Functional Relevance Research Articles

Atopic dermatitis-associated genetic variants regulate LOC100294145 expression implicating interleukin-27 production and type 1 interferon signaling

BackgroundAtopic dermatitis (AD) is a complex inflammatory disease with a strong genetic component. A singular approach of genome wide association studies (GWAS) can identify AD-associated genetic variants, but is unable to explain their functional relevance in AD. This study aims to characterize AD-associated genetic variants and elucidate the mechanisms leading to AD through a multi-omics approach. MethodsGWAS identified an association between genetic variants at 6p21.32 locus and AD. Genotypes of 6p21.32 locus variants were evaluated against LOC100294145 expression in peripheral blood mononuclear cells (PBMCs). Their influence on LOC100294145 promoter activity was measured in vitro via a dual-luciferase assay. The function of LOC100294145 was then elucidated through a combination of co-expression analyses and gene enrichment with g:Profiler. Mendelian randomization was further used to assess the causal regulatory effect of LOC100294145 on its co-expressed genes. ResultsMinor alleles of rs116160149 and rs115388857 at 6p21.32 locus were associated with increased AD risk (p = 2.175 × 10−8, OR = 1.552; p = 2.805 × 10−9, OR = 1.55) and higher LOC100294145 expression in PBMCs (adjusted p = 0.0182; 8.267 × 10−12). LOC100294145 expression was also found to be increased in those with AD (adjusted p = 3.653 × 10−2). The genotype effect of 6p21.32 locus on LOC100294145 promoter activity was further validated in vitro. Co-expression analyses predicted LOC100294145 protein's involvement in interleukin-27 and type 1 interferon signaling, which was further substantiated through mendelian randomization. ConclusionGenetic variants at 6p21.32 locus increase AD susceptibility through raising LOC100294145 expression. A multi-omics approach enabled the deduction of its pathogenesis model comprising dysregulation of hub genes involved in type 1 interferon and interleukin 27 signaling.

A novel enzyme-based functional correlation algorithm for multi-omics reveals the potential mechanisms of traditional Chinese medicines: Taking Jian-Pi-Yi-Shen formula as an example

The integrated analysis of host metabolome and intestinal microbiome is an opportunity to explore the complex therapeutic mechanisms of traditional Chinese medicines. Currently, researchers mainly employ various statistical correlation analytical methods to investigate metabolome-microbiome correlations. However, these conventional correlation techniques often focus on statistical correlations and their biological meanings are always ignored, especially the functional relevance between them. Here, we developed a novel enzyme-based functional correlation (EBFC) algorithm to further improve the interpretability and the identified scope of microbe-metabolite correlations based on the conventional Spearman’s analysis. The proposed EBFC algorithm is successfully utilized to reveal the therapeutic mechanisms of Jian-Pi-Yi-Shen (JPYS) formula on the treatment of adenine-induced chronic kidney disease (CKD) rats. JPYS, a TCM formula for treating CKD, has beneficial clinical effects. We tentatively revealed the potential mechanism of JPYS for treating CKD rats from the perspective of the serum metabolome, gut microbiome, and their interactions. Specifically, 11 metabolites and 19 bacterial genera in the CKD rats were significantly regulated to approaching normal status after JPYS treatment, suggesting that JPYS could ameliorate the pathological symptoms of CKD rats by reshaping the disturbed metabolome and gut microbiota. Further correlation analysis between the significantly perturbed metabolites, microbiota, and the related enzymes provided more strong evidence for the study of host metabolism-microbiota interactions and the therapeutic mechanism of JPYS on CKD rats. In conclusion, these findings will help us to deeply understand the pathogenesis of CKD and provide new insights into the therapeutic mechanism of JPYS.

