Gene Literature Dashboard

Huntington's disease (HD) is a neurodegenerative disorder caused by a poly-CAG expansion in the first exon of the HTT gene, resulting in an extended poly-glutamine tract in the N-terminal domain of the Huntingtin (Htt) protein product. Proteolytic fragments of the poly-glutamine-containing N-terminal domain form intranuclear aggregates that are correlated with HD. Post-translational modification of Htt has been shown to alter its function and aggregation properties. However, the effect of N-terminal Htt acetylation has not yet been considered. Here, we developed a bacterial system to produce unmodified or N-terminally acetylated and aggregation-inducible Htt protein. We used this system together with biochemical, biophysical, and imaging studies to confirm that the Htt N-terminus is an in vitro substrate for the NatA N-terminal acetyltransferase and show that N-terminal acetylation promotes aggregation. These studies represent the first link between N-terminal acetylation and the promotion of a neurodegenerative disease and implicates NatA-mediated Htt acetylation as a new potential therapeutic target in HD.

Efforts to grasp the significance of radiologic changes similar to interstitial lung disease (ILD) in undiagnosed individuals have intensified in the recent decade. The term interstitial lung abnormalities (ILA) is an emerging definition of such changes, defined by visual examination of computed tomography scans. Substantial insights have been made in the origins and clinical consequences of these changes, as well as automated measures of early lung fibrosis, which will likely lead to increased recognition of early fibrotic lung changes among clinicians and researchers alike. Interstitial lung abnormalities have an estimated prevalence of 7-10% in elderly populations. They correlate with many ILD risk factors, both epidemiologic and genetic. Additionally, histopathological similarities with IPF exist in those with ILA. While no established blood biomarker of ILA exists, several have been suggested. Distinct imaging patterns indicating advanced fibrosis correlate with worse clinical outcomes. ILA are also linked with adverse clinical outcomes such as increased mortality and risk of lung cancer. Progression of ILA has been noted in a significant portion of those with ILA and is associated with many of the same features as ILD, including advanced fibrosis. Those with ILA progression are at risk of accelerated FVC decline and increased mortality. Radiologic changes resembling ILD have also been attained by automated measures. Such measures associate with some, but not all the same factors as ILA. ILA and similar radiologic changes are in many ways analogous to ILD and likely represent a precursor of ILD in some cases. While warranting an evaluation for ILD, they are associated with poor clinical outcomes beyond possible ILD development and thus are by themselves a significant finding. Among the present objectives of this field are the stratification of patients with regards to progression and the discovery of biomarkers with predictive value for clinical outcomes.

The gene <i>TP53</i>, which encodes the tumor suppressor protein p53, is mutated in about 50% of cancers. In response to cell stressors like DNA damage and after treatment with DNA-damaging therapeutic agents, p53 acts as a transcription factor to activate subsets of target genes which carry out cell fates such as apoptosis, cell cycle arrest, and DNA repair. Target gene selection by p53 is controlled by a complex regulatory network whose response varies across contexts including treatment type, cell type, and tissue type. The molecular basis of target selection across these contexts is not well understood. Knowledge gained from examining p53 regulatory network profiles across different DNA-damaging agents in different cell types and tissue types may inform logical ways to optimally manipulate the network to encourage p53-mediated tumor suppression and anti-tumor immunity in cancer patients. This may be achieved with combination therapies or with p53-reactivating targeted therapies. Here, we review the basics of the p53 regulatory network in the context of differential responses to DNA-damaging agents; discuss recent efforts to characterize differential p53 responses across treatment types, cell types, and tissue types; and examine the relevance of evaluating these responses in the tumor microenvironment. Finally, we address open questions including the potential relevance of alternative p53 transcriptional functions, p53 transcription-independent functions, and p53-independent functions in the response to DNA-damaging therapeutics.

STAT3 is an oncogenic transcription factor that controls the expression of genes associated with oncogenesis and malignant progression. Persistent activation of STAT3 is observed in human malignancies, including hepatocellular carcinoma (HCC) and multiple myeloma (MM). Here, we have investigated the action of Tris(dibenzylideneacetone) dipalladium 0 (Tris DBA) on STAT3 signaling in HCC and MM cells. Tris DBA decreased cell viability, increased apoptosis, and inhibited IL-6 induced/constitutive activation of STAT3, JAK1, JAK2, and Src in HCC and MM cells. Tris DBA downmodulated the nuclear translocation of STAT3 and reduced its DNA binding ability. It upregulated the expression of SHP2 (protein and mRNA) to induce STAT3 dephosphorylation, and the inhibition of SHP2 reversed this effect. Tris DBA downregulated the expression of STAT3-driven genes, suppressed cell migration/invasion. Tris DBA significantly inhibited tumor growth in xenograft MM and orthotopic HCC preclinical mice models with a reduction in the expression of various prosurvival biomarkers in MM tumor tissues without displaying significant toxicity. Overall, Tris DBA functions as a good inhibitor of STAT3 signaling in preclinical HCC and MM models.

Tuberculosis (TB) is the world's most prevalently infectious disease. Molecular mechanisms behind tuberculosis remain unknown. microRNA (miRNA) is involved in a wide variety of diseases. To validate the significant genes and miRNAs in the current sample, two messenger RNA (mRNA) expression profile datasets and three miRNA expression profile datasets were downloaded from the Gene Expression Omnibus (GEO) database. The differentially expressed (DE) genes (DEGs) and miRNAs (DE miRNAs) between healthy and TB patients were filtered out. Enrichment analysis was executed, and a protein-protein interaction (PPI) network was developed to understand the enrich pathways and hub genes of TB. Additionally, the target genes of miRNA were predicted and overlapping target genes were identified. We studied a total of 181 DEGs (135 downregulated and 46 upregulated genes) and two DE miRNAs (2 downregulated miRNAs) from two gene profile datasets and three miRNA profile datasets, respectively. 10 hub genes were defined based on high degree of connectivity. A PPI network's top module was constructed. The 23 DEGs identified have a significant relationship with miRNAs. 25 critically significant Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were discovered. The detailed study revealed that, in tuberculosis, the DE miRNA and DEGs form an interaction network. The identification of novel target genes and main pathways would aid with our understanding of miRNA's function in tuberculosis progression.

Breast cancer (BC) and colon cancer (CRC) are the two most deadly cancers in the world. These cancers partly share the same genetic background and are partially regulated by the same genes. The outcomes of traditional chemoradiotherapy and surgery remain suboptimal, with high postoperative recurrence and a low survival rate. It is, therefore, urgent to innovate and improve the existing treatment measures. Many studies primarily reported that the microRNA (miRNA) sponge functions of circular RNA (circRNA) in BC and CRC have an indirect relationship between the circRNA-miRNA axis and malignant behaviors. With a covalent ring structure, circRNAs can regulate the expression of target genes in multiple ways, especially by acting as miRNA sponges. Therefore, this review mainly focuses on the roles of circRNAs as miRNA sponges in BC and CRC based on studies over the last three years, thus providing a theoretical reference for finding new therapeutic targets in the future.

No abstract available.

<h4>Objective: </h4> Polycystic ovary syndrome (PCOS) is characterized by reproductive dysfunctions and metabolic disorders. This study aims to compare the therapeutic effectiveness of glucagon-like peptide-1 receptor agonist (GLP-1RA) + Metformin (Met) versus co-cyprindiol (cyproterone acetate/ethinylestradiol, CPA/EE) + Met in overweight PCOS women and identify potential biomarkers. <h4>Methods:</h4> In this prospective, open-label randomized controlled trial, we recruited 60 overweight PCOS women into two groups at a 1:1 ratio to receive CPA/EE (2 mg/day) + Met (1,500 mg/day) or GLP-1RA (liraglutide, 0.6-1.2 mg/day) + Met (1,500 mg/day) for 12 weeks. The clinical effectiveness and adverse effects were evaluated, followed by plasma proteomic analysis and verification of critical biomarkers by ELISA. <h4>Results:</h4> Both interventions improved menstrual cycle, polycystic ovaries, LH levels, and LH/FSH ratio; meanwhile reduced the body weight, BMI, HbA1c, FBG, OGTT-30 min insulin, IL-6 and TNF-α. Whereas, GLP-1RA + Met showed a more robust improvement on HbA1c, HOMA-IR, lipid profiles, inflammatory parameters, and ovulation. CPA/EE + Met was more effective in reducing hyperandrogenemia. Plasma proteomic analysis revealed that the interventions altered proteins involved in reactive oxygen species detoxification (PRDX6, GSTO1, GSTP1, GSTM2), platelet degranulation (FN1), and the immune response (SERPINB9). <h4>Conclusions:</h4> CPA/EE+Met or GLP-1RA + Met treatment improved reproductive functions and alleviated metabolic disorders in overweight PCOS women. GLP-1RA + Met had a superior improvement in metabolism and inflammation. The novel plasma biomarkers PRDX6, FN1, and SERPINB9, might be indicators and targets for PCOS treatment.

Spinocerebellar ataxia type 3 is the most common autosomal dominant inherited ataxia worldwide, caused by a CAG repeat expansion in the Ataxin-3 gene resulting in a polyglutamine (polyQ)-expansion in the corresponding protein. The disease is characterized by neuropathological, phenotypical, and specific transcriptional changes in affected brain regions. So far, there is no mouse model available representing all the different aspects of the disease, yet highly needed for a better understanding of the disease pathomechanisms. Here, we characterized a novel Ataxin-3 knock-in mouse model, expressing a heterozygous or homozygous expansion of 304 CAACAGs in the murine Ataxin-3 locus using biochemical, behavioral, and transcriptomic approaches. We compared neuropathological, and behavioral features of the new knock-in model with the in SCA3 research mostly used YAC84Q mouse model. Further, we compared transcriptional changes found in cerebellar samples of the SCA3 knock-in mice and post-mortem human SCA3 patients. The novel knock-in mouse is characterized by the expression of a polyQ-expansion in the murine Ataxin-3 protein, leading to aggregate formation, especially in brain regions known to be vulnerable in SCA3 patients, and impairment of Purkinje cells. Along these neuropathological changes, the mice showed a reduction in body weight accompanied by gait and balance instability. Transcriptomic analysis of cerebellar tissue revealed age-dependent differential expression, enriched for genes attributed to myelinating oligodendrocytes. Comparing these changes with those found in cerebellar tissue of SCA3 patients, we discovered an overlap of differentially expressed genes pointing towards similar gene expression perturbances in several genes linked to myelin sheaths and myelinating oligodendrocytes.

<h4>Background</h4>Rheumatoid arthritis (RA) is a chronic autoimmune disease, which commonly affects women. Accumulating evidence shows that differentially expressed circular RNAs (circRNAs) play crucial roles in the progress of RA. However, the roles of circRNAs in female RA remains unclear. This study explores potential role and diagnostic value of hsa_circ_0140271 from peripheral blood mononuclear cells (PBMC) in female RA.<h4>Methods</h4>Differential expression of circRNAs was determined by RNA-sequencing in PBMC from 4 healthy controls (HC) and 4 RA patients, and we further measured the level of hsa_circ_0140271 in a validation cohort consisting of 47 RA and 47 HC via RT-qPCR. Besides, correlation studies with clinical variables were also examined. What's more, we performed bioinformatics analysis to predict the potential role of hsa_circ_0140271.<h4>Results</h4>PBMC expression of hsa_circ_0140271 of female RA was significantly higher than that of female HC, and it was positively correlated with antistreptolysin (ASO). Furthermore, the receiver operating characteristic (ROC) curve indicated that hsa_circ_0140271 could distinguish female RA from female HC and female patients with ankylosing spondylitis (AS) or osteoarthritis (OA). Besides, the combined diagnosis anti-cyclic citrullinated peptide (Anti-CCP) + hsa_circ_0140271 could improve diagnostic accuracy with an area under the curve (AUC) of 0.818 to compared with Anti-CCP. Furthermore, KEGG pathway enrichment analysis indicated hsa_circ_0140271 may act as microRNA sponge and participate in fatty acid metabolism pathways.<h4>Conclusion</h4>Hsa_circ_0140271 was likely to be used as a promising diagnostic biomarker for female RA; it may act as microRNA sponge to regulate fatty acid metabolism pathways in RA.

<h4>Background</h4>Non-alcoholic steatohepatitis (NASH) is frequently associated with obesity, and its standard treatment is weight loss with diet and exercise; a dy% weight reduction has been associated with improvement in liver histological and analytical abnormalities. However, less than 25% of subjects achieve this goal. Laparoscopic sleeve gastrectomy (LSG) represents the most common procedure of bariatric surgery, providing effective weight loss and improvement in comorbidities such as NASH, but it is associated with several postoperative complications. Endoscopic bariatric techniques are currently on the rise as a new tool in the fight against obesity, offering patients an alternative to more invasive surgery. However, their efficacy and safety compared with LSG is unclear.<h4>Methods</h4>The TESLA-NASH study is a randomized, controlled, open-label, unicentric clinical trial with a medical device. The aim of this study is to evaluate and compare the efficacy and safety of endoscopic sleeve gastroplasty (ESG) versus laparoscopic sleeve gastrectomy (LSG) in liver histology improvement of patients with obesity +/- metabolic syndrome and NASH. A total of 30 patients will be randomized 1:1 to the experimental or control group.<h4>Discussion</h4>LSG is an effective treatment for weight reduction and for the remission of hepatic alterations. However, LSG is associated with acute and chronic postoperative complications. Bariatric endoscopic techniques promise less invasive and more cost-effective approaches to the treatment of obesity and metabolic comorbidities. ESG represents one of the most promising novel endoscopic interventions and it is mainly proposed for patients with mild-to-moderate obesity, but there are still no guidelines that specify its applicability criteria. This clinical trial will help us apply different tactics to the treatment of obesity and NASH.<h4>Trial registration</h4>ClinicalTrials.gov NCT04060368. Registered on Nov 15, 2019.

<h4>Background</h4>Although numerous studies demonstrate the role of cancer stem cells in occurrence, recurrence, and distant metastases in gastric cancer (GC), little is known about the evolving genetic and epigenetic changes in the stem and progenitor cells. The purpose of this study was to identify the stem cell subtypes in GC and examine their clinical relevance.<h4>Methods</h4>Two publicly available datasets were used to identify GC stem cell subtypes, and consensus clustering was performed by unsupervised machine learning methods. The cancer stem cell (CSC) typing-related risk scoring (RS) model was established through multivariate Cox regression analysis.<h4>Results</h4>Cross-platform dataset-based two stable GC stem cell subtypes, namely low stem cell enrichment (SCE_L) and high stem cell enrichment (SCE_H), were prudently identified. Gene set enrichment analysis revealed that the classical oncogenic pathways, immune-related pathways, and regulation of stem cell division were active in SCE_H; ferroptosis, NK cell activation, and post-mutation repair pathways were active in SCE_L. GC stem cell subtypes could accurately predict clinical outcomes in patients, tumor microenvironment cell-infiltration characteristics, somatic mutation landscape, and potential responses to immunotherapy, targeted therapy, and chemotherapy. Additionally, a CSC typing-related RS model was established; it was strongly independent and could accurately predict the patient's overall survival.<h4>Conclusions</h4>This study demonstrated the complex oncogenic mechanisms underlying GC. The findings provide a basis and reference for the diagnosis and treatment of GC.

Biogenic polyamines (PAs) are involved in the growth and development of normal cells, and their intracellular concentration is stable. The concentration of PAs in cancer cells is significantly increased to promote and sustain their rapid proliferation. Over the years, synthetic PAs, which differ in their structure, have demonstrated high antitumor activity and are involved in clinical trials. The chemical synthesis of PAs and their conjugates require the correct choice of synthetic pathways-methods for constructing conjugates and the orthogonal protection of amino groups. The most common methods of synthesis of PA conjugates are acylation of regioselectively protected PAs or their alkylation under the conditions of the Fukuyama reaction. One of the most promising methods of PA synthesis is the use of a multicomponent Ugi reaction, which allows various PAs to be obtained in high yields. In this review, we describe and analyze various approaches that are used in the synthesis of polyamines and their conjugates.

The 2-phenoxybenzamide <b>1</b> from the Medicines for Malaria Venture Malaria Box Project has shown promising multi-stage activity against different strains of <i>P. falciparum</i>. It was successfully synthesized via a retrosynthetic approach. Subsequently, twenty-one new derivatives were prepared and tested for their in vitro activity against blood stages of the NF54 strain of <i>P. falciparum</i>. Several insights into structure-activity relationships were revealed. The antiplasmodial activity and cytotoxicity of compounds strongly depended on the substitution pattern of the anilino partial structure as well as on the size of substituents. The diaryl ether partial structure had further impacts on the activity. Additionally, several physicochemical and pharmacokinetic parameters were calculated (log P, log D₇.₄ and ligand efficiency) or determined experimentally (passive permeability and CYP3A4 inhibition). The <i>tert</i>-butyl-4-{4-[2-(4-fluorophenoxy)-3-(trifluoromethyl)benzamido]phenyl}piperazine-1-carboxylate possesses high antiplasmodial activity against <i>P. falciparum</i> NF54 (<i>Pf</i>NF54 IC₅₀ = 0.2690 µM) and very low cytotoxicity (L-6 cells IC₅₀ = 124.0 µM) resulting in an excellent selectivity index of 460. Compared to the lead structure <b>1</b> the antiplasmodial activity was improved as well as the physicochemical and some pharmacokinetic parameters.

In the last decade, Autism has broadened and often shifted its diagnostics criteria, allowing several neuropsychiatric and neurological disorders of known etiology. This has resulted in a highly heterogeneous spectrum with apparent exponential rates in prevalence. I ask if it is possible to leverage existing genetic information about those disorders making up Autism today and use it to stratify this spectrum. To that end, I combine genes linked to Autism in the SFARI database and genomic information from the DisGeNET portal on 25 diseases, inclusive of non-neurological ones. I use the GTEx data on genes' expression on 54 human tissues and ask if there are overlapping genes across those associated to these diseases and those from SFARI-Autism. I find a compact set of genes across all brain-disorders which express highly in tissues fundamental for somatic-sensory-motor function, self-regulation, memory, and cognition. Then, I offer a new stratification that provides a distance-based orderly clustering into possible Autism subtypes, amenable to design personalized targeted therapies within the framework of Precision Medicine. I conclude that viewing Autism through this physiological (Precision) lens, rather than viewing it exclusively from a psychological behavioral construct, may make it a more manageable condition and dispel the Autism epidemic myth.

Acute myeloid leukemia (AML) is characterized by an increasing number of clonal myeloid blast cells which are incapable of differentiating into mature leukocytes. AML risk stratification is based on genetic background, which also serves as a means to identify the optimal treatment of individual patients. However, constant refinements are needed, and the inclusion of significant measurements, based on the various omics approaches that are currently available to researchers/clinicians, have the potential to increase overall accuracy with respect to patient management. Using both nontargeted (label-free mass spectrometry) and targeted (multiplex immunoassays) proteomics, a range of proteins were found to be significantly changed in AML patients with different genetic backgrounds. The inclusion of validated proteomic biomarker panels could be an important factor in the prognostic classification of AML patients. The ability to measure both cellular and secreted analytes, at diagnosis and during the course of treatment, has advantages in identifying transforming biological mechanisms in patients, assisting important clinical management decisions.

<h4>Background</h4> Autosomal-dominant Alzheimer’s disease (ADAD) is caused by pathogenic mutations in APP, PSEN1 , and PSEN2 , which usually lead to an early age at onset (<65). Circular RNAs are a family of non-coding RNAs highly expressed in the nervous system and especially in synapses. We aimed to investigate differences in brain gene expression of linear and circular transcripts from the three ADAD genes in controls, sporadic AD, and ADAD. <h4>Methods</h4> We obtained and sequenced RNA from brain cortex using standard protocols. Linear counts were obtained using the TOPMed pipeline; circular counts, using python package DCC. After stringent quality control (QC), we obtained the counts for PSEN1, PSEN2 and APP genes. Only circ PSEN1 passed QC. We used DESeq2 to compare the counts across groups, correcting for biological and technical variables. Finally, we performed in-silico functional analyses using the Circular RNA interactome website and DIANA mirPath software. <h4>Results</h4> Our results show significant differences in gene counts of circ PSEN1 in ADAD individuals, when compared to sporadic AD and controls (ADAD=22, AD=274, Controls=25 – ADADvsCO: log2FC=0.786, p=9.08×10-05, ADADvsAD: log2FC=0.576, p=2.00×10-03). The high gene counts are contributed by two circ PSEN1 species (hsa_circ_0008521 and hsa_circ_0003848). No significant differences were observed in linear PSEN1 gene expression between cases and controls, indicating that this finding is specific to the circular forms. In addition, the high circ PSEN1 levels do not seem to be specific to PSEN1 mutation carriers; the counts are also elevated in APP and PSEN2 mutation carriers. In-silico functional analyses suggest that circ PSEN1 is involved in several pathways such as axon guidance (p=3.39×10 −07 ), hippo signaling pathway (p=7.38×10 −07 ), lysine degradation (p=2.48×10 −05 ) or Wnt signaling pathway (p=5.58×10 −04 ) among other KEGG pathways. Additionally, circ PSEN1 counts were able to discriminate ADAD from sporadic AD and controls with an AUC above 0.70. <h4>Conclusions</h4> Our findings show the differential expression of circ PSEN1 is increased in ADAD. Given the biological function previously ascribed to circular RNAs and the results of our in-silico analyses, we hypothesize that this finding might be related to neuroinflammatory events that lead or that are caused by the accumulation of amyloid-beta.

<h4>Background</h4>This study aimed to probe and verify aberrantly methylated and expressed genes in hepatoblastoma and to analyze their interactions with tumor immune microenvironment.<h4>Methods</h4>Aberrantly methylated and expressed genes were obtained by comprehensively analyzing gene expression and DNA methylation profiles from GSE81928, GSE75271 and GSE78732 datasets. Their biological functions were predicted by the STRING and Metascape databases. CIBERSORT was utilized for inferring the compositions of tumor-infiltrating immune cells (TIICs) in each sample. Correlation between hub genes and immune cells was then analyzed. Hub genes were validated in hepatoblastoma tissues via western blot or immunohistochemistry. After transfection with sh-NOTUM, migration and invasion of HuH-6 and HepG2 cells were investigated. The nude mouse tumorigenesis model was constructed.<h4>Results</h4>Totally, 83 aberrantly methylated and expressed genes were determined in hepatoblastoma, which were mainly involved in metabolic and cancer-related pathways. Moreover, their expression was liver-specific. 13 hub genes were screened, which were closely related to immune cells in hepatoblastoma tissues. Among them, it was confirmed that AXIN2, LAMB1 and NOTUM were up-regulated and SERPINC1 was down-regulated in hepatoblastoma than normal tissues. NOTUM knockdown distinctly weakened migration and invasion of HuH-6 and HepG2 cells and tumor growth in vivo.<h4>Conclusions</h4>This study identified aberrantly methylated and expressed signatures that were in relation to immune microenvironment in hepatoblastoma. Targeting NOTUM hub gene could suppress migration and invasion of hepatoblastoma cells. Thus, these aberrantly methylated and expressed genes might act as therapeutic agents in hepatoblastoma therapy.

<h4>Introduction</h4>Sex-based clinical outcome differences in sickle cell disease (SCD) remain largely unknown despite evidence that female sex is associated with an increased lifespan. To better characterize sex-based differences in SCD, we assessed pain, treatment characteristics, laboratory measures and complications among males and females currently enrolled in the Sickle Cell Disease Implementation Consortium (SCDIC) registry.<h4>Methods</h4>The SCDIC consists of eight comprehensive SCD centers and one data coordinating center that received funding from the National Heart Lung and Blood Institute to improve outcomes for individuals with SCD. Eligibility criteria included: 15 to 45 years of age and a confirmed diagnosis of SCD. Self-report surveys were completed and data were also abstracted from the participants' medical records.<h4>Results</h4>A total of 2,124 participants were included (mean age: 27.8 years; 56% female). The majority had hemoglobin SS SCD genotype. Females had worse reports of pain severity (mean (SD) T-score 51.6 (9.6) vs 49.3 (10), p<0.001), more vaso-occlusive episodes (p = 0.01) and a higher occurrence of 3 or more hospital admissions in the past year (30.9% vs. 25.5, p = 0.03). On multivariable analysis, males had higher odds of acute chest syndrome (odds ratio (OR) 1.4, p = 0.002), cardiovascular (OR 1.70, p<0.001) and musculoskeletal (OR 1.33, p = 0.0034) complications and lower odds of depression (OR 0.77, p = 0.0381). Females had higher fetal hemoglobin levels with and without hydroxyurea use (9.6% vs 8.5%, p = 0.03 and 3% vs 2.2%, p = 0.0005, respectively).<h4>Conclusion</h4>Our data suggests that sex differences in clinical outcomes do occur among individuals with SCD. Future research needs to explore the mechanisms underlying these differences.

<h4>Background</h4>Lung adenocarcinoma (LUAD) is a malignant tumor with a high fatality rate and poor overall survival, while molecular targets diagnosing and alleviating lung cancer remain inadequate.<h4>Methods</h4>In this article, we highlighted the upregulation of microRNA-423-3p (miR-423-3p) in LUAD, especially in smokers aged over 40, and revealed that the high expression of miR-423-3p was significantly associated with smoker, age, and pathologic stage of LUAD patients.<h4>Results</h4>Moreover, overexpressing miR-423-3p could facilitate LUAD cell proliferation, invasion, adhesion, and epithelial-mesenchymal transition (EMT) process, while depleted miR-423-3p caused repressive influence upon it. Mechanically, we identified that miR-423-3p could activate FAK signaling pathway through binding to the 3'-UTR of cytochrome B reductase 1 (CYBRD1). Furthermore, we demonstrated that CYBRD1 was lowly expressed in LUAD, and miR-423-3p overexpression could rescue the impairment of LUAD cell proliferation, invasion, adhesion, and EMT caused by CYBRD1 depletion. Noticeably, miR-423-3p depletion efficiently hindered LUAD tumor growth in vivo.<h4>Conclusion</h4>Collectively, our findings demonstrated that miR-423-3p/CYBRD1 axis could be regarded as a promising biomarker to alleviate the poor LUAD prognosis.

<h4>Background</h4>miR-124-3p can inhibit integrin β3 (ITGB3) expression to suppress the migration and invasion of gastric cancer (GC), and in the process lncRNA HOXA11-AS may act as a molecular sponge.<h4>Methods</h4>Luciferase reporter assay was conducted to verify the binding of miR-124-3p and HOXA11-AS. RT-PCR and western blot were performed to detect the expression of HOXA11-AS, miR-124-3p and ITGB3 in GC tissues and cells. Gene silence and overexpression experiments as well as cell migration and invasion assays on GC cell lines were performed to determine the regulation of molecular pathways, HOXA11-AS/miR-124-3p/ITGB3. Furthermore, the role of HOXA11-AS in GC was confirmed in mice models.<h4>Results</h4>We found HOXA11-AS is up-regulated in GC tissues and can bind with miR-124-3p. Through overexpression/knockdown experiments and function tests in vitro, we demonstrated HOXA11-AS can promote ITGB3 expression by sponging miR-124-3p, consequently enhance the proliferation, migration, and invasion of GC cells. Meanwhile, we validated that HOXA11-AS promotes migration and invasion of GC cells via down-regulating miR-124-3p and up-regulating ITGB3 in vivo.<h4>Conclusions</h4>We demonstrated that lncRNA HOXA11-AS can increase ITGB3 expression to promote the migration and invasion of gastric cancer by sponging miR-124-3p. Our results suggested that HOXA11-AS may reasonably serve as a promising diagnostic biomarker and a potential therapeutic target of GC.

Histone modification is an important form of epigenetic regulation. Thereinto, histone methylation is a critical determination of chromatin states, participating in multiple cellular processes. As a conserved histone methylation mark, histone 3 lysine 36 trimethylation (H3K36me3) can mediate multiple transcriptional-related events, such as the regulation of transcriptional activity, transcription elongation, pre-mRNA alternative splicing, and RNA m⁶A methylation. Additionally, H3K36me3 also contributes to DNA damage repair. Given the crucial function of H3K36me3 in genome regulation, the roles of H3K36me3 and its sole methyltransferase SETD2 in pathogenesis, especially malignancies, have been emphasized in many studies, and it is conceivable that disruption of histone methylation regulatory network composed of "writer", "eraser", "reader", and the mutation of H3K36me3 codes have the capacity of powerfully modulating cancer initiation and development. Here we review H3K36me3-mediated biological processes and summarize the latest findings regarding its role in cancers. We highlight the significance of epigenetic combination therapies in cancers.

The Hippo pathway effector TAZ promotes cellular growth, survival, and stemness through regulating gene transcription. Recent studies suggest that TAZ liquid-liquid phase separation (LLPS) compartmentalizes key cofactors to activate transcription. However, how TAZ LLPS is achieved remains unknown. Here, it is shown that the paraspeckle protein NONO is required for TAZ LLPS and activation in the nucleus. NONO is a TAZ-binding protein. Their interaction shows temporal regulation parallel to the interaction between TAZ and TEAD as well as to the expression of TAZ target genes. NONO depletion reduces nuclear TAZ LLPS, while ectopic NONO expression promotes the LLPS. Accordingly, NONO depletion reduces TAZ interactions with TEAD, Rpb1, and enhancers. In glioblastoma, expressions of NONO and TAZ are both upregulated and predict poor prognosis. Silencing NONO expression in an orthotopic glioblastoma mouse model inhibits TAZ-driven tumorigenesis. Together, this study suggests that NONO is a nuclear factor that promotes TAZ LLPS and TAZ-driven oncogenic transcriptional program.

<h4>Purpose</h4>Hydroxyapatite (HA) scaffolds are common replacement materials used in the clinical management of critical-sized bone defects. This study was undertaken to examine the potential benefits of fluoridated derivatives of hydroxyapatite, fluorapatite (FA), and fluorohydroxyapatite (FHA) as bone scaffolds in conjunction with adipose-derived stem cells (ADSCs). If FHA and FA surfaces could drive the differentiation of stem cells to an osteogenic phenotype, the combination of these ceramic scaffolds with ADSCs could produce materials with mechanical strength and remodeling potential comparable to autologous bone. This study was designed to investigate the ability of the apatite surfaces HA, FA, and FHA produced at different sintering temperatures to drive ADSCs toward osteogenic lineages.<h4>Methods</h4>HA, FHA, and FA surfaces sintered at 1150 °C and 1250 °C were seeded with ADSCs and evaluated for cell growth and gene and protein expression of osteogenic markers at 2 and 10 days post-seeding.<h4>Results</h4>In vitro, ADSC cells were viable on all surfaces; however, differentiation of these cells into osteoblastic lineage only observed in apatite surfaces. ADSCs seeded on FA and FHA expressed genes and proteins related to osteogenic differentiation markers to a greater extent by Day 2 when compared to HA and cell culture controls. By day 10, HA, FA, and FHA all expressed more bone differentiation markers compared to cell culture controls.<h4>Conclusion</h4>FA and FHA apatite scaffolds may promote the differentiation of ADSCs at an earlier time point than HA surfaces. Combining apatite scaffolds with ADSCs has the potential to improve bone regeneration following bone injury.

Lianpu drink (LPD) is a traditional Chinese medicine (TCM) formula for the treatment of chronic gastritis (CG), and its clinical effects have been effectively verified. However, due to the complexity of the chemical composition of TCM formulas, its mechanism of action has not yet been clearly explained. Many studies have shown that the principal drugs in the TCM formula play a major therapeutic role. Therefore, in this study, the principal drugs <i>Coptidis Rhizoma</i> (CR) and <i>Magnolia officinalis Rehd. et Wils</i>. (MOR) in LPD were used as the main research objects to predict the mechanism of LPD on CG. We contrasted a "compounds-targets-diseases" network and screened the putative targets of CR and MOR in LPD related to CG, respectively. Furthermore, common targets of CR and MOR related to CG were selected as candidate targets. In this study, the specific target proteins of CR, MOR, and CG were combined by protein-protein interaction (PPI) to construct a pharmacological network of "components-targets-diseases." In addition, we investigated the effects of CR and MOR on the TNF signaling pathway, which mediated the remission of CG. This study preliminarily revealed that CR and MOR play a key role in the treatment of CG. Animal experiments also showed that CR and MOR could significantly improve CG by inhibiting MKK6/<i>p</i>38 and RIP/<i>p</i>38 pathway.

Patients with inflammatory bowel disease (IBD) are at increased risk of developing colorectal cancer (CRC), despite decreases in CRC incidence in recent years. Chronic inflammation is the driver of neoplastic progression, resulting in dysplastic precursor lesions that may arise in multiple areas of the colon through a process of field cancerization. Colitis-associated CRC shares many molecular similarities with sporadic CRC, and preclinical investigations have demonstrated a potential role for the microbiome in concert with the host immune system in the development of colitis-associated colorectal cancer (CAC). Some unique molecular differences occur in CAC, but their role in the pathogenesis and behavior of inflammation-associated cancers remains to be elucidated. Nonconventional types of dysplasia have been increasingly recognized, but their natural history is not well defined, and they have not been incorporated into surveillance algorithms. The concept of cumulative inflammatory burden highlights the importance of considering histologic inflammation over time as an important risk factor for CAC. Dysplasia is arguably the most important risk factor for developing CAC, and advances have been made in the endoscopic detection and removal of precancerous lesions, thereby deferring or avoiding surgical resection. Some of the agents used to treat IBD are chemopreventive. It is hoped that by gaining better control of the underlying inflammation with newer medications and better endoscopic detection and management, a more sophisticated appreciation of clinicopathologic risk factors, and growing awareness of the genetic, immunologic, and environmental causes of colitis- associated neoplasia, that colitis-associated colorectal neoplasia will become even more predictable and manageable in the coming years.

Corpus luteum (CL), a transitory gland, undergoes rapid growth in a limited time to produce progesterone (P4) followed by its regression. A complex molecular signaling is involved in controlling luteal P4 production. In the present study, 2D gel electrophoresis-based proteomics and in silico functional analysis were used to identify changes in key proteins and pathways in CL along the different stages of the estrous cycle as its development progresses from early (Day 3) to mid-luteal phase (Day 9), effective functioning (Day 12) followed by regression (Day 15) or, in the case of pregnancy, rescue of function (Day 15). A total of 273 proteins were identified by MALDI-MS/MS analysis that showed significant changes in abundances at different stages of CL development or regression and rescue. Functional annotation of differentially abundant proteins suggested enrichment of several important pathways and functions during CL development and function maintenance including cell survival, endocytosis, oxidative stress response, estradiol metabolism, and angiogenesis. On the other hand, differentially abundant proteins during CL regression were associated with decreased steroid synthesis and metabolism and increased apoptosis, necrosis, and infiltration of immune cells. Establishment of pregnancy rescues CL from regression by maintaining the expression of proteins that support steroidogenesis as pathways such as the super-pathway of cholesterol biosynthesis, RhoA signaling, and functions such as fatty acid metabolism and sterol transport were enriched in CL of pregnancy. In this study, some novel proteins were identified along CL development that advances our understanding of CL survival and steroidogenesis.

Protein palmitoylation is a reversible post-translational modification by fatty acids (FA), mainly a palmitate (C16:0). Palmitoylation allows protein shuttling between the plasma membrane and cytosol to regulate protein stability, sorting and signaling activity and its deficiency leads to diseases. We aimed to characterize the palmitoyl-proteome of ovarian follicular cells and molecular machinery regulating protein palmitoylation within the follicle. For the first time, 84 palmitoylated proteins were identified from bovine granulosa cells (GC), cumulus cells (CC) and oocytes by acyl-biotin exchange proteomics. Of these, 32 were transmembrane proteins and 27 proteins were detected in bovine follicular fluid extracellular vesicles (ffEVs). Expression of palmitoylation and depalmitoylation enzymes as palmitoyltransferases (ZDHHCs), acylthioesterases (LYPLA1 and LYPLA2) and palmitoylthioesterases (PPT1 and PPT2) were analysed using transcriptome and proteome data in oocytes, CC and GC. By immunofluorescence, ZDHHC16, PPT1, PPT2 and LYPLA2 proteins were localized in GC, CC and oocyte. In oocyte and CC, abundance of palmitoylation-related enzymes significantly varied during oocyte maturation. These variations and the involvement of identified palmitoyl-proteins in oxidation-reduction processes, energy metabolism, protein localization, vesicle-mediated transport, response to stress, G-protein mediated and other signaling pathways suggests that protein palmitoylation may play important roles in oocyte maturation and ffEV-mediated communications within the follicle.

