosis and eye abnormalities. Genomewide-association studies (GWAS) showed that <i>LRP5</i> p.Val667Met (V667M) variant is associated with low bone mineral density (BMD) and increased fractures. However, despite association with a bone phenotype in humans and knockout mice, the impact of the variant in bone and eye remains to be investigated. Here, we aimed to evaluate the bone and ocular impact of the V667M variant. We recruited 11 patients carrying the V667M variant or other loss-of-function variants of <i>LRP5</i> and generated an <i>Lrp5</i> ^V667M mutated mice. Patients had low lumbar and hip BMD <i>Z</i>-score and altered bone microarchitecture evaluated by HR-pQCT compared with an age-matched reference population. Murine primary osteoblasts from <i>Lrp5</i> ^V667M mice showed lower differentiation capacity, alkaline phosphatase activity, and mineralization capacity in vitro. Ex vivo, mRNA expression of <i>Osx</i>, <i>Col1</i>, and <i>osteocalcin</i> was lower in <i>Lrp5</i> ^V667M bones than controls (all <i>p</i> < 0.01). <i>Lrp5</i> ^V667M 3-month-old mice, compared with control (CTL) mice, had decreased BMD at the femur (<i>p</i> < 0.01) and lumbar spine (<i>p</i> < 0.01) with normal microarchitecture and bone biomarkers. However, <i>Lrp5</i> ^V667M mice revealed a trend toward a lower femoral and vertebral stiffness (<i>p</i> = 0.14) and had a lower hydroxyproline/proline ratio compared with CTL, (<i>p</i> = 0.01), showing altered composition and quality of the bone matrix. Finally, higher tortuosity of retinal vessels was found in the <i>Lrp5</i> ^V667M mice and unspecific vascular tortuosity in two patients only. In conclusion, <i>Lrp5</i> ^V667M variant is associated with low BMD and impaired bone matrix quality. Retinal vascularization abnormalities were observed in mice. © 2023 The Authors. <i>JBMR Plus</i> published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

<h4>Introduction</h4>diarrhoea disease is a global health concern, persisting as one of the top five causes of morbidity and mortality in children. Viral aetiology of childhood diarrhoea is often associated with rotavirus infection of which preventable vaccines exist. Here we document circulating strains of rotavirus in the Kassena-Nankana Districts of Northern Ghana nearly a decade after the introduction of the rotavirus vaccine.<h4>Methods</h4>a cross-sectional survey of children aged 0-60 months was conducted in six health facilities within the Kassena-Nankana Districts. Faecal samples obtained from the children were analysed and characterized for rotavirus detection and genotyping using Semi-Nested Polymerase Chain Reaction.<h4>Results</h4>a total of 263 stool samples were analyzed. Out of which 14.8% and 18.6% of the diarrhoea cases were of rotavirus and parasitic etiologies respectively, with 17.4% being co-infections. Almost 27.5% of rotavirus diarrhoeal cases resulted in hospitalization. Household size (p=0.035), location (p=0.018), treatment outcome (p=0.007), vomiting (p=0.039), season (p=0.017) and month of sampling (p=0.000) were significantly associated with rotavirus infection. The rotavirus genotypes identified were G1P8, G3P6, G4P9, G10P6 and G12P8. Rotavirus vaccine-type, G1P8 was absent in Kassena-Nankana West District.<h4>Conclusion</h4>the prevalence of rotavirus was low compared to the pre-vaccination era. Also, a new rotavirus strain, G4P9 was identified to be circulating in the study area which calls for surveillance measures and more studies to better understand the situation for appropriate public health intervention.

In the present work, we reported on a method to combine amino β-cyclodextrins (CD1) with reduced graphene oxide (obtained by the electrochemical reduction of graphene oxide, erGO) to produce a glassy carbon electrode (GCE) modified with both CD1 and erGO (CD1-erGO/GCE). This procedure avoids the use of organic solvents such as hydrazine or long reaction times and high temperatures. The material combining both CD1 and erGO (CD1-erGO/GCE) was characterized by SEM, ATR-FTIR, Raman, XPS, and electrochemical techniques. As proof-of-concept, the determination of the pesticide carbendazim was carried out. The spectroscopic measurements, especially XPS, proved that CD1 was covalently attached to the surface of the erGO/GCE electrode. The attachment of cyclodextrin at the reduced graphene oxide produced an increase in the electrochemical behavior of the electrode. The cyclodextrin-functionalized reduced graphene oxide, CD1-erGO/GCE, showed a larger sensitivity (1.01 μA/μM) and a lower limit of detection for carbendazim (LOD = 0.50 μM) compared with the non-functionalized material, erGO/GCE, (sensitivity = 0.63 μA/μM and LOD = 4.32 μM, respectively). Overall, the results of the present work show that this simple method is suitable to attach cyclodextrins to graphene oxide, maintaining their inclusion abilities.

In this study, the DCC-MIDAS approach and its extension are adopted to reveal the long-run correlations among Chinese currency and those of ASEAN countries, and the role of RMB internationalization in driving the movements of the long-run currency correlations. The findings show that: (1) significant long-run currency correlations have been identified in the China-ASEAN Free Trade Area in general, however, the correlations are weakened during the COVID-19 pandemic; (2) the degree of correlation highly relates to the economic development of a country and Singapore plays a leading role in the ASEAN foreign exchange markets; (3) RMB internationalization is the main driving force to enhance the currency correlations in the region and the importance of Singapore dollar tends to be partly replaced by China. With respect to the increasing impact of the RMB in the China-ASEAN Free Trade Area, we provide policy implications to the Chinese government to maintain the stability of its currency in the region for the potential transition of the currency regionalization driven by the RMB. We contribute to the literature on currency linkage and integration by analyzing the long-run relationship to avoid the biased results given by the irregular short-run shocks and we make the first attempt to reveal the impact of RMB internationalization in shaping the long-run currency correlations in the free trade area dominated by China.

<h4>Background</h4>SARS-CoV-2 has been shown to predominantly infect the airways and the respiratory tract and too often have an unpredictable and different pathologic pattern compared to other respiratory diseases. Current clinical diagnostical tools in pulmonary medicine expose patients to harmful radiation, are too unspecific or even invasive. Proteomic analysis of exhaled breath particles (EBPs) in contrast, are non-invasive, sample directly from the pathological source and presents as a novel explorative and diagnostical tool.<h4>Methods</h4>Patients with PCR-verified COVID-19 infection (COV-POS, n = 20), and patients with respiratory symptoms but with > 2 negative polymerase chain reaction (PCR) tests (COV-NEG, n = 16) and healthy controls (HCO, n = 12) were prospectively recruited. EBPs were collected using a "particles in exhaled air" (PExA 2.0) device. Particle per exhaled volume (PEV) and size distribution profiles were compared. Proteins were analyzed using liquid chromatography-mass spectrometry. A random forest machine learning classification model was then trained and validated on EBP data achieving an accuracy of 0.92.<h4>Results</h4>Significant increases in PEV and changes in size distribution profiles of EBPs was seen in COV-POS and COV-NEG compared to healthy controls. We achieved a deep proteome profiling of EBP across the three groups with proteins involved in immune activation, acute phase response, cell adhesion, blood coagulation, and known components of the respiratory tract lining fluid, among others. We demonstrated promising results for the use of an integrated EBP biomarker panel together with particle concentration for diagnosis of COVID-19 as well as a robust method for protein identification in EBPs.<h4>Conclusion</h4>Our results demonstrate the promising potential for the use of EBP fingerprints in biomarker discovery and for diagnosing pulmonary diseases, rapidly and non-invasively with minimal patient discomfort.

Environmental cues, such as physical forces and heterotypic cell interactions play a critical role in cell function, yet their collective contributions to transcriptional changes are unclear. Focusing on human endothelial cells, we performed broad individual sample analysis to identify transcriptional drifts associated with environmental changes that were independent of genetic background. Global gene expression profiling by RNA sequencing and protein expression by liquid chromatography-mass spectrometry directed proteomics distinguished endothelial cells in vivo from genetically matched culture (in vitro) samples. Over 43% of the transcriptome was significantly changed by the in vitro environment. Subjecting cultured cells to long-term shear stress significantly rescued the expression of approximately 17% of genes. Inclusion of heterotypic interactions by co-culture of endothelial cells with smooth muscle cells normalized approximately 9% of the original in vivo signature. We also identified novel flow dependent genes, as well as genes that necessitate heterotypic cell interactions to mimic the in vivo transcriptome. Our findings highlight specific genes and pathways that rely on contextual information for adequate expression from those that are agnostic of such environmental cues.

Histone acetylation is a pivotal epigenetic modification that controls chromatin structure and regulates gene expression. It plays an essential role in modulating zygotic transcription and cell lineage specification of developing embryos. While the outcomes of many inductive signals have been described to require enzymatic activities of histone acetyltransferases and deacetylases (HDACs), the mechanisms by which HDACs confine the utilization of the zygotic genome remain to be elucidated. Here, we show that histone deacetylase 1 (Hdac1) progressively binds to the zygotic genome from mid-blastula and onward. The recruitment of Hdac1 to the genome at blastula is instructed maternally. <i>Cis</i>-regulatory modules (CRMs) bound by Hdac1 possess epigenetic signatures underlying distinct functions. We highlight a dual function model of Hdac1 where Hdac1 not only represses gene expression by sustaining a histone hypoacetylation state on inactive chromatin, but also maintains gene expression through participating in dynamic histone acetylation-deacetylation cycles on active chromatin. As a result, Hdac1 maintains differential histone acetylation states of bound CRMs between different germ layers and reinforces the transcriptional program underlying cell lineage identities, both in time and space. Taken together, our study reveals a comprehensive role for Hdac1 during early vertebrate embryogenesis.

Egg storage duration can affect embryo mortality, hatching characteristics, hatching time, and post-hatch chick quality. In order to assess these effects, the impact of storage duration (5 days, 10 days, 15 days) and short incubation period during egg storage (SPIDES) investigated further 18, 900 eggs of broiler breeder (ROSS 308) in 3 × 2 factorial arrangement design. In the SPIDES treatment, the egg shell temperature was raised from its storage temperature (18 °C) and held at 100 °F for 3.5 h. Storage periods could significantly (P < 0.05) influence on embryo mortality (total, early, middle, and late), hatchability of both the total eggs and fertile eggs. The SPIDES treatment had a significant (P < 0.05) impact on a lower embryonic death rate and improved egg hatchability. Eggs stored for 5 days and eggs treated with SPIDES significantly (P < 0.001) shorten hatching time, batch's 90% hatching time (T 90% H), mean hatching time (MHT), maximal hatching period (MHP), and hatching window (HW). Chick quality was also determined, whereas storing eggs for 5 days and using the SPIDES treatment resulted in enhanced (P < 0.001) chick weight relative to egg weight (CW/EW), activity (AC), and chick quality score (CQS). The residual yolk sac weight (RYSW), unhealed navel (UHN %), and dirty feather (DF%) recorded the lowest (P < 0.001) values compared to long storage periods and control group. Finally, stored for 5 days treated by SPIDES positively affected the hatchability characteristics, the shortening hatching time, and the quality of chicks. Regarding the results, it was confirmed that using the SPIDES treatment to prevent the harmful effects of broiler eggs being stored for an extended period of time is a viable option.

The pannexin 2 channel (PANX2) participates in multiple physiological processes including skin homeostasis, neuronal development, and ischemia-induced brain injury. However, the molecular basis of PANX2 channel function remains largely unknown. Here, we present a cryo-electron microscopy structure of human PANX2, which reveals pore properties contrasting with those of the intensely studied paralog PANX1. The extracellular selectivity filter, defined by a ring of basic residues, more closely resembles that of the distantly related volume-regulated anion channel (VRAC) LRRC8A, rather than PANX1. Furthermore, we show that PANX2 displays a similar anion permeability sequence as VRAC, and that PANX2 channel activity is inhibited by a commonly used VRAC inhibitor, DCPIB. Thus, the shared channel properties between PANX2 and VRAC may complicate dissection of their cellular functions through pharmacological manipulation. Collectively, our structural and functional analysis provides a framework for development of PANX2-specific reagents that are needed for better understanding of channel physiology and pathophysiology.

There is significant evidence linking a 'reward deficiency syndrome' (RDS), comprising decreased availability of striatal dopamine D2-like receptors (DD2lR) and addiction-like behaviors underlying substance use disorders and obesity. Regarding obesity, a systematic review of the literature with a meta-analysis of such data is lacking. Following a systematic review of the literature, we performed random-effects meta-analyses to determine group differences in case-control studies comparing DD2lR between individuals with obesity and non-obese controls and prospective studies of pre- to post-bariatric surgery DD2lR changes. Cohen's d was used to measure effect size. Additionally, we explored factors potentially associated with group differences in DD2lR availability, such as obesity severity, using univariate meta-regression. In a meta-analysis including positron emission tomography (PET) and single-photon emission computed tomography (SPECT) studies, striatal DD2lR availability did not significantly differ between obesity and controls. However, in studies comprising patients with class III obesity or higher, group differences were significant, favoring lower DD2lR availability in the obesity group. This effect of obesity severity was corroborated by meta-regressions showing inverse associations between the body mass index (BMI) of the obesity group and DD2lR availability. Post-bariatric changes in DD2lR availability were not found, although a limited number of studies were included in this meta-analysis. These results support lower DD2lR in higher classes of obesity which is a more targeted population to explore unanswered questions regarding the RDS.

The emergence of consciousness from anesthesia, once assumed to be a passive process, is now considered as an active and controllable process. In the present study, we show in mice that, when the brain is forced into a minimum responsive state by diverse anesthetics, a rapid downregulation of K⁺/Cl^- cotransporter 2 (KCC2) in the ventral posteromedial nucleus (VPM) serves as a common mechanism by which the brain regains consciousness. Ubiquitin-proteasomal degradation is responsible for KCC2 downregulation, which is driven by ubiquitin ligase Fbxl4. Phosphorylation of KCC2 at Thr1007 promotes interaction between KCC2 and Fbxl4. KCC2 downregulation leads to γ-aminobutyric acid type A receptor-mediated disinhibition, enabling accelerated recovery of VPM neuron excitability and emergence of consciousness from anesthetic inhibition. This pathway to recovery is an active process and occurs independent of anesthetic choice. The present study demonstrates that ubiquitin degradation of KCC2 in the VPM is an important intermediate step en route to emergence of consciousness from anesthesia.

It is common to think about and depict biological processes as being governed by fixed pathways with specific components interconnected by concrete positive and negative interactions. However, these models may fail to effectively capture the regulation of cell biological processes that are driven by chemical mechanisms that do not rely absolutely on specific metabolites or proteins. Here, we discuss how ferroptosis, a non-apoptotic cell death mechanism with emerging links to disease, may be best understood as a highly flexible mechanism that can be executed and regulated by many functionally related metabolites and proteins. The inherent plasticity of ferroptosis has implications for how to define and study this mechanism in healthy and diseased cells and organisms.

Kinesin family member C1 (KIFC1) is a kinesin-14 motor protein, and its abnormal upregulation promotes the malignant behavior of cancer cells. N6-methyladenosine (m6A) RNA methylation is a common modification of eukaryotic messenger RNA and affects RNA expression. In this study, we explored how KIFC1 regulated head and neck squamous cell carcinoma (HNSCC) tumorigenesis and how m6A modification affected KIFC1 expression. A bioinformatics analysis was performed to screen for genes of interest, and in vitro and in vivo studies were carried out to investigate the function and mechanism of KIFC1 in HNSCC tissues. We observed that the expression of KIFC1 in HNSCC tissues was significantly higher than that in normal or adjacent normal tissues. Patients with cancer with higher KIFC1 expression have a lower tumor differentiation status. Demethylase alkB homolog 5, a cancer-promoting factor in HNSCC tissues, could interact with KIFC1 messenger RNA and posttranscriptionally activate KIFC1 through m6A modification. KIFC1 downregulation suppressed HNSCC cell growth and metastasis in vivo and in vitro. However, overexpression of KIFC1 promoted these malignant behaviors. We demonstrated that KIFC1 overexpression activated the oncogenic Wnt/β-catenin pathway. KIFC1 interacted with the small GTPase Ras-related C3 botulinum toxin substrate 1 (Rac1) at the protein level and increased its activity. The Rho GTPase Rac1 was indicated to be an upstream activator of the Wnt/β-catenin signaling pathway, and its Rac1 inhibitor, NSC-23766, treatment reversed the effects caused by KIFC1 overexpression. Those observations demonstrate that abnormal expression of KIFC1 may be regulated by demethylase alkB homolog 5 in an m6A-dependent manner and promote HNSCC progression via the Rac1/Wnt/β-catenin pathway.

<h4>Background</h4>Chemokines have been reported to play an important role in cancer immunotherapy. This study aimed to explore the chemokines involved in lung cancer immunotherapy.<h4>Methods</h4>All the public data were downloaded from The Cancer Genome Atlas Program database. Quantitative real time-PCR was used to detect the mRNA level of specific molecules and Western blot was used for the protein level. Other experiments used include luciferase reporter experiments, flow cytometric analysis, Chromatin immunoprecipitation assay, ELISA and co-cultured system.<h4>Results</h4>We found that the CCL7, CCL11, CCL14, CCL24, CCL25, CCL26, CCL28 had a higher level, while the CCL17, CCL23 had a lower level in immunotherapy non-responders. Also, we found that immunotherapy non-responders had a higher level of CD56dim NK cells, NK cells, Th1 cells, Th2 cells and Treg, yet a lower level of iDC and Th17 cells. Biological enrichment analysis indicated that in the patients with high Treg infiltration, the pathways of pancreas beta cells, KRAS signaling, coagulation, WNT BETA catenin signaling, bile acid metabolism, interferon alpha response, hedgehog signaling, PI3K/AKT/mTOR signaling, apical surface, myogenesis were significantly enriched in. CCL7, CCL11, CCL26 and CCL28 were selected for further analysis. Compared with the patients with high CCL7, CCL11, CCL26 and CCL28 expression, the patients with low CCL7, CCL11, CCL26 and CCL28 expression had a better performance of immunotherapy response and this effect might partly be due to Treg cells. Furthermore, biological exploration and clinical correlation of CCL7, CCL11, CCL26 and CCL28 were conducted, Finally, CCL28 was selected for validation. Experiments showed that under the hypoxia condition, HIF-1α was upregulated, which can directly bind to the promoter region of CCL28 and lead to its higher level. Also, CCL28 secreted by lung cancer cells could induce Tregs infiltration.<h4>Conclusion</h4>Our study provides a novel insight focused on the chemokines in lung cancer immunotherapy. Also, CCL28 was identified as an underlying biomarker for lung cancer immunotherapy.

Titanium (Ti) and its alloys have been widely used as orthopedic implants, because of their favorable mechanical properties, corrosion resistance and biocompatibility. Despite their significant success in various clinical applications, the probability of failure, degradation and revision is undesirably high, especially for the patients with low bone density, insufficient quantity of bone or osteoporosis, which renders the studies on surface modification of Ti still active to further improve clinical results. It is discerned that surface physicochemical properties directly influence and even control the dynamic interaction that subsequently determines the success or rejection of orthopedic implants. Therefore, it is crucial to endow bulk materials with specific surface properties of high bioactivity that can be performed by surface modification to realize the osseointegration. This article first reviews surface characteristics of Ti materials and various conventional surface modification techniques involving mechanical, physical and chemical treatments based on the formation mechanism of the modified coatings. Such conventional methods are able to improve bioactivity of Ti implants, but the surfaces with static state cannot respond to the dynamic biological cascades from the living cells and tissues. Hence, beyond traditional static design, dynamic responsive avenues are then emerging. The dynamic stimuli sources for surface functionalization can originate from environmental triggers or physiological triggers. In short, this review surveys recent developments in the surface engineering of Ti materials, with a specific emphasis on advances in static to dynamic functionality, which provides perspectives for improving bioactivity and biocompatibility of Ti implants.