Dynamic Prediction with Statistical Uncertainty Evaluation of Phosphorus Content Based on Functional Relevance Vector Machine

In the steelmaking process, inaccurate composition of raw materials, experimental process parameter control, and other factors bring about large statistical uncertainty to the phosphorus content prediction of molten steel. Meanwhile, lots of models mainly predict the end‐point phosphorus content, but the composition change during the whole production process is still in the gray box condition, where the exact refining state is unknown. These two problems increase the difficulty in process parameter optimization and control. In order to improve the phosphorus content control in the steelmaking process, this work proposes the functional relevance vector machine (FRVM) method. This method smooths the time series of process parameters to continuous functions by functional data analysis to predict the phosphorus content change during the whole production process, and estimates the probabilistic distributions of regression weights based on the Bayesian framework to directly output the probabilistic confidence interval of the phosphorus content. The real‐world steelmaking dataset validates that the mean relative prediction error of phosphorus content by the FRVM method is less than 18.04% during the whole production process and the end‐point hit rate is 86.46% when the prediction error is within ±0.005 wt%.

∆Np63α inhibits Rac1 activation and cancer cell invasion through suppression of PREX1

ΔNp63α, a member of the p53 family of transcription factors, plays a critical role in maintaining the proliferative potential of stem cells in the stratified epithelium. Although ΔNp63α is considered an oncogene and is frequently overexpressed in squamous cell carcinoma, loss of ΔNp63α expression is associated with increased tumor cell invasion and metastasis. We recently identified a ΔNp63α/miR-320a/PKCγ signaling axis that regulates cancer cell invasion by inhibiting phosphorylation of the small GTPase Rac1, a master switch of cell motility that positively regulates cell invasion in multiple human cancers. In this study, we identified a novel mechanism by which ΔNp63α negatively regulates Rac1 activity, by inhibiting the expression of the Rac-specific Guanine Exchange Factor PREX1. ΔNp63α knockdown in multiple squamous cell carcinoma cell lines leads to increased Rac1 activation, which is abrogated by treatment with the Rac1 inhibitor NSC23766. Furthermore, ΔNp63α negatively regulates PREX1 transcript and protein levels. Using a Rac-GEF activation assay, we also showed that ΔNp63α reduces the levels of active PREX1. The inhibition of the PREX1-Rac1 signaling axis by ΔNp63α leads to impaired cell invasion, thus establishing the functional relevance of this link. Our results elucidated a novel molecular mechanism by which ΔNp63α negatively affects cancer cell invasion and identifies the ΔNp63α/Rac1 axis as a potential target for metastasis.

Studying SARS-CoV-2 interactions using phage-displayed receptor binding domain as a model protein

SARS-CoV-2 receptor binding domain (RBD) mediates viral entry into human cells through its interaction with angiotensin converting enzyme 2 (ACE2). Most neutralizing antibodies elicited by infection or vaccination target this domain. Such a functional relevance, together with large RBD sequence variability arising during viral spreading, point to the need of exploring the complex landscape of interactions between RBD-derived variants, ACE2 and antibodies. The current work was aimed at developing a simple platform to do so. Biologically active and antigenic Wuhan-Hu-1 RBD, as well as mutated RBD variants found in nature, were successfully displayed on filamentous phages. Mutational scanning confirmed the global plasticity of the receptor binding motif within RBD, highlighted residues playing a critical role in receptor binding, and identified mutations strengthening the interaction. The ability of vaccine-induced antibodies to inhibit ACE2 binding of many mutated RBD variants, albeit at different extents, was shown. Amino acid replacements which could compromise such inhibitory potential were underscored. The expansion of our approach could be the starting point for a large-scale phage-based exploration of diversity within RBD of SARS-CoV-2 and related coronaviruses, useful to understand structure–function relationships, to engineer RBD proteins, and to anticipate changes to watch during viral evolution.

The impact of physical activity on promoter-specific methylation of genes involved in the redox-status and disease progression: A longitudinal study on post-surgery female breast cancer patients undergoing medical treatment