During plant embryogenesis, regardless of whether it begins with a fertilized egg cell (zygotic embryogenesis) or an induced somatic cell (somatic embryogenesis), significant epigenetic reprogramming occurs with the purpose of parental or vegetative transcript silencing and establishment of a next-generation epigenetic patterning. To ensure genome stability of a developing embryo, large-scale transposon silencing occurs by an RNA-directed DNA methylation (RdDM) pathway, which introduces methylation patterns <i>de novo</i> and as such potentially serves as a global mechanism of transcription control during developmental transitions. RdDM is controlled by a two-armed mechanism based around the activity of two RNA polymerases. While PolIV produces siRNAs accompanied by protein complexes comprising the methylation machinery, PolV produces lncRNA which guides the methylation machinery toward specific genomic locations. Recently, RdDM has been proposed as a dominant methylation mechanism during gamete formation and early embryo development in <i>Arabidopsis thaliana</i>, overshadowing all other methylation mechanisms. Here, we bring an overview of current knowledge about different roles of DNA methylation with emphasis on RdDM during plant zygotic and somatic embryogenesis. Based on published chromatin immunoprecipitation data on PolV binding sites within the <i>A. thaliana</i> genome, we uncover groups of auxin metabolism, reproductive development and embryogenesis-related genes, and discuss possible roles of RdDM at the onset of early embryonic development via targeted methylation at sites involved in different embryogenesis-related developmental mechanisms.

Addition of a soluble or a supported Cr^III-salophen complex as a co-catalyst greatly enhances the catalytic activity of Bu₄NBr for the formation of styrene carbonate from styrene epoxide and CO₂. Their combination with a very low co-catalyst:Bu₄NBr:styrene oxide molar ratio = 1:2:112 (corresponding to 0.9 mol% of Cr^III co-catalyst) led to an almost complete conversion of styrene oxide after 7 h at 80°C under an initial pressure of CO₂ of 11 bar and to a selectivity in styrene carbonate of 100%. The covalent heterogenization of the complex was achieved through the formation of an amide bond with a functionalized {NH₂}-SBA-15 silica support. In both conditions, the use of these Cr^III catalysts allowed excellent conversion of styrene already at 50°C (69 and 47% after 24 h, respectively, in homogeneous and heterogeneous conditions). Comparison with our previous work using other metal cations from the transition metals particularly highlights the preponderant effect of the nature of the metal cation as a co-catalyst in this reaction, that may be linked to its calculated binding energy to the epoxides. Both co-catalysts were successfully reused four times without any appreciable loss of performance.

The objective of this study was to elucidate the impacts of irregular eating patterns on gut microbiota and transcriptomic responses in a pig model with different feeding regimens. The experiment involved 24 growing pigs (Duroc × Landrace × Large White, 48 days of age) which were randomly allocated to one of three feeding patterns: one-meal (M1), three-meals (M3), or five-meals (M5) per day with the same daily feed intake. The results showed that different feeding frequencies had no significant effects on the microbial composition of ileal digesta, colonic digesta, colon mucosa, as well as the concentration of SCFAs in colonic digesta. Mucosa transcriptomic profiling data showed the pathways related to vitamin metabolism were enriched in the ileum and colon of pigs in the pairwise comparison between M3 and M1 groups. On the other hand, the pathways related to lipid metabolism were enriched in the ileum and colon of pigs in the pairwise comparison between M5 and M1 groups. Lastly, the pathways related to protein metabolism were enriched in the colon in the pairwise comparison between M3 and M1 groups, M5 and M1 groups, M5 and M3 groups, while the ileum was not enriched. Differentially expressed genes (DEG) related to metabolism showed that carbohydrate transport was suppressed in the ileum and enhanced in the colon in M5 and M3 groups compared with the M1 group. Compared with the M3 group, carbohydrate transport in the ileum was enhanced in the M5 group, while in the colon was inhibited. With the increase of feeding frequency, the catabolism, biosynthesis, and transport of lipid in the ileum were suppressed, while those in the colon were enhanced. Compared with the M1 group, amino acid transport in the ileum and colon in the M3 group was enhanced. Amino acid catabolism in the ileum in the M5 group was enhanced compared with M1 and M3 groups. In summary, different feeding frequencies affected the transport of carbohydrate, lipid, and amino acid in the ileum and colon, and affected the catabolism and biosynthesis of lipid in the ileum and colon with a low impact on intestinal microbiota.

Organophosphate pesticides (OPPs) are one of the most widely used insecticides. OPPs exert their neurotoxic effects by inhibiting acetylcholine esterase (AChE). Most of the gross developmental abnormalities observed in OPP-treated fish, on the other hand, may not be explained solely by AChE inhibition. To understand the overall molecular mechanisms involved in OPP toxicity, we used the zebrafish (ZF) model. We exposed ZF embryos to an OPP, phosmet, for 96 h, and then analyzed developmental abnormalities and performed whole transcriptome analysis. Phenotypic abnormalities, such as bradycardia, spine curvature, and growth retardation, were observed in phosmet-treated ZF (PTZF). Whole transcriptome analysis revealed 2190 differentially expressed genes (DEGs), with 822 and 1368 significantly up-and downregulated genes, respectively. System process and sensory and visual perception were among the top biological pathways affected by phosmet toxicity. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed significant enrichment of metabolic pathways, calcium signaling pathway, regulation of actin cytoskeleton, cardiac muscle contraction, drug metabolism-other enzymes, and phototransduction. Quantitative real-time PCR results of six DEGs agreed with the sequencing data expression profile trend. Our findings provide insights into the consequences of phosmet exposure in ZF, as well as an estimate of the potential risk of OPPs to off-target species.

Large-scale genomic studies of schizophrenia have identified hundreds of genetic loci conferring risk to the disorder. This progress offers an important route toward defining the biological basis of the condition and potentially developing new treatments. In this review, we discuss insights from recent genome-wide association study, copy number variant, and exome sequencing analyses of schizophrenia, together with functional genomics data from the pre- and postnatal brain, in relation to synaptic development and function. These data provide strong support for the view that synaptic dysfunction within glutamatergic and GABAergic (gamma-aminobutyric acidergic) neurons of the cerebral cortex, hippocampus, and other limbic structures is a central component of schizophrenia pathophysiology. Implicated genes and functional genomic data suggest that disturbances in synaptic connectivity associated with susceptibility to schizophrenia begin in utero but continue throughout development, with some alleles conferring risk to the disorder through direct effects on synaptic function in adulthood. This model implies that novel interventions for schizophrenia could include broad preventive approaches aimed at enhancing synaptic health during development as well as more targeted treatments aimed at correcting synaptic function in affected adults.

<h4>Introduction</h4>This study aims to describe the occurrence of postoperative complications related to cholesteatoma surgery and to determine factors influencing the most common complication, i.e. postoperative surgical site infection (SSI) in cases with and without mastoid obliteration.<h4>Materials and methods</h4>Retrospective analyses were performed on surgically treated cholesteatomas in our hospital between 2013 and 2019. Patient characteristics, peri- and postoperative management and complications were reviewed. The cases were divided into two groups based on whether mastoid obliteration was performed or not.<h4>Results</h4>A total of 336 cholesteatoma operations were performed, of which 248 cases received mastoid obliteration. In total 21 complications were observed, of which SSI was the most common (15/21). No difference in occurrence of any postoperative complication was seen between the obliteration and no-obliteration group (<i>p</i> = 0.798), especially not in the number of SSI (<i>p</i> = 0.520). Perioperative and/or postoperative prophylactic antibiotics were not associated to the development of an SSI in both groups. In the no-obliteration group a younger age <i>(p</i> = 0.015), as well as primary surgery (<i>p</i> = 0.022) increased the risk for SSI. In the obliteration group the use of bioactive glass (BAG) S53P4 was identified as independent predictor of SSI (<i>p</i> = 0.008, OR 5.940).<h4>Discussion</h4>SSI is the most common postoperative complication in cholesteatoma surgery. The causes of SSI are multifactorial, therefore further prospective research is needed to answer which factors can prevent the development of an SSI in cholesteatoma surgery.

<h4>ABSTRACT</h4> Condensin is a Structural Maintenance of Chromosomes (SMC) complex needed for the compaction of DNA into chromatids during mitosis. Lengthwise DNA compaction by condensin is facilitated by ATPase-driven loop extrusion, a process that is believed to be the fundamental activity of most, if not all SMC complexes. In order to obtain molecular insights, we obtained cryo-EM structures of yeast condensin in the presence of a slowly-hydrolysable ATP analogue and linear, as well as circular DNAs. The DNAs were shown to be “clamped” between the engaged heterodimeric SMC ATPase heads and the Ycs4 subunit, in a manner similar to previously reported DNA-bound SMC complex structures. Ycgl, the other non-SMC subunit was only flexibly bound to the complex, while also binding DNA tightly, and often remaining at a distance from the head module. In the clamped state, the DNA is encircled, or topologically entrapped, by the kleisin Brnl and the two engaged head domains of Smc2 and Smc4, and this tripartite ring is closed at all interfaces, including at the neck of Smc2. We show that the neck gate opens upon head engagement in the absence of DNA, but it remains shut when DNA is present. Our work demonstrates that condensin and other SMC complexes go through similar conformations of the head modules during their ATPase cycle. In contrast, the behaviour of the Ycgl subunit in the condensin complex might indicate differences in the implementation of the extrusion reactions and our findings will constrain further mechanistic models of loop extrusion by SMC complexes. <h4>SIGNIFICANCE STATEMENT</h4> DNA needs to be compacted dramatically to fit into nuclei and during cell division, when dense chromatids are formed for their mechanical segregation, a process that depends on the protein complex condensin. It forms and enlarges loops in DNA through loop extrusion. Our work resolves the atomic structure of a DNA-bound state of condensin in which ATP has not been hydrolysed. The DNA is clamped within a compartment that has been reported previously in other SMC complexes, including Rad50, cohesin and MukBEF. With the caveat of important differences that we also uncovered, it means that all SMC complexes cycle through at least some similar states and undergo similar conformational changes in their head modules, while hydrolysing ATP and translocating DNA.

We report the first synthesis and immunological evaluation of a new glycoconjugate design based on streamlined saponin adjuvants and the Tn carbohydrate antigen. While the novel synthetic constructs induced moderate antibody responses in mice, the versatile chemical platform is amenable to further structure-activity optimizations for the development of self-adjuvanting glycoconjugate cancer vaccines.

Understanding how nano-sized objects are taken up by cells is important for applications within medicine (nanomedicine), as well as to avoid unforeseen hazard due to nanotechnology (nanosafety). Even within the same cell population, one typically observes a large cell-to-cell variability in nanoparticle uptake, raising the question of the underlying cause(s). Here we investigate cell-to-cell variability in polystyrene nanoparticle uptake by HeLa cells, with generalisations of the results to silica nanoparticles and liposomes, as well as to A549 and primary human umbilical vein endothelial cells. We show that uptake of nanoparticles is correlated with cell size within a cell population, thereby reproducing and generalising previous reports highlighting the role of cell size in nanoparticle uptake. By repeatedly isolating (using fluorescence-activated cell sorting) the cells that take up the most and least nanoparticles, respectively, and performing RNA sequencing on these cells separately, we examine the underlying gene expression that contributes to high and low polystyrene nanoparticle accumulation in HeLa cells. We can thereby show that cell size is not the sole driver of cell-to-cell variability, but that other cellular characteristics also play a role. In contrast to cell size, these characteristics are more specific to the object (nanoparticle or protein) being taken up, but are nevertheless highly heterogeneous, complicating their detailed identification. Overall, our results highlight the complexity underlying the cellular features that determine nanoparticle uptake propensity.

Hepatocellular carcinoma (HCC) is the sixth most common cancer with a high mortality rate. Early diagnosis and treatment before tumor progression into an advanced stage is ideal. The current diagnosis of HCC is mainly based on imaging modalities such as ultrasound, computed tomography, and magnetic resonance imaging. These methods have some limitations including diagnosis in the case of very small tumors with atypical imaging patterns. Extracellular vesicles (EVs) are nanosized vesicles which have been shown to act as an important vector for cell-to-cell communication. In the past decade, EVs have been investigated with regard to their roles in HCC formation. Since these EVs contain biomolecular cargo such as nucleic acid, lipids, and proteins, it has been proposed that they could be a potential source of tumor biomarkers and a vector for therapeutic cargo. In this review, reports on the roles of HCC-derived EVs in tumorigenesis, and clinical investigations using circulating EVs as a biomarker for HCC and their potential diagnostic roles have been comprehensively summarized and discussed. In addition, findings from in vitro and in vivo reports investigating the potential roles of EVs as therapeutic interventions are also presented. These findings regarding the potential benefits of EVs will encourage further investigations and may allow us to devise novel strategies using EVs in the early diagnosis as well as for treatment of HCC in the future.

Subarachnoid hemorrhage (SAH), a common devastating cerebrovascular accident, is a great threat to human health and life. Exploration of the potential therapeutic target of SAH is urgently needed. Previous studies showed that long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) promotes cell apoptosis in various diseases, while its role in SAH remains unclear. In our study, we established a mouse model of SAH and used the oxyhemoglobin (OxyHb) to induce neuronal injury in vitro. Interestingly, MALAT1 was found upregulated in brain tissues of SAH mice and OxyHb-stimulated neurons. In addition, knockdown of MALAT1 attenuated apoptosis and decreased reactive oxygen species (ROS) production in OxyHb-stimulated neurons. Mechanistically, we demonstrated that MALAT1 bound with miR-499-5p. Furthermore, our findings indicated that miR-499-5p bound to SOX6 3' untranslated region (UTR) and negatively regulated SOX6 mRNA and protein levels. Rescue assays suggested that SOX6 overexpression counteracted the effects of MALAT1 knockdown on neurocyte apoptosis, and ROS production in OxyHb-stimulated neurons. The in vivo assays indicated that knockdown of MALAT1 improved brain injury of SAH mice. Our study demonstrates that silencing of MALAT1 alleviates neurocyte apoptosis and reduces ROS production through the miR-499-5p/SOX6 axis after SAH injury.

COVID-19-associated-mucormycosis, commonly referred to as the "Black Fungus," is a rare secondary fungal infection in COVID-19 patients prompted by a group of mucor molds. Association of this rare fungal infection with SARS-CoV-2 infection has been declared as an endemic in India, with minor cases in several other countries around the globe. Although the fungal infection is not contagious like the viral infection, the causative fungal agent is omnipresent. Infection displays an overall mortality rate of around 50%, with many other secondary side effects posing a potential threat in exacerbating COVID-19 mortality rates. In this review, we have accessed the role of free iron availability in COVID-19 patients that might correlate to the pathogenesis of the causative fungal agent. Besides, we have analyzed the negative consequences of using immunosuppressive drugs in encouraging this opportunistic fungal infection.

<h4>Background</h4>Acute myeloid leukemia (AML) is a heterogeneous group of leukemias with an overall poor prognosis. Circular RNAs (circRNAs) have been verified to play important regulatory roles in AML progression. However, the role and molecular mechanism of circ_0009910 in AML development have not be completely clarified.<h4>Methods</h4>The expression levels of circ_0009910, microRNA-491-5p (miR-491-5p), and β-1, 4-galactosyltransferase 5 (B4GALT5) were measured by quantitative real-time polymerase chain reaction (qRT-PCR) or Western blot. Cell proliferation and self-renewal ability were assessed via Cell Counting Kit-8 (CCK-8) and sphere formation assay. Cell cycle distribution and cell apoptosis were evaluated by flow cytometry. Caspase-3 activity was tested by Caspase-3 Activity Assay Kit. Western blot was used to examine the protein levels of autophagy-related markers and PI3K/AKT pathway-related markers. The interaction between miR-491-5p and circ_0009910 or B4GALT5 was confirmed by dual-luciferase reporter assay, RNA immunoprecipitation (RIP) assay, or RNA pull-down assay.<h4>Results</h4>Circ_0009910 was highly expressed in AML tissues and cells. Silenced circ_0009910 could significantly inhibit the proliferation, sphere formation, and autophagy and promoted the apoptosis of AML cells. Circ_0009910 bound to miR-491-5p in AML cells, and circ_0009910 promoted AML progression partly through sponging miR-491-5p in vitro. B4GALT5 was a target of miR-491-5p, and miR-491-5p overexpression-mediated influences in AML cells were effectually overturned by the addition of B4GALT5 overexpression plasmid. Furthermore, circ_0009910 could regulate the expression of B4GALT5 by downregulating miR-491-5p in AML cells. Additionally, circ_0009910 could activate the PI3K/AKT signaling pathway by sponging miR-491-5p.<h4>Conclusion</h4>Circ_0009910 could suppress the proliferation, sphere formation, and autophagy and accelerated apoptosis by modulating B4GALT5 expression and activating the PI3K/AKT signaling pathway via sponging miR-491-5p in AML cells, suggesting that circ_0009910 might be a potential biomarker for the treatment of AML.

The risks associated with re-identification of human genetic data are severely limiting open data sharing in life sciences, even in studies where donor-related genetic variant information is not of primary interest. Here, we developed BAMboozle, a versatile tool to eliminate critical types of sensitive genetic information in human sequence data by reverting aligned reads to the genome reference sequence. Applying BAMboozle to functional genomics data, such as single-cell RNA-seq (scRNA-seq) and scATAC-seq datasets, confirmed the removal of donor-related single nucleotide polymorphisms (SNPs) and indels in a manner that did not disclose the altered positions. Importantly, BAMboozle only removes the genetic sequence variants of the sample (i.e., donor) while preserving other important aspects of the raw sequence data. For example, BAMboozled scRNA-seq data contained accurate cell-type associated gene expression signatures, splice kinetic information, and can be used for methods benchmarking. Altogether, BAMboozle efficiently removes genetic variation in aligned sequence data, which represents a step forward towards open data sharing in many areas of genomics where the genetic variant information is not of primary interest.

Circular RNA (circRNA) are a recently discovered class of RNA characterized by a covalently-bonded back-splice junction. As circRNAs are inherently more stable than other RNA species, they may be detected extracellularly in peripheral biofluids and provide novel biomarkers. While circRNA have been identified previously in peripheral biofluids, there are few datasets for circRNA junctions from healthy controls. We collected 134 plasma and 114 urine samples from 54 healthy, male college athlete volunteers, and used RNASeq to determine circRNA content. The intersection of six bioinformatic tools identified 965 high-confidence, characteristic circRNA junctions in plasma and 72 in urine. Highly-expressed circRNA junctions were validated by qRT-PCR. Longitudinal samples were collected from a subset, demonstrating circRNA expression was stable over time. Lastly, the ratio of circular to linear transcripts was higher in plasma than urine. This study provides a valuable resource for characterization of circRNA in plasma and urine from healthy volunteers, one that can be developed and reassessed as researchers probe the circRNA contents of biofluids across physiological changes and disease states.

Selenophosphate synthetase 1 (SEPHS1) plays an essential role in cell growth and survival. However, the underlying molecular mechanisms remain unclear. In the present study, the pathways regulated by SEPHS1 during gastrulation were determined by bioinformatical analyses and experimental verification using systemic knockout mice targeting <i>Sephs1</i>. We found that the coagulation system and retinoic acid signaling were most highly affected by SEPHS1 deficiency throughout gastrulation. Gene expression patterns of altered embryo morphogenesis and inhibition of Wnt signaling were predicted with high probability at E6.5. These predictions were verified by structural abnormalities in the dermal layer of <i>Sephs1^-/-</i> embryos. At E7.5, organogenesis and activation of prolactin signaling were predicted to be affected by <i>Sephs1</i> knockout. Delay of head fold formation was observed in the <i>Sephs1^-/-</i> embryos. At E8.5, gene expression associated with organ development and insulin-like growth hormone signaling that regulates organ growth during development was altered. Consistent with these observations, various morphological abnormalities of organs and axial rotation failure were observed. We also found that the gene sets related to redox homeostasis and apoptosis were gradually enriched in a time-dependent manner until E8.5. However, DNA damage and apoptosis markers were detected only when the <i>Sephs1^-/-</i> embryos aged to E9.5. Our results suggest that SEPHS1 deficiency causes a gradual increase of oxidative stress which changes signaling pathways during gastrulation, and afterwards leads to apoptosis.

2-Hydroxypropyl-β-cyclodextrin (HP-β-CyD) is widely used as an enabling excipient in pharmaceutical formulations. We previously demonstrated that HP-β-CyD disrupted cholesterol homeostasis, and inhibited the proliferation of leukemia cells by inducing apoptosis and cell-cycle arrest. Recently developed drug delivery systems using folic acid (FA) and folic acid receptors (FR) are currently being used in cancer treatment. To confer tumor cell-selectivity to HP-β-CyD, we synthesized folate-appended HP-β-CyD (FA-HP-β-CyD) and evaluated the potential of FA-HP-β-CyD as an anticancer agent using chronic myeloid leukemia (CML) cells in vitro and in vivo. FA-HP-β-CyD inhibited the growth of FR-expressing cells but not that of FR-negative cells. FA-HP-β-CyD had stronger anti-leukemia and cell-binding activities than HP-β-CyD in CML cells. Unlike HP-β-CyD, FA-HP-β-CyD entered CML cells through endocytosis and induced both apoptosis and autophagy via mitophagy. FA-HP-β-CyD increased the inhibitory effects of the ABL tyrosine kinase inhibitors imatinib mesylate and ponatinib, which are commonly used in CML. In vivo experiments in a BCR-ABL leukemia mouse model showed that FA-HP-β-CyD was more effective than HP-β-CyD at a ten-fold lower dose. These results indicate that FA-HP-β-CyD may be a novel tumor-targeting agent for the treatment of leukemia.

<b>Background:</b> The evaluation of treatment response to antidepressant therapy commonly depends on neuropsychologic assessments, as there are currently no suitable biomarkers. Previous research has identified a panel of increased proteins in patients with major depressive disorder (MDD), including antithrombin III (ATIII), as potential biomarkers of depression. <b>Methods:</b> A total of 90 MDD patients were recruited. Of these, 74 patients received occipital repetitive transcranial magnetic stimulation (rTMS) as individualized, standard, or sham treatment for 5 days, and underwent the complete procedure, including clinical assessments, blood collection, and protein measurement. <b>Results:</b> After treatment, ATIII was significantly decreased in both the individualized and standard groups (both <i>p</i> < 0.001) relative to the sham group. In the individualized group, reduction in ATIII was associated with improvements in several neuropsychological assessments. Furthermore, ATIII at baseline in the standard group and after individualized rTMS showed good performance for evaluating or predicting the response to five-day treatment (AUC = 0.771, 95% CI, 0.571-0.971; AUC = 0.875, 95% CI, 0.714-1.000, respectively) and remission at follow-up (AUC = 0.736, 95% CI, 0.529-0.943; AUC = 0.828, 95% CI, 0.656-1.000, respectively). Lastly, both baseline ATIII and change in ATIII showed good predictive value for the 24-item Hamilton Depression Rating Scale at follow-up (<i>p</i> = 0.024 and 0.023, respectively). <b>Conclusion:</b> Our study revealed a reduction in ATIII after occipital rTMS in MDD patients and a relationship between change in ATIII and therapeutic response. Taken together, these findings provide evidence for the potential of ATIII as a biomarker for the evaluation and prediction of antidepressive effects.

Allicin (diallyl thiosulfinate) is the major thiol-reactive organosulfur compound produced by garlic plants (<i>Allium sativum</i>) upon tissue damage. Allicin exerts its strong antimicrobial activity against bacteria and fungi via <i>S</i>-thioallylation of protein thiols and low molecular weight thiols. Here, we investigated the effect of allicin on SARS-CoV-2 infected Vero E6 and Calu-3 cells. Toxicity tests revealed that Calu-3 cells showed greater allicin tolerance, probably due to >4-fold higher GSH levels compared to the very sensitive Vero E6 cells. Exposure of infected Vero E6 and Calu-3 cells to biocompatible allicin doses led to a ∼60-70% decrease of viral RNA and infectious viral particles. Label-free quantitative proteomics was used to investigate the changes in the Calu-3 proteome after SARS-CoV-2 infection and the effect of allicin on the host-virus proteome. SARS-CoV-2 infection of Calu-3 cells caused a strong induction of the antiviral interferon-stimulated gene (ISG) signature, including several antiviral effectors, such as cGAS, Mx1, IFIT, IFIH, IFI16, IFI44, OAS, and ISG15, pathways of vesicular transport, tight junctions (KIF5A/B/C, OSBPL2, CLTCL1, and ARHGAP17) and ubiquitin modification (UBE2L3/5), as well as reprogramming of host metabolism, transcription and translation. Allicin treatment of infected Calu-3 cells reduced the expression of IFN signaling pathways and ISG effectors and reverted several host pathways to levels of uninfected cells. Allicin further reduced the abundance of the structural viral proteins N, M, S and ORF3 in the host-virus proteome. In conclusion, our data demonstrate the antiviral and immunomodulatory activity of biocompatible doses of allicin in SARS-CoV-2-infected cell cultures. Future drug research should be directed to exploit the thiol-reactivity of allicin derivatives with increased stability and lower human cell toxicity as antiviral lead compounds.

Pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor characterized by rapid progression, early metastasis, high recurrence, and limited responsiveness to conventional therapies. The 5-year survival rate of PDAC is extremely low (<8%), which lacks effective prognostic evaluation indicators. In this study, we used xCell to analyze infiltrating immune cells in a tumor and through the univariate and multivariate Cox analyses screened out two prognosis-related immune cells, CD4⁺T_N and common lymphoid progenitor (CLP), which were used to construct a Cox model and figure out the risk-score. It was found that the constructed model could greatly improve the sensitivity of prognostic evaluation, that the higher the risk-score, the worse the prognosis. In addition, the risk-score could also identify molecular subtypes with poor prognosis and immunotherapy sensitivity. Through transcriptome and whole-exome sequencing analysis of PDAC dataset from The Cancer Genome Atlas (TCGA), it was found that copy number deletion and low expression of CCL19 might be crucial factors to affect the risk-score. Lastly, validation of the above findings was confirmed not only in Gene Expression Omnibus (GEO) datasets but also in our PDAC patient samples, Peking2020 cohort.

The chronic irreversible regression of cognitive ability and memory function in human immunodeficiency virus (HIV)-associated dementia (HAND) is linked with late-stage HIV infection in the brain. The molecular-level signatures of neuroinflammation and neurodegeneration are linked with dysfunction in HAND patients. Protein expression changes and posttranslational modification are epigenetic cues for dementia and neurodegenerative disease. In this study quantitative proteome analysis was performed to comprehensively elucidate changes in protein profiles in HIV-positive (HIV+) human brains. Frontal and temporal lobes of normal and HIV+ brains were subjected to label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis using the data-independent acquisition method. Comprehensive proteomic identification and quantification analysis revealed that 3294 total proteins and 251 proteins were differentially expressed in HIV+ brains; specifically, HIV+ frontal and temporal lobes had 132 and 119 differentially expressed proteins, respectively. Proteomic and bioinformatic analyses revealed protein alterations predominantly in the HIV+ frontal lobe region. The expression of GOLPH3, IMPDH2, DYNLL1, RPL11, and GPNMB proteins was significantly altered in HIV+ frontal lobes compared to that in normal brains. These proteins are associated with metabolic pathways, neurodegenerative disorders, and dementia. These proteomic-level changes may be potential biological markers and therapeutic targets to relieve the dementia-associated symptoms in individuals with HAND.

This paper concerns 3'-untranslated regions (3'UTRs) of mRNAs, which are non-coding regulatory platforms that control stability, fate and the correct spatiotemporal translation of mRNAs. Many mRNAs have polymorphic 3'UTR regions. Controlling 3'UTR length and sequence facilitates the regulation of the accessibility of functional effectors (RNA binding proteins, miRNAs or other ncRNAs) to 3'UTR functional boxes and motifs and the establishment of different regulatory landscapes for mRNA function. In this context, shortening of 3'UTRs would loosen miRNA or protein-based mechanisms of mRNA degradation, while 3'UTR lengthening would strengthen accessibility to these effectors. Alterations in the mechanisms regulating 3'UTR length would result in widespread deregulation of gene expression that could eventually lead to diseases likely linked to the loss (or acquisition) of specific miRNA binding sites. Here, we will review the mechanisms that control 3'UTR length dynamics and their alterations in human disorders. We will discuss, from a mechanistic point of view centered on the molecular machineries involved, the generation of 3'UTR variability by the use of alternative polyadenylation and cleavage sites, of mutually exclusive terminal alternative exons (exon skipping) as well as by the process of exonization of Alu cassettes to generate new 3'UTRs with differential functional features.

<h4>Background/aim</h4>The recovery pattern of hepatitis C virus (HCV)-associated metabolic alteration after sustained virological response (SVR) following direct-acting antivirals (DAAs) remains elusive.<h4>Methods</h4>A prospective cohort study of chronic HCV-infected (CHC) patients (n = 415) receiving DAAs (n = 365) was conducted. Metabolic profiles were examined in SVR patients (n = 360) every 3-6 months after therapy and compared with those of sex- and age-matched controls (n = 470).<h4>Results</h4>At baseline, of 415, 168 (40.5%) had insulin resistance (IR). The following were associated: levels of high-density lipoprotein cholesterol (HDL-C), triglycerides (TGs), HCV RNA, fibrosis-4 score, and interferon-λ3-rs12979860 genotype with total cholesterol (TC) levels; and TG levels and BMI with HOMA-IR. Over a 3-year follow-up, in SVR patients, BMI and TC levels and TG/HDL-C ratios increased from baseline, while HOMA-IR trended downward by 72 weeks after therapy and then increased. The increased HDL-C levels began to decrease after 72 weeks after therapy. TC and HOMA-IR were negatively associated with each other until 24 weeks after therapy. Earlier increases in BMI and decreases in HOMA-IR were noted in SVR patients with than in those without baseline IR. Compared with controls, in the subgroup without baseline IR, SVR patients had increased BMI and HOMA-IR levels. Metabolic profiles were similar between SVR patients and controls in the subgroup with baseline IR.<h4>Conclusions</h4>In SVR patients treated with DAAs, the recovery of altered lipid and glucose metabolism was not coupled until 72-week post-therapy, when HOMA-IR reached its nadir. SVR patients with baseline IR recovered from HCV-associated metabolic alterations earlier than those without baseline IR.

Mitochondria, as the powerhouse of most cells, are not only responsible for the generation of adenosine triphosphate (ATP) but also play a decisive role in the regulation of apoptotic cell death, especially of cancer cells. Safe potential delivery systems which can achieve organelle-targeted therapy are urgently required. In this study, for effective pancreatic cancer therapy, a novel mitochondria-targeted and ROS-triggered drug delivery nanoplatform was developed from the TPP-TK-CPI-613 (<b>TTCI</b>) prodrug, in which the ROS-cleave thioketal functions as a linker connecting mitochondrial targeting ligand TPP and anti-mitochondrial metabolism agent CPI-613. DSPE-PEG2000 was added as an assistant component to increase accumulation in the tumor via the EPR effect. This new nanoplatform showed effective mitochondrial targeting, ROS-cleaving capability, and robust therapeutic performances. With active mitochondrial targeting, the formulated nanoparticles (<b>TTCI</b> NPs) demonstrate much higher accumulation in mitochondria, facilitating the targeted delivery of CPI-613 to its acting site. The results of in vitro antitumor activity and cell apoptosis revealed that the IC₅₀ values of <b>TTCI</b> NPs in three types of pancreatic cancer cells were around 20~30 µM, which was far lower than those of CPI-613 (200 µM); 50 µM <b>TTCI</b> NPs showed an increase in apoptosis of up to 97.3% in BxPC3 cells. Therefore, this mitochondria-targeted prodrug nanoparticle platform provides a potential strategy for developing safe, targeting and efficient drug delivery systems for pancreatic cancer therapy.

Non-alcoholic fatty liver disease (NAFLD) is closely associated with type 2 diabetes mellitus (T2D), and these two metabolic diseases demonstrate bidirectional influences. The identification of microbiome profiles that are specific to liver injury or impaired glucose metabolism may assist understanding of the role of the gut microbiota in the relationship between NAFLD and T2D. Here, we studied a biopsy-proven Asian NAFLD cohort (n = 329; 187 participants with NAFLD, 101 with NAFLD and T2D, and 41 with neither) and identified <i>Enterobacter</i>, <i>Romboutsia</i>, and <i>Clostridium sensu stricto</i> as the principal taxa associated with the severity of NAFLD and T2D, whereas <i>Ruminococcus</i> and <i>Megamonas</i> were specific to NAFLD. In particular, the taxa that were associated with both severe liver pathology and T2D were also significantly associated with markers of diabetes, such as fasting blood glucose and Hb1Ac. Enterotype analysis demonstrated that participants with NAFLD had a significantly higher proportion of <i>Bacteroides</i> and a lower proportion of <i>Ruminococcus</i> than a Korean healthy twin cohort (n = 756). However, T2D could not be clearly distinguished from NAFLD. Analysis of an independent T2D cohort (n = 185) permitted us to validate the T2D-specific bacterial signature identified in the NAFLD cohort. Functional inference analysis revealed that endotoxin biosynthesis pathways were significantly enriched in participants with NAFLD and T2D, compared with those with NAFLD alone. These findings may assist with the development of effective therapeutic approaches for metabolic diseases that are associated with specific bacterial signatures.

Colon cancer is initiated by stem cells that escape the strict control. This process is often driven through aberrant activation of Wnt signaling by mutations in components acting downstream of the receptor complex that unfetter tumor cells from the need for Wnts. Here we describe a class of colon cancer that does not depend on mutated core components of the Wnt pathway. Genetically blocking Wnt secretion from epithelial cells of such tumors results in apoptosis, reduced expression of colon cancer markers, followed by enhanced tumor differentiation. In contrast to the normal colonic epithelium, such tumor cells autosecrete Wnts to maintain their uncontrolled proliferative behavior. In humans, we determined certain cases of colon cancers in which the Wnt pathway is hyperactive, but not through mutations in its core components. Our findings illuminate the path in therapy to find further subtypes of Wnt-dependent colon cancer that might be responsive to Wnt secretion inhibitors.

Excessive ethanol consumption is associated with an increased risk of developing health complications, especially in individuals with pre-existing thrombocytopenia and cirrhosis. Here, we describe a case of a patient with a history of alcoholic cirrhosis, hypertension, and thrombocytopenia, presenting with significant decline following an incidence of binge drinking. Radiography identified a large non-lobar intraparenchymal hemorrhage. However, due to severe thrombocytopenia that was unresponsive to platelet therapy, the possibility of pursuing any form of surgical intervention was negated. Surgical contraindication and a lack of response to subsequent medical management contributed to the family's decision to opt for conservative medical treatment and comfort care. This case showcases the potential for liver cirrhosis in the setting of chronic alcohol use disorder to pave the way for terminal intracerebral hemorrhage.

Until the etiopathogenic factor(s) of autoimmune and autoinflammatory rheumatic disorders will be identified, their classification into entities will continue. However, their similar clinical manifestations, overlapping syndromes, evolution from one entity into another, as well as common autoantibody responses, suggest that autoimmune and autoinflammatory disorders may constitute distinct pathophysiologic processes on the basis of a different genetic background. Prognosis and effective therapeutic regimens are mostly based on the clinico-pathologic severity of the involved tissues or organs and not on the disease label.