Mitochondrial dysfunction and vesicular trafficking alterations have been implicated in the pathogenesis of several neurodegenerative diseases. It has become clear that pathogenetic pathways leading to neurodegeneration are often interconnected. Indeed, growing evidence suggests a concerted contribution of impaired mitophagy and vesicles formation in the dysregulation of neuronal homeostasis, contributing to neuronal cell death. Among the molecular factors involved in the trafficking of vesicles, Ras analog in brain (Rab) proteins seem to play a central role in mitochondrial quality checking and disposal through both canonical PINK1/Parkin-mediated mitophagy and novel alternative pathways. In turn, the lack of proper elimination of dysfunctional mitochondria has emerged as a possible causative/early event in some neurodegenerative diseases. Here, we provide an overview of major findings in recent years highlighting the role of Rab proteins in dysfunctional mitochondrial dynamics and mitophagy, which are characteristic of neurodegenerative diseases. A further effort should be made in the coming years to clarify the sequential order of events and the molecular factors involved in the different processes. A clear cause-effect view of the pathogenetic pathways may help in understanding the molecular basis of neurodegeneration.

Inborn errors of immunity (IEIs) are a group of inherited disorders caused by mutations in the protein-coding genes involved in innate and/or adaptive immunity. Hematopoietic stem cell transplantation (HSCT) is a mainstay definitive therapy for many severe IEIs. However, the lack of HLA-matched donors increases the risk of developing severe immunological complications. Gene therapy provides long-term clinical benefits and could be an attractive therapeutic strategy for IEIs. In this review, we describe the development and evolution of clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated proteins (Cas) gene-editing systems, including double-strand break (DSB)-based gene editing and DSB-free base editing or prime editing systems. Here, we discuss the advances in and issues associated with CRISPR/Cas gene editing tools and their potential as therapeutic alternatives for IEIs. We also highlight the progress of preclinical studies for the treatment of human genetic diseases, including IEIs, using CRISR/Cas and ongoing clinical trials based on this versatile technology.

Circular RNAs are highly stable single-stranded circular RNAs and enriched in the brain. Previous studies showed that circRNAs, as part of competing endogenous RNAs (ceRNAs) network, play an important role in neurodegenerative and psychiatric diseases. However, the mechanism of circRNA-related ceRNA networks in postoperative cognitive dysfunction (POCD) has not been elucidated yet. POCD usually occurs in elderly patients and is characterized by hippocampal dysfunction. Here, aged C57BL/6 mice were subjected to exploratory laparotomy under sevoflurane anesthesia, and this POCD model was verified by Morris water maze test. Whole-transcriptome sequencing was performed on the hippocampus of control group (Con) and surgery group. One hundred and seventy-seven DEcircRNAs, 221 DEmiRNAs and 2,052 DEmRNAs were identified between two groups. A ceRNA network was established with 92 DEcircRNAs having binding sites with 76 DEmiRNAs and 549 target DEmRNAs. In functional enrichment analysis, a pathological pattern of POCD was highlighted in the ceRNA network: Abnormal metabolic process in neural cells, including oxygen metabolism, could promote apoptosis and then affect the synaptic function, which may undermine the neural plasticity and eventually lead to changes in cognitive function and other behavioral patterns. In conclusion, this specific ceRNA network of circRNAs-miRNAs-mRNAs has provided novel insights into the regulatory mechanisms of POCD and revealed potential therapeutic gene targets.

<b>Background:</b> As one of the most common autoimmune diseases, myasthenia gravis (MG) severely affects the quality of life of patients. Therefore, exploring the role of dysregulated genes between MG and healthy controls in the diagnosis of MG is beneficial to reveal new and promising diagnostic biomarkers and clinical therapeutic targets. <b>Methods:</b> The GSE85452 dataset was downloaded from the Gene Expression Omnibus (GEO) database and differential gene expression analysis was performed on MG and healthy control samples to identify differentially expressed genes (DEGs). The functions and pathways involved in DEGs were also explored by functional enrichment analysis. Significantly associated modular genes were identified by weighted gene co-expression network analysis (WGCNA), and MG dysregulated gene co-expression modular-based diagnostic models were constructed by gene set variance analysis (GSVA) and least absolute shrinkage and selection operator (LASSO). In addition, the effect of model genes on tumor immune infiltrating cells was assessed by CIBERSORT. Finally, the upstream regulators of MG dysregulated gene co-expression module were obtained by Pivot analysis. <b>Results:</b> The green module with high diagnostic performance was identified by GSVA and WGCNA. The LASSO model obtained NAPB, C5orf25 and ERICH1 genes had excellent diagnostic performance for MG. Immune cell infiltration results showed a significant negative correlation between green module scores and infiltration abundance of Macrophages M2 cells. <b>Conclusion:</b> In this study, a diagnostic model based on the co-expression module of MG dysregulated genes was constructed, which has good diagnostic performance and contributes to the diagnosis of MG.

Follicular lymphoma (FL) is the most common indolent lymphoma originating from germinal center B cells. FL represents a clinically and biologically heterogeneous disease. Most patients have favorable outcomes, but a subset of patients experiences early progression or transformation and has a poor prognosis. Abnormalities in FL cells and tumor microenvironment have been revealed using multi-omics techniques, including genomic, epigenomic, transcriptomic and proteomic analysis. Recurrent somatic gene aberrations mainly involve epigenetic modifiers, transcription factors, oncogenic pathways and microenvironment modulators. Single-cell transcriptomic analysis show marked inter- and intra-patient FL subclone heterogeneity. In addition, a comprehensive profile of microenvironmental components is provided, unveiling the crosstalk between tumor and microenvironment that induce FL progression and facilitate immune escape. Together, these studies provide insights into the mechanisms and biomarkers of high-risk FL populations, as well as the potential targeted and immunotherapy options. Future research should focus on integrating multi-omics aberrations to optimize therapeutic strategies in FL.

Bone tissue engineering (BTE) aims to improve the healing of bone fractures using scaffolds that mimic the native extracellular matrix. For successful bone regeneration, scaffolds should promote simultaneous bone tissue formation and blood vessel growth for nutrient and waste exchange. However, a significant challenge in regenerative medicine remains the development of grafts that can be vascularized successfully. Amongst other things, optimization of physicochemical conditions of scaffolds is key to achieving appropriate angiogenesis in the period immediately following implantation. Calcium phosphates and collagen scaffolds are two of the most widely studied biomaterials for BTE, due to their close resemblance to inorganic and organic components of bone, respectively, and their bioactivity, tunable biodegradability and the ability to produce tailored architectures. While various strategies exist to enhance vascularization of these scaffolds <i>in vivo</i>, further <i>in vitro</i> assessment is crucial to understand the relation between physicochemical properties of a biomaterial and its ability to induce angiogenesis. While mono-culture studies can provide evidence regarding cell-material interaction of a single cell type, a co-culture procedure is crucial for assessing the complex mechanisms involved in angiogenesis. A co-culture more closely resembles the natural tissue both physically and biologically by stimulating natural intercellular interactions and mimicking the organization of the <i>in vivo</i> environment. Nevertheless, a co-culture is a complex system requiring optimization of various parameters including cell types, cell ratio, culture medium and seeding logistics. Gaining fundamental knowledge of the mechanism behind the bioactivity of biomaterials and understanding the contribution of surface and architectural features to the vascularization of scaffolds, and the biological response in general, can provide an invaluable basis for future optimization studies. This review gives an overview of the available literature on scaffolds for BTE, and trends are extracted on the relationship between architectural features, biochemical properties, co-culture parameters and angiogenesis.

One obstacle to the development of gene therapies for the central nervous system is the lack of workflows for quantifying transduction efficiency in affected neural networks and ultimately predicting therapeutic potential. We integrated data from a brain cell atlas with 3D or 2D semi-automated quantification of transduced cells in segmented images to predict AAV transduction efficiency in multiple brain regions. We used this workflow to estimate the transduction efficiency of AAV2/rh.10 and AAV2.retro co-injection in the corticostriatal network affected in Huntington's disease. We then validated our pipeline in gene editing experiments targeting both human and mouse huntingtin genes in transgenic and wild-type mice, respectively. Our analysis predicted that 54% of striatal cells and 7% of cortical cells would be edited in highly transduced areas. Remarkably, in the treated animals, huntingtin gene inactivation reached 54.5% and 9.6%, respectively. These results demonstrate the power of this workflow to predict transduction efficiency and the therapeutic potential of gene therapies in the central nervous system.

The greatest risk factor for cognitive decline is aging. The biological mechanisms for this decline remain enigmatic due, in part, to the confounding of normal aging mechanisms and those that contribute to cognitive impairment. Importantly, many individuals exhibit impaired cognition in age, while some retain functionality despite their age. Here, we establish a behavioral testing paradigm to characterize age-related cognitive heterogeneity in inbred aged C57BL/6 mice and reliably separate animals into cognitively "intact" (resilient) and "impaired" subgroups using a high-resolution home-cage testing paradigm for spatial discrimination. RNA sequencing and subsequent pathway analyses of cognitively stratified mice revealed molecular signatures unique to cognitively impaired animals, including transcriptional down-regulation of genes involved in mitochondrial oxidative phosphorylation (OXPHOS) and sirtuin (<i>Sirt1</i> and <i>Sirt3</i>) expression in the hippocampus. Mitochondrial function assessed using high-resolution respirometry indicated a reduced OXPHOS coupling efficiency in cognitively impaired animals with subsequent hippocampal analyses revealing an increase in the oxidative damage marker (3-nitrotyrosine) and an up-regulation of antioxidant enzymes (Sod2, Sod1, Prdx6, etc.). Aged-impaired animals also showed increased levels of <i>IL-6</i> and <i>TNF-α</i> gene expression in the hippocampus and increased serum levels of proinflammatory cytokines, including IL-6. These results provide critical insight into the diversity of brain aging in inbred animals and reveal the unique mechanisms that separate cognitive resilience from cognitive impairment. Our data indicate the importance of cognitive stratification of aging animals to delineate the mechanisms underlying cognitive impairment and test the efficacy of therapeutic interventions.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality globally. In recent decades, clinical research has made significant advances, resulting in improved survival and recovery rates for patients with CVD. Despite this progress, there is substantial residual CVD risk and an unmet need for better treatment. The complex and multifaceted pathophysiological mechanisms underlying the development of CVD pose a challenge for researchers seeking effective therapeutic interventions. Consequently, exosomes have emerged as a new focus for CVD research because their role as intercellular communicators gives them the potential to act as noninvasive diagnostic biomarkers and therapeutic nanocarriers. In the heart and vasculature, cell types such as cardiomyocytes, endothelial cells, vascular smooth muscle, cardiac fibroblasts, inflammatory cells, and resident stem cells are involved in cardiac homeostasis via the release of exosomes. Exosomes encapsulate cell-type specific miRNAs, and this miRNA content fluctuates in response to the pathophysiological setting of the heart, indicating that the pathways affected by these differentially expressed miRNAs may be targets for new treatments. This review discusses a number of miRNAs and the evidence that supports their clinical relevance in CVD. The latest technologies in applying exosomal vesicles as cargo delivery vehicles for gene therapy, tissue regeneration, and cell repair are described.

Electrochemical biosensors are superior technologies that are used to detect or sense biologically and environmentally significant analytes in a laboratory environment, or even in the form of portable handheld or wearable electronics. Recently, imprinted and implantable biosensors are emerging as point-of-care devices, which monitor the target analytes in a continuous environment and alert the intended users to anomalies. The stability and performance of the developed biosensor depend on the nature and properties of the electrode material or the platform on which the biosensor is constructed. Therefore, the biosensor platform plays an integral role in the effectiveness of the developed biosensor. Enormous effort has been dedicated to the rational design of the electrode material and to fabrication strategies for improving the performance of developed biosensors. Every year, in the search for multifarious electrode materials, thousands of new biosensor platforms are reported. Moreover, in order to construct an effectual biosensor, the researcher should familiarize themself with the sensible strategies behind electrode fabrication. Thus, we intend to shed light on various strategies and methodologies utilized in the design and fabrication of electrochemical biosensors that facilitate sensitive and selective detection of significant analytes. Furthermore, this review highlights the advantages of various electrode materials and the correlation between immobilized biomolecules and modified surfaces.

<h4>Background & aims</h4>Around 20% of patients with non-alcoholic fatty liver disease (NAFLD) are lean. Increasing evidence suggests that lean NAFLD is a unique subtype of the disease. We aimed to explore the metabolic profile, genetic basis, causal risk factors, and clinical sequelae underlying lean NAFLD.<h4>Methods</h4>NAFLD was diagnosed by whole liver proton density fat fraction ≥5%. Whole liver proton density fat fraction and hepatic iron were quantified using magnetic resonance imaging in the UK Biobank. Individuals in this study were stratified according to the World Health Organization criteria of obesity, into lean, overweight, and obese. Mediation analysis, Mendelian randomisation analysis, and Bayesian networks were used to identify a risk factor or a clinical sequela of lean/obese NAFLD.<h4>Results</h4>Lean NAFLD manifested a distinct metabolic profile, featured by elevated hepatic iron and fasting glucose. Four loci, namely, <i>HFE</i> rs1800562, <i>SLC17A3-SLC17A2-TRIM38</i> rs9348697, <i>PNPLA3</i> rs738409, and <i>TM6SF2</i> rs58542926, were associated with lean NAFLD (<i>p</i> <5 × 10^-8). <i>HFE</i> rs1800562 was specifically associated with lean NAFLD and demonstrated a significant mediation effect through elevating hepatic iron. Type 2 diabetes was the most pronounced clinical sequela of lean NAFLD, followed by liver cirrhosis.<h4>Conclusions</h4>Our study suggested that <i>HFE</i> plays a potential steatogenic role rather than regulating iron homoeostasis in patients with lean NAFLD. The increased liver iron deposition is associated with lean NAFLD, whereas obese NAFLD is not related to hepatic iron. The clinical management of patients with lean NAFLD shall be concerned with the prevention and treatment of type 2 diabetes and liver cirrhosis.<h4>Impact and implications</h4>Lean NAFLD has a distinct natural history from obese NAFLD. This study underscored liver iron content and the genetic variant of the iron homoeostasis gene HFE as major risks of lean NAFLD, in addition to the unique metabolic profile. The development of type 2 diabetes or liver cirrhosis shall be closely monitored and prevented in patients with lean NAFLD.

Multiple primary malignancies (MPMs) are defined as the presence of two or more malignancies in different organs, without a subordinate relationship. Although rarely reported, hepatocellular carcinoma (HCC) occasionally presents with simultaneous or metachronous primary malignancies in other organs. In this report, we describe a patient with lung adenocarcinoma and lymph node and bone metastases, treated with five chemotherapeutic regimens for 24 months. Changing the chemotherapy regimen based on the suspicion of metastasis of a new liver mass did not lead to improvements. This prompted a liver biopsy and a revised diagnosis of HCC. Sixth-line treatment with the concurrent use of cisplatin-paclitaxel for lung cancer and sorafenib for HCC, stabilized the disease. The concurrent treatment was not tolerated and was discontinued owing to adverse events. Considering our findings, treatment with increased efficacy and lower toxicity for MPMs is warranted.

<h4>Objectives</h4> Characterization of tissue laxity and dysautonomia symptoms in Ehlers-Danlos syndrome (EDS) uncovered similarities with those of post-infectious SARS-CoV-2 or long COVID19, prompting detailed comparison of their findings and influencing genes. <h4>Methods</h4> Holistic assessment of 1261 EDS outpatients for 120 history-physical findings populated a deidentified database that includes 568 patients with 317 variant genes obtained by commercial NextGen sequencing. Findings were compared to 15 of long COVID19 compiled in an extensive review, genes to 104 associated with COVID19 severity in multiple molecular studies. <h4>Results</h4> Fifteen symptoms common to Ehlers-Danlos versus long COVID19 ranged from brain fog (27-80 versus 30-70%), chronic fatigue (38-91; 30-60%), dyspnea (32-52; 29-52%) to irritable bowel (67-89; 14-78%), muscle weakness (22-49; 15-25%), and arthritis (32-94; 15-27%). Genes relevant to EDS included 6 identical to those influencing COVID19 severity ( F2 , LIFR , NLRP3 , STAT1 , T1CAM1 , TNFRSF13B ) and 18 similar including POLG - POLD4 , SLC6A2-SLC6A20 , and NFKB1-NFKB2 . Both gene sets had broad genomic distribution, many mitochondrial genes influencing EDS and many involved with immunity-inflammation modifying COVID19 severity. Recurring DNA variants in EDS that merit evaluation in COVID19 resistance include those impacting connective tissue elements--51 in COL5 (joint), 29 in COL1/2/9/11 (bone), 13 in COL3 (vessel), and 18 in FBN1 (vessel-heart)--or neural function--93 in mitochondrial DNA, 28 in COL6/12 , 16 in SCN9A/10A/11A , 14 in POLG , and 11 in genes associated with porphyria. <h4>Conclusions</h4> Holistic ascertainment of finding pattern and exome variation in EDS defined tissue laxity, neuromuscular, and autonomic correlations that transcend single abnormalities or types. Implied networks of nuclear and mitochondrial genes are linked to findings like brain fog, fatigue, and frailty in EDS, their similarity to long COVID19 supporting shared therapies for disorders affecting a minimum 0.1% of the global population.

53BP1 acts at the crossroads between DNA repair and p53-mediated stress response. With its interactor USP28, it is part of the mitotic surveillance pathway (MSP), a sensor that monitors the duration of cell division, promoting p53-dependent cell cycle arrest when a critical time threshold is surpassed. 53BP1 dynamically associates with kinetochores, being recruited during prophase, and then undergoing a time-dependent loss of affinity. However, the relevance of this behaviour remains unclear. Here, we identify CENP-F as an interaction partner and kinetochore receptor for 53BP1. By engineering human cells with a CENP-F point mutation, we demonstrate that preventing 53BP1 kinetochore localization does not reduce MSP proficiency. Strikingly, however, preventing the loss of 53BP1 from the kinetochore by inhibiting Polo-like kinase 1 (PLK1) restrains MSP activity, a phenomenon that is abrogated in the CENP-F mutant condition. Taken together, we demonstrate that kinetochore-loaded 53BP1 represents an MSP functionally inhibited state and that PLK1-dependent re-localization of 53BP1 represents an important layer of MSP regulation.