Most anticancer treatments act on oxidative-stress pathways by producing reactive oxygen species (ROS) to kill cancer cells, commonly resulting in consequential drug-induced systemic cytotoxicity. Physical activity (PA) has arisen as an integrative cancer therapy, having positive health effects, including in redox-homeostasis. Here, we investigated the impact of an online supervised PA program on promoter-specific DNA methylation, and corresponding gene expression/activity, in 3 antioxidants- (SOD1, SOD2, and CAT) and 3 breast cancer (BC)-related genes (BRCA1, L3MBTL1 and RASSF1A) in a population-based sample of women diagnosed with primary BC, undergoing medical treatment. We further examined mechanisms involved in methylating and demethylating pathways, predicted biological pathways and interactions of exercise-modulated molecules, and the functional relevance of modulated antioxidant markers on parameters related to aerobic capacity/endurance, physical fatigue and quality of life (QoL).PA maintained levels of SOD activity in blood plasma, and at the cellular level significantly increased SOD2 mRNA (≈+77 %), contrary to their depletion due to medical treatment. This change was inversely correlated with DNA methylation in SOD2 promoter (≈−20 %). Similarly, we found a significant effect of PA only on L3MBTL1 promoter methylation (≈−25 %), which was inversely correlated with its mRNA (≈+43 %). Finally, PA increased TET1 mRNA levels (≈+15 %) and decreased expression of DNMT3B mRNA (≈−28 %).Our results suggest that PA-modulated DNA methylation affects several signalling pathways/biological activities involved in the cellular oxidative stress response, chromatin organization/regulation, antioxidant activity and DNA/protein binding. These changes may positively impact clinical outcomes and improve the response to cancer treatment in post-surgery BC patients.

The T2T-CHM13 reference assembly uncovers essential WASH1 and GPRIN2 paralogues.

The recently published T2T-CHM13 reference assembly completed the annotation of the final 8% of the human genome. It introduced 1956 genes, close to 100 of which are predicted to be coding because they have a protein coding parent gene. Here, we confirm the coding status and functional relevance of two of these genes, paralogues of WASHC1 and GPRIN2. We find that LOC124908094, one of four novel subtelomeric WASH1 genes uncovered in the new assembly, produces the WASH1 protein that forms part of the vital actin-regulatory WASH complex. Its coding status is supported by abundant proteomics, conservation, and cDNA evidence. It was previously assumed that gene WASHC1 produced the functional WASH1 protein, but new evidence shows that WASHC1 is a human-derived duplication and likely to be one of 12 WASH1 pseudogenes in the human gene set. We also find that the T2T-CHM13 assembly has added a functionally important copy of GPRIN2 to the human gene set. We demonstrate that uniquely mapping peptides from proteomics databases support the novel LOC124900631 rather than the GRCh38 assembly GPRIN2 gene. These new additions to the set of human coding genes underlines the importance of the new T2T-CHM13 assembly. None.

Identification of clinical prognostic factors and analysis of ferroptosis-related gene signatures in the bladder cancer immune microenvironment

BackgroundBladder cancer (BLCA) is a prevalent malignancy affecting the urinary system and poses a significant burden in terms of both incidence and mortality rates on a global scale. Among all BLCA cases, non-muscle invasive bladder cancer constitutes approximately 75% of the total. In recent years, the concept of ferroptosis, an iron-dependent form of regulated cell death marked by the accumulation of lipid peroxides, has captured the attention of researchers worldwide. Nevertheless, the precise involvement of ferroptosis-related genes (FRGs) in the anti-BLCA response remains inadequately elucidated.MethodsThe integration of BLCA samples from the TCGA and GEO datasets facilitated the quantitative evaluation of FRGs, offering potential insights into their predictive capabilities. Leveraging the wealth of information encompassing mRNAsi, gene mutations, CNV, TMB, and clinical features within these datasets further enriched the analysis, augmenting its robustness and reliability. Through the utilization of Lasso regression, a prediction model was developed, enabling accurate prognostic assessments within the context of BLCA. Additionally, co-expression analysis shed light on the complex relationship between gene expression patterns and FRGs, unraveling their functional relevance and potential implications in BLCA.ResultsFRGs exhibited increased expression levels in the high-risk cohort of BLCA patients, even in the absence of other clinical indicators, suggesting their potential as prognostic markers. GSEA revealed enrichment of immunological and tumor-related pathways specifically in the high-risk group. Furthermore, notable differences were observed in immune function and m6a gene expression between the low- and high-risk groups. Several genes, including MYBPH, SOST, SPRR2A, and CRNN, were found to potentially participate in the oncogenic processes underlying BLCA. Additionally, CYP4F8, PDZD3, CRTAC1, and LRTM1 were identified as potential tumor suppressor genes. Significant discrepancies in immunological function and m6a gene expression were observed between the two risk groups, further highlighting the distinct molecular characteristics associated with different prognostic outcomes. Notably, strong correlations were observed among the prognostic model, CNVs, SNPs, and drug sensitivity profiles.ConclusionsFRGs are associated with the onset and progression of BLCA. A FRGs signature offers a viable alternative to predict BLCA, and these FRGs show a prospective research area for BLCA targeted treatment in the future.