In this study, peripheral blood mononuclear cells from young and old patients with COVID-19 were examined phenotypically, transcriptionally and functionally to reveal age-, time- and severity-specific adaptations. Gene signatures within memory B cells and plasmablasts correlated with reduced frequency of antigen-specific B cells and neutralizing antibodies in older patients with severe COVID-19. Moreover, these patients exhibited exacerbated T cell lymphopenia, which correlated with lower plasma interleukin-2, and diminished antigen-specific T cell responses. Single-cell RNA sequencing revealed augmented signatures of activation, exhaustion, cytotoxicity and type I interferon signaling in memory T and natural killer cells with age. Although cytokine storm was evident in both age groups, older individuals exhibited elevated levels of myeloid cell recruiting factors. Furthermore, we observed redistribution of monocyte and dendritic cell subsets and emergence of a suppressive phenotype with severe disease, which was reversed only in young patients over time. This analysis provides new insights into the impact of aging on COVID-19.

No abstract available.

<h4>Background: </h4> The impact of corticosteroids on severe patients with coronavirus disease 2019 (COVID-19)/ chronic hepatitis B virus (HBV) co-infection is currently unknown. We aimed to investigate effect of corticosteroid on these subgroup patients. <h4>Methods: </h4>. In this retrospective multicenter study including 5447 confirmed COVID-19 patients from Jan 1, 2020 to Apr 18, 2020, severe patients with COVID-19/HBV co-infection were identified. To minimize the bias of confounding variables on effect of corticosteroid treatment, inverse probability of treatment weighting (IPTW) based on propensity score was employed. <h4>Results: </h4>. The prevalence of HBV co-infection in hospitalization COVID-19 patients was 4.1%. 105 severe patients with COVID-19/HBV co-infection were enrolled (median age 62 years, 57.1% male). Fifty-five patients received corticosteroid treatment and 50 patients did not. Corticosteroid treatment was associated with high D-dimer level, neutrophil count (all P <0.05). With IPTW analysis, corticosteroid treatment worsen acute liver injury (OR, 1.767, 95%CI, 1.018-3.065, P =0.043). Corticosteroids might delay SARS-CoV-2 viral RNA clearance (OR, 4.963, 95%CI, 2.717-9.065, P <0.001). The 28-day and in-hospital mortality were both significantly higher in corticosteroid treatment group than non-corticosteroid treatment group (OR, 8.738, 95%CI, 2.826-27.022, P <0.001; OR, 10.122, 95%CI, 3.291-31.129, P <0.001, respectively). In multivariable analysis, higher D-dimer level (>1µg/ml) (OR, 10.686, 95%CI, 2.421-47.159, P =0.002) and corticosteroid therapy (OR, 11.236, 95%CI, 1.273-99.154, P =0.029) were independently associated with 28-day mortality. Methylprednisolone dose per day and cumulative dose in non-survivors was significantly higher than in survivors. <h4>Conclusions: </h4>. In severe patients with COVID-19/HBV co-infection, corticosteroid treatment may increase mortality. Therefore, corticosteroid therapy should be prescribed with caution in the subset of patients.

<h4>ABSTRACT</h4> Eicosanoids, oxidized fatty acids that serve as cell-signaling molecules, have been broadly implicated in tumorigenesis. To identify eicosanoids relevant to pancreatic tumorigenesis, we profiled normal pancreas and pancreatic ductal adenocarcinoma (PDAC) in mouse models and patient samples using mass spectrometry. We interrogated RNA sequencing datasets for eicosanoid synthase or receptor expression. Findings were confirmed by immunostaining. In murine models, we identified elevated levels of PGD 2 , prostacyclin, and thromboxanes in neoplasia while PGE 2 , 12-HHTre, HETEs, and HDoHEs are elevated specifically in tumors. Analysis of scRNA-seq datasets suggests that PGE 2 and prostacyclins are derived from fibroblasts, PGD 2 and thromboxanes from myeloid cells, and PGD 2 and 5-HETE from tuft cells. In patient samples, we identified a transition from PGD 2 to PGE 2 -producing enzymes in the epithelium during the transition to PDAC, fibroblast/tumor expression of PTGIS, and myeloid/tumor cell expression of TBXAS1. Altogether, our analyses identify key changes in eicosanoid species during pancreatic tumorigenesis and the cell types responsible for their synthesis.

Huntington's disease (HD) is a progressively debilitating neurodegenerative disease exhibiting autosomal-dominant inheritance. It is caused by an unstable expansion in the CAG repeat tract of HD gene, which transforms the disease-specific Huntingtin protein (HTT) to a mutant form (mHTT). The profound neuronal death in cortico-striatal circuits led to its identification and characterisation as a neurodegenerative disease. However, equally disturbing are the concomitant whole-body manifestations affecting nearly every organ of the diseased individuals, at varying extents. Altered central and peripheral metabolism of energy, proteins, nucleic acids, lipids and carbohydrates encompass the gross pathology of the disease. Intense fluctuation of body weight, glucose homeostasis and organ-specific subcellular abnormalities are being increasingly recognised in HD. Many of these metabolic abnormalities exist years before the neuropathological manifestations such as chorea, cognitive decline and behavioural abnormalities develop, and prove to be reliable predictors of the disease progression. In this review, we provide a consolidated overview of the central and peripheral metabolic abnormalities associated with HD, as evidenced from clinical and experimental studies. Additionally, we have discussed the potential of metabolic biomolecules to translate into efficient biomarkers for the disease onset as well as progression. Finally, we provide a brief outlook on the efficacy of existing therapies targeting metabolic remediation. While it is clear that components of altered metabolic pathways can mark many aspects of the disease, it is only conceivable that combinatorial therapies aiming for neuronal protection in consort with metabolic upliftment will prove to be more efficient than the existing symptomatic treatment options.

Circadian rhythms regulate diverse aspects of gastrointestinal physiology ranging from the composition of microbiota to motility. However, development of the intestinal circadian clock and detailed mechanisms regulating circadian physiology of the intestine remain largely unknown. In this report, we show that both pluripotent stem cell-derived human intestinal organoids engrafted into mice and patient-derived human intestinal enteroids possess circadian rhythms and demonstrate circadian phase-dependent necrotic cell death responses to Clostridium difficile toxin B (TcdB). Intriguingly, mouse and human enteroids demonstrate anti-phasic necrotic cell death responses to TcdB. RNA-Seq analysis shows that ~3-10% of the detectable transcripts are rhythmically expressed in mouse and human enteroids. Remarkably, we observe anti-phasic gene expression of Rac1, a small GTPase directly inactivated by TcdB, between mouse and human enteroids, and disruption of Rac1 abolishes clock-dependent necrotic cell death responses. Our findings uncover robust functions of circadian rhythms regulating clock-controlled genes in both mouse and human enteroids governing organism-specific, circadian phase-dependent necrotic cell death responses, and lay a foundation for human organ- and disease-specific investigation of clock functions using human organoids for translational applications.

The study of parental lifespan has emerged as an innovative tool to advance aging biology and our understanding of the genetic architecture of human longevity and aging-associated diseases. Here, we leveraged summary statistics of a genome-wide association study including over one million parental lifespans to identify genetically regulated genes from the Genotype-Tissue Expression project. Through a combination of multi-tissue transcriptome-wide association analyses and genetic colocalization, we identified novel genes that may be associated with parental lifespan. Mendelian randomization (MR) analyses also identified circulating proteins and metabolites causally associated with parental lifespan and chronic diseases offering new drug repositioning opportunities such as those targeting apolipoprotein-B-containing lipoproteins. Liver expression of HP, the gene encoding haptoglobin, and plasma haptoglobin levels were causally linked with parental lifespan. Phenome-wide MR analyses were used to map genetically regulated genes, proteins and metabolites with other human traits as well as the disease-related phenome in the FinnGen cohorts (n = 135,638). Altogether, this study identified new candidate genes, circulating proteins and metabolites that may influence human aging as well as potential therapeutic targets for chronic diseases that warrant further investigation.

Clostridioides difficile infection (CDI) is the most common hospital-acquired infection in the United States. Antibiotic-induced dysbiosis is the primary cause of susceptibility, and fecal microbiota transplantation (FMT) has emerged as an effective therapy for recurrence. We previously demonstrated in the mouse model of CDI that antibiotic-induced dysbiosis reduced colonic expression of interleukin 25 (IL-25) and that FMT protected in part by restoring IL-25 signaling. Here, we conducted a prospective study in humans to test if FMT induced IL-25 expression in the colons of patients with recurrent CDI (rCDI). Colonic biopsy specimens and blood were collected at the time of FMT and 60 days later. Colon biopsy specimens were analyzed for IL-25 protein levels, total tissue transcriptome, and epithelium-associated microbiota before and after FMT, and peripheral immune cells were immunophenotyped. FMT increased alpha diversity of the colonic microbiota and levels of IL-25 in colonic tissue. In addition, FMT increased expression of homeostatic genes and repressed inflammatory genes. Finally, circulating Th17 cells were decreased post-FMT. The increase in levels of the cytokine IL-25 accompanied by decreased inflammation is consistent with FMT acting in part to protect from recurrent CDI via restoration of commensal activation of type 2 immunity. <b>IMPORTANCE</b> Fecal microbiota transplantation (FMT) is an effective treatment for C. difficile infection for most patients; however, introducing a complex mixture of microbes also has had unintended consequences for some patients. Attempts to create a standardized probiotic therapeutic that recapitulates the efficacy of FMT have been unsuccessful to date. We sought to understand what immune markers are changed in patients undergoing FMT to treat recurrent C. difficile infection and identified an immune signaling molecule, IL-25, that was restored by FMT. This finding indicates that adjunctive therapy with IL-25 could be useful in treating C. difficile infection.

The paraventricular nucleus of the hypothalamus (PVH) contains a heterogeneous cluster of <i>Sim1</i>-expressing neurons critical for feeding regulation. <i>Sim1</i> haploinsufficiency results in hyperphagic obesity with disruption of PVH neurons, yet the molecular profiles of PVH neurons and the mechanism underlying the defects of <i>Sim1</i> haploinsufficiency are not well understood. By single-cell RNA sequencing, we identified two major populations of <i>Sim1</i>⁺ PVH neurons, which are differentially affected by <i>Sim1</i> haploinsufficiency. The <i>Iroquois</i> homeobox genes <i>Irx3</i> and <i>Irx5</i> have been implicated in the hypothalamic control of energy homeostasis. We found that <i>Irx3</i> and <i>Irx5</i> are ectopically expressed in the <i>Sim1</i>⁺ PVH cells of <i>Sim1</i>^+/− mice. By reducing their dosage and PVH-specific deletion of <i>Irx3</i>, we demonstrate that misexpression of <i>Irx3</i> and <i>Irx5</i> contributes to the defects of <i>Sim1</i>^+/− mice. Our results illustrate abnormal hypothalamic activities of <i>Irx3</i> and <i>Irx5</i> as a central mechanism disrupting PVH development and feeding regulation in <i>Sim1</i> haploinsufficiency.

<h4>Background</h4>The giant panda (Ailuropoda melanoleuca) is an endangered mammalian species native to China. Fewer than 2500 giant pandas are known to exist, many of which are bred in captivity as a means to preserve and repopulate the species. Like other captive mammals, giant pandas acquire age-related cataracts, reducing their quality of life. Recent comparative genome-wide methylation analysis revealed 110 differentially methylated genes associated with cataract formation including six also associated with the formation of age-related cataracts in humans.<h4>Results</h4>To investigate the pathological pathway in greater detail, here we used RNA-Seq analysis to investigate the differential expression profiles of genes in three giant pandas with cataracts and three healthy controls. We identified more than 700 differentially expressed genes, 29 of which were selected for further analysis based on their low q-value. We found that many of the genes encoded regulatory and signaling proteins associated with the control of cell growth, migration, differentiation and apoptosis, supporting previous research indicating a key role for apoptosis in cataract formation.<h4>Conclusion</h4>The identification of genes involved in the formation of age-related cataracts could facilitate the development of predictive markers, preventative measures and even new therapies to improve the life of captive animals.

<h4>Background</h4>Triatoma sordida is one of the main Chagas disease vectors in Brazil. In addition to Brazil, this species has already been reported in Bolivia, Argentina, Paraguay, and Uruguay. It is hypothesized that the insects currently identified as T. sordida are a species subcomplex formed by three cytotypes (T. sordida sensu stricto [s.s.], T. sordida La Paz, and T. sordida Argentina). With the recent description of T. rosai from the Argentinean specimens, it became necessary to assess the taxonomic status of T. sordida from La Paz, Bolivia, since it was suggested that it may represent a new species, which has taxonomic, evolutionary, and epidemiological implications. Based on the above, we carried out molecular and experimental crossover studies to assess the specific status of T. sordida La Paz.<h4>Methods</h4>To evaluate the pre- and postzygotic barriers between T. sordida La Paz and T. sordida s.s., experimental crosses and intercrosses between F1 hybrids and between F2 hybrids were conducted. In addition, cytogenetic analyses of the F1 and F2 hybrids were applied with an emphasis on the degree of pairing between the homeologous chromosomes, and morphological analyses of the male gonads were performed to evaluate the presence of gonadal dysgenesis. Lastly, the genetic distance between T. sordida La Paz and T. sordida s.s. was calculated for the CYTB, ND1, and ITS1 genes.<h4>Results</h4>Regardless of the gene used, T. sordida La Paz showed low genetic distance compared to T. sordida s.s. (below 2%). Experimental crosses resulted in offspring for both directions, demonstrating that there are no prezygotic barriers installed between these allopatric populations. Furthermore, postzygotic barriers were not observed either (since the F1 × F1 and F2 × F2 intercrosses resulted in viable offspring). Morphological and cytogenetic analyses of the male gonads of the F1 and F2 offspring demonstrated that the testes were not atrophied and did not show chromosome pairing errors.<h4>Conclusion</h4>Based on the low genetic distance (which configures intraspecific variation), associated with the absence of prezygotic and postzygotic reproductive barriers, we confirm that T. sordida La Paz represents only a chromosomal polymorphism of T. sordida s.s.

Varying differentiation of myeloid cells is common in tumors, inflammation, autoimmune diseases, and metabolic diseases. The release of cytokines from myeloid cells is an important driving factor that leads to severe COVID-19 cases and subsequent death. This review briefly summarizes the results of single-cell sequencing of peripheral blood, lung tissue, and cerebrospinal fluid of COVID-19 patients and describes the differentiation trajectory of myeloid cells in patients. Moreover, we describe the function and mechanism of abnormal differentiation of myeloid cells to promote disease progression. Targeting myeloid cell-derived cytokines or checkpoints is essential in developing a combined therapeutic strategy for patients with severe COVID-19.

Haematopoietic malignancies are frequently characterized by karyotypic abnormalities. The development of targeted drugs has been pioneered with compounds against gene products of fusion genes caused by chromosomal translocations. While polysomies are equally frequent as translocations, for many of them we are lacking therapeutic approaches aimed at synthetic lethality. Here, we report two new cell lines, named MBU-7 and MBU-8, that differ in complete trisomy of chromosome18, a partial trisomy of chromosome 7 and a tetrasomy of the p-arm of chromosome 8, but otherwise share the same mutational pattern and complex karyotype. Both cell lines are divergent clones of U-937 cells and have the morphology and immunoprofile of monocytic cells. The distinct karyotypic differences between MBU-7 and MBU-8 are associated with a difference in the specific response to nucleoside analogues. Taken together, we propose the MBU-7 and MBU-8 cell lines described here as suitable in vitro models for screening and testing vulnerabilities that are associated with the disease-relevant polysomies of chromosome 7, 8 and 18.

This study hypothesized that female peri-conceptional undernutrition evokes transcriptomic alterations in the pig myometrium during the peri-implantation period. Myometrium was collected on days 15-16 of pregnancy from pigs fed a normal- (n = 4) or restricted-diet (n = 4) from conception until day 9th of pregnancy, and the transcriptomic profiles of the tissue were compared using Porcine (V2) Expression Microarrays 4 × 44 K. In restricted diet-fed pigs, 1021 differentially expressed genes (DEGs) with fold change ≥ 1.5, P ≤ 0.05 were revealed, and 708 of them were up-regulated. Based on the count score, the top within GOs was GO cellular components "extracellular exosome", and the top KEGG pathway was the metabolic pathway. Ten selected DEGs, i.e. hydroxysteroid (17β) dehydrogenase 8, cyclooxygenase 2, prostaglandin F receptor, progesterone receptor membrane component 1, progesterone receptor membrane component 2, annexin A2, homeobox A10, S-phase cyclin A-associated protein in the ER, SRC proto-oncogene, non-receptor tyrosine kinase, and proliferating cell nuclear antigen were conducted through qPCR to validate microarray data. In conclusion, dietary restriction during the peri-conceptional period causes alterations in the expression of genes encoding proteins involved i.a. in the endocrine activity of the myometrium, embryo-maternal interactions, and mechanisms regulating cell cycle and proliferation.

This study aims to analyse human bones exposed to low/medium temperatures (200-650°C) under experimentally controlled conditions, both oxidizing and reducing, using complementary optical and neutron vibrational spectroscopy techniques. Clear differences were observed between the aerobically and anaerobically heated bones. The organic constituents disappeared at lower temperatures for the former (<i>ca</i> 300°C), while they lingered for higher temperatures in anaerobic environments (<i>ca</i> 450-550°C). Unsaturated non-graphitizing carbon species (chars) were detected mainly for anaerobically heated samples, and cyanamide formation occurred only at 650°C in reducing settings. Overall, the main changes were observed from 300 to 400°C in anaerobic conditions and from 450 to 500°C in aerobic environments. The present results enabled the identification of specific spectroscopic biomarkers of the effect of moderate temperatures (less than or equal to 650°C) on human bone, thus contributing to a better characterization of forensic and archaeological skeletal remains subject to heating under distinct environmental settings. In particular, these data may provide information regarding cannibalism or ancient bone boiling and defleshing rituals.

<h4>Purpose</h4>Small molecule modified antitumor drug conjugate nanoparticles have the advantages of high drug loading, simple synthesis and preparation, and better biocompatibility. Due to the large demand for exogenous α-linolenic acid (ALA) by tumor cells, we synthesized α-linolenic acid-paclitaxel conjugate (ALA-PTX) and prepared α-linolenic acid-paclitaxel conjugate nanoparticles (ALA-PTX NPs), in order to obtain better tumor cellular uptake and antitumor activity in vitro and in vivo.<h4>Methods</h4>We synthesized and characterized ALA-PTX, and then prepared and characterized ALA-PTX NPs. The cellular uptake, uptake pathways, intracellular behavior, in vitro and in vivo antitumor activity of ALA-PTX NPs were evaluated.<h4>Results</h4>The size of ALA-PTX NPs was approximately 110.7±1.7 nm. The drug loading was approximately 90% (w/w) with CrEL-free and organic solvent-free characteristics. The cellular uptake of ALA-PTX NPs was significantly higher than that of PTX injection by MCF-7, MCF-7/ADR and HepG2 cells. In these three cell lines, the cellular uptake of ALA-PTX NPs at 6h was approximately 1.5-2.6 times higher than that of PTX injection. ALA-PTX NPs were ingested through clathrin-mediated endocytosis, then transferred to lysosomes, and could dissolve in cells to play an antitumor activity. The in vitro and in vivo antitumor activity of ALA-PTX NPs was confirmed in MCF-7/ADR and HepG2 cell models and tumor-bearing nude mouse models.<h4>Conclusion</h4>ALA-PTX NPs developed in our study could provide a new method for the preparation of nano-delivery systems suitable for antitumor therapy that could increase tumor cellular uptake and enhance antitumor activity.

Time processing over intervals of hundreds of milliseconds to minutes, also known as interval timing, is associated with the striatum. Huntington's disease patients (HD) with striatal degeneration have impaired interval timing, but the extent and specificity of these deficits remain unclear. Are they specific to the temporal domain, or do they extend to the spatial domain too? Do they extend to both the perception and production of interval timing? Do they appear before motor symptoms in Huntington's disease (Pre-HD)? We addressed these issues by assessing both temporal abilities (in the seconds range) and spatial abilities (in the cm range) in 20 Pre-HD, 25 HD patients, and 25 healthy Controls, in discrimination, bisection and production paradigms. In addition, all participants completed a questionnaire assessing temporal and spatial disorientation in daily life, and the gene carriers (i.e., HD and Pre-HD participants) underwent structural brain MRI. Overall, HD patients were more impaired in the temporal than in the spatial domain in the behavioral tasks, and expressed a greater disorientation in the temporal domain in the daily life questionnaire. In contrast, Pre-HD participants showed no sign of a specific temporal deficit. Furthermore, MRI analyses indicated that performances in the temporal discrimination task were associated with a larger striatal grey matter volume in the striatum in gene carriers. Altogether, behavioral, brain imaging and questionnaire data support the hypothesis that the striatum is a specific component of interval timing processes. Evaluations of temporal disorientation and interval timing processing could be used as clinical tools for HD patients.

Metabolic and hormonal outcomes of polycystic ovary syndrome (PCOS) have implications on telomere biology and physical activity may prevent telomere erosion. We sought to observe the effects of continuous (CAT) and intermittent (IAT) aerobic training on telomere length, inflammatory biomarkers, and its correlation with metabolic, hormonal, and anthropometric parameters of PCOS. This randomized controlled clinical trial study included 87 PCOS randomly stratified according to body mass index (BMI) in CAT (<i>n</i> = 28), IAT (<i>n</i> = 29) and non-training control group (CG, <i>n</i> = 30). The exercises were carried out on a treadmill, three times per week for 16 weeks. The participants' anthropometric characteristics and biochemical and hormonal concentrations were measured before and after aerobic training or observation period, as the telomere length that was evaluated using quantitative real-time PCR. Four months of aerobic exercises (CAT or IAT) did not alter telomere length and inflammatory biomarkers in PCOS women. Obesity index as BMI and waist circumference (WC), and inflammatory biomarkers negatively affect telomeres. The hyper-andro-genism measured by testosterone levels was reduced after both exercises (CAT, <i>p</i> ≤ 0.001; IAT, <i>p</i> = 0.019). In particular, the CAT reduced WC (<i>p</i> = 0.045), hip circumference (<i>p</i> = 0.032), serum cholesterol (<i>p</i> ≤ 0.001), and low-density lipoprotein (<i>p</i> = 0.030). Whereas, the IAT decreased WC (<i>p</i> = 0.014), waist-to-hip ratio (<i>p</i> = 0.012), free androgen index (FAI) (<i>p</i> = 0.037). WC (<i>p</i> = 0.049) and body fat (<i>p</i> = 0.015) increased in the non-training group while total cholesterol was reduced (<i>p</i> = 0.010). Booth exercises reduced obesity indices and hyperandrogenism on PCOS women without changes in telomere length or inflammatory biomarkers.

The process of cheese-making has long been part of human food culture and nowadays dairy represents a large sector of the food industry. Being the main byproduct of cheese-making, the revalorization of milk whey is nowadays one of the primary goals in alignment with the principles of the circular economy. In the present paper, a deep and detailed investigation of short endogenous peptides in milk and its byproducts (whole whey, skimmed whey, and whey permeate) was carried out by high-resolution mass spectrometry, with a dedicated suspect screening data acquisition and data analysis approach. A total of 79 short peptides was tentatively identified, including several sequences already known for their exerted biological activities. An unsupervised chemometric approach was then employed for highlighting the differences in the short peptide content among the four sets of samples. Whole and skimmed whey showed not merely a higher content of short bioactive peptides compared to whole milk, but also a peculiar composition of peptides that are likely generated during the process of cheese-making. The results clearly demonstrate that whey represents a valuable source of bioactive compounds and that the set-up of processes of revalorization of milk byproducts is a promising path in the obtention of high revenue-generating products from dairy industrial waste.

RHO GTPases are critical signal transducers that regulate cell adhesion, polarity, and migration through multiple signaling pathways. While all these cellular processes are crucial for the maintenance of normal cell homeostasis, disturbances in RHO GTPase-associated signaling pathways contribute to different human diseases, including many malignancies. Several members of the RHO GTPase family are frequently upregulated in human tumors. Abnormal gene regulation confirms the pivotal role of lncRNAs as critical gene regulators, and thus, they could potentially act as oncogenes or tumor suppressors. lncRNAs most likely act as sponges for miRNAs, which are known to be dysregulated in various cancers. In this regard, the significant role of miRNAs targeting RHO GTPases supports the view that the aberrant expression of lncRNAs may reciprocally change the intensity of RHO GTPase-associated signaling pathways. In this review article, we summarize recent advances in lncRNA research, with a specific focus on their sponge effects on RHO GTPase-targeting miRNAs to crucially mediate gene expression in different cancer cell types and tissues. We will focus in particular on five members of the RHO GTPase family, including RHOA, RHOB, RHOC, RAC1, and CDC42, to illustrate the role of lncRNAs in cancer progression. A deeper understanding of the widespread dysregulation of lncRNAs is of fundamental importance for confirmation of their contribution to RHO GTPase-dependent carcinogenesis.

<b>Background:</b> Postpartum depression (PPD) is commonly seen in women after birth and can lead to adverse effects on both the health of mothers and child(ren) development. In Vietnam, there have been a number of studies examining the rate and risk factors of PPD, but none has provided a systematic review. <b>Aim:</b> This current literature review aims to summarize and synthesize the current state of knowledge of studies conducted in Vietnam to provide a comprehensive understanding of the PPD phenomena during the last 10 years. <b>Data Sources:</b> A literature search was conducted relying on the most common online databases-MEDLINE/PubMed, ScienceDirect, and Google Scholar, which included articles if they (i) examined prevalence or risk factors of PPD; (ii) were conducted among Vietnamese participants using either quantitative, qualitative, or mixed-method, and (iii) were published from 2010 to 2020. After the filtering process, 18 articles were eligible to be reviewed. <b>Results:</b> Research studies in Vietnam on PPD are conducted among women at and after 1-month delivery. The rate of PPD reported in Vietnam among mothers at postnatal time points from 1 to 12 months ranged from 8.2 to 48.1%. Risk factors can be clustered into three groups: personal factors, family factors, and environmental factors. <b>Recommendation:</b> Further research studies should focus on examining PPD at an earlier stage within the first month after birth. The investigation of risk factors in a comprehensive manner for Vietnamese mothers would also be recommended.

Marburg virus (MARV) is a member of the filovirus family that causes hemorrhagic disease with high case fatality rates. MARV is on the priority list of the World Health Organization for countermeasure development highlighting its potential impact on global public health. We developed a vesicular stomatitis virus (VSV)-based vaccine expressing the MARV glycoprotein (VSV-MARV) and previously demonstrated uniform protection of nonhuman primates (NHPs) with a single dose. Here, we investigated the fast-acting potential of this vaccine by challenging NHPs with MARV 14, 7 or 3 days after a single dose vaccination with VSV-MARV. We found that 100% of the animals survived when vaccinated 7 or 14 days and 75% of the animal survived when vaccinated 3 days prior to lethal MARV challenge. Transcriptional analysis of whole blood samples indicated activation of B cells and antiviral defense after VSV-MARV vaccination. In the day -14 and -7 groups, limited transcriptional changes after challenge were observed with the exception of day 9 post-challenge in the day -7 group where we detected gene expression profiles indicative of a recall response. In the day -3 group, transcriptional analysis of samples from surviving NHPs revealed strong innate immune activation. In contrast, the animal that succumbed to disease in this group lacked signatures of antiviral immunity. In summary, our data demonstrate that the VSV-MARV is a fast-acting vaccine suitable for the use in emergency situations like disease outbreaks in Africa.

Colorectal cancer (CRC), being one of the most commonly diagnosed cancers worldwide, endangers human health. Because the pathological mechanism of CRC is not fully understood, there are many challenges in the prevention, diagnosis, and treatment of this disease. Long non-coding RNAs (lncRNAs) have recently drawn great attention for their potential roles in the different stages of CRC formation, invasion, and progression, including regulation of molecular signaling pathways, apoptosis, autophagy, angiogenesis, tumor metabolism, immunological responses, cell cycle, and epithelial-mesenchymal transition (EMT). This review aims to discuss the potential mechanisms of several oncogenic lncRNAs, as well as several suppressor lncRNAs, in CRC occurrence and development to aid in the discovery of new methods for CRC diagnosis, treatment, and prognosis assessment.

Neurosecretory protein VGF (non-acronymic) belongs to the granin family of neuropeptides. VGF and VGF-derived peptides have been repeatedly identified in well-powered and well-designed multi-omic studies as dysregulated in neurodegenerative and psychiatric diseases. New therapeutics is urgently needed for these devastating and costly diseases, as are new biomarkers to improve disease diagnosis and mechanistic understanding. From a list of 537 genes involved in Alzheimer's disease pathogenesis, VGF was highlighted by the Accelerating Medicines Partnership in Alzheimer's disease as the potential therapeutic target of greatest interest. VGF levels are consistently decreased in brain tissue and CSF samples from patients with Alzheimer's disease compared to controls, and its levels correlate with disease severity and Alzheimer's disease pathology. In the brain, VGF exists as multiple functional VGF-derived peptides. Full-length human VGF_1-615 undergoes proteolytic processing by prohormone convertases and other proteases in the regulated secretory pathway to produce at least 12 active VGF-derived peptides. In cell and animal models, these VGF-derived peptides have been linked to energy balance regulation, neurogenesis, synaptogenesis, learning and memory, and depression-related behaviours throughout development and adulthood. The C-terminal VGF-derived peptides, TLQP-62 (VGF_554-615) and TLQP-21 (VGF_554-574) have differential effects on Alzheimer's disease pathogenesis, neuronal and microglial activity, and learning and memory. TLQP-62 activates neuronal cell-surface receptors and regulates long-term hippocampal memory formation. TLQP-62 also prevents immune-mediated memory impairment, depression-like and anxiety-like behaviours in mice. TLQP-21 binds to microglial cell-surface receptors, triggering microglial chemotaxis and phagocytosis. These actions were reported to reduce amyloid-β plaques and decrease neuritic dystrophy in a transgenic mouse model of familial Alzheimer's disease. Expression differences of VGF-derived peptides have also been associated with frontotemporal lobar dementias, amyotrophic lateral sclerosis, Lewy body diseases, Huntington's disease, pain, schizophrenia, bipolar disorder, depression and antidepressant response. This review summarizes current knowledge and highlights questions for future investigation regarding the roles of VGF and its dysregulation in neurodegenerative and psychiatric disease. Finally, the potential of VGF and VGF-derived peptides as biomarkers and novel therapeutic targets for neurodegenerative and psychiatric diseases is highlighted.

Grape pomace is commonly considered a waste product of monovarietal red wine production. Methods: HPLC-DAD analysis was performed to determine the polyphenol and flavonoid contents of all the extracts obtained from Montepulciano d'Abruzzo red wine and grape skins whereas, GC-MS was applied to the determination of fatty acid composition in grape seeds oil. Biological characterization involves antioxidant and antimicrobial assays for all the extracts and seeds oil; Their ability to inhibit α-glucosidase, α-amylase, α-tyrosinase, and ChE enzymes was also detected, together with anti-inflammatory activity on wine, grape skin extracts, and seeds oil by lipoxygenase (5-LOX) and LPS-stimulated macrophage release assays. Data indicate significative polyphenols content (199.31 ± 7.21 mgGAE/g), antioxidant (CUPRAC assay (1036.98 mgTE/g)), enzymatic inhibition (α-tyrosinase: 151.30 ± 1.20 mgKAE/g) and anti-inflammatory activities for wine-organic extract 2, while the antimicrobial activity of grape skin decoction is higher than those reported by wine extracts on three bacterial strains. Interestingly only dealcoholized wine and wine-aqueous extract exerts inhibitory effects on α-glucosidase (20.62 ± 0.23 mmolACAE/g and 19.81 ± 0.03 mmolACAE/g, respectively), while seeds oil is rich in oleic and linoleic acids. These results confirm the strong antioxidant properties of Montepulciano d'Abruzzo grape pomace, suggesting the potential use of this waste product as functional food supplements in the human diet and in cosmeceutics.

Mineral trioxide aggregate (MTA) is a common biomaterial used in endodontics regeneration due to its antibacterial properties, good biocompatibility and high bioactivity. Surface modification technology allows us to endow biomaterials with the necessary biological targets for activation of specific downstream functions such as promoting angiogenesis and osteogenesis. In this study, we used caffeic acid (CA)-coated MTA/polycaprolactone (PCL) composites and fabricated 3D scaffolds to evaluate the influence on the physicochemical and biological aspects of CA-coated MTA scaffolds. As seen from the results, modification of CA does not change the original structural characteristics of MTA, thus allowing us to retain the properties of MTA. CA-coated MTA scaffolds were shown to have 25% to 55% higher results than bare scaffold. In addition, CA-coated MTA scaffolds were able to significantly adsorb more vascular endothelial growth factors (<i>p</i> < 0.05) secreted from human dental pulp stem cells (hDPSCs). More importantly, CA-coated MTA scaffolds not only promoted the adhesion and proliferation behaviors of hDPSCs, but also enhanced angiogenesis and osteogenesis. Finally, CA-coated MTA scaffolds led to enhanced subsequent in vivo bone regeneration of the femur of rabbits, which was confirmed using micro-computed tomography and histological staining. Taken together, CA can be used as a potently functional bioactive coating for various scaffolds in bone tissue engineering and other biomedical applications in the future.

Membrane proteins reside in the lipid bilayer of biomembranes and the structure and function of these proteins are closely related to their interactions with lipid molecules. Structural analyses of interactions between membrane proteins and lipids or detergents that constitute biological or artificial model membranes are important for understanding the functions and physicochemical properties of membrane proteins and biomembranes. Determination of membrane protein structures is much more difficult when compared with that of soluble proteins, but the development of various new technologies has accelerated the elucidation of the structure-function relationship of membrane proteins. This review summarizes the development of heavy atom derivative detergents and lipids that can be used for structural analysis of membrane proteins and their interactions with detergents/lipids, including their application with X-ray free-electron laser crystallography.

Magnesium alloys are considered the most suitable absorbable metals for bone fracture fixation implants. The main challenge in absorbable magnesium alloys is their high corrosion/degradation rate that needs to be controlled. Various coatings have been applied to magnesium alloys to slow down their corrosion rates to match their corrosion rate to the regeneration rate of the bone fracture. In this review, a bioactive coating is proposed to slow down the corrosion rate of magnesium alloys and accelerate the bone fracture healing process. The main aim of the bioactive coatings is to enhance the direct attachment of living tissues and thereby facilitate osteoconduction. Hydroxyapatite, collagen type I, recombinant human bone morphogenetic proteins 2, simvastatin, zoledronate, and strontium are six bioactive agents that show high potential for developing a bioactive coating system for high-performance absorbable magnesium bone implants. In addition to coating, the substrate itself can be made bioactive by alloying magnesium with calcium, zinc, copper, and manganese that were found to promote bone regeneration.