Although animal dispersal is known to play key roles in ecological and evolutionary processes such as colonization, population extinction and local adaptation, little is known about its genetic basis, particularly in vertebrates. Untapping the genetic basis of dispersal should deepen our understanding of how dispersal behaviour evolves, the molecular mechanisms that regulate it and link it to other phenotypic aspects in order to form the so-called dispersal syndromes. Here, we comprehensively combined quantitative genetics, genome-wide sequencing and transcriptome sequencing to investigate the genetic basis of natal dispersal in a known ecological and evolutionary model of vertebrate dispersal: the common lizard, Zootoca vivipara. Our study supports the heritability of dispersal in semi-natural populations, with less variation attributable to maternal and natal environment effects. In addition, we found an association between natal dispersal and both variation in the carbonic anhydrase (CA10) gene, and in the expression of several genes (TGFB2, SLC6A4, NOS1) involved in central nervous system functioning. These findings suggest that neurotransmitters (serotonin and nitric oxide) are involved in the regulation of dispersal and shaping dispersal syndromes. Several genes from the circadian clock (CRY2, KCTD21) were also differentially expressed between disperser and resident lizards, supporting that the circadian rhythm, known to be involved in long-distance migration in other taxa, might affect dispersal as well. Since neuronal and circadian pathways are relatively well conserved across vertebrates, our results are likely to be generalisable, and we therefore encourage future studies to further investigate the role of these pathways in shaping dispersal in vertebrates.

Single-cell approaches have become an increasingly popular way of understanding the genetic factors behind disease. Isolation of DNA and RNA from human tissues is necessary to analyze multi-omic data sets, providing information on the single-cell genome, transcriptome, and epigenome. Here, we isolated high-quality single-nuclei from postmortem human heart tissues for DNA and RNA analysis. Postmortem human tissues were obtained from 106 individuals, 33 with a history of myocardial disease, diabetes, or smoking, and 73 controls without heart disease. We demonstrated that the Qiagen EZ1 instrument and kit consistently isolated genomic DNA of high yield, which can be used for checking DNA quality before conducting single-cell experiments. Here, we provide a method for single-nuclei isolation from cardiac tissue, otherwise known as the SoNIC method, which allows for the isolation of single cardiomyocyte nuclei from postmortem tissue by nuclear ploidy status. We also provide a detailed quality control measure for single-nuclei whole genome amplification and a pre-amplification method for confirming genomic integrity.

There is a large unmet medical need to develop disease-modifying treatment options for individuals with age-related degenerative diseases of the central nervous system. The sigma-2 receptor (S2R), encoded by <i>TMEM97</i>, is expressed in brain and retinal cells, and regulates cell functions via its co-receptor progesterone receptor membrane component 1 (PGRMC1), and through other protein-protein interactions. Studies describing functions of S2R involve the manipulation of expression or pharmacological modulation using exogenous small-molecule ligands. These studies demonstrate that S2R modulates key pathways involved in age-related diseases including autophagy, trafficking, oxidative stress, and amyloid-β and α-synuclein toxicity. Furthermore, S2R modulation can ameliorate functional deficits in cell-based and animal models of disease. This review summarizes the current evidence-based understanding of S2R biology and function, and its potential as a therapeutic target for age-related degenerative diseases of the central nervous system, including Alzheimer's disease, α-synucleinopathies, and dry age-related macular degeneration.

Although the proteome of sperm has been characterized, there is still a lack of high-throughput studies on dysregulated proteins in sperm from subfertile men, with only a few studies on the sperm proteome in asthenozoospermic and oligoasthenozoospermic men. Using liquid chromatography-mass spectrometry (LC-MS/MS) along with bioinformatics analyses, we investigated the proteomic landscape of sperm collected from subfertile men (<i>n</i> = 22), i.e., asthenozoospermic men (<i>n</i> = 13), oligoasthenozoospermic men (<i>n</i> = 9) and normozoospermic controls (<i>n</i> = 31). We identified 4412 proteins in human sperm. Out of these, 1336 differentially abundant proteins were identified in 70% of the samples. In subfertile men, 32 proteins showed a lower abundance level and 34 showed a higher abundance level when compared with normozoospermic men. Compared to normozoospermic controls, 95 and 8 proteins showed a lower abundance level, and 86 and 1 proteins showed a higher abundance level in asthenozoospermic and oligoasthenozoospermic men, respectively. Sperm motility and count were negatively correlated with 13 and 35 and positively correlated with 37 and 20 differentially abundant proteins in asthenozoospermic and oligoasthenozoospermic men, respectively. The combination of the proteins APCS, APOE, and FLOT1 discriminates subfertile males from normozoospermic controls with an AUC value of 0.95. Combined APOE and FN1 proteins discriminate asthenozoospermic men form controls with an AUC of 1, and combined RUVBL1 and TFKC oligoasthenozoospermic men with an AUC of 0.93. Using a proteomic approach, we revealed the proteomic landscape of sperm collected from asthenozoospermic or oligoasthenozoospermic men. Identified abundance changes of several specific proteins are likely to impact sperm function leading to subfertility. The data also provide evidence for the usefulness of specific proteins or protein combinations to support future diagnosis of male subfertility.

<h4>Introduction and objectives</h4>The agreement of elastography techniques in chronic Hepatitis B (CHB) needs evaluation. We aimed to evaluate, in CHB, the agreement between transient elastography (TE) and two-dimensional shear wave elastography (2D-SWE), analyzing the factors related to the disagreement of measures.<h4>Materials and methods</h4>CHB patients underwent liver stiffness measures with both TE and 2D-SWE on the same day. For concordance analysis, we defined liver fibrosis as F0/1 vs. F ≥ 2, F0/1-F2 vs. F ≥ 3 and F0/1-F2-F3 vs. F4 for both methods. Logistic regression analysis was used to identify the variables independently associated with the disagreement between methods.<h4>Results</h4>A total of 150 patients were enrolled. Liver fibrosis categorization according to TE was: F0-F1 = 73 (50.4%), F ≥ 2 = 40 (27.6%), F ≥ 3 = 21 (14.5%) and F4 = 11 (7.6%), and according to 2D-SWE was: F0/F1 = 113 (77.9%), F ≥ 2 = 32 (22.1%), F≥ 3 = 25 (17.2%) and F4 = 11 (7.6%). It was observed that 20.0% of the sample had steatosis (CAP≥ 275 dB/m). TE and SD-SWE estimated equal fibrosis stages in 79.3% of cases. Spearman's correlation coefficient was 0.71 (<i>p</i> < 0.01). Kappa values for F ≥ 2, F ≥ 3 and F = 4 were: 0.78, <i>p</i> < 0.001; 0.73, <i>p</i> < 0.001; and 0.64, <i>p</i> < 0.001, respectively. Diabetes mellitus (DM) (OR 5.04; 95%CI: 1.89-13.3; <i>p</i> < 0.001) and antiviral treatment (OR 6.79; 95%CI: 2.33-19.83; <i>p</i> < 0.001) were independently associated with discordance between both methods.<h4>Conclusions</h4>In CHB, there is strong correlation and good agreement between TE and 2D-SWE in identifying fibrosis stages. Diabetes mellitus and antiviral therapy may impact the agreement of stiffness measures obtained with these elastographic methods.

Laron syndrome (LS) is a rare genetic disorder characterized by low levels of insulin-like growth factor 1 (IGF1) and high levels of growth hormone (GH) due to mutations in the growth hormone receptor gene (<i>GHR</i>). A <i>GHR</i>-knockout (<i>GHR</i>-KO) pig was developed as a model for LS, which displays many of the same features as humans with LS-like transient juvenile hypoglycemia. This study aimed to investigate the effects of impaired GHR signaling on immune functions and immunometabolism in <i>GHR</i>-KO pigs. GHR are located on various cell types of the immune system. Therefore, we investigated lymphocyte subsets, proliferative and respiratory capacity of peripheral blood mononuclear cells (PBMCs), proteome profiles of CD4^- and CD4⁺ lymphocytes and IFN-α serum levels between wild-type (WT) controls and <i>GHR</i>-KO pigs, which revealed significant differences in the relative proportion of the CD4⁺CD8α^- subpopulation and in IFN-α levels. We detected no significant difference in the respiratory capacity and the capacity for polyclonal stimulation in PBMCs between the two groups. But proteome analysis of CD4⁺ and CD4^- lymphocyte populations revealed multiple significant protein abundance differences between <i>GHR</i>-KO and WT pigs, involving pathways related to amino acid metabolism, beta-oxidation of fatty acids, insulin secretion signaling, and oxidative phosphorylation. This study highlights the potential use of <i>GHR</i>-KO pigs as a model for studying the effects of impaired GHR signaling on immune functions.

Recent development of human three-dimensional organoid cultures has opened new doors and opportunities ranging from modelling human development in vitro to personalised cancer therapies. These new in vitro systems are opening new horizons to the classic understanding of human development and disease. However, the complexity and heterogeneity of these models requires cutting-edge techniques to capture and trace global changes in gene expression to enable identification of key players and uncover the underlying molecular mechanisms. Rapid development of sequencing approaches made possible global transcriptome analyses and epigenetic profiling. Despite challenges in organoid culture and handling, these techniques are now being adapted to embrace organoids derived from a wide range of human tissues. Here, we review current state-of-the-art multi-omics technologies, such as single-cell transcriptomics and chromatin accessibility assays, employed to study organoids as a model for development and a platform for precision medicine.

High myopia (HM) is a leading cause of visual impairment in the world. To expand the genotypic and phenotypic spectra of HM in the Chinese population, we investigated genetic variations in a cohort of 113 families with nonsyndromic early-onset high myopia from northwestern China by whole-exome sequencing, with focus on 17 known genes. Sixteen potentially pathogenic variants predicted to affect protein function in eight of seventeen causative genes for HM in fifteen (13.3%) families were revealed, including seven novel variants, c.767 + 1G > A in ARR3, c.3214C > A/p.H1072N, and c.2195C > T/p.A732V in ZNF644, c.1270G > T/p.V424L in CPSF1, c.1918G > C/p.G640R and c.2786T > G/p.V929G in XYLT1, c.601G > C/p.E201Q in P4HA2; six rare variants, c.799G > A/p.E267K in NDUFAF7, c.1144C > T/p.R382W in TNFRSF21, c.1100C > T/p.P367L in ZNF644, c.3980C > T/p.S1327L in CPSF1, c.145G > A/p.E49K and c.325G > T/p.G109W in SLC39A5; and three known variants, c.2014A > G/p.S672G and c.3261A > C/p.E1087D in ZNF644, c.605C > T/p.P202L in TNFRSF21. Ten of them were co-segregated with HM. The mean (± SD) examination age of these 15 probands was 14.7 (± 11.61) years. The median spherical equivalent was - 9.50 D (IQ - 8.75 ~ - 12.00) for the right eye and - 11.25 D (IQ - 9.25 ~ - 14.13) for the left eye. The median axial length was 26.67 mm (IQ 25.83 ~ 27.13) for the right eye and 26.25 mm (IQ 25.97 ~ 27.32) for the left eye. These newly identified genetic variations not only broaden the genetic and clinical spectra, but also offer convincing evidence that the genes ARR3, NDUFAF7, TNFRSF21, and ZNF644 contribute to hereditable HM. This work improves further understanding of molecular mechanism of HM.

The intervertebral disc (IVD) acts as a fibrocartilaginous joint to anchor adjacent vertebrae. Although several studies have demonstrated the cellular heterogeneity of adult mature IVDs, a single-cell transcriptomic atlas mapping early IVD formation is still lacking. Here, the authors generate a spatiotemporal and single cell-based transcriptomic atlas of human IVD formation at the embryonic stage and a comparative mouse transcript landscape. They identify two novel human notochord (NC)/nucleus pulposus (NP) clusters, SRY-box transcription factor 10 (SOX10)⁺ and cathepsin K (CTSK)⁺ , that are distributed in the early and late stages of IVD formation and they are validated by lineage tracing experiments in mice. Matrisome NC/NP clusters, T-box transcription factor T (TBXT)⁺ and CTSK⁺ , are responsible for the extracellular matrix homeostasis. The IVD atlas suggests that a subcluster of the vertebral chondrocyte subcluster might give rise to an inner annulus fibrosus of chondrogenic origin, while the fibroblastic outer annulus fibrosus preferentially expresseds transgelin and fibromodulin . Through analyzing intercellular crosstalk, the authors further find that notochordal secreted phosphoprotein 1 (SPP1) is a novel cue in the IVD microenvironment, and it is associated with IVD development and degeneration. In conclusion, the single-cell transcriptomic atlas will be leveraged to develop preventative and regenerative strategies for IVD degeneration.

Annexin A2 (A2) is a member of the Annexin family, which contains Ca²⁺ -regulated phospholipid-binding proteins. Annexins associate with S100 proteins to form heterotetramers. The A2/S100A10 heterotetramer (A2t) is the most extensively studied of these heterotetramers. It induces membrane microdomain formation, causes membrane budding, and facilitates proliferation of some cancers. In this work, the first molecular dynamics (MD) study on the complete A2t of 868 amino acids was performed. MD trajectories of more than 600 ns each were generated for complete A2t complexes with and without Ca²⁺ ions. The outward extension of membrane-binding residues A2-K279 and A2-K281 was shown to be inhibited in the absence of Ca²⁺ as they were captured by Ca²⁺ -binding residue D322. F-actin binding residue A2-D339 was observed to occupy either an exposed or buried state in the absence of Ca²⁺ , while it only occupied the buried state in the presence of Ca²⁺ . The observed motions of the A2t subunits are highly organized with a strongly correlated central region which is negatively correlated with the periphery of the complex. The central region contains the S100A10 (p11) dimer, A2-N, and A2-I, while the periphery contains A2-II, A2-III, and A2-IV. Novel interactions between A2 and p11 were identified. A2 residues outside of A2-N (K80, R77, E82, and R145) had strong interactions with p11. Residue R145 of A2 may have a significant effect on the dynamics of the system, with its interaction resulting in asymmetric motions of A2. The presented results provide novel insights to inform future experimental studies.

Esophageal squamous cell carcinoma (ESCC) is malignant while the carcinogenesis is still unclear. Here, we perform a comprehensive multi-omics analysis of 786 trace-tumor-samples from 154 ESCC patients, covering 9 histopathological stages and 3 phases. Proteogenomics elucidates cancer-driving waves in ESCC progression, and reveals the molecular characterization of alcohol drinking habit associated signatures. We discover chromosome 3q gain functions in the transmit from nontumor to intraepithelial neoplasia phases, and find TP53 mutation enhances DNA replication in intraepithelial neoplasia phase. The mutations of AKAP9 and MCAF1 upregulate glycolysis and Wnt signaling, respectively, in advanced-stage ESCC phase. Six major tracks related to different clinical features during ESCC progression are identified, which is validated by an independent cohort with another 256 samples. Hyperphosphorylated phosphoglycerate kinase 1 (PGK1, S203) is considered as a drug target in ESCC progression. This study provides insight into the understanding of ESCC molecular mechanism and the development of therapeutic targets.

Antagonistic interaction refers to opposing beneficial and adverse signaling by a single agent. Understanding opposing signaling is important because pathologic outcomes can result from adverse causative agents or the failure of beneficial mechanisms. To test for opposing responses at a systems level, we used a transcriptome-metabolome-wide association study (TMWAS) with the rationale that metabolite changes provide a phenotypic readout of gene expression, and gene expression provides a phenotypic readout of signaling metabolites. We incorporated measures of mitochondrial oxidative stress (mtOx) and oxygen consumption rate (mtOCR) with TMWAS of cells with varied manganese (Mn) concentration and found that adverse neuroinflammatory signaling and fatty acid metabolism were connected to mtOx, while beneficial ion transport and neurotransmitter metabolism were connected to mtOCR. Each community contained opposing transcriptome-metabolome interactions, which were linked to biologic functions. The results show that antagonistic interaction is a generalized cell systems response to mitochondrial ROS signaling.

Cervical cancer is still an important problem perplexing health management in developing countries. Previous studies have shown that cervical cancer cells show markers of aerobic glycolysis, suggesting that these tumors may secrete lactic acid. Through the biological characterization of lactate gene in tumor and its relationship with immune cells in tumor microenvironment, a lactate scoring system capable of evaluating cancer prognosis was constructed to explore the molecular mechanism of lactate metabolism disorder affecting prognosis. 29 hub genes in this study were differentially expressed in cervical cancer, including 24 genes related to lactate metabolism, LDHA in Lactate dehydrogenase (LDH) group, SLC16A3 in Monocarboxylate transporters (MCT) group and three Histone lactation modification related genes (EP300, ACAT1, ACACA). More importantly, we found that from an epigenetic point of view, histone lactation plays an important role in the pathogenesis and prognosis of cervical cancer. Mainly affect the prognosis of the disease through changes in the infiltration of plasmacytoid Dendritic Cell (pDC) and Central Memory T cell (Tcm) in the tumor immune microenvironment. Lactate inhibition may be a useful tool for anticancer therapy.

Systemic lupus erythematosus (SLE) is caused by a combination of genetic and environmental factors. Recently, analysis of a functional genome database of genetic polymorphisms and transcriptomic data from various immune cell subsets revealed the importance of the oxidative phosphorylation (OXPHOS) pathway in the pathogenesis of SLE. In particular, activation of the OXPHOS pathway is persistent in inactive SLE, and this activation is associated with organ damage. The finding that hydroxychloroquine (HCQ), which improves the prognosis of SLE, targets toll-like receptor (TLR) signaling upstream of OXPHOS suggests the clinical importance of this pathway. IRF5 and SLC15A4, which are regulated by polymorphisms associated with SLE susceptibility, are functionally associated with OXPHOS as well as blood interferon activity and metabolome. Future analyses of OXPHOS-associated disease-susceptibility polymorphisms, gene expression, and protein function may be useful for risk stratification of SLE.

<h4>Background</h4>Cardiovascular disease had a global prevalence of 523 million cases and 18.6 million deaths in 2019. The current standard for diagnosing coronary artery disease (CAD) is coronary angiography either by invasive catheterization (ICA) or computed tomography (CTA). Prior studies employed single-molecule, amplification-independent RNA sequencing of whole blood to identify an RNA signature in patients with angiographically confirmed CAD. The present studies employed Illumina RNAseq and network co-expression analysis to identify systematic changes underlying CAD.<h4>Methods</h4>Whole blood RNA was depleted of ribosomal RNA (rRNA) and analyzed by Illumina total RNA sequencing (RNAseq) to identify transcripts associated with CAD in 177 patients presenting for elective invasive coronary catheterization. The resulting transcript counts were compared between groups to identify differentially expressed genes (DEGs) and to identify patterns of changes through whole genome co-expression network analysis (WGCNA).<h4>Results</h4>The correlation between Illumina amplified RNAseq and the prior SeqLL unamplified RNAseq was quite strong (r = 0.87), but there was only 9 % overlap in the DEGs identified. Consistent with the prior RNAseq, the majority (93 %) of DEGs were down-regulated ~1.7-fold in patients with moderate to severe CAD (>20 % stenosis). DEGs were predominantly related to T cells, consistent with known reductions in Tregs in CAD. Network analysis did not identify pre-existing modules with a strong association with CAD, but patterns of T cell dysregulation were evident. DEGs were enriched for transcripts associated with ciliary and synaptic transcripts, consistent with changes in the immune synapse of developing T cells.<h4>Conclusions</h4>These studies confirm and extend a novel mRNA signature of a Treg-like defect in CAD. The pattern of changes is consistent with stress-related changes in the maturation of T and Treg cells, possibly due to changes in the immune synapse.