The effectiveness of mental health interventions involving non-specialists and digital technology in low-and middle-income countries – a systematic review

BackgroundCombining non-specialists and digital technologies in mental health interventions could decrease the mental healthcare gap in resource scarce countries. This systematic review examined different combinations of non-specialists and digital technologies in mental health interventions and their effectiveness in reducing the mental healthcare gap in low-and middle-income countries.MethodsLiterature searches were conducted in four databases (September 2023), three trial registries (January–February 2022), and using forward and backward citation searches (May–June 2022). The review included primary studies on mental health interventions combining non-specialists and digital technologies in low-and middle-income countries. The outcomes were: (1) the mental health of intervention receivers and (2) the competencies of non-specialists to deliver mental health interventions. Data were expressed as standardised effect sizes (Cohen’s d) and narratively synthesised. Risk of bias assessment was conducted using the Cochrane risk-of-bias tools for individual and cluster randomised and non-randomised controlled trials.ResultsOf the 28 included studies (n = 32 interventions), digital technology was mainly used in non-specialist primary-delivery treatment models for common mental disorders or subthreshold symptoms. The competencies of non-specialists were improved with digital training (d ≤ 0.8 in 4/7 outcomes, n = 4 studies, 398 participants). The mental health of receivers improved through non-specialist-delivered interventions, in which digital technologies were used to support the delivery of the intervention (d > 0.8 in 24/40 outcomes, n = 11, 2469) or to supervise the non-specialists’ work (d = 0.2–0.8 in 10/17 outcomes, n = 3, 3096). Additionally, the mental health of service receivers improved through digitally delivered mental health services with non-specialist involvement (d = 0.2–0.8 in 12/27 outcomes, n = 8, 2335). However, the overall certainty of the evidence was poor.ConclusionIncorporating digital technologies into non-specialist mental health interventions tended to enhance non-specialists’ competencies and knowledge in intervention delivery, and had a positive influence on the severity of mental health problems, mental healthcare utilization, and psychosocial functioning outcomes of service recipients, primarily within primary-deliverer care models. More robust evidence is needed to compare the magnitude of effectiveness and identify the clinical relevance of specific digital functions. Future studies should also explore long-term and potential adverse effects and interventions targeting men and marginalised communities.

GLP-1 in patients with myocardial infarction complicated by cardiogenic shock-an IABP-SHOCK II-substudy.

Glucagon-like peptide-1 (GLP-1) is a gut-derived peptide secreted in response to nutritional and inflammatory stimuli. Elevated GLP-1 levels predict adverse outcome in patients with acute myocardial infarction or sepsis. GLP-1 holds cardioprotective effects and GLP-1 receptor agonists reduce cardiovascular events in high-risk patients with diabetes. In this study, we aimed to investigate the capacity of GLP-1 to predict outcome in patients with cardiogenic shock (CS) complicating myocardial infarction. Circulating GLP-1 levels were serially assessed in 172 individuals during index PCI and day 2 in a prospectively planned biomarker substudy of the IABP-SHOCK II trial. All-cause mortality at short- (30days), intermediate- (1year), and long-term (6years) follow-up was used for outcome assessment. Patients with fatal short-term outcome (n = 70) exhibited higher GLP-1 levels [86 (interquartile range 45-130) pM] at ICU admission in comparison to patients with 30-day survival [48 (interquartile range 33-78) pM; p < 0.001] (n = 102). Repeated measures ANOVA revealed a significant interaction of GLP-1 dynamics from baseline to day 2 between survivors and non-survivors (p = 0.04). GLP-1 levels above vs. below the median proved to be predictive for short- [hazard ratio (HR) 2.43; 95% confidence interval (CI) 1.50-3.94; p < 0.001], intermediate- [HR 2.46; 95% CI 1.62-3.76; p < 0.001] and long-term [HR 2.12; 95% CI 1.44-3.11; p < 0.001] outcome by multivariate Cox-regression analysis. Elevated plasma levels of GLP-1 are an independent predictor for impaired prognosis in patients with myocardial infarction complicated by CS. The functional relevance of GLP-1 in this context is currently unknown and needs further investigations. www. gov Identifier: NCT00491036.