<title>Abstract</title> <p><bold>BACKGROUND</bold>Racial/Ethnic minorities are at higher risk for Severe COVID-19. This may be related to social determinants that lead to chronic inflammatory states. The aims of the study were to determine if there are racial/ethnic differences between the inflammatory markers of survivors and non-survivors and if there was a dose dependent association of methylprednisolone to in hospital survival. <bold>METHODS</bold>This was a secondary analysis of a retrospective cohort. Patients were older than 18 years of age and admitted for severe COVID-19 Pneumonia Between March to June 2020 in 13 Hospitals in New Jersey, United States. Comparison of inflammatory markers used Kruskal-Wallis followed by pairwise comparison using two-sided Wilcoxon rank sum test. A Youden Index Method was used to determine the cut-off between low dose and high dose methylprednisolone. For each racial/ethnic group, cox regression was used to determine the association to survival between no methylprednisolone and methylprednisolone (high dose versus low dose). <bold>RESULTS</bold>Propensity matched sample (n=759) between no methylprednisolone (n=380) and methylprednisolone (n=379) had 338 Whites, 102 Blacks, 61 Asian/Indians, and 251 Non-Black Non-White Hispanics. Interleukin-6, C-reactive protein, ferritin, and d-dimer values were higher in non-survivors compared to survivors except in Asian/Indian survivors who had higher ferritin values compared to non-survivors (median: 1,265 vs 418 ug/L, P=0.0211). Black and Hispanic survivors had persistently elevated C-reactive protein, (10.2 mg/mL) and (13.70 mg/mL) respectively. Low dose methylprednisolone was associated with prolonged 60 days in hospital survival over no methylprednisolone in Whites (P<0.0001), Asian/Indians (P=0.0180), and Hispanics (P=0.0004). Regardless of dose, methylprednisolone was not associated with prolonged survival in Blacks. High dose methylprednisolone was associated with worse survival in Hispanics. (P=0.0181). <bold>CONCLUSION</bold>Racial/Ethnic disparities with inflammatory markers in survivors and non-survivors preclude the use of one marker as predictor of survival. Low dose methylprednisolone is associated with prolonged survival in Asian/Indians, Hispanics, and Whites. Methylprednisolone, regardless of dose, was not associated with prolonged survival in Blacks.</p>

Compared to the major histocompatibility complex (MHC) of typical mammals, the chicken BF/BL region is small and simple, with most of the genes playing central roles in the adaptive immune response. However, some genes of the chicken MHC are almost certainly involved in innate immunity, such as the complement component C4 and the lectin-like receptor/ligand gene pair BNK and Blec. The poorly expressed classical class I molecule BF1 is known to be recognised by natural killer (NK) cells and, analogous to mammalian immune responses, the classical class I molecules BF1 and BF2, the CD1 homologs and the butyrophilin homologs called BG may be recognised by adaptive immune lymphocytes with semi-invariant receptors in a so-called adaptate manner. Moreover, the TRIM and BG regions next to the chicken MHC, along with the genetically unlinked Y and olfactory/scavenger receptor regions on the same chromosome, have multigene families almost certainly involved in innate and adaptate responses. On this chicken microchromosome, the simplicity of the adaptive immune gene systems contrasts with the complexity of the gene systems potentially involved in innate immunity.

The present study aimed to explore the potential hub genes and pathways of ischaemic cardiomyopathy (ICM) and to investigate the possible associated mechanisms. Two microarray data sets (GSE5406 and GSE57338) were downloaded from the Gene Expression Omnibus (GEO) database. The limma package was used to analyse the differentially expressed genes (DEGs). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, Disease Ontology (DO) and Gene Ontology (GO) annotation analyses were performed. A protein-protein interaction (PPI) network was set up using Cytoscape software. Significant modules and hub genes were identified by the Molecular Complex Detection (MCODE) app. Then, further functional validation of hub genes in other microarrays and survival analysis were performed to judge the prognosis. A total of 1065 genes were matched, with an adjusted p < 0.05, and 17 were upregulated and 25 were downregulated with|log₂ (fold change)|≥1.2. After removing the lengthy entries, GO identified 12 items, and 8 pathways were enriched at adjusted p < 0.05 (false discovery rate, FDR set at <0.05). Three modules with a score >8 after MCODE analysis and MYH6 were ultimately identified. When validated in GSE23561, MYH6 expression was lower in patients with CAD than in healthy controls (p < 0.05). GSE60993 data suggested that MYH6 expression was also lower in AMI patients (p < 0.05). In the GSE59867 data set, MYH6 expression was lower in CAD patients than in AMI patients and lower in heart failure (HF) patients than in non-HF patients. However, there was no difference at different periods within half a year, and HF was increased when MYH6 expression was low (p < 0.05-0.01). We performed an integrated analysis and validation and found that MYH6 expression was closely related to ICM and HF. However, whether this marker can be used as a predictor in blood samples needs further experimental verification.

Messenger RNA (mRNA) can be transported and targeted to different subcellular compartments and locally translated. Local translation is an evolutionally conserved mechanism that in mammals, provides an important tool to exquisitely regulate the subcellular proteome in different cell types, including neurons. Local translation in axons is involved in processes such as neuronal development, function, plasticity, and diseases. Here, we summarize the current progress on axonal mRNA transport and translation. We focus on the regulatory mechanisms governing how mRNAs are transported to axons and how they are locally translated in axons. We discuss the roles of axonally synthesized proteins, which either function locally in axons, or are retrogradely trafficked back to soma to achieve neuron-wide gene regulation. We also examine local translation in neurological diseases. Finally, we give a critical perspective on the remaining questions that could be answered to uncover the fundamental rules governing local translation, and discuss how this could lead to new therapeutic targets for neurological diseases.

Furin is one of the nine-member proprotein convertase family. Furin cleaves proteins with polybasic residues, which includes many viral glycoproteins such as SARS-Cov-2 spike protein. The cleavage is required for the activation of the proteins. Currently, the mechanisms that regulate Furin activity remain largely unknown. Here we demonstrated that Furin is a novel heparin/heparan sulfate binding protein by the use of biochemical and genetic assays. The K_D is 9.78 nM based on the biolayer interferometry assay. Moreover, we found that sulfation degree, site-specific sulfation (N-sulfation and 3-O-sulfation), and iduronic acid are the major structural determinants for the binding. Furthermore, we found that heparin inhibits the enzymatic activity of Furin when pre-mixes heparin with either Furin or Furin substrate. We also found that the Furin binds with cells of different origin and the binding with the cells of lung origin is the strongest one. These data could advance our understanding of the working mechanism of Furin and will benefit the Furin based drug discovery such as inhibitors targeting the interaction between heparan sulfate and Furin for inhibition of viral infection.

In this study, the novel application of ATR-FTIR spectroscopy and macro ATR-FTIR spectroscopic imaging overcame an analytical challenge in conservation science: the time-resolved, chemical, and spatial investigation of the reaction of inorganic treatments for stone conservation (ammonium oxalate, AmOx; ammonium phosphate, DAP) occurring in water-based solutions. The aim was to (1) assess the composition and localization of reaction products and their phase variation during the reaction in real time and directly in an aqueous environment and (2) investigate the reaction of AmOx and DAP with calcite and the transformations induced to the substrate with a time-resolved approach. The new analytical results showed that for both treatments, the formation of new crystalline phases initiated at the early stages of the reaction. Their composition changed during the treatment and led to more stable phases. The reactivity of the stone substrate to the treatments varied as a function of the stone material features, such as the specific surface area. A clear influence of post-treatment rinsing on the final composition of reaction phases was observed. Above all, our research demonstrates the actual feasibility, practicality, and high potential of an advanced ATR-FTIR spectroscopic approach to investigate the behavior of conservation treatments and provided new analytical tools to address the choices of conservation in pilot worksites. Lastly, this study opens novel analytical perspectives based on the new possible applications of ATR-FTIR spectroscopic imaging in the field of conservation science, materials science, and analytical chemistry.

No abstract available.

<h4>Background</h4>The immune infiltration of patients with colon cancer (CC) is closely associated with RNA-binding proteins (RBPs). However, immune-associated RBPs (IARBPs) in CC remain unexplored.<h4>Methods</h4>The data were downloaded from The Cancer Genome Atlas (TCGA) and the patients were divided into four immune subgroups by single sample gene set enrichment analysis (ssGSEA), in which weighted gene correlation network analysis (WGCNA) identified modules of co-expressed genes correlated with immune infiltration. Univariate (UCR) and multivariate Cox regression (MCR) analyses were applied to screen survival-associated IARBPs. Then, a prognostic signature was performed on TCGA dataset. Risk model was constructed based on the TCGA dataset. Based on the median risk score, CC patients were subdivided into low- and high-risk groups. Furthermore, the accuracy and prognostic value of this signature were validated by using Kaplan-Meier (K-M) curve, receiver operating characteristic (ROC). We further validated the findings in Gene Expression Omnibus (GEO) database. Finally, we evaluated the association between gene expression level and drug sensitivity.<h4>Results</h4>Based on the infiltration of immune cells, the TCGA patients were divided into four subgroups. In total, we identified 25 IARBPs, after differential expression and WGCNA analysis. Subsequently, two IARBP signatures (FBXO17 and PPARGC1A) were identified to be significantly associated with the overall survival (OS) of CC patients. K-M survival analysis revealed that the low-risk group correlated with prolonged OS. The prognostic signature was an independent prognostic factor and reflects the immune status of CC patients. Finally, FBXO17 was related with drug sensitivity of bleomycin, gemcitabine, and lenvatinib. PPARGC1A was related to drug sensitivity of dabrafenib, vemurafenib, and trametinib.<h4>Conclusion</h4>A novel two immune-associated RBPs that was established that may be useful in predicting survival and individualized treatment.

<h4>Background</h4>Non-alcoholic fatty liver disease (NAFLD) patients are at a substantial risk for developing cardiovascular disease (CVD). High-density lipoprotein (HDL) is well known to have protective effects against the development of atherosclerotic CVD. One of the major antiatherogenic effects of HDL is its anti-oxidative function.<h4>Objectives</h4>This study investigated the association of anti-oxidative capacity of HDL with subclinical atherosclerosis in NAFLD and non-NAFLD subjects.<h4>Methods</h4>A total of 143 subjects including 51 NAFLD and 92 control subjects were included in this case-control study. HDL oxidative index (HOI) was determined spectrophotometrically using a cell-free method in the presence of a fluorescent substrate dichlorofluorescein diacetate (DCFDA). Paraoxonase 1 (PON1) activity, superoxide dismutase (SOD) activity, and malondialdehyde (MDA) plasma levels were assessed in both groups.<h4>Results</h4>The NAFLD patients with impaired HDL anti-oxidative function (HOI  ≥ 1) had higher MDA levels, aspartate amino transferase (AST), liver stiffness (LS), and carotid intima-media thickness (cIMT) values compared to the controls. HDL oxidative index (HOI) was positively correlated with MDA levels and cIMT and negatively correlated with SOD activity.<h4>Conclusions</h4>Higher circulating levels of MDA were associated with the impaired anti-oxidative function of HDL in NAFLD. The impaired anti-oxidative capacity of HDL might be related to NAFLD severity and subclinical atherosclerosis in NAFLD patients.

<h4>Background</h4>De novo variants in the voltage-gated calcium channel subunit α1 E gene (CACNA1E) have been described as causative of epileptic encephalopathy with contractures, macrocephaly and dyskinesias.<h4>Methods</h4>Following the observation of an index patient with developmental delay and autism spectrum disorder (ASD) without seizures who had a de novo deleterious CACNA1E variant, we screened GeneMatcher for other individuals with CACNA1E variants and neurodevelopmental phenotypes without epilepsy. The spectrum of pathogenic CACNA1E variants was compared to the mutational landscape of variants in the gnomAD control population database.<h4>Results</h4>We identified seven unrelated individuals with intellectual disability, developmental regression and ASD-like behavioral profile, and notably without epilepsy, who had de novo heterozygous putatively pathogenic variants in CACNA1E. Age of onset of clinical manifestation, presence or absence of regression and degree of severity were variable, and no clear-cut genotype-phenotype association could be recognized. The analysis of disease-associated variants and their comparison to benign variants from the control population allowed for the identification of regions in the CACNA1E protein that seem to be intolerant to substitutions and thus more likely to harbor pathogenic variants. As in a few reported cases with CACNA1E variants and epilepsy, one patient showed a positive clinical behavioral response to topiramate, a specific calcium channel modulator.<h4>Limitations</h4>The significance of our study is limited by the absence of functional experiments of the effect of identified variants, the small sample size and the lack of systematic ASD assessment in all participants. Moreover, topiramate was given to one patient only and for a short period of time.<h4>Conclusions</h4>Our results indicate that CACNA1E variants may result in neurodevelopmental disorders without epilepsy and expand the mutational and phenotypic spectrum of this gene. CACNA1E deserves to be included in gene panels for non-specific developmental disorders, including ASD, and not limited to patients with seizures, to improve diagnostic recognition and explore the possible efficacy of topiramate.

The mechanisms underlying retinal development have not been completely elucidated. Extracellular vesicles (EVs) are novel essential mediators of cell-to-cell communication with emerging roles in developmental processes. Nevertheless, the identification of EVs in human retinal tissue, characterization of their cargo, and analysis of their potential role in retina development has not been accomplished. Three-dimensional retinal tissue derived from human induced pluripotent stem cells (hiPSC) provide an ideal developmental system to achieve this goal. Here we report that hiPSC-derived retinal organoids release exosomes and microvesicles with small noncoding RNA cargo. EV miRNA cargo-predicted targetome correlates with Gene Ontology (GO) pathways involved in mechanisms of retinogenesis relevant to specific developmental stages corresponding to hallmarks of native human retina development. Furthermore, uptake of EVs by human retinal progenitor cells leads to changes in gene expression correlated with EV miRNA cargo predicted gene targets, and mechanisms involved in retinal development, ganglion cell and photoreceptor differentiation and function.

Glial cells, including astrocytes, oligodendrocytes, and microglia, are the major components in the central nervous system (CNS). Studies have revealed the heterogeneity of each glial cell type and that they each may play distinct roles in physiological processes and/or neurological diseases. Single-cell sequencing (scRNA-seq) technology developed in recent years has extended our understanding of glial cell heterogeneity from the perspective of transcriptome profiling. This review summarizes the marker genes of major glial cells in the CNS and reveals their heterogeneity in different species, CNS regions, developmental stages, and pathological states (Alzheimer's disease and spinal cord injury), expanding our knowledge of glial cell heterogeneity on both molecular and functional levels.

<h4>Background</h4>The anti-tumor properties of curcumin have been demonstrated for many types of cancer. However, a systematic functional and biological analysis of its target proteins has yet to be fully documented. The aim of this study was to explore the underlying mechanisms of curcumin and broaden the perspective of targeted therapies.<h4>Methods</h4>Direct protein targets (DPTs) of curcumin were searched in the DrugBank database. Using the STRING database, the interactions between curcumin and DPTs and indirect protein targets (IPTs) weres documented. The protein-protein interaction (PPI) network of curcumin-mediated proteins was visualized using Cytoscape. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was performed for all curcumin-mediated proteins. Furthermore, the cancer targets were searched in the Comparative Toxicogenomics Database (CTD). The overlapping targets were studied using Kaplan-Meier analysis to evaluate cancer survival. Further genomic analysis of overlapping genes was conducted using the cBioPortal database. Lastly, MTT, quantitative polymerase chain reaction (qPCR), and western blot (WB) analysis were used to validate the predicted results on hepatocellular carcinoma (HCC) cells.<h4>Results</h4>A total of five DPTs and 199 IPTs were found. These protein targets were found in 121 molecular pathways analyzed <i>via</i> KEGG enrichment. Based on the anti-tumor properties of curcumin, two pathways were selected, including pathways in cancer (36 genes) and HCC (22 genes). Overlapping with 505 HCC-related gene sets identified in CTD, five genes (TP53, RB1, TGFB1, GSTP1, and GSTM1) were finally identified. High mRNA levels of TP53, RB1, and GSTM1 indicated a prolonged overall survival (OS) in HCC, whereas elevated mRNA levels of TGFB1 were correlated with poor prognosis. The viability of both HepG2 cells and Hep3B cells was significantly reduced by curcumin at concentrations of 20 or 30 μM after 48 or 72 h of culture. At a concentration of 20 μM curcumin cultured for 48 h, the expression of TGFB1 and GSTP1 in Hep3B cells was reduced significantly in qPCR analysis, and reduced TGFB1 protein expression was also found in Hep3B cells.

Autophagy is considered an indispensable process that scavenges toxins, recycles complex macromolecules, and sustains the essential cellular functions. In addition to its housekeeping role, autophagy plays a substantial role in many pathophysiological processes such as cancer. Certainly, it adapts cancer cells to thrive in the stress conditions such as hypoxia and starvation. Cancer cells indeed have also evolved by exploiting the autophagy process to fulfill energy requirements through the production of metabolic fuel sources and fundamentally altered metabolic pathways. Occasionally autophagy as a foe impedes tumorigenesis and promotes cell death. The complex role of autophagy in cancer makes it a potent therapeutic target and has been actively tested in clinical trials. Moreover, the versatility of autophagy has opened new avenues of effective combinatorial therapeutic strategies. Thereby, it is imperative to comprehend the specificity of autophagy in cancer-metabolism. This review summarizes the recent research and conceptual framework on the regulation of autophagy by various metabolic pathways, enzymes, and their cross-talk in the cancer milieu, including the implementation of altered metabolism and autophagy in clinically approved and experimental therapeutics.

Ferroptosis is an iron- and lipid peroxidation-dependent form of regulated cell death. The release of labile iron is one of the important factors affecting sensitivity to ferroptosis. Yes-associated protein (YAP) controls intracellular iron levels by affecting the transcription of <i>ferritin heavy chain (FTH)</i> and <i>transferrin receptor (TFRC)</i>. However, whether YAP regulates iron metabolism through other target genes remains unknown. Here, we observed that the system Xc^- inhibitor erastin inhibited the binding of the WW domain and PSY motif between YAP and transcription factor CP2 (TFCP2), and then suppressed the transcription of <i>ferritin light chain (FTL)</i> simultaneously mediated by YAP, TFCP2 and forkhead box A1 (FOXA1). Furthermore, inhibition of FTL expression abrogated ferroptosis-resistance in cells with sustained YAP expression. Unlike <i>FTH</i>, which exhibited first an increase and then a decrease in transcription, <i>FTL</i> transcription continued to decline after the addition of erastin, and a decrease in lysine acetyltransferase 5 (KAT5)-dependent acetylation of <i>FTL</i> was also observed. In lung adenocarcinoma (LUAD) tissues, lipid peroxidation and labile iron decreased, while YAP, TFCP2 and FTL increased compared to their adjacent normal tissues, and the lipid peroxidation marker 4-hydroxynonenal (4-HNE) was negatively correlated with the level of FTL or the degree of LUAD malignancy, but LUAD tissues with lower levels of 4-HNE showed a higher sensitivity to ferroptosis. In conclusion, the findings from this study indicated that the suppression of <i>FTL</i> transcription through the inhibition of the YAP-TFCP2-KAT5 complex could be another mechanism for elevating ferroptosis sensitivity and inducing cell death, and ferroptotic therapy is more likely to achieve better results in LUAD patients with a lower degree of lipid peroxidation.

<b>Background:</b> Lymph node (LN) metastasis is considered one of the most important risk factors affecting the prognosis of distal cholangiocarcinoma (DCC). This study aimed to demonstrate the superiority of log odds of positive lymph nodes (LODDS) compared with other LN stages, and to establish a novel prognostic nomogram to predict the cancer-specific survival (CSS) of DCC. <b>Methods:</b> From the Surveillance, Epidemiology and End Results (SEER) database, the data of 676 patients after DCC radical operation were screened, and patients were randomly divided into training (<i>n</i> = 474) and validation sets (<i>n</i> = 474). The prognostic evaluation performance of the LODDS and American Joint Commission on Cancer (AJCC) N stage and lymph node ratio (LNR) were compared using the Akaike information criteria, receiver operating characteristic area under the curve (AUC), and C-index. Multivariate Cox analysis was used to screen independent risk factors, and a LODDS-based nomogram prognostic staging model was established. The nomogram's precision was verified by C-index, calibration curves, and AUC, and the results were compared with those of the AJCC TNM staging system. <b>Results:</b>Compared with the other two stages of LN metastasis, LODDS was most effective in predicting CSS in patients with DCC. Multivariate analysis proved that LODDS, histologic grade, SEER historic stage, and tumor size were independent risk factors for DCC. The C-index of the nomogram, based on the above factors, in the validation set was 0.663. The 1-, 3-, and 5-y AUCs were 0.735, 0.679, and 0.745, respectively. Its good performance was also verified by calibration curves. In addition, the C-index and Kaplan-Meier analysis showed that the nomogram performed better than the AJCC TNM staging system. <b>Conclusion:</b>For postoperative patients with DCC, the LODDS stage yielded better prognostic efficiency than the AJCC N and LNR stages. Compared with the AJCC TNM staging system, the nomogram, based on the LODDS, demonstrated superior performance.

<b>Background:</b> Interactions between genetic and environmental risk factors (GxE) contribute to an increased risk of venous thromboembolism (VTE). Understanding how these factors interact provides insight for the early identification of at-risk groups within a population and creates an opportunity to apply appropriate preventive and curative measures. <b>Objective:</b> To estimate and compare GxE for VTE risk in the general Hungarian and Roma populations. <b>Methods:</b> The study was based on data extracted from a database consisting of results previously obtained from a complex health survey with three pillars (questionnaire-based, physical, and laboratory examinations) involving 406 general Hungarian and 395 Roma subjects. DNA was genotyped for rs121909567 (SERPINC1), rs1799963 (F2), rs2036914 (F11), rs2066865 (FGG), rs6025 (F5), and rs8176719 (ABO) polymorphisms. After allele frequency comparisons, the odds ratio (OR) was calculated for individual SNPs. Furthermore, genetic risk scores (weighted GRS, unweighted GRS) were computed to estimate the joint effect of the genetic factors. Multivariable linear regression analysis was applied to test the impact of GxE on VTE risk after interaction terms were created between genetic and VTE risk factors [diabetes mellitus (DM), cancer, chronic kidney diseases (CKD), coronary artery diseases (CAD), migraine, depression, obesity, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high density lipoprotein (HDL-C), triglyceride (TG), and smoking]. <b>Results:</b> Interestingly, the rs121909567 (SERPINC1, ATBp3 mutation) SNP was not present in the general population at all. However, the risk allele frequency was 1% among the Roma population, which might suggest a founder effect in this minority. This polymorphism multiplicatively interacted with CAD, CKD, cancer, DM, depression, migraine, and obesity. Even though interactions were not statistically significant, the trend of interaction showed the probability of an incremental VTE risk among the Roma population. The risk of VTE was 4.7 times higher (<i>p</i> > 0.05) for Roma subjects who had ≥3 wGRS (median value) compared with individuals having lower wGRS values but lower for the general subjects (OR = 3.1 × 10^-8). Additionally, the risk of VTE was 6.6 times higher in the Roma population that had ≥3 risk alleles (median value) than in individuals with the 0-1 risk allele, and the overall risk was much higher for the Roma population (OR = 6.6; <i>p</i> > 0.05) than for the general Hungarian population (OR = 1.5; <i>p</i> > 0.05). Five positive and significant GxE interactions were identified in the Roma population. The risk of VTE was higher among depressive Roma subjects who carried the risk variant rs2036914 (β = 0.819, <i>p</i> = 0.02); however, this interaction was not significant for the general subjects. The joint presence of high levels of LDL-C and rs2066865 (FGG) increased the VTE risk only among Roma individuals (β = 0.389, <i>p</i> = 0.002). The possibility of VTE risk increment, as a result of a multiplicative interaction between rs8176719 (ABO) and cancer, was identified, which was higher for the Roma population (β = 0.370, <i>p</i> < 0.001) than for the general population (β = -0.042, <i>p</i> = 0.6). The VTE risk increased in the Roma population (β = 0.280, <i>p</i> = 0.001), but was higher in the general population (β = 0.423, <i>p</i> = 0.001) as a result of the multiplicative interaction between CAD and rs2036914 (F11). The presence of a multiplicative interaction between rs2066865 (FGG) and CAD increased the VTE risk for the Roma population (β = 0.143, <i>p</i> = 0.046) but not for the general population (β = -0.329, <i>p</i> < 0.001). <b>Conclusions:</b> rs121909567 (SERPINC1, ATBp3) was confirmed as a founder mutation in the Roma population. Our study revealed some evidence on the burden of the joint presence of genetic and environmental risk factors on VTE, although the finding is highly subjected to the selection and observational biases due to the very small number of VTE cases and the observational nature of the study design, respectively. As a result of higher genetic load and GxE interactions, this minority Roma population is at higher risk of VTE than the general Hungarian population. Thus, our results suggest the need for an intensive search for the rs121909567 (SERPINC1; ATBp3) founder mutation, which might be an important factor for the assessment of thrombotic disease susceptibility among the Roma population. In addition, we strongly recommend further studies among a large number of VTE cases to explore the more precise impact of genetic and environmental risk factors on VTE in the study populations.

Triple-negative breast cancer (TNBC) can be further classified into androgen receptor (AR)-positive TNBC and AR-negative TNBC or quadruple-negative breast cancer (QNBC). Here, we investigated genomic instability in 53 clinical cases by array-CGH and miRNA expression profiling. Immunohistochemical analysis revealed that 64% of TNBC samples lacked AR expression. This group of tumors exhibited a higher level of copy number alterations (CNAs) and a higher frequency of cases affected by CNAs than TNBCs. CNAs in genes of the chromosome instability 25 (CIN25) and centrosome amplification (CA) signatures were more frequent in the QNBCs and were similar between the groups, respectively. However, expression levels of CIN25 and CA20 genes were higher in QNBCs. miRNA profiling revealed 184 differentially expressed miRNAs between the groups. Fifteen of these miRNAs were mapped at cytobands with CNAs, of which eight (miR-1204, miR-1265, miR-1267, miR-23c, miR-548ai, miR-567, miR-613, and miR-943), and presented concordance of expression and copy number levels. Pathway enrichment analysis of these miRNAs/mRNAs pairings showed association with genomic instability, cell cycle, and DNA damage response. Furthermore, the combined expression of these eight miRNAs robustly discriminated TNBCs from QNBCs (AUC = 0.946). Altogether, our results suggest a significant loss of AR in TNBC and a profound impact in genomic instability characterized by CNAs and deregulation of miRNA expression.

The complex pathology of Alzheimer's disease (AD) emphasises the need for comprehensive modelling of the disease, which may lead to the development of efficient treatment strategies. To address this challenge, we analysed transcriptome data of post-mortem human brain samples of healthy elders and individuals with late-onset AD from the Religious Orders Study and Rush Memory and Aging Project (ROSMAP) and Mayo Clinic (MayoRNAseq) studies in the AMP-AD consortium. In this context, we conducted several bioinformatics and systems medicine analyses including the construction of AD-specific co-expression networks and genome-scale metabolic modelling of the brain in AD patients to identify key genes, metabolites and pathways involved in the progression of AD. We identified <i>AMIGO1</i> and <i>GRPRASP2</i> as examples of commonly altered marker genes in AD patients. Moreover, we found alterations in energy metabolism, represented by reduced oxidative phosphorylation and ATPase activity, as well as the depletion of hexanoyl-CoA, pentanoyl-CoA, (2E)-hexenoyl-CoA and numerous other unsaturated fatty acids in the brain. We also observed that neuroprotective metabolites (e.g., vitamins, retinoids and unsaturated fatty acids) tend to be depleted in the AD brain, while neurotoxic metabolites (e.g., β-alanine, bilirubin) were more abundant. In summary, we systematically revealed the key genes and pathways related to the progression of AD, gained insight into the crucial mechanisms of AD and identified some possible targets that could be used in the treatment of AD.

The design, synthesis, and physicochemical characterization of conjugates are arduous and tedious processes. Several synthetic pathways for polymeric conjugation have been reported; however, conjugation through monomers with suitable reaction conditions can be a simple and robust approach. In the present study, three different conjugates of hydrophilic <i>N</i>-2-hydroxypropyl methacrylamide (HPMA) and hydrophobic polycaprolactone (PCL) were synthesized. The followed synthetic pathway not only was simple and robust but also reduced the overall synthetic steps as well as harsh reaction conditions significantly. In a nutshell, three conjugates, i.e., <i>N</i>-2-hydroxypropyl methacrylamide and polycaprolactone (HP-PCL), <i>n</i>-butanol-polycaprolactone-<i>N</i>-2-hydroxypropyl methacrylamide (nBu-PCL-HP), and isoamyl alcohol-polycaprolactone-<i>N</i>-2-hydroxypropyl methacrylamide (ISAL-PCL-HP), were synthesized through this simple synthetic strategy following the monomer conjugation approach along with exhaustive spectroscopic and rheological characterization. The conjugates HP-PCL, nBu-PCL-HP, and ISAL-PCL-HP were characterized by Fourier transform infrared (FT-IR) and NMR (¹³C and ¹H) spectroscopies. The size and ζ potential of conjugates were determined through the dynamic light scattering (DLS) method. The nBu-PCL-HP conjugate displayed a hexagonal-like shape, as evidenced by scanning electron microscopy (SEM) with an obtained size of 237.9 ± 0.21 nm. X-ray diffraction (XRD) analysis proved the crystalline nature of nBu-PCL-HP conjugates. The results of smartly synthesized conjugates intrigued us to study their flow properties in detail. Rheological evaluation resulted in their non-Newtonian type of flow with the best-fit behavior for all of the conjugates followed as per the Herschel-Bulkley and power-law models applied herein. Conclusively, the synthesized HPMA and PCL conjugates may have applications in the preparation of blends, fibers, etc. in the future. The study portrayed that the explored synthetic scheme using monomers and initiators could be a suitable approach for the synthesis of HPMA and PCL conjugates.

Male reproductive aging, or andropause, is associated with gradual age-related changes in testicular properties, sperm production, and erectile function. The testis, which is the primary male reproductive organ, produces sperm and androgens. To understand the transcriptional changes underlying male reproductive aging, we performed transcriptome analysis of aging testes in mice. A total of 31,386 mRNAs and 9387 long non-coding RNAs (lncRNAs) were identified in the mouse testes of diverse age groups (3, 6, 12, and 18 months old) by total RNA sequencing. Of them, 1571 mRNAs and 715 lncRNAs exhibited changes in their levels during testicular aging. Most of these aging-related transcripts exhibited slight and continuous expression changes during aging, whereas some (9.6%) showed larger expression changes. The aging-related transcripts could be classified into diverse expression patterns, in which the transcripts changed mainly at 3-6 months or at 12-18 months. Our subsequent in silico analysis provided insight into the potential features of testicular aging-related mRNAs and lncRNAs. We identified testis-specific aging-related transcripts (121 mRNAs and 25 lncRNAs) by comparison with a known testis-specific transcript profile, and then predicted the potential reproduction-related functions of the mRNAs. By selecting transcripts that are altered only between 3 and 18 months, we identified 46 mRNAs and 34 lncRNAs that are stringently related to the terminal stage of male reproductive aging. Some of these mRNAs were related to hormonal regulation. Finally, our in silico analysis of the 34 aging-related lncRNAs revealed that they co-localized with 19 testis-expressed protein-coding genes, 13 of which are considered to show testis-specific or -predominant expression. These nearby genes could be potential targets of <i>cis</i>-regulation by the aging-related lncRNAs. Collectively, our results identify a number of testicular aging-related mRNAs and lncRNAs in mice and provide a basis for the future investigation of these transcripts in the context of aging-associated testicular dysfunction.

Besides their role in cell metabolism, mitochondria display many other functions. Mitochondrial DNA (mtDNA), the own genome of the organelle, plays an important role in modulating the inflammatory immune response. When released from the mitochondrion to the cytosol, mtDNA is recognized by cGAS, a cGAMP which activates a pathway leading to enhanced expression of type I interferons, and by NLRP3 inflammasome, which promotes the activation of pro-inflammatory cytokines Interleukin-1beta and Interleukin-18. Furthermore, mtDNA can be bound by Toll-like receptor 9 in the endosome and activate a pathway that ultimately leads to the expression of pro-inflammatory cytokines. mtDNA is released in the extracellular space in different forms (free DNA, protein-bound DNA fragments) either as free circulating molecules or encapsulated in extracellular vesicles. In this review, we discussed the latest findings concerning the molecular mechanisms that regulate the release of mtDNA from mitochondria, and the mechanisms that connect mtDNA misplacement to the activation of inflammation in different pathophysiological conditions.

Gene therapy and DNA vaccination are among the most expected biotechnological and medical advances for the coming years. However, the lack of cost-effective large-scale production and purification of pharmaceutical-grade plasmid DNA (pDNA) still hampers their wide application. Downstream processing, which is mainly chromatography-based, of pDNA remains the key manufacturing step. Despite its high resolution, the scaling-up of chromatography is usually difficult and presents low capacity, resulting in low yields. Alternative methods that are based on aqueous two-phase systems (ATPSs) have been studied. Although higher yields may be obtained, its selectivity is often low. In this work, modified polymers based on poly(ethylene glycol) (PEG) derivatisation with amino groups (PEG-amine) or conjugation with positively charged amino acids (PEG-lysine, PEG-arginine, and PEG-histidine) were studied to increase the selectivity of PEG-dextran systems towards the partition of a model plasmid. A two-step strategy was employed to obtain suitable pure formulations of pDNA. In the first step, a PEG-dextran system with the addition of the affinity ligand was used with the recovery of the pDNA in the PEG-rich phase. Then, the pDNA was re-extracted to an ammonium-sulphate-rich phase in the second step. After removing the salt, this method yielded a purified preparation of pDNA without RNA and protein contamination.

The blood-brain barrier (BBB) is a fundamental component of the central nervous system (CNS). Its functional and structural integrity is vital to maintain the homeostasis of the brain microenvironment by controlling the passage of substances and regulating the trafficking of immune cells between the blood and the brain. The BBB is primarily composed of highly specialized microvascular endothelial cells. These cells' special features and physiological properties are acquired and maintained through the concerted effort of hemodynamic and cellular cues from the surrounding environment. This complex multicellular system, comprising endothelial cells, astrocytes, pericytes, and neurons, is known as the neurovascular unit (NVU). The BBB strictly controls the transport of nutrients and metabolites into brain parenchyma through a tightly regulated transport system while limiting the access of potentially harmful substances via efflux transcytosis and metabolic mechanisms. Not surprisingly, a disruption of the BBB has been associated with the onset and/or progression of major neurological disorders. Although the association between disease and BBB disruption is clear, its nature is not always evident, specifically with regard to whether an impaired BBB function results from the pathological condition or whether the BBB damage is the primary pathogenic factor prodromal to the onset of the disease. In either case, repairing the barrier could be a viable option for treating and/or reducing the effects of CNS disorders. In this review, we describe the fundamental structure and function of the BBB in both healthy and altered/diseased conditions. Additionally, we provide an overview of the potential therapeutic targets that could be leveraged to restore the integrity of the BBB concomitant to the treatment of these brain disorders.

The use of biological drugs has improved outcomes in pediatric inflammatory bowel disease (IBD). Prediction of the response to biological drugs would be extremely useful in IBD, and even more so in children, who are still growing physically and psychologically. Specific clinical, biochemical, and genetic parameters are considered predictive of response to biological drugs, although few studies have been carried out in children with IBD. In this review, we present current evidence on biological treatments used in pediatric IBD and the available biomarkers of response. We examine demographics, clinical characteristics, biomarkers (genetic, genomic, and cellular), and microbiota.

This review summarizes the results reported on the production of biphasic calcium phosphate (BCP) materials derived from fish wastes (i.e., heads, bones, skins, and viscera), known as fish discards, and offers an in-depth discussion on their promising potential for various applications in many fields, especially the biomedical one. Thus, considerable scientific and technological efforts were recently focused on the capability of these sustainable materials to be transformed into economically attractive and highly valuable by-products. As a consequence of using these wastes, plenty of beneficial social effects, with both economic and environmental impact, will arise. In the biomedical field, there is a strong and continuous interest for the development of innovative solutions for healthcare improvement using alternative materials of biogenic origin. Thus, the orthopedic field has witnessed a significant development due to an increased demand for a large variety of implants, grafts, and/or scaffolds. This is mainly due to the increase of life expectancy and higher frequency of bone-associated injuries and diseases. As a consequence, the domain of bone-tissue engineering has expanded to be able to address a plethora of bone-related traumas and to deliver a viable and efficient substitute to allografts or autografts by combining bioactive materials and cells for bone-tissue ingrowth. Among biomaterials, calcium phosphate (CaP)-based bio-ceramics are widely used in medicine, in particular in orthopedics and dentistry, due to their excellent bioactive, osteoconductive, and osteointegrative characteristics. Recently, BCP materials (synthetic or natural), a class of CaP, which consist of a mixture of two phases, hydroxyapatite (HA) and beta tricalcium phosphate (β-TCP), in different concentrations, gained increased attention due to their superior overall performances as compared to single-phase formulations. Moreover, the exploitation of BCP materials from by-products of fish industry was reported to be a safe, cheap, and simple procedure. In the dedicated literature, there are many reviews on synthetic HA, β-TCP, or BCP materials, but to the best of our knowledge, this is the first collection of results on the effects of processing conditions on the morphological, compositional, structural, mechanical, and biological properties of the fish discard-derived BCPs along with the tailoring of their features for various applications.