<h4>Background</h4>Risk for venous thromboembolism has a strong genetic component. Whole genome sequencing from the TOPMed program (Trans-Omics for Precision Medicine) allowed us to look for new associations, particularly rare variants missed by standard genome-wide association studies.<h4>Methods</h4>The 3793 cases and 7834 controls (11.6% of cases were individuals of African, Hispanic/Latino, or Asian ancestry) were analyzed using a single variant approach and an aggregate gene-based approach using our primary filter (included only loss-of-function and missense variants predicted to be deleterious) and our secondary filter (included all missense variants).<h4>Results</h4>Single variant analyses identified associations at 5 known loci. Aggregate gene-based analyses identified only <i>PROC</i> (odds ratio, 6.2 for carriers of rare variants; <i>P</i>=7.4×10^-14) when using our primary filter. Employing our secondary variant filter led to a smaller effect size at <i>PROC</i> (odds ratio, 3.8; <i>P</i>=1.6×10^-14), while excluding variants found only in rare isoforms led to a larger one (odds ratio, 7.5). Different filtering strategies improved the signal for 2 other known genes: <i>PROS1</i> became significant (minimum <i>P</i>=1.8×10^-6 with the secondary filter), while <i>SERPINC1</i> did not (minimum <i>P</i>=4.4×10^-5 with minor allele frequency <0.0005). Results were largely the same when restricting the analyses to include only unprovoked cases; however, one novel gene, <i>MS4A1</i>, became significant (<i>P</i>=4.4×10^-7 using all missense variants with minor allele frequency <0.0005).<h4>Conclusions</h4>Here, we have demonstrated the importance of using multiple variant filtering strategies, as we detected additional genes when filtering variants based on their predicted deleteriousness, frequency, and presence on the most expressed isoforms. Our primary analyses did not identify new candidate loci; thus larger follow-up studies are needed to replicate the novel <i>MS4A1</i> locus and to identify additional rare variation associated with venous thromboembolism.

Previous research has revealed an association between endometriosis and various autoimmune diseases, while recent data suggest, for the first time, an association between endometriosis and the risk of developing ankylosing spondylitis (AS). AS, the prototype of spondyloarthritides diseases, is a systemic, chronic, immune‑mediated inflammatory arthritis, which primarily affects the spine and sacroiliac joints, as well as the axial skeleton with or without extraspinal manifestations. AS is of polygenic inheritance and numerous immunologically relevant genes contribute to its development. Endometriosis is an enigmatic, relatively common, benign, estrogen‑dependent, heterogeneous gynecological disease, influenced by multiple genetic, epigenetic and environmental factors. It is characterized by the growth of endometrial tissue occurring in sites other than the uterine cavity, most commonly in the pelvic cavity, including the ovaries and the uterosacral ligaments, affecting up to 10% of the female population of childbearing age, causing pain and infertility. The present review discusses whether a partially shared genetic background may explain the co‑occurrence of these disorders, as well as potential similarities regarding the underlying pathogenetic mechanisms and specific molecular and cellular pathways.

The central nervous system (CNS) consists of neuron and non-neuron cells including neural stem/precursor cells (NSPCs), neuroblasts, glia cells (mainly astrocyte, oligodendroglia and microglia), which thereby form a precise and complicated network and exert diverse functions through interactions of numerous bioactive ingredients. MicroRNAs (miRNAs), with small size approximately  ~ 21nt and as well-documented post-transcriptional key regulators of gene expression, are a cluster of evolutionarily conserved endogenous non-coding RNAs. More than 2000 different miRNAs has been discovered till now. MicroRNA-124(miR-124), the most brain-rich microRNA, has been validated to possess important functions in the central nervous system, including neural stem cell proliferation and differentiation, cell fate determination, neuron migration, synapse plasticity and cognition, cell apoptosis etc. According to recent studies, herein, we provide a review of this conversant miR-124 to further understand the potential functions and therapeutic and clinical value in brain diseases.

The molecular circadian clock is regulated by a transcriptional translational feedback loop. However, the post-translational control mechanisms are less understood. The NRON complex is a large ribonucleoprotein complex, consisting of a lncRNA and several proteins. Components of the complex play a distinct role in regulating protein phosphorylation, synthesis, stability, and translocation in cellular processes. This includes the NFAT and the circadian clock pathway. PSMD11 is a component of the NRON complex and a lid component of the 26S proteasome. Among the PSMD family members, PSMD11 has a more specific role in circadian clock function. Here, we used cell and biochemical approaches and characterized the role of PSMD11 in regulating the stability and nuclear translocation of circadian clock proteins. We used size exclusion chromatography to enrich the NRON complex in the cytosolic and nuclear fractions. More specifically, PSMD11 knockdown affected the abundance of PER2 and CRY2 proteins and the nuclear translocation of CRY1. This changed the relative abundance of CRY1 and CRY2 in the nucleus. Thus, this work defines the role of PSMD11 in the NRON complex regulating the nuclear translocation of circadian repressors, thereby enabling cellular circadian oscillations.

<h4>Background and objectives</h4>Diabetes mellitus (DM) contributes significantly to metabolic syndrome and cardiovascular events, and it may be a comorbidity of epilepsy. The objective of this study was to investigate whether long-term antiseizure medication (ASM) use is associated with the risk of developing type 2 diabetes.<h4>Methods</h4>We analyzed data from the Chang Gung Research Database. Patients aged ≥45 years who received ASM treatment from January 2001 to May 2019 were identified. Patients with DM-associated diseases and short-term ASM use were excluded. The patients were classified into nonenzyme interaction, enzyme-inducing, enzyme-inhibiting, and mixed ASM groups. The rate of incident diabetes associated with individual ASM was further analyzed. Propensity score weighting was performed to balance between-group differences. Analyses were conducted with Cox proportional regression models and stabilized inverse probability of treatment weighting (IPTW). Hazard ratios (HRs) were calculated at 3, 4, 6, and 9 years after the index date and the end of follow-up.<h4>Results</h4>A total of 5,103 patients were analyzed, of whom 474 took nonenzyme interaction ASMs, 1,156 took enzyme-inducing ASMs, 336 took enzyme-inhibiting ASMs, and 3,137 took mixed ASMs. During follow-up (39,248 person-years), 663 patients developed new-onset DM, and the prevalence was 13.0%. The incidence of DM plateaued at 6-9 years after ASM initiation. Enzyme-inhibiting ASMs were significantly associated with a higher HR starting at the third year and then throughout the study period. The HRs were 1.93 (95% CI 1.33-2.80), 1.85 (95% CI 1.24-2.75), and 2.08 (95% CI 1.43-3.03) in unadjusted, adjusted, and stabilized IPTW models, respectively, at the end of follow-up. The dosing of ASM did not increase the risk of DM, and none of the individual ASM analyses reached statistical significance.<h4>Discussion</h4>The long-term use of enzyme-inhibiting ASMs was associated with an increased risk of incident DM, and the risk increased with the duration of treatment. These findings may guide the choice of drugs in those requiring long-term ASM therapy, particularly in high-risk individuals.<h4>Classification of evidence</h4>This study provides Class IV evidence that enzyme-inhibiting ASMs were associated with an increased risk of developing DM compared with nonenzyme interaction ASMs.

Allergic diseases such as allergic rhinitis (AR), allergic asthma (AAS), atopic dermatitis (AD), food allergy (FA), and eczema are systemic diseases caused by an impaired immune system. Accompanied by high recurrence rates, the steadily rising incidence rates of these diseases are attracting increasing attention. The pathogenesis of allergic diseases is complex and involves many factors, including maternal-fetal environment, living environment, genetics, epigenetics, and the body's immune status. The pathogenesis of allergic diseases exhibits a marked heterogeneity, with phenotype and endotype defining visible features and associated molecular mechanisms, respectively. With the rapid development of immunology, molecular biology, and biotechnology, many new biological drugs have been designed for the treatment of allergic diseases, including anti-immunoglobulin E (IgE), anti-interleukin (IL)-5, and anti-thymic stromal lymphopoietin (TSLP)/IL-4, to control symptoms. For doctors and scientists, it is becoming more and more important to understand the influencing factors, pathogenesis, and treatment progress of allergic diseases. This review aimed to assess the epidemiology, pathogenesis, and therapeutic interventions of allergic diseases, including AR, AAS, AD, and FA. We hope to help doctors and scientists understand allergic diseases systematically.

In addition to constituting the genetic material of an organism, DNA is a tracer for the recognition of foreign pathogens and a trigger of the innate immune system. cGAS functions as a sensor of double-stranded DNA fragments and initiates an immune response via the adaptor protein STING. The cGAS-STING pathway not only defends cells against various DNA-containing pathogens but also modulates many pathological processes caused by the immune response to the ectopic localization of self-DNA, such as cytosolic mitochondrial DNA (mtDNA) and extranuclear chromatin. In addition, macrophages can cause inflammation by forming a class of protein complexes called inflammasomes, and the activation of the NLRP3 inflammasome requires the release of oxidized mtDNA. In innate immunity related to inflammasomes, mtDNA release is mediated by macropores that are formed on the outer membrane of mitochondria via VDAC oligomerization. These macropores are specifically formed in response to mitochondrial stress and tissue damage, and the inhibition of VDAC oligomerization mitigates this inflammatory response. The rapidly expanding area of research on the mechanisms by which mtDNA is released and triggers inflammation has revealed new treatment strategies not only for inflammation but also, surprisingly, for neurodegenerative diseases such as amyotrophic lateral sclerosis.

<h4>Background</h4>Tissue engineering for cartilage regeneration has made great advances in recent years, although there are still challenges to overcome. This study aimed to evaluate the chondrogenic differentiation of human adipose-derived mesenchymal stem cells (hADSCs) on three-dimensional scaffolds based on polyglycerol sebacate (PGS) / polycaprolactone (PCL) / gelatin(Gel) in the presence of Nanohydroxyapatite (nHA).<h4>Materials and methods</h4>In this study, a series of nHA-nanocomposite scaffolds were fabricated using 100:0:0, 60:40:0, and 60:20:20 weight ratios of PGS to PCL: Gel copolymers through salt leaching method. The morphology and porosity of prepared samples was characterized by SEM and EDX mapping analysis. Also, the dynamic contact angle and PBS adsorption tests are used to identify the effect of copolymerization and nanoparticles on scaffolds' hydrophilicity. The hydrolytic degradation properties were also analyzed. Furthermore, cell viability and proliferation as well as cell adhesion are evaluated to find out the biocompatibility. To determine the potential ability of nHA-nanocomposite scaffolds in chondrogenic differentiation, RT-PCR assay was performed to monitor the expression of collagen II, aggrecan, and Sox9 genes as markers of cartilage differentiation.<h4>Results</h4>The nanocomposites had an elastic modulus within a range of 0.71-1.30 MPa and 0.65-0.43 MPa, in dry and wet states, respectively. The PGS/PCL sample showed a water contact angle of 72.44 ± 2.2°, while the hydrophilicity significantly improved by adding HA nanoparticles. It was found from the hydrolytic degradation study that HA incorporation can accelerate the degradation rate compared with PGS and PGS/PCL samples. Furthermore, the in vitro biocompatibility tests showed significant cell attachment, proliferation, and viability of adipose-derived mesenchymal stem cells (ADMSCs). RT-PCR also indicated a significant increase in collagen II, aggrecan and Sox9 mRNA levels.<h4>Conclusions</h4>Our findings demonstrated that these nanocomposite scaffolds promote the differentiation of hADSCs into chondrocytes possibly by the increase in mRNA levels of collagen II, aggrecan, and Sox9 as markers of chondrogenic differentiation. In conclusion, the addition of PCL, Gelatin, and HA into PGS is a practical approach to adjust the general features of PGS to prepare a promising scaffold for cartilage tissue engineering.

<h4>Background</h4>Per- and polyfluoroalkyl substances (PFAS) are chemicals that are resistant to degradation and ubiquitous in our environments. PFAS may impact the developing epigenome, but current human evidence is limited to assessments of total DNA methylation. We assessed associations between first trimester PFAS exposures with newborn DNA methylation, including 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC). DNA methylation mediation of associations between PFAS and birth outcomes were explored in the Michigan Mother Infant Pairs cohort. Nine PFAS were measured in maternal first trimester blood. Seven were highly detected and included for analysis: PFHxS, PFOA, PFOS, PFNA, PFDA, PFUnDA, and MeFOSAA. Bisulfite-converted cord blood DNA (n = 141) and oxidative-bisulfite-converted cord blood (n = 70) were assayed on Illumina MethylationEPIC BeadChips to measure total DNA methylation (5-mC + 5-hmC) and 5-mC/5-hmC. Correcting for multiple comparisons, beta regressions were used to assess associations between levels of PFAS and total methylation, 5-mC, or 5-hmC. Nonlinear mediation analyses were used to assess the epigenetic meditation effect between PFAS and birth outcomes.<h4>Results</h4>PFAS was significantly associated with total methylation (q < 0.05: PFHxS-12 sites; PFOS-19 sites; PFOA-2 sites; PFNA-3 sites; PFDA-4 sites). In 72 female infants and 69 male infants, there were sex-specific associations between five PFAS and DNA methylation. 5-mC and 5-hmC were each significantly associated with thousands of sites for PFHxS, PFOS, PFNA, PFDA, PFUnDA, and MeFOSAA (q < 0.05). Clusters of 5-mC and 5-hmC sites were significant mediators between PFNA and PFUnDA and decreased gestational age (q < 0.05).<h4>Conclusions</h4>This study demonstrates the mediation role of specific types of DNA methylation on the relationship between PFAS exposure and birth outcomes. These results suggest that 5-mC and 5-hmC may be more sensitive to the developmental impacts of PFAS than total DNA methylation.

The CRISPR-Cas system is commonly known for its ability to cleave DNA in a programmable manner, which has democratized gene editing and facilitated recent breakthroughs in gene therapy. However, newer iterations of the technology using nuclease-disabled Cas enzymes have spurred a variety of different types of genetic engineering platforms such as transcriptional modulation using the CRISPR activation (CRISPRa) and CRISPR interference (CRISPRi) systems. This review introduces the creation of these programmable transcriptional modulators, various methods of delivery utilized for these systems, and recent technological developments. CRISPRa and CRISPRi have also been implemented in genetic screens for interrogating gene function and discovering genes involved in various biological pathways. We describe recent compelling examples of how these tools have become powerful means to unravel genetic networks and uncovering important information about devastating diseases. Finally, we provide an overview of preclinical studies in which transcriptional modulation has been used therapeutically, and we discuss potential future directions of these novel modalities.

The transcription factor Nrf2 was originally identified as a master regulator of redox homeostasis, as it governs the expression of a battery of genes involved in mitigating oxidative and electrophilic stress. However, the central role of Nrf2 in dictating multiple facets of the cellular stress response has defined the Nrf2 pathway as a general mediator of cell survival. Recent studies have indicated that Nrf2 regulates the expression of genes controlling ferroptosis, an ironand lipid peroxidation-dependent form of cell death. While Nrf2 was initially thought to have anti-ferroptotic function primarily through regulation of the antioxidant response, accumulating evidence has indicated that Nrf2 also exerts anti-ferroptotic effects via regulation of key aspects of iron and lipid metabolism. In this review, we will explore the emerging role of Nrf2 in mediating iron homeostasis and lipid peroxidation, where several Nrf2 target genes have been identified that encode critical proteins involved in these pathways. A better understanding of the mechanistic relationship between Nrf2 and ferroptosis, including how genetic and/or pharmacological manipulation of Nrf2 affect the ferroptotic response, should facilitate the development of new therapies that can be used to treat ferroptosis-associated diseases.

<h4>Introduction</h4>Osteoarthritis (OA) is a chronic degenerative joint disease accompanied by an elevated macrophage proinflammatory phenotype, which is triggered by persistent pathologically elevated calcium ion levels in mitochondria. However, existing pharmacological compounds targeting the inhibition of mitochondrial calcium ion (m[Ca²⁺]) influx are currently limited in terms of plasma membrane permeability and low specificity for ion channels and transporters. In the present study, we synthesized mesoporous silica nanoparticle-amidated (MSN)-ethylenebis (oxyethylenenitrilo)tetraacetic acid (EGTA)/triphenylphosphine (TPP)-polyethylene glycol (PEG) [METP] nanoparticles (NPs), which specifically target mitochondria and block excess calcium ion influx.<h4>Methods</h4>m[Ca²⁺] overload in OA mouse bone marrow-derived macrophages (BMDMs) was detected by a fluorescence probe. A tissue in situ fluorescence colocalization assay was used to evaluate METP NP uptake by macrophages. BMDMs from healthy mice were pretreated with a concentration gradient of METP NPs followed by lipopolysaccharide (LPS) stimulation and detection of m[Ca²⁺] levels in vitro. The optimal METP NP concentration was further applied, and the endoplasmic reticulum (ER) and cytoplasm calcium levels were detected. The inflammatory phenotype was measured by surface markers, cytokine secretion and intracellular inflammatory gene/protein expression. A Seahorse cell energy metabolism assay was performed to elucidate the mechanism by which METP NPs reverse the BMDM proinflammatory phenotype.<h4>Results</h4>The present study identified calcium overload in BMDM mitochondria of OA mice. We demonstrated that METP NPs reversed the increased m[Ca²⁺] levels in mitochondria and the proinflammatory phenotype of BMDMs, with both in vivo and in vitro experiments, via the inhibition of the mitochondrial aspartate-arginosuccinate shunt and ROS production.<h4>Conclusion</h4>We demonstrated that METP NPs are effective and highly specific regulators of m[Ca²⁺] overload. In addition, we demonstrated that these METP NPs reverse the macrophage proinflammatory phenotype by restoring m[Ca²⁺] homeostasis, thereby inhibiting the tissue inflammatory response and achieving a therapeutic effect for OA.

Diabetes mellitus is a chronic metabolic disorder caused either by inadequate insulin secretion, impaired insulin function, or both. Uncontrolled diabetes is characterized by hyperglycemia which over time leads to fatal damage to both macro-and microvascular systems, causing complications such as cardiovascular diseases, retinopathy and nephropathy. Diabetes management is conventionally delivered through modifications of diet and lifestyle and pharmacological treatment, using antidiabetic drugs, and ultimately insulin injections. However, the side effects and financial cost of medications often reduce patient compliance to treatment, negatively affecting their health outcomes. Natural phytochemicals from edible plants such as fruits and vegetables (F&V) and medicinal herbs have drawn a growing interest as potential therapeutic agents for treating diabetes and preventing the onset and progression of diabetic complications. Flavonoids, the most abundant polyphenols in the human diet, have shown antidiabetic effects in numerous <i>in vitro</i> and preclinical studies. The underlying mechanisms have been linked to their antioxidant, anti-inflammatory and immunomodulatory activities. Carotenoids, another major group of dietary phytochemicals, have also shown antidiabetic potential in recent <i>in vitro</i> and <i>in vivo</i> experimental models, possibly through a mechanism of action similar to that of flavonoids. However, scientific evidence on the efficacy of these phytochemicals in treating diabetes or preventing the onset and progression of its complications in clinical settings is scarce, which delays the translation of animal study evidence to human applications and also limits the knowledge on their modes of actions in diabetes management. This review is aimed to highlight the potential roles of flavonoids and carotenoids in preventing or ameliorating diabetes-related complications based on <i>in vivo</i> study evidence, i.e., an array of preclinical animal studies and human intervention trials. The current general consensus of the underlying mechanisms of action exerted by both groups of phytochemicals is that their anti-inflammatory action is key. However, other potential mechanisms of action are considered. In total, 50 <i>in vivo</i> studies were selected for a review after a comprehensive database search <i>via</i> PubMed and ScienceDirect from January 2002 to August 2022. The key words used for analysis are type-2 diabetes (T2DM), diabetic complications, flavonoids, carotenoids, antioxidant, anti-inflammatory, mechanisms of prevention and amelioration, animal studies and human interventions.

Major depressive disorder (MDD) is a chronic and disabling disorder affecting roughly 280 million people worldwide. While multiple brain areas have been implicated, dysfunction of prefrontal cortex (PFC) circuitry has been consistently documented in MDD, as well as in animal models for stress-induced depression-like behavioral states. During brain development, axonal guidance cues organize neuronal wiring by directing axonal pathfinding and arborization, dendritic growth, and synapse formation. Guidance cue systems continue to be expressed in the adult brain and are emerging as important mediators of synaptic plasticity and fine-tuning of mature neural networks. Dysregulation or interference of guidance cues has been linked to depression-like behavioral abnormalities in rodents and MDD in humans. In this review, we focus on the emerging role of guidance cues in stress-induced changes in adult prefrontal cortex circuitry and in precipitating depression-like behaviors. We discuss how modulating axonal guidance cue systems could be a novel approach for precision medicine and the treatment of depression.

<b>Background:</b> Idiopathic pulmonary fibrosis (IPF), a chronic, progressive lung disease characterized by interstitial remodeling and tissue destruction, affects people worldwide and places a great burden on society. Cellular senescence is thought to be involved in the mechanisms and development of IPF. The aim of this study was to predictively investigate subtypes of IPF according to cellular senescence-related genes and their correlation with the outcome of patients with IPF, providing possible treatment and management options for disease control. <b>Methods:</b> Gene expression profiles and follow-up data were obtained from the GEO database. Senescence-related genes were obtained from the CSGene database and analyzed their correlation with the outcome of IPF. A consensus cluster was constructed to classify the samples based on correlated genes. The GSVA and WGCNA packages in R were used to calculate the immune-related enriched fractions and construct gene expression modules, respectively. Metascape and the clusterProfiler package in R were used to enrich gene functions. The ConnectivityMap was used to probe suitable drugs for potential treatment. <b>Results:</b> A total of 99 cellular senescence-related genes were associated with IPF prognosis. Patients with IPF were divided into two subtypes with significant prognostic differences. Subtype S2 was characterized by enhanced fibrotic progression and infection, leading to acute exacerbation of IPF and poor prognosis. Finally, five cellular senescence-related genes, TYMS, HJURP, UBE2C, BIRC5, and KIF2C, were identified as potential biomarkers in poor prognostic patients with IPF. <b>Conclusion:</b> The study findings indicate that cellular senescence-related genes can be used to distinguish the prognosis of patients with IPF. Among them, five genes can be used as candidate biomarkers to predict patients with a poor prognostic subtype for which anti-fibrosis and anti-infection treatments could be suitable.

Tumor progression and cancer metastasis has been linked to the release of microparticles (MPs), which are shed upon cell activation or apoptosis and display parental cell antigens, phospholipids such as phosphatidylserine (PS), and nucleic acids on their external surfaces. In this review, we highlight the biogenesis of MPs as well as the pathophysiological processes of PS externalization and its involvement in coagulation activation. We review the available evidence, suggesting that coagulation factors (mainly tissue factor, thrombin, and fibrin) assist in multiple steps of tumor dissemination, including epithelial-mesenchymal transition, extracellular matrix remodeling, immune escape, and tumor angiogenesis to support the formation of the pre-metastatic niche. Platelets are not just bystander cells in circulation but are functional players in primary tumor growth and metastasis. Tumor-induced platelet aggregation protects circulating tumor cells (CTCs) from the blood flow shear forces and immune cell attack while also promoting the binding of CTCs to endothelial cells and extravasation, which activates tumor invasion and sustains metastasis. Finally, in terms of therapy, lactadherin can inhibit coagulation by competing effectively with coagulation factors for PS binding sites and may similarly delay tumor progression. Furthermore, we also investigate the therapeutic potential of coagulation factor inhibitors within the context of cancer treatment. The development of multiple therapies targeting platelet activation and platelet-tumor cell interactions may not only reduce the lethal consequences of thrombosis but also impede tumor growth and spread.

Non-alcoholic fatty liver disease (NAFLD) is currently the most prevalent cause of chronic liver disease (CLD). Currently, the only therapeutic recommendation available is a lifestyle change. However, adherence to this approach is often difficult to guarantee. Alteration of the microbiota and an increase in intestinal permeability seem to be key in the development and progression of NAFLD. Therefore, the manipulation of microbiota seems to provide a promising therapeutic strategy. One way to do so is through faecal microbiota transplantation (FMT). Here, we summarize the key aspects of FMT, detail its current indications and highlight the most recent advances in NAFLD.

tRNA-derived small RNAs (tsRNAs) are derived from tRNA and include tRNA halves (tiRNAs) and tRNA fragments (tRFs). tsRNAs have been implicated in a variety of important biological functions, such as cell growth, transcriptional regulation, and apoptosis. Emerging evidence has shown that Ago1-guided and Ago2-guided tsRNAs are expressed at 3 and 30 days in <i>Drosophila</i> and that tRF biogenesis in fruit flies affects tRNA processing and tRNA methylation. However, a wide analysis of tsRNA patterns in different ages of <i>Drosophila</i> have not been reported via the small RNA sequencing method. In the present study, tsRNAs of young (7 days) and old (42 days) <i>Drosophila</i> were sequenced and their expression characteristics were analysed. Then, a specific tRF (named <i>tRF-Trp-CCA-014</i>) was determined and was found to be conserved in fruit flies, mice, and humans. The expression patterns of <i>tRF-Trp-CCA-014</i> in different tissues and stages of fruit flies and mice, and mouse NIH/3T3 cells were detected. Furthermore, mouse embryonic fibroblast NIH/3T3 cells were used as a model to analyse the function and targets of <i>tRF-Trp-CCA-014</i>. The RNA-seq data of six groups (Mimics, Mimic NC, Inhibitors, Inhibitor NC, Aging (adriamycin), and Control (Normal)) in mouse NIH3T3 cells were analysed. The results showed that the number of tsRNAs at 42 days (417) was more than at 7 days (288); thus, it was enriched with age. tRFs-1 were the most enriched, followed by 5'-tRFs and 3'-tRFs. Twenty-one differentially expressed tsRNAs were identified between 7 days and 42 days. Then, the conserved tRF <i>tRF-Trp-CCA-014</i> was identified and found to accumulate in aged fruit flies and aged mouse NIH3T3 cells. RNA-seq data showed that most differentially expressed genes were involved in the immune system, cancer: overview, and signal translation. Furthermore, <i>tRF-Trp-CCA-014</i> was found to bind to the 3'UTR of <i>H3C4</i> in a dual-luciferase reporter gene assay. <i>tRF-Trp-CCA-014</i> and <i>H3C4</i> were detected in the cytoplasm of aged NIH3T3 cells by RNA in situ hybridization. These results suggest that the <i>H3C4</i> gene is the target of <i>tRF-Trp-CCA-014</i>. This study will advance the current understanding of tRF roles and their implication in <i>Drosophila</i> and mouse studies.

Sphingosine-1-phosphate lyase (SPL) is a pyridoxal 5'-phosphate-dependent enzyme involved in the irreversible degradation of sphingosine-1-phosphate (S1P)-a bioactive sphingolipid that modulates a broad range of biological processes (cell proliferation, migration, differentiation and survival; mitochondrial functioning; and gene expression). Although SPL activity leads to a decrease in the available pool of S1P in the cell, at the same time, hexadecenal and phosphoethanolamine, compounds with potential biological activity, are generated. The increased expression and/or activity of SPL, and hence the imbalance between S1P and the end products of its cleavage, were demonstrated in several pathological states. On the other hand, loss-of-function mutations in the SPL encoding gene are a cause of severe developmental impairments. Recently, special attention has been paid to neurodegenerative diseases as the most common pathologies of the nervous system. This review summarizes the current findings concerning the role of SPL in the nervous system with an emphasis on neurodegeneration. Moreover, it briefly discusses pharmacological compounds directed to inhibit its activity.

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Common causes include gram-negative and gram-positive bacteria as well as fungi. Neutrophils are among the first cells to arrive at an infection site where they function as important effector cells of the innate immune system and as regulators of the host immune response. The regulation of neutrophil migration is therefore important both for the infection-directed host response and for the development of organ dysfunctions in sepsis. Downregulation of CXCR4/CXCL12 stimulates neutrophil migration from the bone marrow. This is followed by transmigration/extravasation across the endothelial cell barrier at the infection site; this process is directed by adhesion molecules and various chemotactic gradients created by chemotactic cytokines, lipid mediators, bacterial peptides, and peptides from damaged cells. These mechanisms of neutrophil migration are modulated by sepsis, leading to reduced neutrophil migration and even reversed migration that contributes to distant organ failure. The sepsis-induced modulation seems to differ between neutrophil subsets. Furthermore, sepsis patients should be regarded as heterogeneous because neutrophil migration will possibly be further modulated by the infecting microorganisms, antimicrobial treatment, patient age/frailty/sex, other diseases (e.g., hematological malignancies and stem cell transplantation), and the metabolic status. The present review describes molecular mechanisms involved in the regulation of neutrophil migration; how these mechanisms are altered during sepsis; and how bacteria/fungi, antimicrobial treatment, and aging/frailty/comorbidity influence the regulation of neutrophil migration.

Testicular germ cell tumours (TGCTs) are the most common malignancy in young men. Originating from foetal testicular germ cells that fail to differentiate correctly, TGCTs appear after puberty as germ cell neoplasia in situ cells that transform through unknown mechanisms into distinct seminoma and non-seminoma tumour types. A balance between activin and BMP signalling may influence TGCT emergence and progression, and we investigated this using human cell line models of seminoma (TCam-2) and non-seminoma (NT2/D1). Activin A- and BMP4-regulated transcripts measured at 6 h post-treatment by RNA-sequencing revealed fewer altered transcripts in TCam-2 cells but a greater responsiveness to activin A, while BMP4 altered more transcripts in NT2/D1 cells. Activin significantly elevated transcripts linked to pluripotency, cancer, TGF-β, Notch, p53, and Hippo signalling in both lines, whereas BMP4 altered TGF-β, pluripotency, Hippo and Wnt signalling components. Dose-dependent antagonism of BMP4 signalling by activin A in TCam-2 cells demonstrated signalling crosstalk between these two TGF-β superfamily arms. Levels of the nuclear transport protein, IPO5, implicated in BMP4 and WNT signalling, are highly regulated in the foetal mouse germline. <i>IPO5</i> knockdown in TCam-2 cells using siRNA blunted BMP4-induced transcript changes, indicating that IPO5 levels could determine TGF-β signalling pathway outcomes in TGCTs.

Coatings based on calcium phosphate with thicknesses of 0.5 and 2 μm were obtained by high-frequency magnetron sputtering on NiTi substrates in an argon atmosphere. The coating was characterized using X-ray diffraction, scanning electron microscopy, atomic force microscopy, and in vitro cytocompatibility and bioactivity studies. A biphasic coating of tricalcium phosphate (Ca₃(PO₄)₂) and hydroxyapatite (Ca₁₀(PO₄)₆(OH)₂) with a 100% degree of crystallinity was formed on the surface. The layer enriched in calcium, phosphorus, and oxygen was observed using scanning electron microscopy and energy-dispersive X-ray spectroscopy. Scanning electron microscopy showed that the surface structure is homogeneous without visible defects. The 2 µm thick coating obtained by sputtering with a deposition time of 4 h and a deposition rate of 0.43 µm/h is uniform, contains the highest amount of the calcium phosphate phase, and is most suitable for the faster growth of cells and accelerated formation of apatite layers. Samples with calcium phosphate coatings do not cause hemolysis and have a low cytotoxicity index. The results of immersion in a solution simulating body fluid show that NiTi with the biphasic coating promotes apatite growth, which is beneficial for biological activity.

Biomolecular condensates are subcellular organizations where functionally related proteins and nucleic acids are assembled through liquid-liquid phase separation, allowing them to develop on a larger scale without a membrane. However, biomolecular condensates are highly vulnerable to disruptions from genetic risks and various factors inside and outside the cell and are strongly implicated in the pathogenesis of many neurodegenerative diseases. In addition to the classical view of the nucleation-polymerization process that triggers the protein aggregation from the misfolded seed, the pathologic transition of biomolecular condensates can also promote the aggregation of proteins found in the deposits of neurodegenerative diseases. Furthermore, it has been suggested that several protein or protein-RNA complexes located in the synapse and along the neuronal process are neuron-specific condensates displaying liquid-like properties. As their compositional and functional modifications play a crucial role in the context of neurodegeneration, further research is needed to fully understand the role of neuronal biomolecular condensates. In this article, we will discuss recent findings that explore the pivotal role of biomolecular condensates in the development of neuronal defects and neurodegeneration.

The Buthidae family of scorpions consists of arthropods with significant medical relevance, as their venom contains a diverse range of biomolecules, including neurotoxins that selectively target ion channels in cell membranes. These ion channels play a crucial role in regulating physiological processes, and any disturbance in their activity can result in channelopathies, which can lead to various diseases such as autoimmune, cardiovascular, immunological, neurological, and neoplastic conditions. Given the importance of ion channels, scorpion peptides represent a valuable resource for developing drugs with targeted specificity for these channels. This review provides a comprehensive overview of the structure and classification of ion channels, the action of scorpion toxins on these channels, and potential avenues for future research. Overall, this review highlights the significance of scorpion venom as a promising source for discovering novel drugs with therapeutic potential for treating channelopathies.

Metabolic stress and the increased production of reactive oxygen species (ROS) are two main contributors to neuronal damage and synaptic plasticity in acute ischemic stroke. The superoxide scavenger MnTMPyP has been previously reported to have a neuroprotective effect in organotypic hippocampal slices and to modulate synaptic transmission after in vitro hypoxia and oxygen-glucose deprivation (OGD). However, the mechanisms involved in the effect of this scavenger remain elusive. In this study, two concentrations of MnTMPyP were evaluated on synaptic transmission during ischemia and post-ischemic synaptic potentiation. The complex molecular changes supporting cellular adaptation to metabolic stress, and how these are modulated by MnTMPyP, were also investigated. Electrophysiological data showed that MnTMPyP causes a decrease in baseline synaptic transmission and impairment of synaptic potentiation. Proteomic analysis performed on MnTMPyP and hypoxia-treated tissue indicated an impairment in vesicular trafficking mechanisms, including reduced expression of Hsp90 and actin signalling. Alterations of vesicular trafficking may lead to reduced probability of neurotransmitter release and AMPA receptor activity, resulting in the observed modulatory effect of MnTMPyP. In OGD, protein enrichment analysis highlighted impairments in cell proliferation and differentiation, such as TGFβ1 and CDKN1B signalling, in addition to downregulation of mitochondrial dysfunction and an increased expression of CAMKII. Taken together, our results may indicate modulation of neuronal sensitivity to the ischemic insult, and a complex role for MnTMPyP in synaptic transmission and plasticity, potentially providing molecular insights into the mechanisms mediating the effects of MnTMPyP during ischemia.

In recent years, there has been a significant surge in reports on the health-promoting benefits of winter cherry <i>(Withania somnifera),</i> also known as Ashwagandha. Its current research covers many aspects of human health, including neuroprotective, sedative and adaptogenic effects and effects on sleep. There are also reports of anti-inflammatory, antimicrobial, cardioprotective and anti-diabetic properties. Furthermore, there are reports of reproductive outcomes and tarcicidal hormone action. This growing body of research on Ashwagandha highlights its potential as a valuable natural remedy for many health concerns. This narrative review delves into the most recent findings and provides a comprehensive overview of the current understanding of ashwagandha's potential uses and any known safety concerns and contraindications.

Aging is associated with substantial physiological changes and constitutes a major risk factor for neurological disorders including dementia. Alterations in gene expression upon aging have been extensively studied; however, an in-depth characterization of post-transcriptional regulatory events remains elusive. Here, we profiled the age-related changes of the transcriptome and translatome in the female mouse hippocampus by RNA sequencing of total RNA and polysome preparations at four ages (3-, 6-, 12-, 20-month-old); and we implemented a variety of bioinformatics approaches to unravel alterations in transcript abundance, alternative splicing, and polyadenylation site selection. We observed mostly well-coordinated transcriptome and translatome expression signatures across age including upregulation of transcripts related to immune system processes and neuroinflammation, though transcripts encoding ribonucleoproteins or associated with mitochondrial functions, calcium signaling and the cell-cycle displayed substantial discordant profiles, suggesting translational control associated with age-related deficits in hippocampal-dependent behavior. By contrast, alternative splicing was less preserved, increased with age and was associated with distinct functionally-related transcripts encoding proteins acting at synapses/dendrites, RNA-binding proteins; thereby predicting regulatory roles for RBM3 and CIRBP. Only minor changes in polyadenylation site selection were identified, indicating pivotal 3'-end selection in young adults compared to older groups. Overall, our study provides a comprehensive resource of age-associated post-transcriptional regulatory events in the mouse hippocampus, enabling further examination of the molecular features underlying age-associated neurological diseases.

A core transcription regulatory circuitry (CRC) is an interconnected self-regulatory circuitry that is formed by a group of core transcription factors (TFs). These core TFs collectively regulate gene expression by binding not only to their own super enhancers (SEs) but also to the SEs of one another. For most human tissue/cell types, a global view of CRCs and core TFs has not been generated. Here, we identified numerous CRCs using two identification methods and detailed the landscape of the CRCs driven by SEs in large cell/tissue samples. The comprehensive biological analyses, including sequence conservation, CRC activity and genome binding affinity were conducted for common TFs, moderate TFs, and specific TFs, which exhibit different biological features. The local module located from the common CRC network highlighted the essential functions and prognostic performance. The tissue-specific CRC network was highly related to cell identity. Core TFs in tissue-specific CRC networks exhibited disease markers, and had regulatory potential for cancer immunotherapy. Moreover, a user-friendly resource named CRCdb (http://www.licpathway.net/crcdb/index.html) was developed, which contained the detailed information of CRCs and core TFs used in this study, as well as other interesting results, such as the most representative CRC, frequency of TFs, and indegree/outdegree of TFs.

We report the case of acute lymphoblastic leukemia (ALL) in a 29-year-old male with no past medical history who presented with symptoms and signs of heart failure due to possible infiltrative cardiomyopathy as suggested by echocardiography. Workup including different imaging modalities confirmed the diagnosis of ALL. The patient completed his treatment course with a resolution of heart failure symptoms and normalization of cardiac function which was confirmed by different imaging modalities.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. Ginsenoside Rk3, an important and rare saponin in heat-treated ginseng, is generated from Rg1 and has a smaller molecular weight. However, the anti-HCC efficacy and mechanisms of ginsenoside Rk3 have not yet been characterized. Here, we investigated the mechanism by which ginsenoside Rk3, a tetracyclic triterpenoid rare ginsenoside, inhibits the growth of HCC. We first explored the possible potential targets of Rk3 through network pharmacology. Both in vitro (HepG2 and HCC-LM3 cells) and in vivo (primary liver cancer mice and HCC-LM3 subcutaneous tumor-bearing mice) studies revealed that Rk3 significantly inhibits the proliferation of HCC. Meanwhile, Rk3 blocked the cell cycle in HCC at the G1 phase and induced autophagy and apoptosis in HCC. Further proteomics and siRNA experiments showed that Rk3 regulates the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway to inhibit HCC growth, which was validated by molecular docking and surface plasmon resonance. In conclusion, we report the discovery that ginsenoside Rk3 binds to PI3K/AKT and promotes autophagy and apoptosis in HCC. Our data strongly support the translation of ginsenoside Rk3 into novel PI3K/AKT-targeting therapeutics for HCC treatment with low toxic side effects.