Abdominal magnetic resonance imaging (MRI) represents a non-invasive approach allowing the extraction of clinically informative phenotypes. We developed an automated pipeline to segment liver pixels from abdominal MRI images and apply published models to approximate fat fraction, extracellular fluid fraction and iron content in 40,058 MRIs from the UK Biobank. We then conducted a genome-wide association of these traits using imputed variants (N=37,250 individuals, 11,914,698 variants) and exome sequence data (N=35,274 individuals, 8,287,315 variants). For liver fat we identified 8 novel loci in or near genes MARC1, GCKR, ADH1B, MTTP, TRIB1, GPAM, PNPLA2 and APOH. For liver iron we identified 1 novel locus between the genes ASNSD1 and SLC40A1, an iron transporter involved in hemochromatosis. For extracellular fluid fraction we identified 6 novel loci in or near genes AGMAT, NAT2, MRPL4-S1PR2, FADS1, ABO and HFE, with almost all having prior associations to obesity, liver, iron, or lipid traits.

<h4>Background</h4> Drosophila is an excellent model organism for studying human neurodegenerative diseases (NDs), and the rough eye phenotype (REP) assay is a convenient experimental system for analysing the toxicity of ectopically expressed human disease genes. However, the association between REP and axonal degeneration, an early sign of ND, remains unclear. To address this question, we developed a method to evaluate axonal degeneration by quantifying the number of retinal R7 axons in Drosophila ; however, it requires expertise and is time-consuming. Therefore, there is a need for an easy-to-use software that can automatically quantify the axonal degeneration. <h4>Result</h4> We created MeDUsA (a ‘ me thod for the quantification of d egeneration us ing fly a xons’), which is a standalone executable computer program based on Python that combines a pre-trained deep-learning masking tool with an axon terminal counting tool. This software automatically quantifies the number of axons from a confocal z-stack image series. Using this software, we have demonstrated for the first time directly that axons degenerate when the causative factors of NDs (αSyn, Tau, TDP-43, HTT) were expressed in the Drosophila eye. Furthermore, we compared axonal toxicity of the representative causative genes of NDs and their pathological alleles with REP and found no significant correlation between them. <h4>Conclusions</h4> MeDUsA rapidly and accurately quantifies axons in Drosophila eye. By simplifying and automating time-consuming manual efforts requiring significant expertise, it enables large-scale, complex research efforts on axonal degeneration, such as screening to identify genes or drugs that mediate axonal toxicity caused by ND disease proteins.

The aim of this study was to evaluate the effect of 1 µmol/l zearalenone (ZEN) and 1 µmol/l matairesinol (MAT), alone or in combination, on the morphology of in vitro-cultured ovarian preantral follicles. Ovaries from four adult sheep were collected at a local slaughterhouse and fragmented, and the ovarian pieces were submitted to in vitro culture for 3 days in the presence or absence of the test compounds. The morphology of primordial and primary follicles was impaired by ZEN. The plant lignan MAT alone did not maintain the morphology of the ovarian follicles; its combination with ZEN counteracted the negative effects observed when follicles were cultured in the presence of the mycotoxin alone. However, MAT was not able to promote the in vitro development of the ovarian follicles.

Precision oncology benefits from effective early phase drug discovery decisions. Recently, drugging inactive protein conformations has shown impressive successes, raising the cardinal questions of which targets can profit and what are the principles of the active/inactive protein pharmacology. Cancer driver mutations have been established to mimic the protein activation mechanism. We suggest that the decision whether to target an inactive (or active) conformation should largely rest on the protein mechanism of activation. We next discuss the recent identification of double (multiple) same-allele driver mutations and their impact on cell proliferation and suggest that like single driver mutations, double drivers also mimic the mechanism of activation. We further suggest that the structural perturbations of double (multiple) in cis mutations may reveal new surfaces/pockets for drug design. Finally, we underscore the preeminent role of the cellular network which is deregulated in cancer. Our structure-based review and outlook updates the traditional Mechanism of Action, informs decisions, and calls attention to the intrinsic activation mechanism of the target protein and the rewired tumor-specific network, ushering innovative considerations in precision medicine.

<h4>Background</h4>Metastatic prostate cancer (PCa) is a lethal tumor. However, the molecular mechanisms underlying PCa progression have not been fully elucidated.<h4>Methods</h4>Transcriptome expression profiling and clinical information on primary and metastatic PCa samples were obtained from TCGA. R software was used to screen the DEGs, and LASSO logistical regression method was utilized to identify the pivotal PCa metastasis-related DEGs. The transcriptional expression levels of the key genes were analyzed using the UALCAN database, and the corresponding protein expression were validated by Immunohistochemistry (IHC). Survival analysis of the key genes was performed using the GEPIA database. Wound healing assay and Transwell assay were conducted to determine whether knockdown of the key genes influence the migration and invasion abilities of PCa cells (22Rv1 and PC3). GSEA was performed to predict key genes-mediated signaling pathways for the development of PCa. Western blotting was used to evaluate the expression changes of E-cadherin, Twist1, and Vimentin in PCa cells with the key genes silencing. An in vivo mouse metastatic model for PCa was also generated to verify the important role of ISG15 and CST2 in PCa metastasis.<h4>Results</h4>A comparison between primary and metastatic PCa tissues was conducted, and 19 DEGs were screened. Among these, three key genes were identified that might be closely associated with PCa progression according to the LASSO logistical analysis, namely ISG15, DNAH8, and CST2. Further functional experiments revealed that knockdown of ISG15 and CST2 suppressed wound healing, migration, and invasion of PCa cells. To explore the molecular mechanism of ISG15 and CST2 in the development of PCa, GSEA was performed, and it was found that both genes play crucial roles in cell adhesion molecules, extracellular matrix-receptor interaction, and focal adhesion. Western blotting results exhibited that inhibiting ISG15 and CST2 led to increase the expression of E-cadherin and decrease the expression of Twist1 and Vimentin. Additionally, the metastatic in vivo study demonstrated that both PC3 and 22Rv1 cells expressing with luciferase-shISG15 and luciferase-shCST2 had significantly lower detectable bioluminescence than that in the control PCa cells.<h4>Conclusion</h4>ISG15 and CST2 may participate in PCa metastasis by regulating the epithelial-mesenchymal transition (EMT) signaling pathway. These findings may help to better understand the pathogenetic mechanisms governing PCa and provide promising therapeutic targets for metastatic PCa therapy.

<h4>Background</h4>The act of smoking has been associated with the automatic activation of approach biases towards smoking-related stimuli. However, previous research has produced mixed findings when smokers are trained to avoid such smoking-related stimuli through the application of Approach Bias Modification (ApBM). As such, this study aimed to test an improved ApBM (ApBM +), where smokers were trained to approach personalized alternative activities for smoking in the context of increased craving, in addition to training smoking-avoidance responses.<h4>Methods</h4>Sixty-seven daily smokers motivated to quit (M age = 29.27, 58.2% female) were randomly assigned to seven sessions of either ApBM + (n = 26), standard-ApBM (n = 19), or sham-ApBM (n = 22), after a brief motivational smoking intervention. Primary outcomes of approach biases for smoking and for alternative activities and secondary outcomes of smoking-related behaviors were assessed at pre-test, post-test, and 1-month follow-up.<h4>Results</h4>Overall, no group differences by condition were demonstrated in changing approach biases or smoking-related behaviors at post-test and 1-month follow-up. A trend level indication for differences in changes of smoking-approach biases between sham-ApBM and ApBM + for relatively heavy smokers was found at post-test. This was primarily driven by a significant increase in smoking-approach biases within the sham-ApBM condition and a trend decrease in smoking-approach biases within the ApBM + condition.<h4>Conclusions</h4>Our findings did not provide support for the current ApBM + concerning improved effects across the whole sample. Diverging training effects on approach biases for smoking in relatively heavy smokers warrants further research, for which we provide some suggestions.

Cell state changes are associated with proteome remodeling to serve newly emergent cell functions. Here, we show that NGN2-driven conversion of human embryonic stem cells to induced neurons (iNeurons) is associated with increased PINK1-independent mitophagic flux that is temporally correlated with metabolic reprogramming to support oxidative phosphorylation. Global multiplex proteomics during neurogenesis revealed large-scale remodeling of functional modules linked with pluripotency, mitochondrial metabolism, and proteostasis. Differentiation-dependent mitophagic flux required BNIP3L and its LC3-interacting region (LIR) motif, and BNIP3L also promoted mitophagy in dopaminergic neurons. Proteomic analysis of ATG12^-/- iNeurons revealed accumulation of endoplasmic reticulum, Golgi, and mitochondria during differentiation, indicative of widespread organelle remodeling during neurogenesis. This work reveals broad organelle remodeling of membrane-bound organelles during NGN2-driven neurogenesis via autophagy, identifies BNIP3L's central role in programmed mitophagic flux, and provides a proteomic resource for elucidating how organelle remodeling and autophagy alter the proteome during changes in cell state.

Human Vγ2Vδ2 (also termed Vγ9Vδ2) T cells play important roles in microbial and tumor immunity by monitoring foreign- and self-prenyl pyrophosphate metabolites in isoprenoid biosynthesis. Accumulation of isoprenoid metabolites after bisphosphonate treatment allows Vγ2Vδ2 T cells to recognize and kill tumors independently of their MHC expression or burden of non-synonymous mutations. Clinical trials with more than 400 patients show that adoptive immunotherapy with Vγ2Vδ2 T cells has few side effects but has resulted in only a few partial and complete remissions. Here, we have tested Vγ2Vδ2 T cells for expression of inhibitory receptors and determined whether adding PD-1 checkpoint blockade to adoptively transferred Vγ2Vδ2 T cells enhances immunity to human PC-3 prostate tumors in an NSG mouse model. We find that Vγ2Vδ2 T cells express PD-1, CTLA-4, LAG-3, and TIM-3 inhibitory receptors during the 14-day ex vivo expansion period, and PD-1, LAG-3, and TIM-3 upon subsequent stimulation by pamidronate-treated tumor cells. Expression of PD-L1 on PC-3 prostate cancer cells was increased by co-culture with activated Vγ2Vδ2 T cells. Importantly, anti-PD-1 mAb treatment enhanced Vγ2Vδ2 T cell immunity to PC-3 tumors in immunodeficient NSG mice, reducing tumor volume nearly to zero after 5 weeks. These results demonstrate that PD-1 checkpoint blockade can enhance the effectiveness of adoptive immunotherapy with human γδ T cells in treating prostate tumors in a preclinical model.

Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, is mainly characterized by chronic and progressive inflammation that damages the gastrointestinal mucosa. Increasing studies have enlightened that dysregulated cell death occurs in the inflamed sites, leading to the disruption of the intestinal barrier and aggravating inflammatory response. Ferroptosis, a newly characterized form of regulated cell death, is driven by the lethal accumulation of lipid peroxides catalyzed by cellular free iron. It has been widely documented that the fundamental features of ferroptosis, including iron deposition, GSH exhaustion, GPX4 inactivation, and lipid peroxidation, are manifested in the injured gastrointestinal tract in IBD patients. Furthermore, manipulation of the critical ferroptotic genes could alter the progression, severity, or even morbidity of the experimental colitis. Herein, we critically summarize the recent advances in the field of ferroptosis, focusing on interpreting the potential engagement of ferroptosis in the pathogenesis of IBD. Moreover, we are attempting to shed light on a perspective insight into the possibility of targeting ferroptosis as novel therapeutic designs for the clinical intervention of these gastrointestinal diseases.

Macrophages play an important role in maintaining tissue homeostasis, from regulating the inflammatory response to pathogens to resolving inflammation and aiding tissue repair. The surfactant protein A (SP-A) receptor SP-R210 (MYO18A) has been shown to affect basal and inflammatory macrophage states. Specifically, disruption of the longer splice isoform SP-R210_L/MYO18Aα renders macrophages hyper-inflammatory, although the mechanism by which this occurs is not well understood. We asked whether disruption of the L isoform led to the hyper-inflammatory state via alteration of global genomic responses. RNA sequencing analysis of L isoform-deficient macrophages (SP-R210_L(DN)) revealed basal and influenza-induced upregulation of genes associated with inflammatory pathways, such as TLR, RIG-I, NOD, and cytoplasmic DNA signaling, whereas knockout of both SP-R210 isoforms (L and S) only resulted in increased RIG-I and NOD signaling. Chromatin immunoprecipitation sequencing (ChIP-seq) analysis showed increased genome-wide deposition of the pioneer transcription factor PU.1 in SP-R210_L(DN) cells, with increased representation around genes relevant to inflammatory pathways. Additional ChIP-seq analysis of histone H3 methylation marks showed decreases in both repressive H3K9me3 and H3K27me3 marks with a commensurate increase in transcriptionally active (H3K4me3) histone marks in the L isoform deficient macrophages. Influenza A virus (IAV) infection, known to stimulate a wide array of anti-viral responses, caused a differential redistribution of PU.1 binding between proximal promoter and distal sites and decoupling from Toll-like receptor regulated gene promoters in SP-R210_L(DN) cells. These finding suggest that the inflammatory differences seen in SP-R210_L-deficient macrophages are a result of transcriptional differences that are mediated by epigenetic changes brought about by differential expression of the SP-R210 isoforms. This provides an avenue to explore how the signaling pathways downstream of the receptor and the ligands can modulate the macrophage inflammatory response.

The mammalian skeleton develops through two distinct modes of ossification: intramembranous ossification and endochondral ossification. During the process of skeletal development, SRY-box containing gene 9 (Sox9), runt-related transcription factor 2 (Runx2), and Sp7 work as master transcription factors (TFs) or transcriptional regulators, underlying cell fate specification of the two distinct populations: bone-forming osteoblasts and cartilage-forming chondrocytes. In the past two decades, core transcriptional circuits underlying skeletal development have been identified mainly through mouse genetics and biochemical approaches. Recently emerging next-generation sequencer (NGS)-based studies have provided genome-scale views on the gene regulatory landscape programmed by the master TFs/transcriptional regulators. With particular focus on Sox9, Runx2, and Sp7, this review aims to discuss the gene regulatory landscape in skeletal development, which has been identified by genome-scale data, and provide future perspectives in this field.

γδT cell receptors (γδTCRs) recognize a broad range of malignantly transformed cells in mainly a major histocompatibility complex (MHC)-independent manner, making them valuable additions to the engineered immune effector cell therapy that currently focuses primarily on αβTCRs and chimeric antigen receptors (CARs). As an exception to the rule, we have previously identified a γδTCR, which exerts antitumor reactivity against HLA-A*24:02-expressing malignant cells, however without the need for defined HLA-restricted peptides, and without exhibiting any sign of off-target toxicity in humanized HLA-A*24:02 transgenic NSG (NSG-A24:02) mouse models. This particular tumor-HLA-A*24:02-specific Vγ5Vδ1TCR required CD8αα co-receptor for its tumor reactive capacity when introduced into αβT cells engineered to express a defined γδTCR (TEG), referred to as TEG011; thus, it was only active in CD8⁺ TEG011. We subsequently explored the concept of additional redirection of CD4⁺ T cells through co-expression of the human CD8α gene into CD4⁺ and CD8⁺ TEG011 cells, later referred as TEG011_CD8α. Adoptive transfer of TEG011_CD8α cells in humanized HLA-A*24:02 transgenic NSG (NSG-A24:02) mice injected with tumor HLA-A*24:02⁺ cells showed superior tumor control in comparison to TEG011, and to mock control groups. The total percentage of mice with persisting TEG011_CD8α cells, as well as the total number of TEG011_CD8α cells per mice, was significantly improved over time, mainly due to a dominance of CD4⁺CD8⁺ double-positive TEG011_CD8α, which resulted in higher total counts of functional T cells in spleen and bone marrow. We observed that tumor clearance in the bone marrow of TEG011_CD8α-treated mice associated with better human T cell infiltration, which was not observed in the TEG011-treated group. Overall, introduction of transgenic human CD8α receptor on TEG011 improves antitumor reactivity against HLA-A*24:02⁺ tumor cells and further enhances <i>in vivo</i> tumor control.

<b>Objective:</b> The genetic markers for the detection or treatment of cervical squamous cell carcinoma (CESC) are not yet complete. This study aimed to identify the role of MSMO1 (Alternative name: SC4MOL) in the occurrence and development of CESC. <b>Methods:</b> We evaluated the significance of MSMO1 expression in CESC by using analysis of a public dataset from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. Oncomine and GEPIA2 were used to validate MSMO1 as an independent prognostic factor in CESC. Multiple tools were used to analyze the factors and functions associated with MSMO1, such as methylation, miRNA, and co-expressed genes. Furthermore, TIMER and TISIDB were used to study the relationship between MSMO1 expression and immunization in CESC. <b>Results:</b> MSMO1 was highly expressed in tumor specimens and could be used as an independent prognostic factor of CESC (<i>p</i> < 0.05). But Casiopeinas chemotherapeutics and p63 loss could reduce the expression of MSMO1. The level of methylation MSMO1 was significantly increased in tumor tissues but there was an insignificant effect on the prognosis. MSMO1 was also closely related to hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-miR-130b-3p, and gene IDI1. Specifically, the expression level of MSMO1 had a significant negative correlation with the infiltration level of CD4⁺T cells, Macrophages, Neutrophils, and DCs in CESC. In addition, GSEA identified differential enrichment in systemic lupus erythematosus, vascular smooth muscle contraction, cytokine receptor interaction, focal adhesion, chemokine signaling pathway, and Leishmania infection pathway in KEGG. <b>Conclusion:</b> Our findings provide evidence of the implications of MSMO1 in tumors, suggesting that MSMO1 is a promising prognostic biomarker in CESC.

<h4>Background</h4>Gene expression (RNA-seq) and overall survival (OS) in TCGA were combined using chromosome accessibility (ATAC-seq) to search for key molecules affecting liver cancer prognosis.<h4>Methods</h4>We used the assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) to analyse chromatin accessibility in the promoter regions of whole genes in liver hepatocellular carcinoma (LIHC) and then screened differentially expressed genes (DEGs) at the mRNA level by transcriptome sequencing technology (RNA-seq). We obtained genes significantly associated with overall survival (OS) by a one-way Cox analysis. The three were screened by taking intersection and further using a Kaplan-Meier (KM) for validation. A prognostic model was constructed using the obtained genes by LASSO regression analysis.The expression of these genes in hepatocellular carcinomas was then analysed. The protein expression of these genes was verified using the Human Protein Atlas(HPA) online datasets and immunohistochemistry.<h4>Results</h4>ATAC-seq, RNA-seq and survival analysis, combined with a LASSO prediction model, identified signatures of 15 genes (<i>PRDX6, GCLM, HTATIP2, SEMA3F, UCK2, NOL10, KIF18A, RAP2A, BOD1, GDI2, ZIC2, GTF3C6 SLC1A5, ERI3</i> and <i>SAC3D1</i>), all of which were highly expressed in hepatocellular carcinoma. The LASSO prognostic model showed that this risk score had high predictive accuracy for the survival prognosis at 1, 3 and 5 years. A KM curve analysis showed that high expression of all 15 gene signatures was significantly associated with a poor prognosis in LIHC patients. HPA analysis of protein expression showed that <i>PRDX6</i>, <i>GCLM</i>, <i>HTATIP2</i>, <i>NOL10</i>, <i>KIF18A</i>, <i>RAP2A</i> and <i>GDI2</i> were highly expressed in the hepatocellular carcinoma tissues compared with normal control tissues.<h4>Conclusions</h4>PRDX6, GCLM, HTATIP2, SEMA3F, UCK2, NOL10, KIF18A, RAP2A, BOD1, GDI2, ZIC2, GTF3C6, SLC1A5, ERI3 and SAC3D1 may affect the prognosis of LIHC.

Beyond their fundamental role in hemostasis, platelets importantly contribute to other processes aimed at maintaining homeostasis. Indeed, platelets are a natural source of growth factors and also release many other substances-such as fibronectin, vitronectin, sphingosine 1-phosphate-that are important in maintaining healthy tissues, and ensuring regeneration and repair. Despite rare thrombotic events have been documented in astronauts, some <i>in vivo</i> and <i>in vitro</i> studies demonstrate that microgravity affects platelet's number and function, thus increasing the risk of hemorrhages and contributing to retard wound healing. Here we provide an overview about events linking platelets to the impairment of wound healing in space, also considering, besides weightlessness, exposure to radiation and psychological stress. In the end we discuss the possibility of utilizing platelet rich plasma as a tool to treat skin injuries eventually occurring during space missions.

<b>Background:</b> Lung cancer is the leading cause of cancer-related death worldwide, of which lung adenocarcinoma (LUAD) is one of the main histological subtypes. Mitochondria are vital for maintaining the physiological function, and their dysfunction has been found to be correlated with tumorigenesis and disease progression. Although, some mitochondrial-related genes have been found to correlate with the clinical outcomes of multiple tumors solely. The integrated relationship between nuclear mitochondrial genes (NMGs) and the prognosis of LUAD remains unclear. <b>Methods:</b> The list of NMGs, gene expression data, and related clinical information of LUAD were downloaded from public databases. Bioinformatics methods were used and obtained 18 prognostic related NMGs to construct a risk signature. <b>Results:</b> There were 18 NMGs (<i>NDUFS2</i>, <i>ATP8A2</i>, <i>SCO1</i>, <i>COX14</i>, <i>COA6</i>, <i>RRM2B</i>, <i>TFAM</i>, <i>DARS2</i>, <i>GARS</i>, <i>YARS2</i>, <i>EFG1</i>, <i>GFM1</i>, <i>MRPL3</i>, <i>MRPL44</i>, <i>ISCU</i>, <i>CABC1</i>, <i>HSPD1</i>, and <i>ETHE1</i>) identified by LASSO regression analysis. The mRNA expression of these 18 genes was positively correlated with their relative linear copy number alteration (CNA). Meanwhile, the established risk signature could effectively distinguish high- and low-risk patients, and its predictive capacity was validated in three independent gene expression omnibus (GEO) cohorts. Notably, a significantly lower prevalence of actionable EGFR alterations was presented in patients with high-risk NMGs signature but accompanied with a more inflame immune tumor microenvironment. Additionally, multicomponent Cox regression analysis showed that the model was stable when risk score, tumor stage, and lymph node stage were considered, and the 1-, 3-, and 5-year AUC were 0.74, 0.75, and 0.70, respectively. <b>Conclusion:</b> Together, this study established a signature based on NMGs that is a prognostic biomarker for LUAD patients and has the potential to be widely applied in future clinical settings.

Resembling the development of cancer by multistep carcinogenesis, the evolution towards metastasis involves several passages, from local invasion and intravasation, encompassing surviving anoikis into the circulation, landing at distant sites and therein establishing colonization, possibly followed by the outgrowth of macroscopic lesions. Within this cascade, epithelial to mesenchymal transition (EMT) works as a pleiotropic program enabling cancer cells to overcome local, systemic, and distant barriers against diffusion by replacing traits and functions of the epithelial signature with mesenchymal-like ones. Along the transition, a full-blown mesenchymal phenotype may not be accomplished. Rather, the plasticity of the program and its dependency on heterotopic signals implies a pendulum with oscillations towards its reversal, that is mesenchymal to epithelial transition. Cells in intermixed E⇔M states can also display stemness, enabling their replication together with the epithelial reversion next to successful distant colonization. If we aim to include the EMT among the hallmarks of cancer that could modify clinical practice, the gap between the results pursued in basic research by animal models and those achieved in translational research by surrogate biomarkers needs to be filled. We review the knowledge on EMT, derived from models and mechanistic studies as well as from translational studies, with an emphasis on gastrointestinal cancers (GI).

Although dry mouth, dry eye, and swollen salivary glands are the hallmark manifestations of Sjögren's syndrome (pSS), a wide spectrum of other conditions should be considered for differential diagnosis. The diagnostic challenge is mainly encountered in patients presenting with dry eyes and/or dry mouth, who do not meet the full established classification criteria for pSS. Presented case-based review highlights the relationship between dry eye, parotid swelling, and psychiatric disorders. The obsessive-compulsive disorder may be separately be a cause of dryness symptoms even were not using any psychiatric drugs. The presented review widely discussed this problem and the aim is to shed new light on the interpretation of the dryness symptom and the necessity of individual patient assessment, excluding causes other than pSS before making a final diagnosis and making a decision on the treatment method.

Epilepsy is one of the most common neurological disorders, characterized by recurrent seizures, resulting from abnormally synchronized episodic neuronal discharges. Around 70 million people worldwide are suffering from epilepsy. The available antiepileptic medications are capable of controlling seizures in around 60-70% of patients, while the rest remain refractory. Poor seizure control is often associated with neuro-psychiatric comorbidities, mainly including memory impairment, depression, psychosis, neurodegeneration, motor impairment, neuroendocrine dysfunction, etc., resulting in poor prognosis. Effective treatment relies on early and correct detection of epileptic foci. Although there are currently a few well-established diagnostic techniques for epilepsy, they lack accuracy and cannot be applied to patients who are unsupportive or harbor metallic implants. Since a single test result from one of these techniques does not provide complete information about the epileptic foci, it is necessary to develop novel diagnostic tools. Herein, we provide a comprehensive overview of the current diagnostic tools of epilepsy, including electroencephalography (EEG) as well as structural and functional neuroimaging. We further discuss recent trends and advances in the diagnosis of epilepsy that will enable more effective diagnosis and clinical management of patients.

Ceramides are a class of sphingolipids which have recently been shown to be better cardiovascular disease (CVD) risk predictors than traditional CVD risk biomarkers. Tyrosol (TYR) is a dietary phenolic compound known to possess cardioprotective effects per se or through its in vivo active metabolite hydroxytyrosol. The purpose of this study was to evaluate the effects of the co-administration of white wine (WW) and TYR on circulating levels of ceramides and other lipids in humans at high CVD risk. Volunteers underwent a randomized controlled crossover clinical trial (4-week duration per intervention) with three different interventions: control, WW, and WW enriched with a capsule of TYR (WW + TYR). Endothelial function cardiovascular biomarkers and plasma lipidomic profile were assessed before and after each intervention. It was found that the WW + TYR intervention resulted in lower levels of three ceramide ratios, associated with an improvement of endothelial function (Cer C16:0/Cer C24:0, Cer C18:0/Cer C24:0, and Cer C24:1/Cer C24:0), when compared to the control intervention. Moreover, WW + TYR was able to minimize the alterations in plasma diacylglycerols concentrations observed following WW. Overall, the results obtained show that the antioxidant TYR administered with WW exerts beneficial effects at the cardiovascular level, in part by modulating blood lipid profile.

Meniere Disease (MD) is a multifactorial disorder of the inner ear characterized by vertigo attacks associated with sensorineural hearing loss and tinnitus with a significant heritability. Although MD has been associated with several genes, no epigenetic studies have been performed on MD. Here we performed whole-genome bisulfite sequencing in 14 MD patients and six healthy controls, with the aim of identifying an MD methylation signature and potential disease mechanisms. We observed a high number of differentially methylated CpGs (DMC) when comparing MD patients to controls (<i>n</i>= 9545), several of them in hearing loss genes, such as <i>PCDH15,</i>&nbsp;<i>ADGRV1</i> and <i>CDH23</i>. Bioinformatic analyses of DMCs and cis-regulatory regions predicted phenotypes related to abnormal excitatory postsynaptic currents, abnormal NMDA-mediated receptor currents and abnormal glutamate-mediated receptor currents when comparing MD to controls. Moreover, we identified various DMCs in genes previously associated with cochleovestibular phenotypes in mice. We have also found 12 undermethylated regions (UMR) that were exclusive to MD, including two UMR in an inter CpG island in the <i>PHB</i> gene. We suggest that the DNA methylation signature allows distinguishing between MD patients and controls. The enrichment analysis confirms previous findings of a chronic inflammatory process underlying MD.

Bovine viral diarrhea virus's (BVDV) entry into bovine cells involves attachment of virions to cellular receptors, internalization, and pH-dependent fusion with endosomal membranes. The primary host receptor for BVDV is CD46; however, the complete set of host factors required for virus entry is unknown. The Madin-Darby bovine kidney (MDBK) cell line is susceptible to BVDV infection, while a derivative cell line (CRIB) is resistant at the level of virus entry. We performed complete genome sequencing of each to identify genomic variation underlying the resistant phenotype with the aim of identifying host factors essential for BVDV entry. Three large compound deletions in the BVDV-resistant CRIB cell line were identified and predicted to disrupt the function or expression of the genes <i>PTPN12</i>, <i>GRID2</i>, and <i>RABGAP1L</i>. However, CRISPR/Cas9 mediated knockout of these genes, individually or in combination, in the parental MDBK cell line did not impact virus entry or replication. Therefore, resistance to BVDV in the CRIB cell line is not due to the apparent spontaneous loss of <i>PTPN12</i>, <i>GRID2</i>, or <i>RABGAP1L</i> gene function. Identifying the functional cause of BVDV resistance in the CRIB cell line may require more detailed comparisons of the genomes and epigenomes.

Obese Asians are more susceptible to metabolic diseases than obese Caucasians of the same body mass index (BMI). We hypothesized that the genetic variants associated with obesity risk interact with the lifestyles of middle-aged and elderly adults, possibly allowing the development of personalized interventions based on genotype. We aimed to examine this hypothesis in a large city hospital-based cohort in Korea. The participants with cancers, thyroid diseases, chronic kidney disease, or brain-related diseases were excluded. The participants were divided into case and control according to their BMI: ≥25 kg/m² (case; <i>n</i> = 17,545) and <25 kg/m² (control; <i>n</i> = 36,283). The genetic variants that affected obesity risk were selected using a genome-wide association study, and the genetic variants that interacted with each other were identified by generalized multifactor dimensionality reduction analysis. The selected genetic variants were confirmed in the Ansan/Ansung cohort, and polygenetic risk scores (PRS)-nutrient interactions for obesity risk were determined. A high BMI was associated with a high-fat mass (odds ratio (OR) = 20.71) and a high skeletal muscle-mass index (OR = 3.38). A high BMI was positively related to metabolic syndrome and its components, including lipid profiles, whereas the initial menstruation age was inversely associated with a high BMI (OR = 0.78). The best model with 5-SNPs included <i>SEC16B</i>_rs543874, <i>DNAJC27</i>_rs713586, <i>BDNF</i>_rs6265, <i>MC4R</i>_rs6567160, and <i>GIPR</i>_rs1444988703. The high PRS with the 5-SNP model was positively associated with an obesity risk of 1.629 (1.475-1.798) after adjusting for the covariates. The 5-SNP model interacted with the initial menstruation age, fried foods, and plant-based diet for BMI risk. The participants with a high PRS also had a higher obesity risk when combined with early menarche, low plant-based diet, and a high fried-food intake than in participants with late menarche, high plant-based diet, and low fried-food intake. In conclusion, people with a high PRS and earlier menarche age are recommended to consume fewer fried foods and a more plant-based diet to decrease obesity risk. This result can be applied to personalized nutrition for preventing obesity.

Synovial hyperplasia is the main cause of chronic rheumatoid arthritis (RA), but the mechanism of synovial hyperplasia is still unclear. Etodolac (ETD) is a selective COX-2 inhibitor for relieving pain and stiffness in RA, but the disease modifying effect is still lack of evidence. Proteomics method was used to study the differential proteome of synovial tissue in collagen induced arthritis (CIA) in rats. With the help of STRING analysis, the upregulated proteins enriched in the cluster of complement and coagulation cascades and platelet degranulation were highlighted, these proteins with fibrogenic factors Lum, CIV, CXI and Tgfbi participated in the synovial inflammation, fibrosis and hyperplasia in CIA. Based on KOG function class analysis, the proteins involved in the events of the central dogma was explored. They might be hyperplasia related proteins for most of them are related to the proliferation of cancer. ETD significantly attenuated synovial inflammation, fibrosis and hyperplasia in CIA rats by downregulating these proteins. Several proteins have not been observed in RA so far, such as Tmsb4x, Pura, Nfic, Ruvbl1, Snrpd3, U2af2, Srrm2, Srsf7, Elavl1, Hnrnph1, Wars, Yars, Bzw2, Mcts1, Eif4b, Ctsh, Lamp1, Dpp7, Ptges3, Cdc37 and Septin9, they might be potentials targets for RA. Blood biochemistry tests showed the safety of 7 months use of ETD on rats. In conclusion, present study displayed a comprehensive mechanism of synovial hyperplasia in CIA rats, on this basis, the clinical value of ETD in the treatment of RA was well confirmed.

The study is aimed to investigate the protective effect and potential mechanisms of sodium butyrate (NaBT) on soyasaponins (SA) induced intestinal epithelial cells (IECs) injury <i>in vitro</i>. The primary IECs of turbot were developed and treated with 0.4, 1 and 4 mM NaBT in the presence of 0.4 mg/mL SA for 6 h to explore the protective effects of NaBT. The results showed that the addition of NaBT significantly down-regulated gene expression of inflammatory cytokine TNF-α, IL-1β and IL-8, pro-apoptosis relevant gene BAX, caspase-3, caspase-7 and caspase-9 induced by SA, while up-regulated anti-apoptosis gene Bcl-2. SA stimulation did not induce reactive oxygen species production, but elevated gene expression of antioxidant enzyme heme oxygenase-1 and superoxide dismutase. Moreover, the gene expression of those antioxidant enzyme was further up-regulated in NaBT groups. Furthermore, NaBT supplementation decreased the acid phosphatase and alkaline phosphatase activities and suppressed phosphorylation of p38 and c-Jun N-terminal kinase (JNK). In conclusion, NaBT could mitigate SA-induced inflammation and apoptosis and elevate gene expression of antioxidant enzymes on IECs of turbot and p38 and JNK signaling pathway participated in those processes.

<title>Abstract</title> <p>Human Phosphatidylethanolamine Binding Protein 1 (hPEBP1) is a novel target affecting numerous cellular signaling pathways involving in the formation of metastases. It can be used in the treatment of many cases of cancer. For these reasons, the Pharmaceutical Companies use computational approaches, including Multi-QSAR (2D, 3D, and Hologram QSAR) analysis, Homology modeling and molecular docking analysis and molecular dynamic simulations to accelerate the drug discovery process. In this paper, QSAR modeling was conducted using two quantum chemistry optimization methods (AM1 and DFT levels). As per PLS results, we found that DFT (B3LYP(d, p)) method present high predictability according to 2D-QSAR, CoMFA, CoMSIA, and Hologram QSAR studies, with Q² of 0.81, 0.67, 0.79 and 0.67 respectively, and external power with R²_predof 0.78, 0.58, 0.66 and 0.56, respectively. This results has been validated by CoMFA/CoMSIA graphics, which suggests that electrostatic fields combined with hydrogen bond donor/acceptor fields are beneficial to the antiproliferative activity. While the Hologram QSAR models show the contributions of each fragment in improving the activity. The results from QSAR analyses revealed that Ursolic Acids with heterocyclic ring could improve the activities. However, Ramachandran plot validated the modeled PEBP1 protein. Whereas, molecular docking and MDs simulations revealed that the hydrophobic and hydrogen bond interactions are dominant in the PEBP1's pocket. These results, were used to predict the structures of three new compounds with high anticancer activity<italic> In Silico</italic>, Similarly, molecular docking stability studies and molecular dynamics simulations were conducted.</p>

Understanding the relative importance of soil microbial diversity, plants and nutrient management is crucial to implement an effective bioremediation approach to xenobiotics-contaminated soils. To date, knowledge on the interactive effects of soil microbiome, plant and nutrient supply on influencing biodegradation potential of soils remains limited. In this study, we evaluated the individual and interactive effects of soil initial bacterial diversity, nutrient amendments (organic and inorganic) and plant presence on the biodegradation rate of pyrene, a polycyclic aromatic hydrocarbon. Initial bacterial diversity had a strong positive impact on soil biodegradation potential, with soil harbouring higher bacterial diversity showing ~ 2 times higher degradation rates than soils with lower bacterial diversity. Both organic and inorganic nutrient amendments consistently improved the degradation rate in lower diversity soils and had negative (inorganic) to neutral (organic) effect in higher diversity soils. Interestingly, plant presence/type did not show any significant effect on the degradation rate in most of the treatments. Structural equation modelling demonstrated that initial bacterial diversity had a prominent role in driving pyrene biodegradation rates. We provide novel evidence that suggests that soil initial microbial diversity, and nutrient amendments should be explicitly considered in the design and employment of bioremediation management strategies for restoring natural habitats disturbed by organic pollutants.

<h4>Background</h4>Studies have shown that human polyomavirus infection may be associated with various human cancers. We investigated the potential relationship between the prevalence of JCPyVor BKPyV and prostate cancer (PC) in patients from Taiwan.<h4>Methods</h4>Patients with PC and benign prostate hypertrophy (BPH; 76 and 30 patients, respectively) were recruited for this study. Paraffin-embedded tissues and clinical information of the patients were obtained. The tissue sections were used for viral DNA detection and immunohistochemistry analysis was performed for examining viral large T (LT) and VP1 proteins. Regression analysis was used to evaluate the relationship between the clinical characteristics of the patients and the risk of JCPyV/BKPyV infection.<h4>Results</h4>The prevalence of JCPyV/BKPyV DNA was different in PC and BPH tissues (27/76 [35.52%] and 2/30 [6.7%], respectively, p = 0.003)]. The LT and VP1 proteins were detected in 27 (35.52%) and 29 PC (38.2%) specimens, respectively, but neither protein was detected in BPH samples (p < 0.001). PC cells were more susceptible to JCPyV infection than BPH tissues [odds ratio (OR) 7.71, 95% CI: 1.71-34.09, p = 0.003). Patients with PC showing high levels of prostate-specific antigen and high Gleason scores were associated with a high risk of viral infection (ORs 1.1, 95% CI 1.000-1.003; p = 0.045 and ORs 6.18, 95% CI 1.26-30.33, p = 0.025, respectively). The expression of LT protein associated with the risk of PC increased 2923.39-fold (95% CI 51.19-166,963.62, p < 0.001).<h4>Conclusions</h4>The findings indicate that JCPyV infection in PC cells may be associated with prostate cancer progression and prognosis.

<h4>Purpose</h4>The transcription factor Fra-2 affects the invasive potential of breast cancer cells by dysregulating adhesion molecules in vitro. Previous results suggested that it upregulates the expression of E- and P-selectin ligands. Such selectin ligands are important members of the leukocyte adhesion cascade, which govern the adhesion and transmigration of cancer cells into the stroma of the host organ of metastasis. As so far, no in vivo data are available, this study was designed to elucidate the role of Fra-2 expression in a spontaneous breast cancer metastasis xenograft model.<h4>Methods</h4>The effect of Fra-2 overexpression in two stable Fra-2 overexpressing clones of the human breast cancer cell line MDA MB231 on survival and metastatic load was studied after subcutaneous injection into scid and E- and P-selectin-deficient scid mice.<h4>Results</h4>Fra-2 overexpression leads to a significantly shorter overall survival and a higher amount of spontaneous lung metastases not only in scid mice, but also in E- and P-deficient mice, indicating that it regulates not only selectin ligands, but also selectin-independent adhesion processes.<h4>Conclusion</h4>Thus, Fra-2 expression influences the metastatic potential of breast cancer cells by changing the expression of adhesion molecules, resulting in increased adherence to endothelial cells in a breast cancer xenograft model.

Neurovascular disorders, which involve the vascular and nervous systems, are common. Research on such disorders usually focuses on either vascular or nervous components, without looking at how they interact. Adopting a neurovascular perspective is essential to improve current treatments. Therefore, comparing molecular processes known to be involved in both systems separately can provide insight into promising areas of future research. Since development and regeneration share many mechanisms, comparing signaling molecules involved in both the developing vascular and nervous systems and shedding light to those that they have in common can reveal processes, which have not yet been studied from a regenerative perspective, yet hold great potential. Hence, this review discusses and compares processes involved in the development of the vascular and nervous systems, in order to provide an overview of the molecular mechanisms, which are most promising with regards to treatment for neurovascular disorders. Vascular endothelial growth factor, semaphorins, and ephrins are found to hold the most potential, while fibroblast growth factor, bone morphogenic protein, slits, and sonic hedgehog are shown to participate in both the developing vascular and nervous systems, yet have not been studied at the neurovascular level, therefore being of special interest for future research.

Recently, viral infectious diseases, including COVID-19 and Influenza, are the subjects of major concerns worldwide. One strategy for addressing these concerns focuses on nasal vaccines, which have great potential for achieving successful immunization via safe, easy, and affordable approaches. However, conventional nasal vaccines have major limitations resulting from fast removal when pass through nasal mucosa and mucociliary clearance hindering their effectiveness. Herein a nanoparticulate vaccine (NanoVac) exhibiting photochemical immunomodulation and constituting a new self-assembled immunization system of a photoactivatable polymeric adjuvant with influenza virus hemagglutinin for efficient nasal delivery and antigen-specific immunity against pathogenic influenza viruses is described. NanoVac increases the residence period of antigens and further enhances by spatiotemporal photochemical modulation in the nasal cavity. As a consequence, photochemical immunomodulation of NanoVacs successfully induces humoral and cellular immune responses followed by stimulation of mature dendritic cells, plasma cells, memory B cells, and CD4⁺ and CD8⁺ T cells, resulting in secretion of antigen-specific immunoglobulins, cytokines, and CD8⁺ T cells. Notably, challenge with influenza virus after nasal immunization with NanoVacs demonstrates robust prevention of viral infection. Thus, this newly designed vaccine system can serve as a promising strategy for developing vaccines that are active against current hazardous pathogen outbreaks and pandemics.

The use of agents to inhibit the production of reactive oxygen species (ROS) has been proposed for the treatment of Acute Lung Injury (ALI). However, this approach also inhibits the bactericidal activity of polymorphonuclear leucocytes (PMN) and other cells, raising the possibility of aggravating lung injury in ALI associated with bacterial infection. We used the cecal ligation and puncture (CLP) model of ALI associated with sepsis to investigate the effect of inhibiting NADPH oxidase 2 (NOX2)-derived ROS production, the main source of ROS in lungs. A phospholipase A₂ inhibitor called peroxiredoxin 6 inhibitory peptide-2 (PIP-2) was used to inhibit NOX2 activation; the peptide prevents liberation of Rac, a necessary NOX2 co-factor. At 18 h after intravenous treatment with 2 µg PIP-2 /gram body weight (wt), the number of colony-forming bacteria in lungs and peritoneal fluid of mice with CLP was approximately doubled as compared to untreated mice. Treatment with 10 µg PIP-2/g body wt resulted in 100% mortality within 18 h. Antibiotic treatment abolished both the increase in lung bacteria with low dose PIP-2 and the increased mortality with high dose PIP-2. Treatment with PIP-2 plus antibiotics resulted in significantly improved lung histology, decreased PMN infiltration, decreased lung fluid accumulation, and decreased oxidative lung injury compared to antibiotics alone. We conclude that the administration of PIP-2 provides partial protection against lung injury in a model of ALI due to bacterial infection, while concurrent antibiotic treatment abolishes the deleterious effects of PIP-2 on lung bacterial clearance. These results suggest that addition of PIP-2 to the antibiotic regimen is beneficial for treatment of ALI associated with bacterial infection.

Mushrooms supplementation with iron (Fe) is usually limited, and therefore it would be beneficial to search for other vital elements able to improve the process. The aim of this study was to verify a possible interaction between Fe and calcium (Ca) to estimate the role of the addition of the latter metal to stimulate Fe accumulation in <i>Pholiota nameko</i>. Additionally, an analysis of phenolic compounds and low molecular weight organic acids (LMWOAs) was performed. The increase of Fe concentration in the substrate caused a significantly higher accumulation of this metal in <i>P. nameko</i>. The addition of Ca (5 or 10 mM) stimulated Fe accumulation, just as Fe concentration in the substrate stimulated Ca accumulation, which pointed to a synergism between these metals. The obtained results show that the presence of Fe in the substrate may also promote K, Mg, Mn, Na, P, and S accumulation. In contrast, the addition of Ca stimulates and/or inhibits their content in fruit bodies. The phenolic and organic acids profile was poor. Only gallic, 4-hydroxybenzoic, sinapic and syringic acids (phenolics), as well as citric and succinic acids (LMWOAs), were quantified in some combinations in <i>P. nameko</i> fruiting bodies.

Elastography has emerged as a preferred non-invasive imaging technique for the clinical assessment of liver fibrosis. Elastography methods provide liver stiffness measurement (LSM) as a surrogate quantitative biomarker for fibrosis burden in chronic liver disease (CLD). Elastography can be performed either with ultrasound or MRI. Currently available ultrasound-based methods include strain elastography, two-dimensional shear wave elastography (2D-SWE), point shear wave elastography (pSWE), and vibration-controlled transient elastography (VCTE). MR Elastography (MRE) is widely available as two-dimensional gradient echo MRE (2D-GRE-MRE) technique. US-based methods provide estimated Young's modulus (eYM) and MRE provides magnitude of the complex shear modulus. MRE and ultrasound methods have proven to be accurate methods for detection of advanced liver fibrosis and cirrhosis. Other clinical applications of elastography include liver decompensation prediction, and differentiation of non-alcoholic steatohepatitis (NASH) from simple steatosis (SS). In this review, we briefly describe the different elastography methods, discuss current clinical applications, and provide an overview of advances in the field of liver elastography.

Protein homeostasis, or proteostasis, is essential for cell function and viability. Unwanted, damaged, misfolded and aggregated proteins are degraded by the ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway. Growing evidence indicates that alterations in these major proteolytic mechanisms lead to a demise in proteostasis, contributing to the onset and development of distinct diseases. Indeed, dysregulation of the UPS or autophagy is linked to several neurodegenerative, infectious and inflammatory disorders as well as cancer. Thus, modulation of protein clearance pathways is a promising approach for therapeutics. In this review, we discuss recent findings and open questions on how targeting proteolytic mechanisms could be applied for disease intervention.

<h4>Background & aims</h4>Tumor necrosis factor alpha (TNFα) is considered a major tissue damage-promoting effector in Crohn's disease (CD) pathogenesis. Patient-derived intestinal organoid (enteroid) recapitulates the disease-specific characteristics of the intestinal epithelium. This study aimed to evaluate the intestinal epithelial responses to TNFα in enteroids derived from healthy controls and compare them with those of CD patient-derived enteroids.<h4>Methods</h4>Human enteroids derived from patients with CD and controls were treated with TNFα (30 ng/mL), and cell viability and gene expression patterns were evaluated.<h4>Results</h4>TNFα induced MLKL-mediated necroptotic cell death, which was more pronounced in CD patient-derived enteroids than in control enteroids. Immunohistochemistry and RNA sequencing revealed that treatment with TNFα caused expansion of the intestinal stem cell (ISC) populations. However, expanded ISC subpopulations differed in control and CD patient-derived enteroids, with LGR5+ active ISCs in control enteroids and reserve ISCs, such as BMI1+ cells, in CD patient-derived enteroids. In single-cell RNA sequencing, LGR5+ ISC-enriched cell cluster showed strong expression of TNFRSF1B (TNFR2) and cyclooxygenase-prostaglandin E2 (PGE2) activation. In TNFα-treated CD patient-derived enteroids, exogenous PGE2 (10 nmol/L) induced the expansion of the LGR5+ ISC population and improved organoid-forming efficiency, viability, and wound healing.<h4>Conclusions</h4>TNFα increases necroptosis of differentiated cells and induces the expansion of LGR5+ ISCs. In CD patient-derived enteroids, TNFα causes LGR5+ stem cell dysfunction (expansion failure), and exogenous PGE2 treatment restored the functions of LGR5+ stem cells. Therefore, PGE2 can be used to promote mucosal healing in patients with CD.

Differentiation of multi-potent mesenchymal stromal cells (MSCs) is directed by the activities of lineage-specific transcription factors and co-factors. A subset of these proteins controls the accessibility of chromatin by recruiting histone acetyl transferases or deacetylases that regulate acetylation of the N-termini of H3 and H4 histone proteins. Bromodomain (BRD) proteins recognize these acetylation marks and recruit the RNA pol II containing transcriptional machinery. Our previous studies have shown that Brd4 is required for osteoblast differentiation in vitro. Here, we investigated the role of Brd4 on endochondral ossification in C57BL/6 mice and chondrogenic differentiation in cell culture models. Conditional loss of Brd4 in the mesenchyme (Brd4 cKO, Brd4^fl/fl: Prrx1-Cre) yields smaller mice that exhibit alteration in endochondral ossification. Importantly, abnormal growth plate morphology and delayed long bone formation is observed in juvenile Brd4 cKO mice. One week old Brd4 cKO mice have reduced proliferative and hypertrophic zones within the physis and exhibit a delay in the formation of the secondary ossification center. At the cellular level, Brd4 function is required for chondrogenic differentiation and maturation of both ATDC5 cells and immature mouse articular chondrocytes. Mechanistically, Brd4 loss suppresses Sox9 levels and reduces expression of Sox9 and Runx2 responsive endochondral genes (e.g., Col2a1, Acan, Mmp13 and Sp7/Osx). Collectively, our results indicate that Brd4 is a key epigenetic regulator required for normal chondrogenesis and endochondral ossification.

<h4>Objectives</h4>The postoperative outcomes of patients with oral cavity squamous cell carcinoma (OCSCC) vary greatly. To improve risk stratification, we sought to identify genetic biosignatures by whole-exome sequencing (WES).<h4>Materials and methods</h4>We retrieved patients with OCSCC patients with paired freshly frozen malignant and non-malignant tissue specimens and performed WES by Illumina HiSeq4000 platform. We further applied a tree-based method to analyze copy number variations and obtain signature classification and driver-gene identification. We further confirmed the prognostic impact of the WES biosignature in an external independent validation set.<h4>Results</h4>We examined 168 paired samples from patients with surgically treated OCSCC. Similar to the literature, the most commonly mutated genes were TP53 (66%), FAT1 (32%), and NOTCH1 (24%). The signatures 13 (APOBEC Cytidine deaminase [C > G]), 1 (spontaneous deamination of 5-methylcytosine), and 7 (UV exposure) showed the highest concordance rates. Using the MutSigCV, MuSiC, 20/20+, OncodriveFML, e-Driver, OncodriveCLUST, and tree-based methods, we identified a nine-gene OCSCC panel (RYR1, HLA-B, TSHZ2, PCDH17, DNAH17, GRID1, SBNO2, KSR2, and GCN1L1) predicting survival outcomes in our sample. We used the TCGA database to validate the prognostic value of the panel independently. Furthermore, gene-gene covariance analysis confirmed the coexistence of several gene alterations.<h4>Conclusion</h4>We identified and independently validated a WES biosignature that predicts outcomes in surgically treated OCSCC in Taiwan, a betel-quid-chewing-prevent area. We proposed that the panel might help clinical trial designation for adjuvant therapy based on the risk stratification from the novel gene panel and identify targets for liquid biopsy monitoring during surveillance.

<h4>Purpose</h4>Epstein-Barr virus (EBV) is widely recognised to cause various tumours, and EBV-associated gastric carcinoma (EBVaGC) is a special type of GC. It has obviously different clinical features and pathological manifestations from EBV-negative gastric carcinoma, but its progression remains elusive. The underlying cancer progression of viral infection detected by genome-wide transcriptome analysis has been demonstrated in numerous diseases.<h4>Methods</h4>We performed comparative RNA sequencing to identify gene expression signatures between GC and EBVaGC cell lines. The differentially expressed (DE) genes were analysed using gene ontology and pathway enrichment.<h4>Results</h4>A total of 4438 DE mRNAs, 3650 DE long non-coding RNAs (lncRNAs), and 248 DE circular RNAs (circRNAs) were detected in GC cells after EBV infection, most of which were highly related to oncogenesis. Likewise, EBV-coding RNA and non-coding RNA were also well-supplemented in EBVaGC. According to bioinformatics, DE mRNAs may contribute to the completion of EBV-infected host cells and modulate mitosis. Binding to actin and participating in adherens junctions to promote contact between the virus and cells are a potential function of DE lncRNAs. The roles of DE circRNAs were enriched in DNA repair and protein modification, and a typical example of this is acting as an miRNA sponge. The establishment of a circRNA-miRNA-mRNA network helps to determine the key elements in the progression of EBVaGC.<h4>Conclusion</h4>This study is the first to systematically reveal the transcriptome landscape of EBVaGC, which will provide an essential resource for genomic, genetic, and molecular mechanisms in the future.

Cellular adhesive connections directed by the extracellular matrix (ECM) and maintenance of cellular homeostasis by autophagy are seemingly disparate functions that are molecularly intertwined, each regulating the other. This is an emerging field in the brain where the interplay between adhesion and autophagy functions at the intersection of neuroprotection and neurodegeneration. The ECM and adhesion proteins regulate autophagic responses to direct protein clearance and guide regenerative programs that go awry in brain disorders. Concomitantly, autophagic flux acts to regulate adhesion dynamics to mediate neurite outgrowth and synaptic plasticity with functional disruption contributed by neurodegenerative disease. This review highlights the cooperative exchange between cellular adhesion and autophagy in the brain during health and disease. As the mechanistic alliance between adhesion and autophagy has been leveraged therapeutically for metastatic disease, understanding overlapping molecular functions that direct the interplay between adhesion and autophagy might uncover therapeutic strategies to correct or compensate for neurodegeneration.

The Covid-19 pandemic has spread rapidly across the globe, resulting in more than 3 million deaths worldwide. The symptoms of Covid-19 are usually mild and non-specific, however in some cases patients may develop acute respiratory distress syndrome (ARDS) and systemic inflammation. Individuals with inflammatory or immunocompromising illnesses, such as cancer, are more susceptible to develop ARDS and have higher rates of mortality. This is mediated through an initial hyperstimulated immune response which results in elevated levels of pro-inflammatory cytokines and a subsequent cytokine storm. This potentiates positive feedback loops which are unable to be balanced by anti-inflammatory mediators. Therefore, elevated levels of IL-1β, as a result of NLRP3 inflammasome activation, as well as IL-6 and TNF-α amongst many others, contribute to the progression of various cancer types. Furthermore, Covid-19 progression is associated with the depletion of CD8⁺ and CD4⁺ T cells, B cell and natural killer cell numbers. Collectively, a Covid-19-dependent pro-inflammatory profile and immune suppression promotes the optimal microenvironment for tumourigenesis, initiation and immune evasion of malignant cells, tumour progression and metastasis as well as cancer recurrence. There are, however, therapeutic windows of opportunity that may combat both Covid-19 and cancer to improve patient outcomes.

Ionic liquids are gaining high attention due to their extremely unique physiochemical properties and are being utilized in numerous applications in the field of electrochemistry and bio-nanotechnology. The excellent ionic conductivity and the wide electrochemical window open a new avenue in the construction of electrochemical devices. On the other hand, carbon nanomaterials, such as graphene (GR), graphene oxide (GO), carbon dots (CDs), and carbon nanotubes (CNTs), are highly utilized in electrochemical applications. Since they have a large surface area, high conductivity, stability, and functionality, they are promising in biosensor applications. Nevertheless, the combination of ionic liquids (ILs) and carbon nanomaterials (CNMs) results in the functional ILs-CNMs hybrid nanocomposites with considerably improved surface chemistry and electrochemical properties. Moreover, the high functionality and biocompatibility of ILs favor the high loading of biomolecules on the electrode surface. They extremely enhance the sensitivity of the biosensor that reaches the ability of ultra-low detection limit. This review aims to provide the studies of the synthesis, properties, and bonding of functional ILs-CNMs. Further, their electrochemical sensors and biosensor applications for the detection of numerous analytes are also discussed.

Turner syndrome is a rare disorder resulting from complete or partial loss of the second sex chromosome. Common manifestations include delayed growth, premature ovarian failure, congenital heart defects, endocrine disorders, lymphedema, and webbed neck. People with Turner syndrome have significantly increased mortality risk primarily due to cardiovascular abnormalities. The mechanisms that lead to these defects are not completely understood and are obscured by the significant variability of both karyotype and phenotype without consistent correlation between the two. This paper presents a review of the recent literature surrounding the symptoms, mechanisms, diagnosis, and treatment of Turner syndrome with a focus on cardiovascular manifestations. With technological advancements in genetics, the molecular processes of Turner syndrome have begun to be dissected. Certain genes on the X chromosome that typically escape inactivation have been implicated in both specific manifestations and broader risk categories. Recently identified genome-wide epigenetic changes may help explain the variability in presentation. It remains unclear as to how the combination of these factors results in the overall clinical picture, but advances in genomic, genetic, epigenetic, and -omics technology hold promise for providing insights that will improve the medical management of individuals with Turner syndrome.

<b>Abstract</b>: Background Growing evidences have showed that mucins (MUCs) are linked to occurrence and progression of human cancers. However, a comprehensive study regarding the expression, diagnosis, prognosis and mechanism of MUCs in breast cancer remains absent. <b>Methods:</b> A series of in silico analyses were employed in this study. <b>Results:</b> After performing comprehensive analysis for MUCs, MUC14 was identified as the most potential regulator in breast cancer, with downregulated expression in both mRNA and protein levels and significant diagnostic and prognostic values in breast cancer. Mechanistic exploration revealed that a potential ncRNA-mRNA axis, involving LINC01128/LINC01140/SGMS1-AS1/LINC00667-miR-137/miR-429-BCL2, might be partially responsible for MUC14's functions in breast cancer. <b>Conclusions:</b> Collectively, our study elucidated a key role of MUC14 in breast cancer and also provided some clues for explanation of the molecular action mechanism of MUC14 in breast cancer.

In the wake of the coronavirus disease 2019 (COVID-19) pandemic, global pharmaceutical companies have developed vaccines for the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Some have adopted lipid nanoparticles (LNPs) or viral vectors to deliver the genes associated with the spike protein of SARS-CoV-2 for vaccination. This strategy of vaccination by delivering genes to express viral proteins has been successfully applied to the mRNA vaccines for COVID-19, and is also applicable to gene therapy. However, conventional transfection agents such as LNPs and viral vectors are not yet sufficient to satisfy the levels of safety, stability, and efficiency required for the clinical applications of gene therapy. In this study, we synthesized N-doped graphene quantum dots (NGQDs) for the transfection of various genes, including messenger ribonucleic acids (mRNAs) and plasmid deoxyribonucleic acids (pDNAs). The positively charged NGQDs successfully formed electrostatic complexes with negatively charged mRNAs and pDNAs, and resulted in the efficient delivery and transfection of the genes into target cells. The transfection efficiency of NGQDs is found to be comparable to that of commercially available LNPs. Considering their outstanding stability even at room temperature as well as their low toxicity, NGQDs are expected to be novel universal gene delivery platforms that can outperform LNPs and viral vectors.

DNA methylation (DNAm) is vulnerable to dysregulation by environmental exposures during epigenetic reprogramming that occurs in embryogenesis. Sexual dimorphism in environmentally induced DNAm dysregulation has been identified and therefore it is important to understand sex-specific DNAm patterns. DNAm at several autosomal sites has been consistently associated with sex in cord blood and placental foetal tissues. However, there is limited research comparing sex-specific DNAm across tissues, particularly differentially methylated regions (DMRs). This study leverages DNAm data measured using the Illumina HumanMethylation450 BeadChip in cord blood (N = 179), placenta (N = 229), and umbilical artery samples (N = 229) in the PRogramming of Intergenerational Stress Mechanisms (PRISM) cohort to identify autosomal DMRs and differentially methylated positions (DMPs). A replication analyses was conducted in an independent cohort (GEO Accession GSE129841). We identified 183, 257, and 419 DMRs and 2119, 2281, and 3405 DMPs (<i>p_Bonferroni</i> < 0.05) in cord blood, placenta, and artery samples, respectively. Thirty-nine DMRs overlapped in all three tissues, overlapping with genes involved in spermatogenesis (<i>NKAPL, PIWIL2 and AURKC</i>) and X-inactivation (<i>LRIF1</i>). In replication analysis, 85% of DMRs overlapped with those identified in PRISM. Overall, DMRs and DMPs had higher methylation levels among females in cord blood and artery samples, but higher methylation levels among males in placenta samples. Further research is necessary to understand biological mechanisms that contribute to differences in sex-specific DNAm signatures across tissues, as well as to determine if sexual dimorphism in the epigenome impacts response to environmental stressors.

Therapeutic perspectives of bone tumors such as osteosarcoma remain restricted due to the inefficacy of current treatments. We propose here the construction of a novel anticancer squalene-based nanomedicine with bone affinity and retention capacity. A squalenyl-hydroxybisphosphonate molecule was synthetized by chemical conjugation of a 1-hydroxyl-1,1-bisphosphonate moiety to the squalene chain. This amphiphilic compound was inserted onto squalenoyl-gemcitabine nanoparticles using the nanoprecipitation method. The co-assembly led to nanoconstructs of 75 nm, with different morphology and colloidal properties. The presence of squalenyl-hydroxybisphosphonate enhanced the nanoparticles binding affinity for hydroxyapatite, a mineral present in the bone. Moreover, the in vitro anticancer activity was preserved when tested in commercial and patient-treated derived pediatric osteosarcoma cells. Further in vivo studies will shed light on the potential of these nanomedicines for the treatment of bone sarcomas.

Long non‑coding RNAs (lncRNAs) fulfill important roles in the majority of cellular processes. Previous studies have demonstrated that lncRNAs are involved in the pathogenesis of various diseases, including cancer. However, to date, the functions of only a small number of the known lncRNAs have been well‑documented. lncRNAs comprise a class of multifunctional non‑coding transcripts that are able to interact with different types of biomolecules. Interactions between lncRNAs and RNA‑binding proteins (RBPs) provide an important mechanism through which lncRNAs exert their regulatory functions, mainly through findings on 'generalized RBPs'. Regulatory effects on lncRNAs mediated by RBPs have also been explored. Taking account of the research that has been completed to date, the continued and in‑depth study of the bidirectional interactions between lncRNAs and RBPs will prove to be of major importance for understanding the pathogenesis of cancer and for developing effective therapies. The present review aims to explore the interactions between lncRNAs and RBPs that have been investigated in cancer, taking into consideration several different aspects, including the regulation of expression, subcellular localization and the mediation of diverse functions.

Hibernating mammals undergo a dramatic drop in temperature and blood flow during torpor, yet avoid stasis blood clotting through mechanisms that remain unspecified. The effects of hibernation on hemostasis are especially complex, as cold temperatures generally activate platelets, resulting in platelet clearance and cold storage lesions in the context of blood transfusion. With a hibernating body temperature of 4°C-8°C, 13-lined ground squirrels (<i>Ictidomys tridecemlineatus</i>) provide a model to study hemostasis as well as platelet cold storage lesion resistance during hibernation. Here, we quantified and systematically compared proteomes of platelets collected from ground squirrels at summer (active), fall (entrance), and winter (topor) to elucidate how molecular-level changes in platelets may support hemostatic adaptations in torpor. Platelets were isolated from a total of 11 squirrels in June, October, and January. Platelet lysates from each animal were digested with trypsin prior to 11-plex tandem mass tag (TMT) labeling, followed by LC-MS/MS analysis for relative protein quantification. We measured >700 proteins with significant variations in abundance in platelets over the course of entrance, torpor, and activity-including systems of proteins regulating translation, secretion, metabolism, complement, and coagulation cascades. We also noted species-specific differences in levels of hemostatic, secretory, and inflammatory regulators in ground squirrel platelets relative to human platelets. Altogether, we provide the first ever proteomic characterization of platelets from hibernating animals, where systematic changes in metabolic, hemostatic, and other proteins may account for physiological adaptations in torpor and also inform translational effort to improve cold storage of human platelets for transfusion.

<i>Wolbachia</i> are the most widespread bacterial endosymbionts in animals. Within arthropods, these maternally transmitted bacteria can selfishly hijack host reproductive processes to increase the relative fitness of their transmitting females. One such form of reproductive parasitism called male killing, or the selective killing of infected males, is recapitulated to degrees by transgenic expression of the prophage <i>WO-mediated killing</i> (<i>wmk</i>) gene. Here, we characterize the genotype-phenotype landscape of <i>wmk-</i>induced male killing in <i>D. melanogaster</i> using transgenic expression. While phylogenetically distant <i>wmk</i> homologs induce no sex-ratio bias, closely-related homologs exhibit complex phenotypes spanning no death, male death, or death of all hosts. We demonstrate that alternative start codons, synonymous codons, and notably a single synonymous nucleotide in <i>wmk</i> can ablate killing. These findings reveal previously unrecognized features of transgenic <i>wmk</i>-induced killing and establish new hypotheses for the impacts of post-transcriptional processes in male killing variation. We conclude that synonymous sequence changes are not necessarily silent in nested endosymbiotic interactions with life-or-death consequences.

The Hsp70 and Hsp90 molecular chaperone systems are critical regulators of protein homeostasis (proteostasis) in eukaryotes under normal and stressed conditions. The Hsp70 and Hsp90 systems physically and functionally interact to ensure cellular proteostasis. Co-chaperones interact with Hsp70 and Hsp90 to regulate and to promote their molecular chaperone functions. Mammalian Hop, also called Stip1, and its budding yeast ortholog Sti1 are eukaryote-specific co-chaperones, which have been thought to be essential for substrate ("client") transfer from Hsp70 to Hsp90. Substrate transfer is facilitated by the ability of Hop to interact simultaneously with Hsp70 and Hsp90 as part of a ternary complex. Intriguingly, in prokaryotes, which lack a Hop ortholog, the Hsp70 and Hsp90 orthologs interact directly. Recent evidence shows that eukaryotic Hsp70 and Hsp90 can also form a prokaryote-like binary chaperone complex in the absence of Hop, and that this binary complex displays enhanced protein folding and anti-aggregation activities. The canonical Hsp70-Hop-Hsp90 ternary chaperone complex is essential for optimal maturation and stability of a small subset of clients, including the glucocorticoid receptor, the tyrosine kinase v-Src, and the 26S/30S proteasome. Whereas many cancers have increased levels of Hop, the levels of Hop decrease in the aging human brain. Since Hop is not essential in all eukaryotic cells and organisms, tuning Hop levels or activity might be beneficial for the treatment of cancer and neurodegeneration.

Hemophagocytic lymphohistiocytosis (HLH) is a clinical syndrome of life-threatening inflammation caused by an excessive, prolonged and ineffective immune response. An increasing number of HLH cases is recognized in Poland, but the genetic causes of familial HLH (FHL) have not been reported. We investigated the molecular genetics and associated outcomes of pediatric patients who met HLH criteria. We studied 54 patients with HLH, 36 of whom received genetic studies. Twenty-five patients were subjected to direct sequencing of the PRF1, UNC13D, STX11, XIAP and SH2D1A genes. Additionally, 11 patients were subjected to targeted next-generation sequencing. In our study group, 17 patients (31%) were diagnosed with primary HLH, with bi-allelic FHL variants identified in 13 (36%) patients whereas hemizygous changes were identified in 4 patients with X-linked lymphoproliferative diseases. In addition, one patient was diagnosed with X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection and neoplasia due to a hemizygous MAGT1 variant; another newborn was diagnosed with auto-inflammatory syndrome caused by MVK variants. The majority (65%) of FHL patients carried UNC13D pathogenic variants, whereas PRF1 variants occurred in two patients. Novel variants in UNC13D, PRF1 and XIAP were detected. Epstein-Barr virus was the most common trigger noted in 23 (65%) of the patients with secondary HLH. In three patients with secondary HLH, heterozygous variants of FHL genes were found. Overall survival for the entire study group was 74% with a median of 3.6 years of follow-up. Our results highlight the diversity of molecular causes of primary HLH in Poland.

Immune checkpoint blockade involves targeting immune regulatory molecules with antibodies. Preclinically, complex multiantibody regimes of both inhibitory and stimulatory targets are a promising candidate for the next generation of immunotherapy. However, in this setting, the antibody platform may be limited due to excessive toxicity caused by off target effects as a result of systemic administration. RNA can be used as an alternate to antibodies as it can both downregulate immunosuppressive checkpoints (siRNA) or induce expression of immunostimulatory checkpoints (mRNA). In this study, we demonstrate that the combination of both siRNA and mRNA in a single formulation can simultaneously knockdown and induce expression of immune checkpoint targets, thereby reprogramming the tumor microenvironment from immunosuppressive to immunostimulatory phenotype. To achieve this, RNA constructs were synthesized and formulated into stable nucleic acid lipid nanoparticles (SNALPs); the SNALPs produced were 140-150 nm in size with >80% loading efficiency. SNALPs could transfect macrophages and B16F10 cells <i>in vitro</i> resulting in 75% knockdown of inhibitory checkpoint (PDL1) expression and simultaneously express high levels of stimulatory checkpoint (OX40L) with minimal toxicity. Intratumoral treatment with the proposed formulation resulted in statistically reduced tumor growth, a greater density of CD4+ and CD8+ infiltrates in the tumor, and immune activation within tumor-draining lymph nodes. These data suggest that a single RNA-based formulation can successfully reprogram multiple immune checkpoint interactions on a cellular level. Such a candidate may be able to replace future immune checkpoint therapeutic regimes composed of both stimulatory- and inhibitory-receptor-targeting antibodies.

Soft and hard materials at interfaces exhibit mismatched behaviors, such as mismatched chemical or biochemical reactivity, mechanical response, and environmental adaptability. Leveraging or mitigating these differences can yield interfacial processes difficult to achieve, or inapplicable, in pure soft or pure hard phases. Exploration of interfacial mismatches and their associated (bio)chemical, mechanical, or other physical processes may yield numerous opportunities in both fundamental studies and applications, in a manner similar to that of semiconductor heterojunctions and their contribution to solid-state physics and the semiconductor industry over the past few decades. In this review, we explore the fundamental chemical roles and principles involved in designing these interfaces, such as the (bio)chemical evolution of adaptive or buffer zones. We discuss the spectroscopic, microscopic, (bio)chemical, and computational tools required to uncover the chemical processes in these confined or hidden soft-hard interfaces. We propose a soft-hard interaction framework and use it to discuss soft-hard interfacial processes in multiple systems and across several spatiotemporal scales, focusing on tissue-like materials and devices. We end this review by proposing several new scientific and engineering approaches to leveraging the soft-hard interfacial processes involved in biointerfacing composites and exploring new applications for these composites.

Mammalian chromosomes are three-dimensional entities shaped by converging and opposing forces. Mitotic cell division induces marked chromosome condensation, but following reentry into the G₁ phase of the cell cycle, chromosomes reestablish their interphase organization. Here, we tested the role of RNA polymerase II (RNAPII) in this transition using a cell line that allows its auxin-mediated degradation. In situ Hi-C showed that RNAPII is required for both compartment and loop establishment following mitosis. RNAPs often counteract loop extrusion, and in their absence, longer and more prominent loops arose. Evidence from chromatin binding, super-resolution imaging, and in silico modeling allude to these effects being a result of RNAPII-mediated cohesin loading upon G₁ reentry. Our findings reconcile the role of RNAPII in gene expression with that in chromatin architecture.

Rett syndrome (RTT) is a severe neurodevelopmental disorder caused by loss of function of the X-linked methyl-CpG–binding protein 2 (<i>MECP2</i>). Several case studies report that gross motor function can be improved in children with RTT through treadmill walking, but whether the MeCP2-deficient motor circuit can support actual motor learning remains unclear. We used two-photon calcium imaging to simultaneously observe layer (L) 2/3 and L5a excitatory neuronal activity in the motor cortex (M1) while mice adapted to changing speeds on a computerized running wheel. Despite circuit hypoactivity and weakened functional connectivity across L2/3 and L5a, the <i>Mecp2</i>-null circuit’s firing pattern evolved with improved performance over 2 weeks. Moreover, trained mice became less anxious and lived 20% longer than untrained mice. Because motor deficits and anxiety are core symptoms of RTT, which is not diagnosed until well after symptom onset, these results underscore the benefit of motor learning.