Exosomes are small membrane vesicles containing microRNA, RNA, DNA fragments, and proteins that are transferred from donor cells to recipient cells. Tumor cells release exosomes to reprogram the factors associated with the tumor microenvironment (TME) causing tumor metastasis and immune escape. Emerging evidence revealed that cancer cell-derived exosomes carry immune inhibitory molecule program death ligand 1 (PD-L1) that binds with receptor program death protein 1 (PD-1) and promote tumor progression by escaping immune response. Currently, some FDA-approved monoclonal antibodies are clinically used for cancer treatment by blocking PD-1/PD-L1 interaction. Despite notable treatment outcomes, some patients show poor drug response. Exosomal PD-L1 plays a vital role in lowering the treatment response, showing resistance to PD-1/PD-L1 blockage therapy through recapitulating the effect of cell surface PD-L1. To enhance therapeutic response, inhibition of exosomal PD-L1 is required. Calcium signaling is the central regulator of tumorigenesis and can regulate exosome biogenesis and secretion by modulating Rab GTPase family and membrane fusion factors. Immune checkpoints are also connected with calcium signaling and calcium channel blockers like amlodipine, nifedipine, lercanidipine, diltiazem, and verapamil were also reported to suppress cellular PD-L1 expression. Therefore, to enhance the PD-1/PD-L1 blockage therapy response, the reduction of exosomal PD-L1 secretion from cancer cells is in our therapeutic consideration. In this review, we proposed a therapeutic strategy by targeting calcium signaling to inhibit the expression of PD-L1-containing exosome levels that could reduce the anti-PD-1/PD-L1 therapy resistance and increase the patient's drug response rate.

Coronavirus disease-2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. SARS-CoV-2 virus is internalized by surface receptors, e.g., angiotensin-converting enzyme-2 (ACE2). Clinical reports suggest that non-insulin dependent diabetes mellitus (DM-II) may enhance COVID-19. This study investigated how DM-II augments COVID-19 complications through molecular interactions with cytokines/chemokines, using QIAGEN Ingenuity Pathway Analysis (IPA) and CLC Genomics Workbench 22 (CLCG-22). RNA-sequencing of islet β-cell genomes through CLCG-22 (SRA SRP287500) were analyzed to identify differential expression of islet β-cell genes (Iβ-CG). IPA’s QIAGEN Knowledge Base (QKB) was also used to retrieve 88 total molecules shared between DM-II and SARS-CoV-2 infection to characterize and identify Iβ-CG, due to close association with DM-II. Molecules directly associated with ACE2 and cytokines/chemokines were also identified for their association with SARS-CoV-2 infection. Using IPA, 3 Iβ-CG in common with both diseases, SCL2A2, PPARγ, and CPLX8, were downregulated by DM-II. Their downregulation occurred due to increased activity of cytokines/chemokines and ACE2. Collectively, this network meta-analysis demonstrated that interaction of SARS-CoV-2 with ACE2 could primarily induce endothelial cell dysfunction. Identification of common molecules and signaling pathways between DM-II and SARS-CoV-2 infection in this study may lead to further discovery of therapeutic measures to simultaneously combat both diseases.

<h4>Background</h4>Patients with neutrophil-mediated asthma have poor response to glucocorticoids. The roles and mechanisms of group 3 innate lymphoid cells (ILC3s) in inducing neutrophilic airway inflammation and glucocorticoid resistance in asthma have not been fully clarified.<h4>Methods</h4>ILC3s in peripheral blood were measured by flow cytometry in patients with eosinophilic asthma (EA) and non-eosinophilic asthma (NEA). ILC3s were sorted and cultured in vitro for RNA sequencing. Cytokines production and signaling pathways in ILC3s after IL-1β stimulation and dexamethasone treatment were determined by real-time PCR, flow cytometry, ELISA and western blot.<h4>Results</h4>The percentage and numbers of ILC3s in peripheral blood was higher in patients with NEA compared with EA, and negatively correlated with blood eosinophils. IL-1β stimulation significantly enhanced CXCL8 and CXCL1 production in ILC3s via activation of p65 NF-κB and p38/JNK MAPK signaling pathways. The expression of neutrophil chemoattractants from ILC3s was insensitive to dexamethasone treatment. Dexamethasone significantly increased phosphorylation of glucocorticoid receptor (GR) at Ser226 but only with a weak induction at Ser211 residues in ILC3s. Compared to human bronchial epithelial cell line (16HBE cells), the ratio of p-GR S226 to p-GR S211 (p-GR S226/S211) was significantly higher in ILC3s at baseline and after dexamethasone treatment. In addition, IL-1β could induce Ser226 phosphorylation and had a crosstalk effect to dexamethasone via NF-κB pathway.<h4>Conclusions</h4>ILC3s were elevated in patients with NEA, and associated with neutrophil inflammation by release of neutrophil chemoattractants and were glucocorticoid (GC) resistant. This paper provides a novel cellular and molecular mechanisms of neutrophil inflammation and GC-resistance in asthma. Trial registration The study has been prospectively registered in the World Health Organization International Clinical Trials Registry Platform (ChiCTR1900027125).

<h4>Background</h4>Nonalcoholic fatty liver disease (NAFLD) has a multidirectional relationship with metabolic syndrome (MetS) and used to be considered a hepatic manifestation of MetS. Perirenal fat, as a part of visceral adipose tissue (VAT), was reported to be correlated with MetS components, but data for intraorgan fat are lacking. This study was undertaken to assess the value of peripheral and intraorgan fat to predict MetS in adults with overweight and obesity with suspected NAFLD.<h4>Methods</h4>We studied 134 sequential adults (mean age, 31.5 years; 47% female) with overweight and obesity with suspected NAFLD. All participants underwent abdominal magnetic resonance imaging (MRI) examination. Anthropometric and metabolic parameters and perirenal fat thickness (PRFT), subcutaneous adipose tissue thickness (SATT), liver fat fraction (LFF), pancreas fat fraction (PFF), and lumbar spine fat fraction (LSFF) were collected. MetS was defined according to the International Diabetes Federation (IDF) criteria. Statistical analyses included basic statistics, linear correlation and logistic regression analysis.<h4>Results</h4>A total of 63 adults with MetS and 71 adults with advanced liver steatosis (grades 2 and 3) were included in our study. Patients with MetS had greater PRFT (p = 0.026) and LFF (p < 0.001), as well as greater homeostasis model assessment of insulin resistance (HOMA-IR), alanine transaminase (ALT), aspartate transaminase (AST), and decreased SATT. MetS patients had a higher proportion of advanced steatosis than those without MetS (P < 0.001). The MetS score was associated with PRFT and LFF. Logistic regression analysis showed that the PRFT and LFF were independent predictors of MetS after adjusting for age and sex. A cutoff of 9.15 mm for PRFT and 14.68% for LFF could be predictive of MetS.<h4>Conclusions</h4>This study shows that the absolute cutoff level of 9.15 mm for PRFT and 14.68% for LFF may be clinically important markers for identifying patients who are at high risk of MetS among adults with overweight and obesity with suspected NAFLD, irrespective of sex and age. Moreover, ectopic fat levels in pancreas and lumbar spine are positively associated with PRFT.<h4>Trial registration</h4>Not applicable.

An evolutionary perspective enhances our understanding of biological mechanisms. Comparison of sex determination and X-chromosome dosage compensation mechanisms between the closely related nematode species <i>Caenorhabditis briggsae</i> (<i>Cbr</i>) and <i>Caenorhabditis elegans</i> (<i>Cel</i>) revealed that the genetic regulatory hierarchy controlling both processes is conserved, but the X-chromosome target specificity and mode of binding for the specialized condensin dosage compensation complex (DCC) controlling X expression have diverged. We identified two motifs within <i>Cbr</i> DCC recruitment sites that are highly enriched on X: 13 bp MEX and 30 bp MEX II. Mutating either MEX or MEX II in an endogenous recruitment site with multiple copies of one or both motifs reduced binding, but only removing all motifs eliminated binding in vivo. Hence, DCC binding to <i>Cbr</i> recruitment sites appears additive. In contrast, DCC binding to <i>Cel</i> recruitment sites is synergistic: mutating even one motif in vivo eliminated binding. Although all X-chromosome motifs share the sequence CAGGG, they have otherwise diverged so that a motif from one species cannot function in the other. Functional divergence was demonstrated in vivo and in vitro. A single nucleotide position in <i>Cbr</i> MEX can determine whether <i>Cel</i> DCC binds. This rapid divergence of DCC target specificity could have been an important factor in establishing reproductive isolation between nematode species and contrasts dramatically with the conservation of target specificity for X-chromosome dosage compensation across <i>Drosophila</i> species and for transcription factors controlling developmental processes such as body-plan specification from fruit flies to mice.

Atherosclerosis is characterized by the development of intimal plaque, thrombosis, and stenosis of the vessel lumen causing decreased blood flow and hypoxia precipitating angina. Chronic inflammation in the stable plaque renders it unstable and rupture of unstable plaques results in the formation of emboli leading to hypoxia/ischemia to the organs by occluding the terminal branches and precipitate myocardial infarction and stroke. Such delibitating events could be controlled by the strategies that prevent plaque development or plaque stabilization. Despite the use of statins to stabilize plaques, there is a need for novel targets due to continuously increasing cases of cardiovascular events. Sirtuins (SIRTs), a family of signaling proteins, are involved in sustaining genome integrity, DNA damage response and repair, modulating oxidative stress, aging, inflammation, and energy metabolism. SIRTs play a critical role in modulating inflammation and involves in the development and progression of atherosclerosis. The role of SIRTs in relation to atherosclerosis and plaque vulnerability is scarcely discussed in the literature. Since SIRTs regulate oxidative stress, inflammation, and aging, they may also regulate plaque progression and vulnerability as these molecular mechanisms underlie the pathogenesis of plaque development, progression, and vulnerability. This review critically discusses the role of SIRTs in plaque progression and vulnerability and the possibility of targeting SIRTs to attenuate plaque rupture, focusing on the highlights in genomics, molecular pathways, and cell types involved in the underlying pathophysiology.

Atomic radii play important roles in scientific research. The covalent radii of atoms, ionic radii of ions, and van der Waals (VDW) radii of neutral atoms can all be derived from crystal structures. However, the VDW radii of ions are a challenge to determine because the atomic distances in crystal structures were determined by a combination of VDW interactions and electrostatic interactions, making it unclear how to define the VDW sphere of ions in such an environment. In the present study, we found that VDW radii, which were determined based on the 0.0015 au electron density contour through a wavefunction analysis on atoms, have excellent agreement with the VDW radii of noble-gas atoms determined experimentally. Based on this criterion, we calculated the VDW radii for various atomic ions across the periodic table, providing a systematic set of VDW radii of ions. Previously we have shown that the 12-6 Lennard-Jones nonbonded model could not simultaneously reproduce the hydration free energy (HFE) and ion-oxygen distance (IOD) for an atomic ion when its charge is +2 or higher. Because of this, we developed the 12-6-4 model to reproduce both properties at the same time by explicitly considering the ion-induced dipole interactions. However, recent studies showed it was possible to use the 12-6 model to simulate both properties simultaneously when an ion has the <i>R</i>_min/2 parameter (<i>i.e</i>., the VDW radius) close to the Shannon ionic radius. In the present study, we show that such a "success" is due to an unphysical overfitting, as the VDW radius of an ion should be significantly larger than its ionic radius. Through molecular dynamics simulations, we show that such overfitting causes significant issues when transferring the parameters from ion-water systems to ion-ligand and metalloprotein systems. In comparison, the 12-6-4 model shows significant improvement in comparison to the overfitted 12-6 model, showing excellent transferability across different systems. In summary, although both the 12-6-4 and 12-6 models could reproduce HFE and IOD for an ion, the 12-6-4 model accomplishes such a task based on the consideration of the physics involved, while the 12-6 model accomplishes this through overfitting, which brings significant transferability issues when simulating other systems. Hence, we strongly recommend the use of the 12-6-4 model (or even more sophisticated models) instead of overfitted 12-6 models when simulating complex systems such as metalloproteins.

Growth traits are quantitative traits controlled by multiple micro-effect genes. we identified molecular markers related to sheep growth traits, which formed the basis of molecular breeding. In this study, we randomly selected 100 Qira Black sheep and 84 German Merino sheep for the blood collection the jugular vein to genotype by using the Illumina Ovine SNP 50K Bead Chip. quality control criteria for statistical analysis were: rejection detection rate < 90% and minimum allele frequency (MAF) < 5%. Then, we performed Genome-wide association studies (GWAS) on sheep body weight, body height, body length, and chest circumference using mixed linear models. After getting 55 SNPs with significant correlation, they were annotated by reference genome of Ovis aries genome (Oar_v4.0) and We obtained a total of 84 candidate genes associated with production traits (BMPR1B, HSD17B3, TMEM63C, etc.). We selected BMPR1B for population validation and found a correlation between the FecB locus and body weight traits. Therefore, this study not only supplements the existing knowledge of molecular markers of sheep growth traits, but also has important theoretical significance and reference value for the mining of functional genes of sheep growth traits.

<h4>Background</h4>Hypertrophic cardiomyopathy (HCM) is a grave hazard to human health. Circular RNA (circRNAs) and micro RNA (miRNAs), which are competitive endogenous RNA, have been shown to play a critical role inHCM pathogenicity. However, to a great extent, the biological activities of ceRNA in HCM pathophysiology and prognosis remain to be investigated.<h4>Materials and methods</h4>By analyzing the expression files in the Gene Expression Comprehensive (GEO) database, differentially expressed (DE) circRNAs, miRNAs, and mRNAs in HCM were identified, and the target molecules of circRNAs and miRNAs were predicted. The intersection of the differentially expressed RNA molecules and the expected target was then calculated, and a ceRNA network was subsequently constructed using RNA molecules. Using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, the potential etiology was elucidated. qPCR was used to validate a portion of the hub gene using Angiotensin II to generate a cell hypertrophy model.<h4>Results</h4>Three large-scale HCM sample datasets were extracted from the GEO database. After crossing these molecules with their expected targets, the circRNA-miRNA-mRNA network had two DEcircRNAs, two DEmiRNAs, and thirty DEmRNAs, compared to normal tissues. Functional enrichment analysis of GO and KEGG demonstrated that many of the HCM pathways and mechanisms were associated with calcium channel release, which is also the primary focus of future research. The qPCR results revealed that circRNA, miRNA, and mRNA expression levels were different. They may include novel noninvasive indicators for the early screening and prognostic prediction of HCM.<h4>Conclusion</h4>In this study, we hypothesized a circRNA-miRNA-mRNA regulation network that is closely related to the progression and clinical outcomes of HCM and may contain promising biomarkers and treatment targets for HCM.

Glycolipids with TLR4 agonistic properties can serve either as therapeutic agents or as vaccine adjuvants by stimulating the development of proinflammatory responses. Translating them to the clinical setting is hampered by synthetic difficulties, the lack of stability in biological media, and/or a suboptimal profile of balanced immune mediator secretion. Here, we show that replacement of the sugar fragment by an sp²-iminosugar moiety in a prototypic TLR4 agonist, <b>CCL-34</b>, yields iminoglycolipid analogues that retain or improve their biological activity in vitro and in vivo and can be accessed through scalable protocols with total stereoselectivity. Their adjuvant potential is manifested in their ability to induce the secretion of proinflammatory cytokines, prime the maturation of dendritic cells, and promote the proliferation of CD8⁺ T cells, pertaining to a Th1-biased profile. Additionally, their therapeutic potential for the treatment of asthma, a Th2-dominated inflammatory pathology, has been confirmed in an ovalbumin-induced airway hyperreactivity mouse model.

Neutrophils are formidable defenders. Their vast numbers, constant production, high cytotoxicity and capacity to produce extracellular traps, underlie their ability to efficiently protect in a microorganism-rich world. However, neutrophils are much more than immune sentinels, as evidenced by the expanding repertoire of functions discovered in the context of tissue homeostasis, regeneration or chronic pathologies. In this Perspective, we discuss general functional features of the neutrophil compartment that may be relevant in most, if not all, physiological scenarios in which they participate, including specialization in naïve tissues, transcriptional noise in the bloodstream as a potential strategy for diversification and functional bias in inflammatory sites. We intentionally present the reader with more questions than answers and propose models and approaches that we hope will shed new light onto the biology of these fascinating cells and spark new directions of research.

<h4>Background</h4>Although immune checkpoint blockade (ICB) therapy has brought survival benefits to patients with specific cancer types, most of cancer patients remain refractory to the ICB therapy, which is largely attributed to the immunosuppressive tumor microenvironment. Thereby, it is urgent to profile key molecules and signal pathways responsible for modification of tumor microenvironment.<h4>Methods</h4>Multiple databases of esophageal squamous cell carcinoma (ESCC) were integratively analyzed to screen candidate genes responsible for infiltration of CD8⁺ T cells. Expression of pescadillo ribosomal biogenesis factor 1 (PES1) in clinical ESCC samples was examined by qRT-PCR, western blotting, and immunohistochemistry. The mechanisms of PES1 were investigated via RNA sequencing and mass spectrometry followed by immunoprecipitation and proximity ligation assay. The clinical and therapeutic significance of PES1 in ESCC was comprehensively investigated using ESCC cells and mouse model.<h4>Results</h4>PES1 was significantly upregulated and correlated with poor prognosis in ESCC patients. PES1 knockdown decreased ESCC cell growth in vitro and in vivo and enhanced the efficacy of ICB therapy in mouse model, which was established through subcutaneous inoculation with ESCC cells. Analyses on RNA sequencing and mass spectrometry suggested that PES1 expression was negatively correlated with IL15 and ILF3 was one of the PES1-associated proteins. It has been known that ILF3 interacts with and stabilizes IL15 mRNA to increase IL15 protein level. Our data further indicated that PES1 interfered with the interaction between ILF3 and IL15 mRNA and impaired ILF3-mediated stabilization of IL15 mRNA, which eventually reduced the protein level of IL15. Interestingly, the inhibitory effect of ICB therapy boosted by PES1 knockdown dramatically antagonized by knockdown of IL15, which suppressed the tumor-infiltrated CD8⁺ T cells in ESCC. Finally, we confirmed the relationships among PES1, IL15, and CD8⁺ T cell infiltration in 10 locally advanced ESCC patients receiving ICB neoadjuvant therapy and demonstrated that ICB therapy would be more effective in those with low expression of PES1.<h4>Conclusions</h4>Altogether, our findings herein provided novel insights on biological function and clinical significance of PES1 and suggested that high expression of PES1 could suppress ILF3-IL15 axis-mediated immunosurveillance and promote resistance to ICB through restraining tumor-infiltrated CD8⁺ T cells.