<h4>Background</h4>Children with transfusion-dependent thalassemia (TDT) suffer from secondary hemosiderosis and the delirious effects this iron overload has on their different body organs, including the pancreas. They are also more prone to develop zinc deficiency than the general pediatric population. This study aimed to determine the effect of zinc deficiency and iron overload on the endocrine and exocrine pancreas in TDT children.<h4>Methods</h4>Eighty children, already diagnosed with TDT, were included in this study. We assessed the following in the participant children: serum ferritin, serum zinc, endocrine pancreatic function (oral glucose tolerance test (OGTT), fasting insulin level and from them, HOMA-IR was calculated), and exocrine pancreatic function (serum lipase and serum amylase).<h4>Results</h4>Forty-four TDT children had a subnormal zinc level, while 36 of them had a normal serum zinc level. TDT children with low serum zinc had significantly more impaired endocrine pancreatic function and an abnormally high serum lipase than children with normal serum zinc, p < 0.05 in all. Serum zinc was significantly lower in TDT children with serum ferritin above the ferritin threshold (≥2500 ng/ml) than those below (59.1 ± 20.2 vs. 77.5 ± 28.13), p = 0.02. TDT children, having a serum ferritin ≥2500 ng/ml, had significantly more frequently impaired endocrine pancreatic function and abnormally high serum lipase than TDT children below the ferritin threshold, p < 0.05 in all.<h4>Conclusion</h4>In children with transfusion-dependent thalassemia, zinc deficiency aggravates iron-induced pancreatic exocrine and endocrine dysfunction.

<h4>Background</h4>Severe retinopathy of prematurity (ROP) is associated with adverse outcomes. Relationships between milder ROP and outcomes have not been defined. We hypothesized that children with ROP stage ≤3 who did not receive ophthalmologic intervention would have worse motor, cognitive, and language skills and more vision abnormalities than children without ROP.<h4>Methods</h4>This was a secondary analysis of a randomized trial evaluating the effects of myo-inositol on ROP in the NICHD Neonatal Research Network. Primary outcomes were Bayley Scales of Infant Development composite scores; secondary outcomes included behavioral difficulties and ophthalmologic measures. Outcomes were compared using adjusted linear or modified Poisson models.<h4>Results</h4>Of 506 children, 173 (34%) had no ROP, 262 (52%) had ROP stage ≤3 without intervention, and 71 (14%) had ROP with intervention. There was no difference in motor, cognitive, or language scores between children with ROP stage ≤3 without intervention and children without ROP. Children with ROP stage ≤3 without intervention had a higher rate of strabismus compared to children without ROP (p = 0.040).<h4>Conclusion</h4>Children with ROP stage ≤3 without intervention did not have adverse neurodevelopmental outcomes at 2 years' corrected age compared to children without ROP but did have an increased incidence of strabismus.<h4>Impact</h4>This study addresses a gap in the literature regarding the relationship between milder forms of retinopathy of prematurity (ROP) that regress without intervention and neurodevelopment and vision outcomes. Children with a history of ROP stage ≤3 without intervention have similar neurodevelopmental outcomes at 2 years' corrected age as children born extremely preterm without a history of ROP and better outcomes than children with a history of ROP with ophthalmologic intervention. Counseling about likely neurodevelopment and vision outcomes for children born extremely preterm with a history of ROP may be tailored based on the severity of ROP.<h4>Clinical trial registration</h4>ClinicalTrials.gov ID: Inositol to Reduce Retinopathy of Prematurity Trial: NCT01954082.

The Sry-related high-mobility-group box (SOX) gene family, with 20 known transcription factors in humans, plays an essential role during development and disease processes. Several SOX proteins (SOX4, 11, and 9) are required for normal heart morphogenesis. SOX9 was shown to contribute to cardiac fibrosis. However, differential expression of other SOXs and their roles in the failing human myocardium have not been explored. Here, we used the whole-transcriptome sequencing (RNA-seq), gene co-expression, and meta-analysis to examine whether any SOX factors might play a role in the failing human myocardium. RNA-seq analysis was performed for cardiac tissue samples from heart failure (HF) patients due to dilated cardiomyopathy (DCM), or hypertrophic cardiomyopathy (HCM) and healthy donors (NF). The RNA levels of 20 SOX genes from RNA-seq data were extracted and compared to the 3 groups. Four SOX genes whose RNA levels were significantly upregulated in DCM or HCM compared to NF. However, only SOX4 and SOX8 proteins were markedly increased in the HF groups. A moderate to strong correlation was observed between the RNA level of SOX4/8 and fibrotic genes among each individual. Gene co-expression network analysis identified genes associated and respond similarly to perturbations with SOX4 in cardiac tissues. Using a meta-analysis combining epigenetics and genome-wide association data, we reported several genomic variants associated with HF phenotype linked to SOX4 or SOX8. In summary, our results implicate that SOX4 and SOX8 have a role in cardiomyopathy, leading to HF in humans. The molecular mechanism associated with them in HF warrants further investigation.

Breast and colorectal cancers are two primary malignancies on which most of the research done worldwide investigates the potential genetic and environmental risk factors and thereby tries to develop therapeutic methods to improve prognosis. Breast cancer is the most diagnosed cancer type in women, while colorectal cancer is diagnosed in males as the third most and females as the second most cancer type. Though these two cancer types are predominantly seen in adult patients worldwide, in the current context, these malignancies are diagnosed at a younger age with a significant rate of incidents than previous. Such early-onset cancers are generally present at an advanced stage of the most aggressive type with a poor prognosis. In the past, the focus of the research was mainly on studying possible candidate genes to understand the onset. However, it is now recognized that genetics, epigenetics, and other environmental factors play a pivotal role in cancer susceptibility. Thus, most studies were diversified to study the behavior of host microRNAs, and the involvement of gut microbiota and good communication between them surfaced in the occurrence and state of the disease. It is understood that the impact of these factors affects the outcome of the disease. Out of the adverse outcomes identified relating to the disease, immunosuppression is one of the most concerning outcomes in the current world, where such individuals remain vulnerable to infections. Recent studies revealed that microbiome and microRNA could create a considerable impact on immunosuppression. This review focused on the behavior of host microRNAs and gut microbiome for the onset of the disease and progression, thereby influencing an individual's immunosuppression. Understanding the interactions among microRNA, microbiome, presentation of the disease, and impact on the immune system will be immensely useful for developing future therapeutic strategies based on targeting host microRNA and the patient's gut microbiome. Therapies such as inhibitory-miRNA therapies, miRNA mimic-based therapeutics, immune checkpoint blockade therapies, and bacteria-assisted tumor-targeted therapies help modulate cancer. At the same time, it paid equal attention to potential noninvasive biomarkers in diagnosis, prognosis, and therapeutics in both cancers.

Peripheral nerve injuries can be debilitating to motor and sensory function, with severe cases often resulting in complete limb amputation. Over the past two decades, prosthetic limb technology has rapidly advanced to provide users with crude motor control of up to 20° of freedom; however, the nerve-interfacing technology required to provide high movement selectivity has not progressed at the same rate. The work presented here focuses on the development of a magnetically aligned regenerative tissue-engineered electronic nerve interface (MARTEENI) that combines polyimide "threads" encapsulated within a magnetically aligned hydrogel scaffold. The technology exploits tissue-engineered strategies to address concerns over traditional peripheral nerve interfaces including poor axonal sampling through the nerve and rigid substrates. A magnetically templated hydrogel is used to physically support the polyimide threads while also promoting regeneration in close proximity to the electrode sites on the polyimide. This work demonstrates the utility of magnetic templating for use in tuning the mechanical properties of hydrogel scaffolds to match the stiffness of native nerve tissue while providing an aligned substrate for Schwann cell migration in vitro. MARTEENI devices were fabricated and implanted within a 5-mm-long rat sciatic-nerve transection model to assess regeneration at 6 and 12 weeks. MARTEENI devices do not disrupt tissue remodeling and show axon densities equivalent to fresh tissue controls around the polyimide substrates. Devices are observed to have attenuated foreign-body responses around the polyimide threads. It is expected that future studies with functional MARTEENI devices will be able to record and stimulate single axons with high selectivity and low stimulation regimes.

Testicular toxicity is a major concern in cancer chemotherapy and drug development as it can result in infertility; however, there are no effective biomarkers for this adverse effect. To identify new biomarkers, we investigated the expression of small non-coding RNAs (sncRNAs) in a mouse model of doxorubicin (DXR)-induced testicular toxicity. First, we performed small RNA-seq analysis of sperm from DXR-treated or control mice and observed differential expression of many genome-derived sequences. We then performed real-time RT-PCR validation of these sequences and discovered that sncRNA detected by one primers, dxRN_3, showed similar differential expression as that seen in the RNA-seq experiment. These findings suggest that the sncRNAs present in sperm have potential as clinically acceptable biomarkers for testicular toxicity.

Volumetric magnetic resonance imaging (vMRI) has been widely studied in Huntington's disease (HD) and is commonly used to assess treatment effects on brain atrophy in interventional trials. Global and regional trajectories of brain atrophy in HD, with early involvement of striatal regions, are becoming increasingly understood. However, there remains heterogeneity in the methods used and a lack of widely-accessible multisite, longitudinal, normative datasets in HD. Consensus for standardized practices for data acquisition, analysis, sharing, and reporting will strengthen the interpretation of vMRI results and facilitate their adoption as part of a pathobiological disease staging system. The Huntington's Disease Regulatory Science Consortium (HD-RSC) currently comprises 37 member organizations and is dedicated to building a regulatory science strategy to expedite the approval of HD therapeutics. Here, we propose four recommendations to address vMRI standardization in HD research: (1) a checklist of standardized practices for the use of vMRI in clinical research and for reporting results; (2) targeted research projects to evaluate advanced vMRI methodologies in HD; (3) the definition of standard MRI-based anatomical boundaries for key brain structures in HD, plus the creation of a standard reference dataset to benchmark vMRI data analysis methods; and (4) broad access to raw images and derived data from both observational studies and interventional trials, coded to protect participant identity. In concert, these recommendations will enable a better understanding of disease progression and increase confidence in the use of vMRI for drug development.

A series of eight copper (II) complexes with 3-(4-chloro-3-nitrophenyl)thiourea were designed and synthesized. The cytotoxic activity of all compounds was assessed in three human cancer cell lines (SW480, SW620, PC3) and human normal keratinocytes (HaCaT). The complexes <b>1</b>, <b>3</b>, <b>5</b>, <b>7</b> and <b>8</b> were cytotoxic to the studied tumor cells in the low micromolar range, without affecting the normal cells. The complexes <b>1</b>, <b>3</b>, <b>7</b> and <b>8</b> induced lactate dehydrogenase (LDH) release in all cancer cell lines, but not in the HaCaT cells. They provoked early apoptosis in pathological cells, especially in SW480 and PC3 cells. The ability of compounds <b>1</b>, <b>3</b>, <b>7</b> and <b>8</b> to diminish interleukin-6 (IL-6) concentration in a cell was established. For the first time, the influence of the most promising Cu (II) complexes on intensities of detoxifying and reactive oxygen species (ROS) scavenging the enzymes of tumor cells was studied. The cytotoxic effect of all copper (II) conjugates against standard and hospital bacterial strains was also proved.

Atherosclerotic vascular calcification contributes to increased risk of death in patients with cardiovascular diseases. Assessing the type and severity of inflammation is crucial in the treatment of numerous cardiovascular conditions. IL-1β, a potent proinflammatory cytokine, plays diverse roles in the pathogenesis of atherosclerotic vascular calcification. Several large-scale, population cohort trials have shown that the incidence of cardiovascular events is clinically reduced by the administration of anti-IL-1β therapy. Anti-IL-1β therapy might reduce the incidence of cardiovascular events by affecting atherosclerotic vascular calcification, but the mechanism underlying this effect remains unclear. In this review, we summarize current knowledge on the role of IL-1β in atherosclerotic vascular calcification, and describe the latest results reported in clinical trials evaluating anti-IL-1β therapies for the treatment of cardiovascular diseases. This review will aid in improving current understanding of the pathophysiological roles of IL-1β and mechanisms underlying its activity.

Designing nanocarriers with actions directed at a specific organ or tissue is a very promising strategy since it can significantly reduce the toxicity of a bioactive drug. In this study, an organometallic dendrimer was used to synthesize a biocompatible drug delivery system by attaching aspirin to the periphery of the dendrimer. Our goal is to enhance the bioavailability and anticancer activity of aspirin and reduce its toxicity through successive generations of organoiron dendrimers. The biological activity of aspirin-based dendrimer complexes was evaluated. The result of antimicrobial activity of the synthesized dendrimers also demonstrated an increase in their antimicrobial activity with increased generation of the dendrimers for most types of microorganisms. This study reveals for the first time that organoiron dendrimers linked with aspirin exhibit an excellent Gram-negative activity comparable to the reference drug Gentamicin. All synthesized dendrimers were tested for their anticancer activity against breast cancer cell lines (MCF-7), hepatocellular cell lines (Hep-G2), and a non-cancer cell line, Human Embryonic Kidney (HEK293), using the MTT cell viability assay and compared against a standard anticancer drug, Doxorubicin. Compounds <b>G3-D9-Asp</b> and <b>G4-D12-Asp</b> exhibited noticeable activity against both cell lines, both of which were more effective than aspirin itself. In addition, the in vivo anti-inflammatory activity and histopathology of swollen paws showed that the designed aspirin-based dendrimers displayed significant anti-inflammatory activity; however, <b>G2-D6-Asp</b> showed the best anti-inflammatory activity, which was more potent than the reference drug aspirin during the same period. Moreover, the coupling of aspirin to the periphery of organoiron dendrimers showed a significant reduction in the toxicity of aspirin on the stomach.

Organoid-based studies have revolutionized in vitro preclinical research and hold great promise for the cancer research field, including prostate cancer (PCa). However, experimental variability in organoid drug testing complicates reproducibility. For example, we observed PCa organoids to be less affected by cabazitaxel, abiraterone and enzalutamide as compared to corresponding single cells prior to organoid assembly. We hypothesized that three-dimensional (3D) organoid organization and the use of various 3D scaffolds impact treatment efficacy. Live-cell imaging of androgen-induced androgen receptor (AR) nuclear translocation and taxane-induced tubulin stabilization was used to investigate the impact of 3D scaffolds, spatial organoid distribution and organoid size on treatment effect. Scaffolds delayed AR translocation and tubulin stabilization, with Matrigel causing a more pronounced delay than synthetic hydrogel as well as incomplete tubulin stabilization. Drug effect was further attenuated the more centrally organoids were located in the scaffold dome. Moreover, cells in the organoid core revealed a delayed treatment effect compared to cells in the organoid periphery, underscoring the impact of organoid size. These findings indicate that analysis of organoid drug responses needs careful interpretation and requires dedicated read-outs with consideration of underlying technical aspects.

Iron is an essential element involved in a variety of physiological functions. In the pancreatic beta-cells, being part of Fe-S cluster proteins, it is necessary for the correct insulin synthesis and processing. In the mitochondria, as a component of the respiratory chain, it allows the production of ATP and reactive oxygen species (ROS) that trigger beta-cell depolarization and potentiate the calcium-dependent insulin release. Iron cellular content must be finely tuned to ensure the normal supply but also to prevent overloading. Indeed, due to the high reactivity with oxygen and the formation of free radicals, iron excess may cause oxidative damage of cells that are extremely vulnerable to this condition because the normal elevated ROS production and the paucity in antioxidant enzyme activities. The aim of the present review is to provide insights into the mechanisms responsible for iron homeostasis in beta-cells, describing how alteration of these processes has been related to beta-cell damage and failure. Defects in iron-storing or -chaperoning proteins have been detected in diabetic conditions; therefore, the control of iron metabolism in these cells deserves further investigation as a promising target for the development of new disease treatments.

This study aimed to identify the molecular mechanisms regulated by a combined vaccine against <i>Aeromonas salmonicida</i> and <i>Vibrio anguillarum</i> (O1 serotype). These bacteria cause furunculosis and vibriosis, respectively, and are associated with a high mortality in rainbow trout in Korea. The vaccine upregulated gene expression of TCRα, T-bet, sIgM, and mIgM, markers of an activated adaptive immune response. On days 1, 3, and 5, transcriptome analysis revealed 862 (430 up- and 432 downregulated), 492 (204 up- and 288 downregulated), and 741 (270 up- and 471 downregulated) differentially expressed genes (DEGs), respectively. Gene ontology (GO) enrichment analysis identified 377 (108 MF, 132 CC, 137 BP), 302 (60 MF, 180 CC, 62 BP), and 314 (115 MF, 129 CC, 70 BP) GOs at days 1, 3, and 5, respectively. Kyoto Encyclopedia of Genetic and Genomic enrichment analysis identified eight immune system-related pathways like cytokine-cytokine receptor interaction, NF-kappaB signaling pathway, TNF signaling pathway, NOD-like receptor signaling pathway, cytosolic DNA sensing pathway, cell adhesion molecule, complement and coagulation cascade, and antigen processing and presentation. In the analysis of the protein-protein interaction of immune-related DEGs, a total of 59, 21, and 21 interactional relationships were identified at days 1, 3, and 5, respectively, with TNF having the highest centrality at all three time points.

Anemia is very common in patients with inflammatory disorders. Its prevalence is associated with severity of the underlying disease, and it negatively affects quality of life and cardio-vascular performance of patients. Anemia of inflammation (AI) is caused by disturbances of iron metabolism resulting in iron retention within macrophages, a reduced erythrocyte half-life, and cytokine mediated inhibition of erythropoietin function and erythroid progenitor cell differentiation. AI is mostly mild to moderate, normochromic and normocytic, and characterized by low circulating iron, but normal and increased levels of the storage protein ferritin and the iron hormone hepcidin. The primary therapeutic approach for AI is treatment of the underlying inflammatory disease which mostly results in normalization of hemoglobin levels over time unless other pathologies such as vitamin deficiencies, true iron deficiency on the basis of bleeding episodes, or renal insufficiency are present. If the underlying disease and/or anemia are not resolved, iron supplementation therapy and/or treatment with erythropoietin stimulating agents may be considered whereas blood transfusions are an emergency treatment for life-threatening anemia. New treatments with hepcidin-modifying strategies and stabilizers of hypoxia inducible factors emerge but their therapeutic efficacy for treatment of AI in ill patients needs to be evaluated in clinical trials.

The production of biodiesel through chemical production processes of transesterification reaction depends on suitable catalysts to hasten the chemical reactions. Therefore, the initial selection of catalysts is critical although it is also dependent on the quantity of free fatty acids in a given sample of oil. Earlier forms of biodiesel production processes relied on homogeneous catalysts, which have undesirable effects such as toxicity, high flammability, corrosion, by-products such as soap and glycerol, and high wastewater. Heterogeneous catalysts overcome most of these problems. Recent developments involve novel approaches using biomass and bio-waste resource derived heterogeneous catalysts. These catalysts are renewable, non-toxic, reusable, offer high catalytic activity and stability in both acidic and base conditions, and show high tolerance properties to water. This review work critically reviews biomass-based heterogeneous catalysts, especially those utilized in sustainable production of biofuel and biodiesel. This review examines the sustainability of these catalysts in literature in terms of small-scale laboratory and industrial applications in large-scale biodiesel and biofuel production. Furthermore, this work will critically review natural heterogeneous biomass waste and bio-waste catalysts in relation to upcoming nanotechnologies. Finally, this work will review the gaps identified in the literature for heterogeneous catalysts derived from biomass and other biocatalysts with a view to identifying future prospects for heterogeneous catalysts.

Advances in the Pd-catalyzed synthesis of <i>C</i>-glycosides and branched sugars are summarized herein and the strategies are categorized based on named reactions or types of sugar moieties involved in the reactions. These include cross-coupling reactions, C-H activations, and carbonylative cross-coupling reactions. Applications of Pd-catalyzed <i>C</i>-glycosylation reactions are discussed in the synthesis of natural products and biologically active molecules such as bergenin, papulacandin D, and SGLT2-inhibitors. Important mechanistic cycles are drawn and the mechanisms for how Pd-activates the sugar moieties for various coupling partners are discussed. The directing group-assisted <i>C</i>-glycosylation and some intramolecular C-H activation reactions are also included.

The COVID19 pandemic has resulted in multipronged approaches for treatment of the disease. Since de novo discovery of drugs is time consuming, repurposing of molecules is now considered as one of the alternative strategies to treat COVID19. Antibacterial peptides are being recognized as attractive candidates for repurposing to treat viral infections. In this study, we describe the anti-SARS-CoV-2 activity of gramicidin S and melittin peptides obtained from Bacillus brevis and bee venom respectively. Our in vitro antiviral assay results showed significant decrease in the viral load compared to the untreated group with no/very less cytotoxicity. The EC 50 values for gramicidin S and melittin are calculated as 1.571μg and 0.656μg respectively. Both the peptides treated to the SARS-CoV-2 infected Vero cells showed viral clearance from 12 hours onwards with a maximal clearance after 24 hours post infection. Based on proteome analysis it was found that more than 250 proteins were found to be differentially regulated in the gramicidin S and melittin treated SARS-CoV-2 infected Vero cells against control SARS-CoV-2 infected Vero cells after 24 and 48 hours post infection. The identified proteins were found to be associated in the metabolic and mRNA processing of the Vero cells post-treatment and infection. Both these peptides could be attractive candidates for repurposing to treat SARS-CoV-2 infection.

Infection by SARS-CoV-2 and subsequent COVID-19 can cause viral sepsis and septic shock. Several complications have been observed in patients admitted to the intensive care unit (ICU) with COVID-19, one of those being bacterial superinfection. Based on prior evidence that dysregulated systemwide proteolysis is associated with death in bacterial septic shock, we investigated whether protease activity and proteolysis could be elevated in COVID-19-induced sepsis with bacterial superinfection. In particular, we sought to assess the possible implications on the regulation of protein systems, such as for instance the proteins and enzymes involved in the clotting cascade. Blood samples collected at multiple time points during the ICU stay of four COVID-19 patients were analyzed to quantify: a) the circulating proteome and peptidome by mass spectrometry; b) plasma enzymatic activity of trypsin-like substrates and five clotting factors (plasmin, thrombin, factor VII, factor IX, factor X) by a fluorogenic assay. Of the four patients, one was diagnosed with bacterial superinfection on day 7 after beginning of the study and later died. The other three patients all survived (ICU length-of-stay 11.25±6.55 days, hospital stay of 15.25±7.18 days). Spikes in protease activity (factor VII, trypsin-like activity) were detected on day 7 for the patient who died. Corresponding increases in the total intensity of peptides derived by hydrolysis of plasma proteins, especially of fibrinogen degradation products, and a general reduction of coagulation proteins, were measured as well. A downregulation of endogenous enzymatic inhibitors, in particular trypsin inhibitors, characterized the non-surviving patient throughout her ICU stay. Enzymatic activity was stable in the patients who survived. Our study highlights the potential of multiomics approaches, combined with quantitative analysis of enzymatic activity, to i) shed light on proteolysis as a possible pathological mechanism in sepsis and septic shock, including COVID-19-induced sepsis; ii) provide additional insight into malfunctioning protease-mediated systems, such as the coagulation cascade; and iii) describe the progression of COVID-19 with bacterial superinfection.

Alu RNA are implicated in the poor prognosis of several human disease states. These RNA are transcription products of primate specific transposable elements called Alu elements. These elements are extremely abundant, comprising over 10% of the human genome, and 100 to 1000 cytoplasmic copies of Alu RNA per cell. Alu RNA do not have a single universal functional role aside from selfish self-propagation. Despite this, Alu RNA have been found to operate in a diverse set of translational and transcriptional mechanisms. This review will focus on the current knowledge of Alu RNA involved in human disease states and known mechanisms of action. Examples of Alu RNA that are transcribed in a variety of contexts such as introns, mature mRNA, and non-coding transcripts will be discussed. Past and present challenges in studying Alu RNA, and the future directions of Alu RNA in basic and clinical research will also be examined.

<h4>Background</h4>The management of cytologically indeterminate thyroid nodules is challenging for clinicians. This study aimed to compare the diagnostic performance of the Korean Thyroid Imaging Reporting and Data Systems (K-TIRADS) with that of the American College of Radiology (ACR)-TIRADS for predicting the malignancy risk of indeterminate thyroid nodules.<h4>Methods</h4>Thyroid nodules diagnosed by fine-needle aspiration (FNA) followed by surgery or core needle biopsy at a single referral hospital were enrolled.<h4>Results</h4>Among 200 thyroid nodules, 78 (39.0%) nodules were classified as indeterminate by FNA (Bethesda category III, IV, and V), and 114 (57.0%) nodules were finally diagnosed as malignancy by surgery or core needle biopsy. The area under the curve (AUC) was higher for FNA than for either TIRADS system in all nodules, while all three methods showed similar AUCs for indeterminate nodules. However, for Bethesda category III nodules, applying K-TIRADS 5 significantly increased the risk of malignancy compared to a cytological examination alone (50.0% vs. 26.5%, P=0.028), whereas applying ACR-TIRADS did not lead to a change.<h4>Conclusion</h4>K-TIRADS and ACR-TIRADS showed similar diagnostic performance in assessing indeterminate thyroid nodules, and K-TIRADS had beneficial effects for malignancy prediction in Bethesda category III nodules.

<h4>Background</h4>There are limited data regarding the factors associated with hepatocellular carcinoma (HCC) in non-alcoholic fatty liver disease (NAFLD) patients without cirrhosis. We sought to determine the prevalence and factors associated with HCC in NAFLD patients with or without cirrhosis.<h4>Methods</h4>Adults with NAFLD (June 2015 to May 2020) were identified using the electronic health record database (Explorys Inc, Cleveland, OH) from 26 major integrated US healthcare systems. The prevalence of HCC was calculated. Multivariable analyses adjusting for covariates were performed to evaluate the associated risk factors and the presence of HCC.<h4>Results</h4>A total of 392,800 NAFLD patients were identified. Among 1110 patients with HCC, 170 (15.3%) had no cirrhosis. The prevalence of HCC in non-cirrhotic and cirrhotic NAFLD patients was 4.6/10,000 persons (95% CI 3.9-5.3), and 374.4/10,000 persons (95% CI 350.9-398.8), respectively. Age > 65 years (adjusted OR; 3.37, 95% CI 2.47-4.59), ever had elevated alanine aminotransferase (2.69; 2.14-3.37), male gender (2.57; 1.88-3.49), smoker (1.75; 1.23-2.49), and diabetes (1.56; 1.15-2.11) were associated with HCC in non-cirrhotic NAFLD (all P < 0.05). The prevalence of HCC in the non-cirrhotic with all five risk factors was 45.5/10,000 persons (95% CI 17.4-73.6). The factors associated with HCC in cirrhotic NAFLD included clinical decompensation, age > 65 years, male gender, Hispanic race, elevated alanine aminotransferase, diabetes and smoker (all P < 0.05).<h4>Conclusions</h4>These data identified the major risk factors for the development of HCC in NAFLD patients. In the non-cirrhotics, older male patients with smoking history, diabetes and an elevated alanine aminotransferase had highest risk and may need increased judicious monitoring.

<h4>Background</h4>Bone substrates like hydroxyapatite and tricalcium phosphate have been widely used for promoting spinal fusion and reducing the complications caused by autograft. Whitlockite has been reported to promote better bone formation in rat calvaria models compare with them, but no study investigated its effect on spinal fusion yet. Also, the higher osteoinductivity of whitlockite raised concern of ectopic ossification, which was a complication of spinal fusion surgery that should be avoided.<h4>Methods</h4>In this study, we compared the osteoinductivity of whitlockite, hydroxyapatite, and tricalcium phosphate porous particles with SD rat spine posterolateral fusion model and investigated whether whitlockite could induce ectopic ossification with SD rat abdominal pouch model.<h4>Results</h4>The micro-CT result from the posterolateral fusion model showed whitlockite had slightly but significantly higher percent bone volume than tricalcium phosphate, though none of the materials formed successful fusion with surrounding bone tissue. The histology results showed the bone formed on the cortical surface of the transverse process but did not form a bridge between the processes. The result from the abdominal pouch model showed whitlockite did not induce ectopic bone formation.<h4>Conclusion</h4>Whitlockite had a potential of being a better bone substrate hydroxyapatite and tricalcium phosphate in spinal fusion with low risk of inducing ectopic ossification.

Peritoneal dialysis (PD) is the worldwide recognized preferred dialysis treatment for children affected by end-stage kidney disease (ESKD). However, due to the unphysiological composition of PD fluids, the peritoneal membrane (PM) of these patients may undergo structural and functional alterations, which may cause fibrosis. Several factors may accelerate this process and primary kidney disease may have a causative role. In particular, patients affected by steroid resistant primary focal segmental glomerulosclerosis, a rare glomerular disease leading to nephrotic syndrome and ESKD, seem more prone to develop peritoneal fibrosis. The mechanism causing this predisposition is still unrecognized. To better define this condition, we carried out, for the first time, a new comprehensive comparative proteomic mass spectrometry analysis of mesothelial exosomes from peritoneal dialysis effluent (PDE) of 6 pediatric patients with focal segmental glomerular sclerosis (FSGS) versus 6 patients affected by other primary renal diseases (No FSGS). Our omic study demonstrated that, despite the high overlap in the protein milieu between the two study groups, machine learning allowed to identify a core list of 40 proteins, with ANXA13 as most promising potential biomarker, to distinguish, in our patient population, peritoneal dialysis effluent exosomes of FSGS from No FSGS patients (with 100% accuracy). Additionally, the Weight Gene Co-expression Network Analysis algorithm identified 17 proteins, with PTP4A1 as the most statistically significant biomarker associated to PD vintage and decreased PM function. Altogether, our data suggest that mesothelial cells of FSGS patients are more prone to activate a pro-fibrotic machinery. The role of the proposed biomarkers in the PM pathology deserves further investigation. Our results need further investigations in a larger population to corroborate these findings and investigate a possible increased risk of PM loss of function or development of encapsulating peritoneal sclerosis in FSGS patients, thus to eventually carry out changes in PD treatment and management or implement new solutions.

Gliomas are primary brain tumors with still poor prognosis for the patients despite a combination of cytoreduction via surgery followed by a radio-chemotherapy. One strategy to find effective treatment is to combine two different compounds in one hybrid molecule via linker to add to or at best potentiate their impact on malignant cells. Here, we report on the effects of a newly synthesized hybrid of sulfasalazine (SAS) and dihydroartemisinin (DHA), called AC254. In previous studies, both SAS and DHA have already proved to have anti-tumor properties themselves and to have sensitizing respectively potentiating effects on other treatments against malignant tumors. We investigated the impact of individual drugs SAS and DHA, their 1:1 combination and a novel SAS-DHA hybrid compound (AC254) on rodent and human glioma cells. In our study SAS alone showed no or only a mild effect on glioma, whereas DHA led to a significant reduction of cell viability in a dose-dependent manner. Next we compared the efficacy of the hybrid AC254 to the combinational treatment of its parent compounds SAS and DHA. The hybrid was highly efficient in combating glioma cells compared to single treatment strategies regarding cell viability and cell death. Interestingly, AC254 showed a remarkable advantage over the combinational treatment with both parent compounds in most used concentrations. In addition to its reduction of tumor cell viability and induction of cell death, the hybrid AC254 displayed changes in cell cycle and reduction of cell migration. Taken together, these results demonstrate that clinically established compounds such as SAS and DHA can be potentiated in their anti-cancer effects by chemical hybridization. Thus, this concept provides the opportunity to devise new effective chemotherapeutic agents.

Current inflammatory bowel disease (IBD) therapies are ineffective in a high proportion of patients. Combining bulk and single-cell transcriptomics, quantitative histopathology and in situ localization across three cohorts of patients with IBD (total n = 376), we identify coexpressed gene modules within the heterogeneous tissular inflammatory response in IBD that map to distinct histopathological and cellular features (pathotypes). One of these pathotypes is defined by high neutrophil infiltration, activation of fibroblasts and vascular remodeling at sites of deep ulceration. Activated fibroblasts in the ulcer bed display neutrophil-chemoattractant properties that are IL-1R, but not TNF, dependent. Pathotype-associated neutrophil and fibroblast signatures are increased in nonresponders to several therapies across four independent cohorts (total n = 343). The identification of distinct, localized, tissular pathotypes will aid precision targeting of current therapeutics and provides a biological rationale for IL-1 signaling blockade in ulcerating disease.

Small intestine adenocarcinoma is a rare intestinal malignancy with distinct clinical, pathological, and molecular characteristics. Recently, a fusion of the intestinal stem-cell marker olfactomedin 4 (OLFM4) and the proto-oncogene RET has been identified in a small intestine adenocarcinoma patient. Here we investigated the biological effects of OLFM4-RET fusion and whether it can initiate tumorigenesis in small intestine. OLFM4 expression was found to be frequently lost or reduced in human small intestine adenocarcinoma, and its downregulation correlated with high tumor grade and advanced tumor stage. Expression of OLFM4-RET fusion-induced cellular transformation in HEK293 cells and blocked RET-induced inhibition of colony growth in HuTu 80 small intestine adenocarcinoma cells. Further, expression of OLFM4-RET activated the RAS-RAF-MAPK and STAT3 cell signaling pathways in both HEK293 cells and HuTu 80 cells. OLFM4-RET expression in HEK293 cells upregulated multiple families of genes related to carcinogenesis, cancer progression, and metastasis. Targeted expression of OLFM4-RET in the small intestine led to the development of hyperplasia, adenoma, or adenocarcinoma in transgenic mice. Our study suggests that OLFM4-RET is an oncogenic driver of small intestine tumorigenesis. Therefore, the small intestine adenocarcinoma patients with OLFM4-RET fusion may benefit from treatment with RET kinase inhibitor.

In Parkinson's disease (PD), substantia nigra (SN) dopaminergic (DA) neurons degenerate, while related ventral tegmental area (VTA) DA neurons remain relatively unaffected. Here, we present a methodology that directs the differentiation of mouse and human pluripotent stem cells toward either SN- or VTA-like DA lineage and models their distinct vulnerabilities. We show that the level of WNT activity is critical for the induction of the SN- and VTA-lineage transcription factors Sox6 and Otx2, respectively. Both WNT signaling modulation and forced expression of these transcription factors can drive DA neurons toward the SN- or VTA-like fate. Importantly, the SN-like lineage enriched DA cultures recapitulate the selective sensitivity to mitochondrial toxins as observed in PD, while VTA-like neuron-enriched cultures are more resistant. Furthermore, a proteomics approach led to the identification of compounds that alter SN neuronal survival, demonstrating the utility of our strategy for disease modeling and drug discovery.

<h4>Objective</h4>Dysregulation of cell cycle progression (CCP) is one of the hallmarks of cancer. Here, our study is aimed at developing a CCP-derived gene signature for predicting high-risk population of hepatocellular carcinoma (HCC).<h4>Methods</h4>Our study retrospectively analyzed the transcriptome profiling and clinical information of HCC patients from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) projects. Uni- and multivariate cox regression models were conducted for identifying which hallmarks of cancer were risk factors of HCC. CCP-derived gene signature was developed with LASSO method. The predictive efficacy was verified by ROC curves and subgroup analyses. A nomogram was then generated and validated by ROC, calibration, and decisive curves. Immune cell infiltration was estimated with ssGSEA method. Potential small molecular compounds were predicted via CTRP and CMap analyses. The response to chemotherapeutic agents was evaluated based on the GDSC project.<h4>Results</h4>Among hallmarks of cancer, CCP was identified as a dominant risk factor for HCC prognosis. CCP-derived gene signature displayed the favorable predictive efficacy in HCC prognosis independent of other clinicopathological parameters. A nomogram was generated for optimizing risk stratification and quantifying risk evaluation. CCP-derived signature was in relation to immune cell infiltration, HLA, and immune checkpoint expression. Combining CTRP and CMap analyses, fluvastatin was identified as a promising therapeutic agent against HCC. Furthermore, CCP-derived signature might be applied for predicting the response to doxorubicin and gemcitabine.<h4>Conclusion</h4>Collectively, CCP-derived gene signature was a promising marker in prediction of survival outcomes and therapeutic responses for HCC patients.