<h4>Background</h4>Clear cell renal cell carcinoma(ccRCC) is a frequently occurring malignant tumor of the urinary system. Despite extensive research, the regulatory mechanisms underlying the pathogenesis and progression of ccRCC remain largely unknown.<h4>Methods</h4>We downloaded 5 ccRCC expression profiles from the Gene Expression Omnibus (GEO) database and obtained the list of differentially expressed genes (DEGs). Using String and Cytoscape tools, we determined the hub genes of ccRCC, and then analyzed their relationship with ccRCC patient survival. Ultimately, we identified SERPINE1 as a prognostic factor in ccRCC. Meanwhile, we confirmed the role of SERPINE1 in 786-O cells by cell transfection and in vitro experiments.<h4>Results</h4>Our analysis yielded a total of 258 differentially expressed genes, comprising 105 down-regulated genes and 153 up-regulated genes. Survival analysis of SERPINE1 expression in The Cancer Genome Atlas (TCGA) confirmed its association with the increase of tumor grade, lymph node metastasis, and tumor stage, as well as with shorter survival. Furthermore, we found that SERPINE1 expression levels were associated with CD8 + T cells, CD4 + T cells, B cells, macrophages, neutrophils, and dendritic cells. Cell experiments showed that knockdown SERPINE1 expression could inhibit the proliferation, migration and invasion of ccRCC cells. Among the co-expressed genes with the highest correlation, ITGA5, SLC2A3, SLC2A14, SHC1, CEBPB, and ADA were overexpressed and associated with shorter overall survival (OS) in ccRCC.<h4>Conclusions</h4>In this study, we identified hub genes that are strongly related to ccRCC, and highlights the potential utility of overexpressed SERPINE1 and its co-expressed genes could be used as prognostic and diagnostic biomarkers in ccRCC.

Cell replacement therapy is expected as a new and more radical treatment against brain damage. We previously reported that transplanted human cerebral organoids extend their axons along the corticospinal tract in rodent brains. The axons reached the spinal cord but were still sparse. Therefore, this study optimized the host brain environment by the adeno-associated virus (AAV)-mediated expression of axon guidance proteins in mouse brain. Among netrin-1, SEMA3, and L1CAM, only L1CAM significantly promoted the axonal extension of mouse embryonic brain tissue-derived grafts. L1CAM was also expressed by donor neurons, and this promotion was exerted in a haptotactic manner by their homophilic binding. Primary cortical neurons cocultured on L1CAM-expressing HEK-293 cells supported this mechanism. These results suggest that optimizing the host environment by the AAV-mediated expression of axon guidance molecules enhances the effect of cell replacement therapy.

Associations between human genetic variation and clinical phenotypes have become a foundation of biomedical research. Most repositories of these data seek to be disease-agnostic and therefore lack disease-focused views. The Type 2 Diabetes Knowledge Portal (T2DKP) is a public resource of genetic datasets and genomic annotations dedicated to type 2 diabetes (T2D) and related traits. Here, we seek to make the T2DKP more accessible to prospective users and more useful to existing users. First, we evaluate the T2DKP's comprehensiveness by comparing its datasets with those of other repositories. Second, we describe how researchers unfamiliar with human genetic data can begin using and correctly interpreting them via the T2DKP. Third, we describe how existing users can extend their current workflows to use the full suite of tools offered by the T2DKP. We finally discuss the lessons offered by the T2DKP toward the goal of democratizing access to complex disease genetic results.

Nanometric scale size oscillations seem to be a fundamental feature of all living organisms on Earth. Their detection usually requires complex and very sensitive devices. However, some recent studies demonstrated that very simple optical microscopes and dedicated image processing software can also fulfill this task. This novel technique, termed as optical nanomotion detection (ONMD), was recently successfully used on yeast cells to conduct rapid antifungal sensitivity tests. In this study, we demonstrate that the ONMD method can monitor motile sub-cellular organelles, such as mitochondria. Here, mitochondrial isolates (from HEK 293 T and Jurkat cells) undergo predictable motility when viewed by ONMD and triggered by mitochondrial toxins, citric acid intermediates, and dietary and bacterial fermentation products (short-chain fatty acids) at various doses and durations. The technique has superior advantages compared to classical methods since it is rapid, possesses a single organelle sensitivity, and is label- and attachment-free.

<h4>Background</h4>Regarding the global coronavirus disease 2019 (COVID)-19 pandemic, kidney clear cell carcinoma (KIRC) has acquired a higher infection probability and may induce fatal complications and death following COVID-19 infection. However, effective treatment strategies remain unavailable. Berberine exhibits significant antiviral and antitumour effects. Thus, this study aimed to provide a promising and reliable therapeutic strategy for clinical decision-making by exploring the therapeutic mechanism of berberine against KIRC/COVID-19.<h4>Methods</h4>Based on large-scale data analysis, the target genes, clinical risk, and immune and pharmacological mechanisms of berberine against KIRC/COVID-19 were systematically investigated.<h4>Results</h4>In total, 1,038 and 12,992 differentially expressed genes (DEGs) of COVID-19 and KIRC, respectively, were verified from Gene Expression Omnibus and The Cancer Genome Atlas databases, respectively, and 489 berberine target genes were obtained from official websites. After intersecting, 26 genes were considered potential berberine therapeutic targets for KIRC/COVID-19. Berberine mechanism of action against KIRC/COVID-19 was revealed by protein-protein interaction, gene ontology, and Kyoto Encyclopedia of Genes and Genomes with terms including protein interaction, cell proliferation, viral carcinogenesis, and the PI3K/Akt signalling pathway. In COVID-19 patients, ACOX1, LRRK2, MMP8, SLC1A3, CPT1A, H2AC11, H4C8, and SLC1A3 were closely related to disease severity, and the general survival of KIRC patients was closely related to ACOX1, APP, CPT1A, PLK1, and TYMS. Additionally, the risk signature accurately and sensitively depicted the overall survival and patient survival status for KIRC. Numerous neutrophils were enriched in the immune system of COVID-19 patients, and the lives of KIRC patients were endangered due to significant immune cell infiltration. Molecular docking studies indicated that berberine binds strongly to target proteins.<h4>Conclusion</h4>This study demonstrated berberine as a potential treatment option in pharmacological, immunological, and clinical practice. Moreover, its therapeutic effects may provide potential and reliable treatment options for patients with KIRC/COVID-19.

<h4>Introduction</h4>Sepsis is the leading cause of death in intensive care units and is characterized by multiple organ failure, including dysfunction of the immune system. In the present study, we performed an integrative analysis on publicly available datasets to identify immune-related genes (IRGs) that may play vital role in the pathological process of sepsis, based on which a prognostic IRG signature for 28-day mortality prediction in patients with sepsis was developed and validated.<h4>Methods</h4>Weighted gene co-expression network analysis (WGCNA), Cox regression analysis and least absolute shrinkage and selection operator (LASSO) estimation were used to identify functional IRGs and construct a model for predicting the 28-day mortality. The prognostic value of the model was validated in internal and external sepsis datasets. The correlations of the IRG signature with immunological characteristics, including immune cell infiltration and cytokine expression, were explored. We finally validated the expression of the three IRG signature genes in blood samples from 12 sepsis patients and 12 healthy controls using qPCR.<h4>Results</h4>We established a prognostic IRG signature comprising three gene members (<i>LTB4R</i>, <i>HLA-DMB</i> and <i>IL4R</i>). The IRG signature demonstrated good predictive performance for 28-day mortality on the internal and external validation datasets. The immune infiltration and cytokine analyses revealed that the IRG signature was significantly associated with multiple immune cells and cytokines. The molecular pathway analysis uncovered ontology enrichment in myeloid cell differentiation and iron ion homeostasis, providing clues regarding the underlying biological mechanisms of the IRG signature. Finally, qPCR detection verified the differential expression of the three IRG signature genes in blood samples from 12 sepsis patients and 12 healthy controls.<h4>Discussion</h4>This study presents an innovative IRG signature for 28-day mortality prediction in sepsis patients, which may be used to facilitate stratification of risky sepsis patients and evaluate patients' immune state.

C1q is a crucial component of the complement system, which is activated through the classical pathway to perform non-specific immune functions, serving as the first line of defense against pathogens. C1q can also bind to specific receptors to carry out immune and other functions, playing a vital role in maintaining immune homeostasis and normal physiological functions. In the developing central nervous system (CNS), C1q functions in synapse formation and pruning, serving as a key player in the development and homeostasis of neuronal networks in the CNS. C1q has a close relationship with microglia and astrocytes, and under their influence, C1q may contribute to the development of CNS disorders. Furthermore, C1q can also have independent effects on neurological disorders, producing either beneficial or detrimental outcomes. Most of the evidence for these functions comes from animal models, with some also from human specimen studies. C1q is now emerging as a promising target for the treatment of a variety of diseases, and clinical trials are already underway for CNS disorders. This article highlights the role of C1q in CNS diseases, offering new directions for the diagnosis and treatment of these conditions.

Hallux valgus is a common form of foot deformity, and genetic factors contribute substantially to the pathogenesis of hallux valgus deformity. We conducted a genetic study on the structural variants underlying familial hallux valgus using whole exome sequencing approach. Twenty individuals from five hallux valgus families and two sporadic cases were included in this study. A total of 372 copy number variations were found and passed quality control filtering. Among them, 43 were only present in cases but not in controls or healthy individuals in the database of genomic variants. The genes covered by these copy number variations were enriched in gene sets related to immune signaling pathway, and cytochrome P450 metabolism. The hereditary CNVs demonstrate a dominant inheritance pattern. Two candidate pathogenic CNVs were further validated by quantitative-PCR. This study suggests that hallux valgus is a degenerative joint disease involving the dysregulation of immune and metabolism signaling pathways.

CRC is an adult-onset carcinoma representing the third most common cancer and the second leading cause of cancer-related deaths in the world. EO-CRC (<45 years of age) accounts for 5% of the CRC cases and is associated with cancer-predisposing genetic factors in half of them. Here, we describe the case of a woman affected by BWSp who developed EO-CRC at age 27. To look for a possible molecular link between BWSp and EO-CRC, we analysed her whole-genome genetic and epigenetic profiles in blood, and peri-neoplastic and neoplastic colon tissues. The results revealed a general instability of the tumor genome, including copy number and methylation changes affecting genes of the WNT signaling pathway, CRC biomarkers and imprinted loci. At the germline level, two missense mutations predicted to be likely pathogenic were found in compound heterozygosity affecting the Cystic Fibrosis (CF) gene CFTR that has been recently classified as a tumor suppressor gene, whose dysregulation represents a severe risk factor for developing CRC. We also detected constitutional loss of methylation of the <i>KCNQ1OT1</i>:TSS-DMR that leads to bi-allelic expression of the lncRNA <i>KCNQ1OT1</i> and BWSp. Our results support the hypothesis that the inherited CFTR mutations, together with constitutional loss of methylation of the <i>KCNQ1OT1</i>:TSS-DMR, initiate the tumorigenesis process. Further somatic genetic and epigenetic changes enhancing the activation of the WNT/beta-catenin pathway likely contributed to increase the growth advantage of cancer cells. Although this study does not provide any conclusive cause-effect relationship between BWSp and CRC, it is tempting to speculate that the imprinting defect of BWSp might accelerate tumorigenesis in adult cancer in the presence of predisposing genetic variants.

Several neurodegenerative disorders are characterized by the accumulation of misfolded proteins and are collectively known as proteinopathies. Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD) represent some of the most common neurodegenerative disorders whose steady increase in prevalence is having a major socio-economic impact on our society. Multiple laboratories have reported hundreds of changes in gene expression in selective brain regions of AD, PD, and HD brains. While the mechanisms underlying these changes remain an active area of investigation, alterations in the expression of noncoding RNAs, which are common in AD, PD, and HD, may account for some of the changes in gene expression in proteinopathies. In this review, we discuss the role of miR-128, which is highly expressed in mammalian brains, in AD, PD, and HD. We highlight how alterations in miR-128 may account, at least in part, for the gene expression changes associated with proteinopathies. Indeed, miR-128 is involved, among other things, in the regulation of neuronal plasticity, cytoskeletal organization, and neuronal death, events linked to various proteinopathies. For example, reducing the expression of miR-128 in a mouse model of AD ameliorates cognitive deficits and reduces neuropathology. Overall, the data in the literature suggest that targeting miR-128 might be beneficial to mitigate the behavioral phenotype associated with these diseases.

Gastrointestinal stromal tumors (GISTs) are the most common malignant mesenchymal neoplasms of the gastrointestinal tract. The gold standard for the diagnosis of GISTs is morphologic analysis with an immunohistochemical evaluation plus genomic profiling to assess the mutational status of lesions. The majority of GISTs are driven by gain-of-function mutations in the proto-oncogene c-<i>KIT</i> encoding the tyrosine kinase receptor (TKR) known as KIT and in the platelet-derived growth factor-alpha receptor (<i>PDGFRA</i>) genes. Approved therapeutics are orally available as tyrosine kinase inhibitors (TKIs) targeting KIT and/or PDGFRA oncogenic activation. Among these, <i>imatinib</i> has changed the management of patients with unresectable or metastatic GISTs, improving their survival time and delaying disease progression. Nevertheless, the majority of patients with GISTs experience disease progression after 2-3 years of imatinib therapy due to the development of secondary <i>KIT</i> mutations. Today, based on the identification of new driving oncogenic mutations, targeted therapy and precision medicine are regarded as the new frontiers for GISTs. This article reviews the most important mutations in GISTs and highlights their importance in the current understanding and treatment options of GISTs, with an emphasis on the most recent clinical trials.

Multiple myeloma (MM) is an incurable disease characterized by the presence of malignant plasma cells in the bone marrow that secrete specific monoclonal immunoglobulins into the blood. Obesity has been associated with the risk of developing solid and hematological cancers, but its role as a risk factor for MM needs to be further explored. Here, we evaluated whether 32 genome-wide association study (GWAS)-identified variants for obesity were associated with the risk of MM in 4189 German subjects from the German Multiple Myeloma Group (GMMG) cohort (2121 MM cases and 2068 controls) and 1293 Spanish subjects (206 MM cases and 1087 controls). Results were then validated through meta-analysis with data from the UKBiobank (554 MM cases and 402,714 controls) and FinnGen cohorts (914 MM cases and 248,695 controls). Finally, we evaluated the correlation of these single nucleotide polymorphisms (SNPs) with cQTL data, serum inflammatory proteins, steroid hormones, and absolute numbers of blood-derived cell populations (<i>n =</i> 520). The meta-analysis of the four European cohorts showed no effect of obesity-related variants on the risk of developing MM. We only found a very modest association of the <i>POC5</i>_rs2112347G and <i>ADCY3</i>_rs11676272G alleles with MM risk that did not remain significant after correction for multiple testing (per-allele OR <i>=</i> 1.08, <i>p =</i> 0.0083 and per-allele OR <i>=</i> 1.06, <i>p =</i> 0.046). No correlation between these SNPs and functional data was found, which confirms that obesity-related variants do not influence MM risk.

Huntington's disease (HD) is characterized by clinical motor impairment (e.g., involuntary movements, poor coordination, parkinsonism), cognitive deficits, and psychiatric symptoms. An inhered expansion of the CAG triplet in the huntingtin gene causing a pathogenic gain-of-function of the mutant huntingtin (<i>mHTT</i>) protein has been identified. In this review, we focus on known biomarkers (e.g., mHTT, neurofilament light chains) and on new biofluid biomarkers that can be quantified in plasma or peripheral blood mononuclear cells from mHTT carriers. Circulating biomarkers may fill current unmet needs in HD management: better stratification of patients amenable to etiologic treatment; the initiation of preventive treatment in premanifest HD; and the identification of peripheral pathogenic central nervous system cascades.

Sugar transport through the plasma membrane is one of the most critical events in the cellular transport of nutrients; for example, glucose has a central role in cellular metabolism and homeostasis. The way sugars enter the cell involves complex systems. Diverse protein systems participate in the membrane traffic of the sugars from the extracellular side to the cytoplasmic side. This diversity makes the phenomenon highly regulated and modulated to satisfy the different needs of each cell line. The beautiful thing about this process is how evolutionary processes have diversified a single function: to move glucose into the cell. The deregulation of these entrance systems causes some diseases. Hence, it is necessary to study them and search for a way to correct the alterations and utilize these mechanisms to promote health. This review will highlight the various mechanisms for importing the valuable sugars needed to create cellular homeostasis and survival in all kinds of cells.

N-type voltage-gated calcium channel controls the release of neurotransmitters from neurons. The association of other voltage-gated calcium channels with epilepsy is well-known. The association of N-type voltage-gated calcium channels and pain has also been established. However, the relationship between this type of calcium channel and epilepsy has not been specifically reviewed. Therefore, the present review systematically summarizes existing publications regarding the genetic associations between N-type voltage-dependent calcium channel and epilepsy.

The incidence and mortality due to neoplastic diseases have shown an increasing tendency over the years. Based on GLOBOCAN 2020 published by the International Agency for Research on Cancer (IARC), leukemias are the thirteenth most commonly diagnosed cancer in the world, with 78.6% of leukemia cases diagnosed in countries with a very high or high Human Development Index (HDI). Carcinogenesis is a complex process initiated by a mutation in DNA that may be caused by chemical carcinogens present in polluted environments and human diet. The IARC has identified 122 human carcinogens, e.g., benzene, formaldehyde, pentachlorophenol, and 93 probable human carcinogens, e.g., styrene, diazinone. The aim of the following review is to present the chemical carcinogens involved or likely to be involved in the pathogenesis of leukemia and to summarize the latest reports on the possibility of detecting these compounds in the environment or food with the use of electrochemical sensors.

<i>Ocimum basilicum Linn.</i> (basil) is an aromatic culinary herb that has shown a great potential in therapeutic world. It has many promising pharmacological activities that make it centre for investigations for many researchers. Current study has been planned to determine chemical constituents of basil leaves extracts and their <i>in-vitro</i> and <i>ex-vivo</i> antioxidant and <i>in-vivo</i> antihypertensive potential. GC-MS studies of non-polar extracts showed presence of 75 compounds including monoterpenes, hydrocarbons, sesquiterpenes, triterpenes, phyto-sterols and phthalates. Higher percentages of fatty acids were also identified. The major compounds include linalool (7.65%), terpineol (1.42%), <i>tau</i>-cadinol (13.55%), methyl palmitate (14.24%), palmitic acid (14.31%), linolenic acid (1.30%) and methyl linolenate (17.72%). Electron spray ionization mass spectrometry ESI-HRMS/MS of the polar extracts revealed the presence of alkaloids, phenolic acid, amino acid, coumarin, lignin, flavanoid and terpene derivative. Total phenolic content and total flavonoid content were determined using spectrophotometric technique and calculated as gallic acid equivalents GAE/g dry weight and rutin equivalent RE/g of dry weight respectively. The highest phenolic content and flavonoid content were found in ethyl acetate extract 9.40 mg GAE/g and 15.9 mg RE/g of dry weight. All the extracts showed significant antioxidant activity in DPPH and ABTS cation decolorization assays. Dichloromethane extract possess the highest DPPH scavenging activity, i.e., 64.12% ± 0.23 at concentration of 4 mg/ml. Moreover in <i>ex-vivo</i> studies all the extracts showed prominent effect by inhibiting AAPS induce oxidation in Human erythrocytes being 69.24% ± 0.18 in dichloromethane extract, 64.44% ± 0.04 in ethyl acetate and 53.33% ± 0.09 in acetone extract. The methanol extract of <i>O. basilicum</i> exhibited significant decrease in systolic blood pressure in l-Name induced hypertensive rats at the dose of 50 mg/kg for 28 days. Total phenolic content had a higher linear correlation (r = 0.678) with antihypertensive activity, with a level of significance 95% showing that phenolic compounds in the leaves of the plant has important role in inhibiting l -NAME induced hypertension while flavonoid compounds may play a key role in the antioxidant activities of the plant, through synergism. Conclusively, <i>O. basilicum</i> leaves with bioactive metabolites are a potential source for the development of antihypertensive drugs.