<h4>Background</h4>Emerging evidence implicates the correlation of embryonic germline genes with the tumor progress and patient's outcome. However, the prognostic value of these genes in lung adenocarcinoma (LUAD) has not been fully studied. Here we systematically evaluated this issue, and constructed a novel signature and a nomogram associated with embryonic germline genes for predicting the outcomes of lung adenocarcinoma.<h4>Methods</h4>The LUAD cohorts retrieved from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database were used as training set and testing set, respectively. The embryonic germline genes were downloaded from the website https://venn.lodder.dev. Then, the differentially expressed embryonic germline genes (DEGGs) between the tumor and normal samples were identified by limma package. The functional enrichment and pathway analyses were also performed by clusterProfiler package. The prognostic model was constructed by the least absolute shrinkage and selection operator (LASSO)-Cox regression method. Survival and Receiver Operating Characteristic (ROC) analyses were performed to validate the model using training set and four testing GEO datasets. Finally, a prognostic nomogram based on the signature genes was constructed using multivariate regression method.<h4>Results</h4>Among the identified 269 DEGGs, 249 were up-regulated and 20 were down-regulated. GO and KEGG analyses revealed that these DEGGs were mainly enriched in the process of cell proliferation and DNA damage repair. Then, 103 DEGGs with prognostic value were identified by univariate Cox regression and further filtered by LASSO method. The resulting sixteen DEGGs were included in step multivariate Cox regression and an eleven embryonic germline gene related signature (EGRS) was constructed. The model could robustly stratify the LUAD patients into high-risk and low-risk groups in both training and testing sets, and low-risk patients had much better outcomes. The multi-ROC analysis also showed that the EGRS model had the best predictive efficacy compared with other common clinicopathological factors. The EGRS model also showed robust predictive ability in four independent external datasets, and the area under curve (AUC) was 0.726 (GSE30219), 0.764 (GSE50081), 0.657 (GSE37745) and 0.668 (GSE72094). More importantly, the expression level of some genes in EGRS has a significant correlation with the progression of LUAD clinicopathology, suggesting these genes might play an important role in the progression of LUAD. Finally, based on EGRS genes, we built and calibrated a nomogram for conveniently evaluating patients' outcomes.

Osteoarthritis (OA), which is caused by joint damage, is the most common form of arthritis, affecting millions of people worldwide. This damage can accumulate over time, which is why aging is one of the main contributors to joint damage associated with OA. The OA-related proteins that have been reported to date have been identified by the comparative analysis of OA patients with normal controls, following surgical or pharmacological treatment. For the first time, the present study analyzed OA-related proteins in patients with OA according to the International Cartilage Repair Society (ICRS) scale. Changes in protein expression can be observed during the OA process. The present study demonstrated differential protein expression patterns in articular cartilage from ICRS1- and ICRS3-graded OA patients. ICRS grade-matched OA knee samples from 12 OA patients, 6 ICRS grade 1 patients and 6 ICRS3 patients were subjected to proteomic analysis using the LTQ-Orbitrap mass spectrometry system. A total of 231 unique proteins were identified as expressed across the ICRS1 and ICRS3 OA patient groups. Relative differences in protein expression associated with the following classifications were observed: Biological adhesion, cell killing, cellular process, development process and molecular function. Although some of these proteins have been previously reported to be associated with rheumatoid arthritis, including cartilage oligomeric matrix protein, collagen types, angiogenin, complement C5 and CD59 glycoprotein, numerous additional proteins were newly identified, which may further help our understanding of disease pathogenesis. These findings suggested that these proteins may be used to develop novel therapeutic targets for OA.

Following peripheral nerve injury, transcription factors upregulated in the distal nerve play essential roles in Schwann cell reprogramming, fibroblast activation and immune cell function to create a permissive distal nerve environment for axonal regrowth. In this report, we first analysed four microarray data sets to identify transcription factors that have at least twofold upregulation in the mouse distal nerve stump at day 3 and day 7 post-injury. Next, we compared their relative mRNA levels through the analysis of an available bulk mRNA sequencing data set at day 5 post-injury. We then investigated the expression of identified TFs in analysed single-cell RNA sequencing data sets for the distal nerve at day 3 and day 9 post-injury. These analyses identified 55 transcription factors that have at least twofold upregulation in the distal nerve following mouse sciatic nerve injury. Expression profile for the identified 55 transcription factors in cells of the distal nerve stump was further analysed on the scRNA-seq data. Transcription factor network and functional analysis were performed in Schwann cells. We also validated the expression pattern of Jun, Junb, Runx1, Runx2, and Sox2 in the mouse distal nerve stump by immunostaining. The findings from our study not only could be used to understand the function of key transcription factors in peripheral nerve regeneration but also could be used to facilitate experimental design for future studies to investigate the function of individual TFs in peripheral nerve regeneration.

Marine mammals such as northern elephant seals (NES) routinely experience hypoxemia and ischemia-reperfusion events to many tissues during deep dives with no apparent adverse effects. Adaptations to diving include increased antioxidants and elevated oxygen storage capacity associated with high hemoprotein content in blood and muscle. The natural turnover of heme by heme oxygenase enzymes (encoded by <i>HMOX1</i> and <i>HMOX2</i>) produces endogenous carbon monoxide (CO), which is present at high levels in NES blood and has been shown to have cytoprotective effects in laboratory systems exposed to hypoxia. To understand how pathways associated with endogenous CO production and signaling change across ontogeny in diving mammals, we measured muscle CO and baseline expression of 17 CO-related genes in skeletal muscle and whole blood of three age classes of NES. Muscle CO levels approached those of animals exposed to high exogenous CO, increased with age, and were significantly correlated with gene expression levels. Muscle expression of genes associated with CO production and antioxidant defenses (<i>HMOX1</i>, <i>BVR</i>, <i>GPX3</i>, <i>PRDX1</i>) increased with age and was highest in adult females, while that of genes associated with protection from lipid peroxidation (<i>GPX4</i>, <i>PRDX6</i>, <i>PRDX1</i>, <i>SIRT1</i>) was highest in adult males. In contrast, muscle expression of mitochondrial biogenesis regulators (<i>PGC1A</i>, <i>ESRRA</i>, <i>ESRRG</i>) was highest in pups, while genes associated with inflammation (<i>HMOX2</i>, <i>NRF2</i>, <i>IL1B</i>) did not vary with age or sex. Blood expression of genes involved in regulation of inflammation (<i>IL1B</i>, <i>NRF2</i>, <i>BVR</i>, <i>IL10</i>) was highest in pups, while <i>HMOX1</i>, <i>HMOX2</i> and pro-inflammatory markers (<i>TLR4</i>, <i>CCL4</i>, <i>PRDX1</i>, <i>TNFA</i>) did not vary with age. We propose that ontogenetic upregulation of baseline <i>HMOX1</i> expression in skeletal muscle of NES may, in part, underlie increases in CO levels and expression of genes encoding antioxidant enzymes. <i>HMOX2</i>, in turn, may play a role in regulating inflammation related to ischemia and reperfusion in muscle and circulating immune cells. Our data suggest putative ontogenetic mechanisms that may enable phocid pups to transition to a deep-diving lifestyle, including high baseline expression of genes associated with mitochondrial biogenesis and immune system activation during postnatal development and increased expression of genes associated with protection from lipid peroxidation in adulthood.

Gastric cancer (GC) development trends have identified multiple processes ranging from inflammation to carcinogenesis, however, key pathogenic mechanisms remain unclear. Tissue microenvironment (TME) cells are critical for the progression of malignant tumors. Here, we generated a dynamic transcriptome map of various TME cells during multi-disease stages using single-cell sequencing analysis. We observed a set of key transition markers related to TME cell carcinogenic evolution, and delineated landmark dynamic carcinogenic trajectories of these cells. Of these, macrophages, fibroblasts, and endothelial cells exerted considerable effects toward epithelial cells, suggesting these cells may be key TME factors promoting GC occurrence and development. Our results suggest a phenotypic convergence of different TME cell types toward tumor formation processes in GC. We believe our data would pave the way for early GC detection, diagnosis, and treatment therapies.

Genetic background may be involved in the promotion and progression of non-alcoholic fatty liver disease (NAFLD). Previous studies have suggested that the single nucleotide polymorphisms (SNPs) may be associated with the specific clinical features in the patients with hepatic steatosis; however, data on the patients with diabetes from Southern Italy are lacking. We enrolled 454 patients and 260 of them had type 2 diabetes. We studied the <i>PNPLA3 rs738409, LPIN1 rs13412852, KLF6 rs3750861, SOD2 rs4880, TM6SF2 rs58542926</i>, and <i>ZNF624 rs12603226</i> SNPs and their distribution in the study population. Lipid profile, liver stiffness, and kidney function were also studied to understand the potential role of the SNPs in the development of clinical phenotypes. No differences were observed in the distribution of polymorphisms between the diabetic and non-diabetic subjects. Carriers of risk allele G for <i>PNPLA3 rs738409</i> SNP showed a lower mean value of serum triglycerides and a higher liver stiffness. Risk allele for <i>KLF6 rs3750861</i> and <i>SOD2 rs4880</i> polymorphism had a lower estimated glomerular filtration rate (eGFR) value, whereas no differences in the glucose and glycated hemoglobin level were observed in the subgroups by the different genotypes. Genetic polymorphisms are useful to identify the patients at higher risk of development of liver fibrosis and lower eGFR values in the patients with diabetes and NAFLD. Their use in clinical practice may help the clinicians to identify the patients who require a more strict follow-up program.

Along with sexual maturity, the liver undergoes numerous metabolic processes to adapt the physiological changes associated with egg-laying in hens. However, mechanisms regulating the processes were unclear. In this study, comparative hepatic proteome and acetyl-proteome between pre- and peak-laying hens were performed. The results showed that the upregulated proteins were mainly related to lipid and protein biosynthesis, while the downregulated proteins were mainly involved in pyruvate metabolism and were capable of inhibiting gluconeogenesis and lactate synthesis in peak-laying hens compared with that in pre-laying hens. With unchanged expression level, the significant acetylated proteins were largely functioned on activation of polyunsaturated fatty acid oxidation in peroxisome, while the significant deacetylated proteins were principally used to elevate medium and short fatty acid oxidation in mitochondria and oxidative phosphorylation. Most of the proteins which involved in gluconeogenesis, lipid transport, and detoxification were influenced by both protein expression and acetylation. Taken overall, a novel mechanism wherein an alternate source of acetyl coenzyme A was produced by activation of FA oxidation and pyruvate metabolism to meet the increased energy demand and lipid synthesis in liver of laying hens was uncovered. This study provides new insights into molecular mechanism of adaptation to physiological changes in liver of laying hens.

Huntington's disease (HD) is a neurodegenerative disease that results in motor and cognitive dysfunction, leading to early death. HD is caused by an expansion of CAG repeats in the huntingtin gene (<i>HTT</i>). Here, we review the mouse models of HD. They have been used extensively to better understand the molecular and cellular basis of disease pathogenesis as well as to provide non-human subjects to test the efficacy of potential therapeutics. The first and best-studied <i>in vivo</i> rodent model of HD is the R6/2 mouse, in which a transgene containing the promoter and exon 1 fragment of human <i>HTT</i> with 150 CAG repeats was inserted into the mouse genome. R6/2 mice express rapid, robust behavioral pathologies and display a number of degenerative abnormalities in neuronal populations most vulnerable in HD. The first conditional full-length mutant huntingtin (mHTT) mouse model of HD was the bacterial artificial chromosome (BAC) transgenic mouse model of HD (BACHD), which expresses human full-length m<i>HTT</i> with a mixture of 97 CAG-CAA repeats under the control of endogenous <i>HTT</i> regulatory machinery. It has been useful in identifying the role of mHTT in specific neuronal populations in degenerative processes. In the knock-in (KI) model of HD, the expanded human CAG repeats and human exon 1 are inserted into the mouse <i>Htt</i> locus, so a chimera of the full-length mouse protein with the N-terminal human portion is expressed. Many of aspects of the pathology and behavioral deficits in the KI model better mimic disease characteristics found in HD patients than other models. Accordingly, some have proposed that these mice may be preferable models of the disease over others. Indeed, as our understanding of HD advances, so will the design of animal models to test and develop HD therapies.

Extracellular vesicles (EVs) have emerged in the last decade as critical cell-to-cell communication devices used to carry nucleic acids and proteins between cells. EV cargo includes plasma membrane and endosomal proteins, but EVs also contain material from other cellular compartments, including mitochondria. Within cells, mitochondria are responsible for a large range of metabolic reactions, but they can also produce damaging levels of reactive oxygen species and induce inflammation when damaged. Consistent with this, recent evidence suggests that EV-mediated transfer of mitochondrial content alters metabolic and inflammatory responses of recipient cells. As EV mitochondrial content is also altered in some pathologies, this could have important implications for their diagnosis and treatment. In this review, we will discuss the nature and roles of mitochondrial EVs, with a special emphasis on the nervous system.

Virus-induced neurological sequelae resulting from infection by Theiler's murine encephalomyelitis virus (TMEV) are used for studying human conditions ranging from epileptic seizures to demyelinating disease. Mouse strains are typically considered susceptible or resistant to TMEV infection based on viral persistence and extreme phenotypes, such as demyelination. We have identified a broader spectrum of phenotypic outcomes by infecting strains of the genetically diverse Collaborative Cross (CC) mouse resource. We evaluated the chronic-infection gene expression profiles of hippocampi and thoracic spinal cords for 19 CC strains in relation to phenotypic severity and TMEV persistence. Strains were clustered based on similar phenotypic profiles and TMEV levels at 90 days post-infection, and we categorized distinct TMEV response profiles. The three most common profiles included "resistant" and "susceptible," as before, as well as a "resilient" TMEV response group which experienced both TMEV persistence and mild neurological phenotypes even at 90 days post-infection. Each profile had a distinct gene expression signature, allowing the identification of pathways and networks specific to each TMEV response group. CC founder haplotypes for genes involved in these pathways/networks revealed candidate response-specific alleles. These alleles demonstrated pleiotropy and epigenetic (miRNA) regulation in long-term TMEV infection, with particular relevance for resilient mouse strains.

Most known driver genes of metastatic prostate cancer are frequently mutated. To dig into the long tail of rarely mutated drivers, we performed network-based driver identification on the Hartwig Medical Foundation metastatic prostate cancer data set (HMF cohort). Hereto, we developed GoNetic, a method based on probabilistic pathfinding, to identify recurrently mutated subnetworks. In contrast to most state-of-the-art network-based methods, GoNetic can leverage sample-specific mutational information and the weights of the underlying prior network. When applied to the HMF cohort, GoNetic successfully recovered known primary and metastatic drivers of prostate cancer that are frequently mutated in the HMF cohort (<i>TP53</i>, <i>RB1,</i> and <i>CTNNB1</i>). In addition, the identified subnetworks contain frequently mutated genes, reflect processes related to metastatic prostate cancer, and contain rarely mutated driver candidates. To further validate these rarely mutated genes, we assessed whether the identified genes were more mutated in metastatic than in primary samples using an independent cohort. Then we evaluated their association with tumor evolution and with the lymph node status of the patients. This resulted in forwarding several novel putative driver genes for metastatic prostate cancer, some of which might be prognostic for disease evolution.

Before major athletic events, a taper is often prescribed to facilitate recovery and enhance performance. However, it is unknown which taper model is most effective for peaking maximal strength and positively augmenting skeletal muscle. Thus, the purpose of this study was to compare performance outcomes and skeletal muscle adaptations following a step vs. an exponential taper in strength athletes. Sixteen powerlifters (24.0 ± 4.0 years, 174.4 ± 8.2 cm, 89.8 ± 21.4 kg) participated in a 6-week training program aimed at peaking maximal strength on back squat [initial 1-repetition-maximum (1RM): 174.7 ± 33.4 kg], bench press (118.5 ± 29.9 kg), and deadlift (189.9 ± 41.2 kg). Powerlifters were matched based on relative maximal strength, and randomly assigned to either (a) 1-week overreach and 1-week step taper or (b) 1-week overreach and 3-week exponential taper. Athletes were tested pre- and post-training on measures of body composition, jumping performance, isometric squat, and 1RM. Whole muscle size was assessed at the proximal, middle, and distal vastus lateralis using ultrasonography and microbiopsies at the middle vastus lateralis site. Muscle samples (<i>n</i> = 15) were analyzed for fiber size, fiber type [myosin-heavy chain (MHC)-I, -IIA, -IIX, hybrid-I/IIA] using whole muscle immunohistochemistry and single fiber dot blots, gene expression, and microRNA abundance. There were significant main time effects for 1RM squat (<i>p</i> < 0.001), bench press (<i>p</i> < 0.001), and deadlift, (<i>p</i> = 0.024), powerlifting total (<i>p</i> < 0.001), Wilks Score (<i>p</i> < 0.001), squat jump peak-power scaled to body mass (<i>p</i> = 0.001), body mass (<i>p</i> = 0.005), fat mass (<i>p</i> = 0.002), and fat mass index (<i>p</i> = 0.002). There were significant main time effects for medial whole muscle cross-sectional area (mCSA) (<i>p</i> = 0.006) and averaged sites (<i>p</i> < 0.001). There was also a significant interaction for MHC-IIA fiber cross-sectional area (fCSA) (<i>p</i> = 0.014) with <i>post hoc</i> comparisons revealing increases following the step-taper only (<i>p</i> = 0.002). There were significant main time effects for single-fiber MHC-I% (<i>p</i> = 0.015) and MHC-IIA% (<i>p</i> = 0.033), as well as for MyoD (<i>p</i> = 0.002), MyoG (<i>p</i> = 0.037), and miR-499a (<i>p</i> = 0.033). Overall, increases in whole mCSA, fCSA, MHC-IIA fCSA, and MHC transitions appeared to favor the step taper group. An overreach followed by a step taper appears to produce a myocellular environment that enhances skeletal muscle adaptations, whereas an exponential taper may favor neuromuscular performance.

Ovarian cancer (OC) is a major health threat to females, as it has high morbidity and mortality. Evidence has increasingly demonstrated that long non-coding RNAs (lncRNAs) regulate OC progression and they may have value as early diagnostic biomarkers, prognostic biomarkers and/or therapeutic targets. In the present study, the regulatory mechanisms and prognosis associated with cancer-specific lncRNAs and their related competing endogenous (ce)RNA network in OC were investigated. The differential expression profiles and prognostic significance of lncRNAs and mRNAs were systematically explored based on data from 359 OC cases from The Cancer Genome Atlas and 180 healthy individuals from the Genotype-Tissue Expression database. Functional enrichment analyses, RNA-RNA interactome prediction, ceRNA network analysis, correlation analysis and survival analysis were utilized to identify hub lncRNAs and biomarkers associated with OC diagnosis or prognosis. A total of 1,049 differentially expressed lncRNAs and 6,516 differentially expressed mRNAs between OC and healthy tissues were detected. An lncRNA-micro (mi)RNA-mRNA regulatory network in OC was further established, containing 91 lncRNAs, 23 miRNAs and 179 mRNAs. After survival analysis based on the expression of the RNAs in the ceRNA network, 8 lncRNAs, 4 miRNAs and 11 mRNAs that were significantly associated with OC patient survival (P<0.05) were obtained. Using least absolute shrinkage and selection operator-penalized Cox regression, an eight-lncRNA risk score model was generated, which was able to readily discriminate between OC and healthy individuals and predict the survival of patients with OC. In addition, the differential expression of several key lncRNAs and mRNAs was verified by reverse transcription-quantitative PCR and western blot analysis. The current study presents a novel lncRNA-miRNA-mRNA network, which provides insight into the potential pathogenesis of OC and allows the identification of prognostic biomarkers and treatment strategies for OC.

Cancer stem cells (CSCs) refer to a certain subpopulation within the tumor entity that is characterized by restricted cellular proliferation and multipotent differentiation potency. The existence of CSCs has been proven to contribute to the heterogeneity of malignancies, accounting for intensified tumorigenesis, treatment resistance, and metastatic spread. Dormancy was proposed as a reversible state of cancer cells that are temporarily arrested in the cell cycle, possessing several hallmarks that facilitate their survival within a devastating niche. This transient period is evoked to enter an actively proliferating state by multiple regulatory alterations, and one of the most significant and complex factors comes from local and systemic inflammatory reactions and immune components. Although CSCs and dormant cancer cells share several similarities, the clear relationship between these two concepts remains unclear. Thus, the detailed mechanism of immune cells interacting with CSCs and dormant cancer cells also warrants elucidation for prevention of cancer relapse and metastasis. In this review, we summarize recent findings and prospective studies on CSCs and cancer dormancy to conclude the relationship between these two concepts. Furthermore, we aim to outline the mechanism of immune components in interfering with CSCs and dormant cancer cells to provide a theoretical basis for the prevention of relapse and metastasis.

Protein misfolding and aggregation are implicated in many neurodegenerative diseases. One of these diseases is Huntington's, which is caused by increased glutamine-encoding trinucleotide repeats within the Huntingtin gene. Like other misfolded proteins, mutated Huntingtin proteins with polyglutamine expansions are prone to aggregation. Misfolded proteins exist as soluble monomers, small aggregates, or as large insoluble inclusion bodies. Misfolded protein aggregates are believed to be cytotoxic by stressing the protein degradation machinery, disrupting membrane structure, or sequestering other proteins. We recently showed that expression of misfolded proteins lowers cellular free ubiquitin levels, which compromises the protein degradation machinery. Therefore, the efficient degradation of misfolded proteins is critical to preserve cell health. Cells employ two major mechanisms to degrade misfolded proteins. The first is the ubiquitin-proteasome system (UPS), which ubiquitinates and degrades misfolded proteins with the assistance of segregase Cdc48/p97. The UPS pathway is mainly responsible for the clearance of misfolded proteins present as monomers or smaller aggregates. The second pathway is macroautophagy/autophagy, in which protein aggregates or inclusion bodies are recruited into an autophagosome before transport to the vacuole/lysosome for degradation. This review is focused on the current understanding of the cytotoxicity of misfolded proteins as well as their clearance pathways, with a particular emphasis on mutant Huntingtin.

<h4>Background</h4>Unfortunately, the majority of patients with colorectal cancer liver metastases (CRCLM) experience disease recurrence following hepatic surgery. The key challenge is therefore optimal patient selection, which currently relies on anatomical and clinical parameters. Exploring a potential molecular signature may be predictive for seeing a clinical benefit from CRCLM resection.<h4>Methods</h4>Consecutive patients who underwent CRCLM resection at our medical center between 2006 and 2016 were divided into cohorts of "good prognosis" (GP) or "poor prognosis" (PP) based on the time interval between their resection and disease recurrence. Proteomic analysis was performed on the surgical specimen and correlation analysis was carried out with demographics and clinical outcomes.<h4>Results</h4>Proteomic analysis revealed 99 differentially expressed proteins of which a third were associated with extracellular matrix (ECM) pathways as the matrix metalloproteinases (MMPs). Multivariate analysis yielded a statistically differential proteomic pattern between the cohort regardless of perioperative treatment.<h4>Conclusion</h4>Our results indicate a different proteomic landscape in the cohort of patients who had a clinical benefit from CRCLM resection which appears to be correlated with ECM pathways. Further prospective studies are needed to define the role of ECM pathways in prognostics and patient selection for surgical procedures for CRCLM.

Benign recurrent intrahepatic cholestasis (BRIC) is a rare disease characterized by recurrent severe itching and jaundice. Coronavirus disease 2019 (COVID-19) is a multisystemic acute viral disease and the liver is frequently affected. Here, we wanted to present a BRIC case triggered by COVID-19 infection, discussing it together with current information.

Background We conducted a 2-sample Mendelian randomization study to assess the associations of cardiometabolic, lifestyle, and nutritional factors with varicose veins. Methods and Results Independent single-nucleotide polymorphisms associated with height (positive control), body mass index, type 2 diabetes, diastolic and systolic blood pressure, smoking, alcohol and coffee consumption, 7 circulating vitamins (A, B6, B9, B12, C, 25-hydroxyvitamin D, and E), and 5 circulating minerals (calcium, iron, magnesium, selenium, and zinc) at the genome-wide significance level were used as instrumental variables. Summary-level data for the genetic associations with varicose veins were obtained from the UK Biobank (8763 cases and 352 431 noncases) and the FinnGen consortium (13 928 cases and 153 951 noncases). Genetically predicted higher height, body mass index, smoking, and circulating iron levels were associated with an increased risk of varicose veins. The odds ratios (ORs) per 1-SD increase in the exposure were 1.34 (95% CI, 1.25-1.43) for height, 1.39 (95% CI, 1.27-1.52) for body mass index, 1.12 (95% CI, 1.04-1.22) for the prevalence of smoking initiation, and 1.24 (95% CI, 1.16-1.33) for iron. Higher genetically predicted systolic blood pressure and circulating calcium and zinc levels were associated with a reduced risk of varicose veins, whereas the association for systolic blood pressure did not persist after adjustment for genetically predicted height. The OR was 0.75 (95% CI, 0.62-0.92) per 1-SD increase in calcium levels and 0.97 (95% CI, 0.95-0.98) for zinc. Conclusions This study identified several modifiable risk factors for varicose veins.

<i>Leishmania</i> parasites are the causal agent of leishmaniasis, an endemic disease in more than 90 countries worldwide. Over the years, traditional approaches focused on the parasite when developing treatments against leishmaniasis. Despite numerous attempts, there is not yet a universal treatment, and those available have allowed for the appearance of resistance. Here, we propose and follow a host-directed approach that aims to overcome the current lack of treatment. Our approach identifies potential therapeutic targets in the host cell and proposes known drug interactions aiming to improve the immune response and to block the host machinery necessary for the survival of the parasite. We started analyzing transcription factor regulatory networks of macrophages infected with Leishmania major. Next, based on the regulatory dynamics of the infection and available gene expression profiles, we selected potential therapeutic target proteins. The function of these proteins was then analyzed following a multilayered network scheme in which we combined information on metabolic pathways with known drugs that have a direct connection with the activity carried out by these proteins. Using our approach, we were able to identify five host protein-coding gene products that are potential therapeutic targets for treating leishmaniasis. Moreover, from the 11 drugs known to interact with the function performed by these proteins, 3 have already been tested against this parasite, verifying in this way our novel methodology. More importantly, the remaining eight drugs previously employed to treat other diseases, remain as promising yet-untested antileishmanial therapies. <b>IMPORTANCE</b> This work opens a new path to fight parasites by targeting host molecular functions by repurposing available and approved drugs. We created a novel approach to identify key proteins involved in any biological process by combining gene regulatory networks and expression profiles. Once proteins have been selected, our approach employs a multilayered network methodology that relates proteins to functions to drugs that alter these functions. By applying our novel approach to macrophages during the <i>Leishmania</i> infection process, we both validated our work and found eight drugs already approved for use in humans that to the best of our knowledge were never employed to treat leishmaniasis, rendering our work as a new tool in the box available to the scientific community fighting parasites.

Cardiac hypertrophy is considered as a common pathophysiological process in various cardiovascular diseases. CUG triplet repeat-binding protein 1 (CELF1) is an RNA-binding protein that has been shown to be an important post-transcription regulator and involved in several types of cancer, whereas its role in cardiac remodeling remains unclear. Herein, we found that the expression of CELF1 was significantly increased in pressure overload-induced hypertrophic hearts and angiotensin II (Ang II)-induced neonatal cardiomyocytes. Based on transverse aortic constriction-induced cardiac hypertrophy model, CELF1 deficiency markedly ameliorated cardiac hypertrophy, cardiac fibrosis, oxidative stress, and apoptosis. Accordingly, CELF1 deficiency alleviated the production of reactive oxygen species (ROS) and apoptosis of neonatal cardiomyocytes via inhibition of Raf1, TAK1, ERK1/2, and p38 phosphorylation. Mechanistically, depletion or overexpression of CELF1 negatively regulated the protein expression of phosphatidylethanolamine-binding protein 1 (PEBP1), while the mRNA expression of PEBP1 remained unchanged. RNA immunoprecipitation revealed that CELF1 directly interacted with PEBP1 mRNA. Biotin pull-down analysis and dual-luciferase assay showed that CELF1 directly bound to the fragment 1 within 3'UTR of PEBP1. Moreover, knockdown of PEBP1 partially enhanced the production of ROS and apoptosis of neonatal cardiomyocytes inhibited by CELF1 deficiency. In conclusion, CELF1 binds to the 3'UTR of PEBP1 and acts as an endogenous activator of MAPK signaling pathway. Inhibition of CELF1 attenuates pathological cardiac hypertrophy, oxidative stress, and apoptosis, thus could be a potential therapeutic strategy of pathological cardiac hypertrophy.

The exopolysaccharide galactosaminogalactan (GAG) plays an important role in mediating adhesion, biofilm formation, and virulence in the pathogenic fungus Aspergillus fumigatus. Previous work showed that in A. fumigatus, the Lim domain-binding protein PtaB can form a complex with the sequence-specific transcription factor SomA for regulating GAG biosynthesis, biofilm formation, and asexual development. However, transcriptional coactivators required for biofilm formation in A. fumigatus remain uncharacterized. In this study, Spt20, an orthologue of the subunit of the Saccharomyces cerevisiae transcriptional coactivator Spt-Ada-Gcn5-acetyltransferase (SAGA) complex, was identified as a regulator of biofilm formation and asexual development in A. fumigatus. The loss of <i>spt20</i> caused severe defects in the GAG biosynthesis, biofilm formation, conidiation, and virulence of A. fumigatus. RNA sequence data demonstrated that Spt20 positively regulates the expression of the GAG biosynthesis genes <i>uge3</i> and <i>agd3</i>, the developmental regulator <i>medA</i>, and genes involved in the conidiation pathway. Moreover, more than 10 subunits of the SAGA complex (known from yeast) could be immunoprecipitated with Spt20, suggesting that Spt20 acts as a structural subunit of the SAGA complex. Furthermore, distinct modules of SAGA regulate GAG biosynthesis, biofilm formation, and asexual development in A. fumigatus to various degrees. In summary, the novel biofilm regulator Spt20 is reported, which plays a crucial role in the regulation of fungal asexual development, GAG biosynthesis, and virulence in A. fumigatus. These findings expand knowledge on the regulatory circuits of the SAGA complex relevant for the biofilm formation and asexual development of A. fumigatus. <b>IMPORTANCE</b> Eukaryotic transcription is regulated by a large number of proteins, ranging from sequence-specific DNA-binding factors to transcriptional coactivators (chromatin regulators and the general transcription machinery) and their regulators. Previous research indicated that the sequence-specific complex SomA/PtaB regulates the biofilm formation and asexual development of Aspergillus fumigatus. However, transcriptional coactivators working with sequence-specific transcription factors to regulate A. fumigatus biofilm formation remain uncharacterized. In this study, Spt20, an orthologue of the subunit of the Saccharomyces cerevisiae Spt-Ada-Gcn5-acetyltransferase (SAGA) complex, was identified as a novel regulator of biofilm formation and asexual development in A. fumigatus. The loss of <i>spt20</i> caused severe defects in galactosaminogalactan (GAG) production, conidiation, and virulence. Moreover, nearly all modules of the SAGA complex were required for the biofilm formation and asexual development of A. fumigatus. These results establish the SAGA complex as a transcriptional coactivator required for the biofilm formation and asexual development of A. fumigatus.

Reduction of genome ploidy from diploid to haploid necessitates stable pairing of homologous chromosomes into bivalents before the start of the first meiotic division. Importantly, this chromosome pairing must avoid interlocking of non-homologous chromosomes. In spermatocytes of Drosophila melanogaster, where homolog pairing does not involve synaptonemal complex formation and crossovers, associations between non-homologous chromosomes are broken up by chromosome territory formation in early spermatocytes. Extensive non-homologous associations arise from the coalescence of the large blocks of pericentromeric heterochromatin into a chromocenter and from centromere clustering. Nevertheless, during territory formation, bivalents are moved apart into spatially separate subnuclear regions. The condensin II subunits, Cap-D3 and Cap-H2, have been implicated, but the remarkable separation of bivalents during interphase might require more than just condensin II. For further characterization of this process, we have applied time-lapse imaging using fluorescent markers of centromeres, telomeres and DNA satellites in pericentromeric heterochromatin. We describe the dynamics of the disruption of centromere clusters and the chromocenter in normal spermatocytes. Mutations in Cap-D3 and Cap-H2 abolish chromocenter disruption, resulting in excessive chromosome missegregation during M I. Chromocenter persistence in the mutants is not mediated by the special system, which conjoins homologs in compensation for the absence of crossovers in Drosophila spermatocytes. However, overexpression of Cap-H2 precluded conjunction between autosomal homologs, resulting in random segregation of univalents. Interestingly, Cap-D3 and Cap-H2 mutant spermatocytes displayed conspicuous stretching of the chromocenter, as well as occasional chromocenter disruption, suggesting that territory formation might involve forces unrelated to condensin II. While the molecular basis of these forces remains to be clarified, they are not destroyed by inhibitors of F actin and microtubules. Our results indicate that condensin II activity promotes chromosome territory formation in co-operation with additional force generators and that careful co-ordination with alternative homolog conjunction is crucial.

Due to advances in chip and sequencing technology, several types and numbers of long non-coding RNAs (lncRNAs) have been identified. LncRNAs are defined as non-protein-coding RNA molecules longer than 200 nucleotides, and are now thought as a new frontier in the study of human malignant diseases including NSCLC. Diagnosis of numerous malignant tumors has been closely linked to the differential expression of certain lncRNAs. LncRNAs are involved in gene expression regulation at multiple levels of epigenetics, transcriptional regulation, and post-transcriptional regulation. Mutations, deletions, or abnormal expression levels lead to physiological abnormalities, disease occurrence and are closely associated with human tumor diseases. LncRNAs play a crucial role in cancerous processes as either oncogenes or tumor suppressor genes. The expression of lncRNAs can regulate tumor cell in the proliferation, migration, apoptosis, cycle, invasion, and metastasis. As such, lncRNAs are potential diagnostic and treatment targets for cancer. And that, tumor biomarkers need to be detectable in easily accessible body samples, should be characterized by high specificity and sufficient sensitivity. Herein, it is significant clinical importance to screen and supplement new biomarkers for early diagnosis of lung cancer. This study aimed at systematically describing lncRNAs from five aspects based on recent studies: concepts, classification, structure, molecular mechanism, signal pathway, as well as review lncRNA implications in malignant tumor.

<h4>Background</h4>Osteosarcoma is a highly malignant tumour associated with numerous and complex genetic alterations like copy number alterations. Recent whole genome studies revealed distinct mutations in several candidate oncogenes. While clinical parameters stratify osteosarcoma patients in risk groups, genetic profiles have not yet been used to tailor tumour treatment. However, specific copy number alterations seem to have a prognostic impact in osteosarcoma treatment. Somatic TP53 gene mutation frequently occurs in sporadic osteosarcoma. When arising germline, TP53 mutation leads to Li-Fraumeni syndrome and may result in early life osteosarcoma. The effect of Li-Fraumeni syndrome on the genetic profile of osteosarcoma and the consideration of the syndrome during cancer treatment are topics of current research.<h4>Case presentation</h4>We report a 25-year-old female with pelvic osteosarcoma refusing continuation of therapy. She interrupted neo-adjuvant chemotherapy according to EURAMOS-1/COSS recommendations and declined local or further adjuvant therapy. Surprisingly, she remained in sustained remission for the osteosarcoma but eventually died from newly diagnosed breast cancer. After establishment of breast cancer, we detected TP53 germline mutation and investigated the osteosarcoma material with array-CGH.<h4>Conclusion</h4>Genetic examination of the tumour evidenced several copy number alterations with striking differences to previously reported data. We discuss possible influences of the genetic profile on the unusual clinical course and the significance of Li-Fraumeni syndrome for the genetic profile. Specific loss of (proto-) oncogenes might have contributed to the unusual case. Further large-scale genetics of Li-Fraumeni patients combined with detailed clinical data will help to identify specific genetic risk profiles and improve treatment.