Single-stranded DNA-binding protein (SSB) is a bacterial interaction hub and an appealing target for antimicrobial therapy. Understanding the structural adaptation of the disordered SSB C-terminus (SSB-Ct) to DNA metabolizing enzymes (e.g., ExoI and RecO) is essential for designing high-affinity SSB mimetic inhibitors. Molecular dynamics simulations revealed the transient interactions of SSB-Ct with two hot spots on ExoI and RecO. The residual flexibility of the peptide-protein complexes allows adaptive molecular recognition. Scanning with non-canonical amino acids revealed that modifications at both termini of SSB-Ct could increase the affinity, supporting the two-hot-spot binding model. Combining unnatural amino acid substitutions on both segments of the peptide resulted in enthalpy-enhanced affinity, accompanied by enthalpy-entropy compensation, as determined by isothermal calorimetry. NMR data and molecular modeling confirmed the reduced flexibility of the improved affinity complexes. Our results highlight that the SSB-Ct mimetics bind to the DNA metabolizing targets through the hot spots, interacting with both of segments of the ligands.

Increasingly prevalent acute and chronic human brain diseases are scourges for the elderly. Besides the lack of therapies, these ailments share a neuroinflammation that is triggered/sustained by different innate immunity-related protein oligomers called inflammasomes. Relevant neuroinflammation players such as microglia/monocytes typically exhibit a strong NLRP3 inflammasome activation. Hence the idea that NLRP3 suppression might solve neurodegenerative ailments. Here we review the recent Literature about this topic. First, we update conditions and mechanisms, including RNAs, extracellular vesicles/exosomes, endogenous compounds, and ethnic/pharmacological agents/extracts regulating NLRP3 function. Second, we pinpoint NLRP3-activating mechanisms and known NLRP3 inhibition effects in acute (ischemia, stroke, hemorrhage), chronic (Alzheimer's disease, Parkinson's disease, Huntington's disease, MS, ALS), and virus-induced (Zika, SARS-CoV-2, and others) human brain diseases. The available data show that (i) disease-specific divergent mechanisms activate the (mainly animal) brains NLRP3; (ii) no evidence proves that NLRP3 inhibition modifies human brain diseases (yet ad hoc trials are ongoing); and (iii) no findings exclude that concurrently activated other-than-NLRP3 inflammasomes might functionally replace the inhibited NLRP3. Finally, we highlight that among the causes of the persistent lack of therapies are the species difference problem in disease models and a preference for symptomatic over etiologic therapeutic approaches. Therefore, we posit that human neural cell-based disease models could drive etiological, pathogenetic, and therapeutic advances, including NLRP3's and other inflammasomes' regulation, while minimizing failure risks in candidate drug trials.

<h4>Background: </h4> Disordered lipid metabolism is a novel hallmark of cancer initiation. However, the role of lipid metabolism-associated genes (LAGs) in the immune microenvironment, the prognosis, and the overall survival of lung squamous cell carcinoma (LUSC) remain unclear. <h4>Methods: </h4> This study examined 1064 LAGs in 502 LUSC tumors and 49 normal lung tissues from the Cancer Genome Atlas lung squamous cell carcinoma (TCGA-LUSC) cohort. Using univariate, least absolute shrinkage and selection operator (LASSO), and multivariate Cox regression analysis, a LAG-based gene signature was constructed for predicting the overall survival of patients with LUSC from the TCGA training-set. The predictive power of the gene signature was validated using the TCGA-internal validation cohort and six independent cohorts ( GSE73403, GSE74777, GSE157009, GSE157010, GSE157011, and GSE67061), obtained from the Gene Expression Omnibus (GEO) database.The prognosis was determined using a Kaplan-Meier analysis. The immunological aspects were examined using CIBERSORT, gene set enrichment analysis (GSEA), and tumor immune dysfunction and exclusion (TIDE) analysis. The Human Protein Atlas (HPA) database was utilized to validate the protein expression of the gene signature between LUSC tissues and normal lung tissues via immunohistochemistry staining (IHC) and Immunofluorescent . The expression of the gene signature was also assessed in various lung cancer-associated cell lines using HPA database. In addition, candidate small-molecule therapeutics for treating LUSC, were also identified using the connectivity Map (CMap) database. <h4>Results: </h4> A total of 112 lipid metabolism-associated DEGs (LADEGs) were detected in LUSC. A six-LAG-based prognostic signature ( ALOX15B, CYP24A1, PPP2R2C, PTGIS, SPTSSB, and UGT2B17) was successfully constructed and validated to predict the prognosis of LUSC patients. Functional analysis suggested that the LAGs were significantly enriched in arachidonic acid metabolism, ether lipid metabolism, metabolism of xenobiotics by cytochrome P450 , glycerophospholipid metabolism, steroid hormone biosynthesis, the fatty acid metabolic process, oxidoreductase activity, and PPAR signaling pathways. Furthermore, we determined that the six-gene signature was an independent risk factor. The prognostic model was closely related to immune cell infiltration. The expression of SPTSSB was low in high-risk patients, while ALOX15B, CYP24A1, PPP2R2C, PTGIS , and UGT2B17 were higher in high-risk patients than in low-risk ones. Identical outcomes were seen in the HPA database. In addition, the model showed that the high-risk score group had a worse overall survival (OS), and the validated cohorts showed the same result. Moreover, the prognostic signature of six LAGs predicted overall survival more accurately than conventional clinical characteristics.Based on the CMap dataset, small-molecule drugs exhibiting anticancer properties could be potential therapeutic therapies for LUSC patients. <h4>Conclusions: </h4> This study demonstrated, for the first time, that LAG expression plays a crucial role in LUSC. Furthermore, this high-efficiency six-gene LAG prognostic signature could serve as a predictive model to separate LUSC patients into high- and low-risk groups and potentially facilitate risk-stratified immunotherapy in LUSC patients. In addition, a number of small molecule drugs with significant therapeutic potential for LUSC patients were found.

Epithelial organoids derived from intestinal tissue, called enteroids, recapitulate many aspects of the organ in vitro and can be used for biological discovery, personalized medicine, and drug development. Here, we interrogated the cell signaling environment within the developing human intestine to identify niche cues that may be important for epithelial development and homeostasis. We identified an EGF family member, EPIREGULIN (EREG), which is robustly expressed in the developing human crypt. Enteroids generated from the developing human intestine grown in standard culture conditions, which contain EGF, are dominated by stem and progenitor cells and feature little differentiation and no spatial organization. Our results demonstrate that EREG can replace EGF in vitro, and EREG leads to spatially resolved enteroids that feature budded and proliferative crypt domains and a differentiated villus-like central lumen. Multiomic (transcriptome plus epigenome) profiling of native crypts, EGF-grown enteroids, and EREG-grown enteroids showed that EGF enteroids have an altered chromatin landscape that is dependent on EGF concentration, downregulate the master intestinal transcription factor CDX2, and ectopically express stomach genes, a phenomenon that is reversible. This is in contrast to EREG-grown enteroids, which remain intestine like in culture. Thus, EREG creates a homeostatic intestinal niche in vitro, enabling interrogation of stem cell function, cellular differentiation, and disease modeling.

Osteosarcoma, the most common malignant tumor of the bone, seriously influences people's lives and increases their economic burden. Conventional chemotherapy drugs achieve limited therapeutic effects owing to poor targeting and severe systemic toxicity. Nanocarrier-based drug delivery systems can significantly enhance the utilization efficiency of chemotherapeutic drugs through targeting ligand modifications and reduce the occurrence of systemic adverse effects. A variety of ligand-modified nano-drug delivery systems have been developed for different targeting schemes. Here we review the biological characteristics and the main challenges of current drug therapy of OS, and further elaborate on different targeting schemes and ligand selection for nano-drug delivery systems of osteosarcoma, which may provide new horizons for the development of advanced targeted drug delivery systems in the future.

Cohesins are ATPase complexes that play central roles in cellular processes such as chromosome division, DNA repair, and gene expression. Cohesinopathies arise from mutations in cohesin proteins or cohesin complex regulators and encompass a family of related developmental disorders that present with a range of severe birth defects, affect many different physiological systems, and often lead to embryonic fatality. Treatments for cohesinopathies are limited, in large part due to the lack of understanding of cohesin biology. Thus, characterizing the signaling networks that lie upstream and downstream of cohesin-dependent pathways remains clinically relevant. Here, we highlight alterations in cohesins and cohesin regulators that result in cohesinopathies, with a focus on cardiac defects. In addition, we suggest a novel and more unifying view regarding the mechanisms through which cohesinopathy-based heart defects may arise.

<h4>Background</h4>Non-invasive tests are widely used to diagnose fibrosis in patients with non-alcoholic fatty liver disease (NAFLD), however, the optimal method remains unclear. We compared the accuracy of simple serum models, a serum model incorporating direct measures of fibrogenesis (Hepascore), and Fibroscan®, for detecting fibrosis in NAFLD.<h4>Methods</h4>NAFLD patients undergoing liver biopsy were evaluated with Hepascore, NAFLD Fibrosis Score (NFS), FIB-4 and AST-platelet ratio index (APRI), with a subset (n = 131) undergoing Fibroscan®. Fibrosis on liver biopsy was categorized as advanced (F3-4) or cirrhosis (F4). Accuracy was determined by area under receiving operating characteristic curves (AUC). Indeterminate ranges were calculated using published cut-offs.<h4>Results</h4>In 271 NAFLD patients, 83 (31%) had F3-4 and 47 (17%) cirrhosis. 6/131 (4%) had an unreliable Fibroscan®. For the detection of advanced fibrosis, the accuracy of Hepascore (AUC 0.88) was higher than FIB-4 (0.73), NFS (0.72) and APRI (0.69) (p < 0.001 for all). Hepascore had similar accuracy to Fibroscan® (0.80) overall, but higher accuracy in obese individuals (0.91 vs 0.80, p = 0.001). Hepascore more accurately identified patients with cirrhosis than APRI (AUC 0.85 vs 0.71, p = 0.01) and NFS (AUC 0.73, p = 0.01) but performed similar to FIB-4 and Fibroscan®. For the determination of F3-4, the proportion of patients in indeterminate area was lower for Hepascore (4.8%), compared to FIB-4 (42%), NFS (36%) and APRI (44%) (p < 0.001 for all).<h4>Conclusions</h4>Hepascore has greater accuracy and a lower indeterminate range than simple serum fibrosis tests for advanced fibrosis in NAFLD, and greater accuracy than Fibroscan® in obese individuals.

The transition from a disordered to an assembly-competent monomeric state (N*) in amyloidogenic sequences is a crucial event in the aggregation cascade. Using a well-calibrated model for intrinsically disordered proteins (IDPs), we show that the N* states, which bear considerable resemblance to the polymorphic fibril structures found in experiments, not only appear as excitations in the free energy landscapes of Aβ40 and Aβ42, but also initiate the aggregation cascade. For Aβ42, the transitions to the different N* states are in accord with Ostwald's rule of stages, with the least stable structures forming ahead of thermodynamically favored ones. The Aβ40 and Aβ42 monomer landscapes exhibit different extents of local frustration, which we show have profound implications in dictating subsequent self-assembly. Using kinetic transition networks, we illustrate that the most favored dimerization routes proceed via N* states. We argue that Ostwald's rule also holds for the aggregation of fused in sarcoma and polyglutamine proteins.

In mammalian mitochondria, translation of the AUA codon is supported by 5-formylcytidine (f⁵C) modification in the mitochondrial methionine tRNA anticodon. The 5-formylation is initiated by NSUN3 methylase. Human NSUN3 mutations are associated with mitochondrial diseases. Here we show that Nsun3 is essential for embryonic development in mice with whole-body Nsun3 knockout embryos dying between E10.5 and E12.5. To determine the functions of NSUN3 in adult tissue, we generated heart-specific Nsun3 knockout (Nsun3^HKO) mice. Nsun3^HKO heart mitochondria were enlarged and contained fragmented cristae. Nsun3^HKO resulted in enhanced heart contraction and age-associated mild heart enlargement. In the Nsun3^HKO hearts, mitochondrial mRNAs that encode respiratory complex subunits were not down regulated, but the enzymatic activities of the respiratory complexes decreased, especially in older mice. Our study emphasizes that mitochondrial tRNA anticodon modification is essential for mammalian embryonic development and shows that tissue-specific loss of a single mitochondrial tRNA modification can induce tissue aberration that worsens in later adulthood.

Huntington's disease (HD) is a neurodegenerative disease caused by a CAG repeat expansion in the Huntingtin (HTT) gene. The resulting polyglutamine (polyQ) tract alters the function of the HTT protein. Although HTT is expressed in different tissues, the medium-spiny projection neurons (MSNs) in the striatum are particularly vulnerable in HD. Thus, we sought to define the proteome of human HD patient-derived MSNs. We differentiated HD72-induced pluripotent stem cells and isogenic controls into MSNs and carried out quantitative proteomic analysis. Using data-dependent acquisitions with FAIMS for label-free quantification on the Orbitrap Lumos mass spectrometer, we identified 6323 proteins with at least two unique peptides. Of these, 901 proteins were altered significantly more in the HD72-MSNs than in isogenic controls. Functional enrichment analysis of upregulated proteins demonstrated extracellular matrix and DNA signaling (DNA replication pathway, double-strand break repair, G1/S transition) with the highest significance. Conversely, processes associated with the downregulated proteins included neurogenesis-axogenesis, the brain-derived neurotrophic factor-signaling pathway, Ephrin-A:EphA pathway, regulation of synaptic plasticity, triglyceride homeostasis cholesterol, plasmid lipoprotein particle immune response, interferon-γ signaling, immune system major histocompatibility complex, lipid metabolism, and cellular response to stimulus. Moreover, proteins involved in the formation and maintenance of axons, dendrites, and synapses (e.g., septin protein members) were dysregulated in HD72-MSNs. Importantly, lipid metabolism pathways were altered, and using quantitative image analysis, we found that lipid droplets accumulated in the HD72-MSN, suggesting a deficit in the turnover of lipids possibly through lipophagy. Our proteomics analysis of HD72-MSNs identified relevant pathways that are altered in MSNs and confirm current and new therapeutic targets for HD.

Evidence from human genetics supporting the therapeutic hypothesis increases the likelihood that a drug will succeed in clinical trials. Rare and common disease genetics yield a wide array of alleles with a range of effect sizes that can proxy for the effect of a drug in disease. Recent advances in large scale population collections and whole genome sequencing approaches have provided a rich resource of human genetic evidence to support drug target selection. As the range of phenotypes profiled increases and ever more alleles are discovered across world-wide populations, these approaches will increasingly influence multiple stages across the lifespan of a drug discovery programme.

Heme is the reactive center of several metal-based proteins that are involved in multiple biological processes. However, free heme, defined as the labile heme pool, has toxic properties that are derived from its hydrophobic nature and the Fe-atom. Therefore, the heme concentration must be tightly controlled to maintain cellular homeostasis and to avoid pathological conditions. Therefore, different systems have been developed to scavenge either Hb (i.e., haptoglobin (Hp)) or the free heme (i.e., high-density lipoproteins (HDL), low-density lipoproteins (LDL), hemopexin (Hx), and human serum albumin (HSA)). In the first seconds after heme appearance in the plasma, more than 80% of the heme binds to HDL and LDL, and only the remaining 20% binds to Hx and HSA. Then, HSA slowly removes most of the heme from HDL and LDL, and finally, heme transits to Hx, which releases it into hepatic parenchymal cells. The Hx:heme or HSA:heme complexes are internalized via endocytosis mediated by the CD91 and CD71 receptors, respectively. As heme constitutes a major iron source for pathogens, bacteria have evolved hemophores that can extract and uptake heme from host proteins, including HSA:heme. Here, the molecular mechanisms underlying heme scavenging and delivery from HSA are reviewed. Moreover, the relevance of HSA in disease states associated with increased heme plasma concentrations are discussed.

<h4>Background</h4>Seeing that there are no data about associations between serotonin gene polymorphism and tryptophan catabolite concentration during PEG-IFN-α2a treatment, the aim of the current study is to examine (a) the associations between polymorphisms within the HTR1A, TPH2, and 5-HTT genes and the severity of depression symptoms and (b) the relationships among rs6295, rs4570625, and 5-HTTLPR rs25531polymorphisms and indoleamine 2,3-dioxygenase (IDO) activity, as well as kynurenine (KYN), tryptophan (TRP), kynurenic acid (KA), and anthranilic acid (AA) concentrations.<h4>Materials and methods</h4>The study followed a prospective, longitudinal, single-center cohort design. The severity of the depressive symptoms of 101 adult patients with chronic HCV infections was measured during PEG-IFN-α2a/RBV treatment. We used the Montgomery-Åsberg Depression Rating Scale (MADRS) to assess the severity of depressive symptoms. The subjects were evaluated six times-at baseline and at weeks 2, 4, 8, 12, and 24. At all the time points, MADRS score, as well as KYN, TRP, KA, and AA concentrations, and IDO activity were measured. At baseline, rs6295, rs4570625, and 5-HTTLPR rs25531polymorphisms were assessed.<h4>Results</h4>Subjects with C/C genotypes of 5-HT1A and lower-expressing alleles (S/S, L_G/L_G, and S/L_G) of 5-HTTLPR scored the highest total MADRS scores and recorded the highest increase in MADRS scores during treatment. We found associations between TRP concentrations and the TPH-2 and 5-HTTLPR rs25531 genotypes.<h4>Conclusions</h4>Our findings provide new data that we believe can help better understand infection-induced depression as a distinct type of depression.

Huntington's disease is one of the most common dominantly inherited neurodegenerative disorders caused by an expansion of a polyglutamine (polyQ) stretch in the N-terminal region of huntingtin (Htt). Among all the molecular mechanisms, affected by the mutation, emerging evidence proposes glycosphingolipid dysfunction as one of the major determinants. High levels of sphingolipids have been found to localize in the myelin sheaths of oligodendrocytes, where they play an important role in myelination stability and functions. In this study, we investigated any potential existing link between sphingolipid modulation and myelin structure by performing both ultrastructural and biochemical analyses. Our findings demonstrated that the treatment with the glycosphingolipid modulator THI preserved myelin thickness and the overall structure and reduced both area and diameter of pathologically giant axons in the striatum of HD mice. These ultrastructural findings were associated with restoration of different myelin marker protein, such as myelin-associated glycoprotein (MAG), myelin basic protein (MBP) and 2', 3' Cyclic Nucleotide 3'-Phosphodiesterase (CNP). Interestingly, the compound modulated the expression of glycosphingolipid biosynthetic enzymes and increased levels of GM1, whose elevation has been extensively reported to be associated with reduced toxicity of mutant Htt in different HD pre-clinical models. Our study further supports the evidence that the metabolism of glycosphingolipids may represent an effective therapeutic target for the disease.