CircPVT1 Inhibits the Proliferation and Aids in Prediction of the Prognosis of Bladder Cancer.

Circular RNA PVT1 (circPVT1) is aberrantly expressed in several cancers, but its functional role and clinical relevance in bladder urothelial carcinoma (BLCA) remain unknown. This study aimed to identify the expression level of circPVT1 in BLCA and investigated its functional relevance with BLCA progression both in vitro and in vivo. GEPIA, UALCAN, and OncoLnc were referred to presented data. Quantitative real-time PCR (qPCR) was used for the measurement of transnational expression of genes in BLCA specimens and cell lines. Immunohistochemistry (IHC) and fluorescence in situ hybridization analysis (FISH) assays were performedto detect HER2 amplification, Pearson's correlation analysis to analyze the correlation between circPVT1 expression and clinical characteristics, Cox regression and K-M survival analyses to analyze prognostic factors. A nomogram was constructed for predicting prognosis. The proliferation of cells was measured by CCK-8 and colony formation assay, and the proliferation in vivo was evaluated using nude mouse models. qPCR was used to detect the expression of proliferation-related genes. circPVT1 was but mRNA PVT1 was not significantly overexpressed in BLCA. A high circPVT1 expression was associated with a better survival and negative HER2, but not with age, gender, and T stage. circPVT1 was an independent prognostic factor for the overall survival of BLCA patients. Knocking down circPVT1 promoted BLCA proliferation in vitro and in vivo. Knocking down circPVT1 upregulated ERBB2, MKI67, and PCNA expression and downregulated TP53 expression, but exerted no influence on CCND1 and CCNB1 expression. circPVT1 is a tumor suppressor and novel prognostic biomarker for BLCA.

Multi-Granularity Graph Convolution Network for Major Depressive Disorder Recognition.

Major depressive disorder (MDD) is the most common psychological disease. To improve the recognition accuracy of MDD, more and more machine learning methods have been proposed to mining EEG features, i.e. typical brain functional patterns and recognition methods that are closely related to depression using resting EEG signals. Most existing methods typically utilize threshold methods to filter weak connections in the brain functional connectivity network (BFCN) and construct quantitative statistical features of brain function to measure the BFCN. However, these thresholds may excessively remove weak connections with functional relevance, which is not conducive to discovering potential hidden patterns in weak connections. In addition, statistical features cannot describe the topological structure features and information network propagation patterns of the brain's different functional regions. To solve these problems, we propose a novel MDD recognition method based on a multi-granularity graph convolution network (MGGCN). On the one hand, this method applies multiple sets of different thresholds to build a multi-granularity functional neural network, which can remove noise while fully retaining valuable weak connections. On the other hand, this method utilizes graph neural network to learn the topological structure features and brain saliency patterns of changes between brain functional regions on the multi-granularity functional neural network. Experimental results on the benchmark datasets validate the superior performance and time complexity of MGGCN. The analysis shows that as the granularity increases, the connectivity defects in the right frontal(RF) and right temporal (RT) regions, left temporal(LT) and left posterior(LP) regions increase. The brain functional connections in these regions can serve as potential biomarkers for MDD recognition.

The Prognostic and Therapeutic Roles of ARL-6 Gene in Hepatocellular Carcinoma.

Background: Hepatocellular carcinoma (HCC) is one of the most prevalent human cancers. ARL-6, a member of the ADP ribosylation factor (like) (ARF) protein family, has gained attention as a potential therapeutic target in various malignancies and a prognostic biomarker. However, its specific roles in HCC, both prognostically and biochemically, remain largely unclear. Methods: To examine the functional relevance of ARL-6 in HCC, we acquired data from GEPIA, UALCAN, TIMER, TCGA, GeneMANIA, and Metascape databases. Then, we conducted immunohistochemistry on a replication sample comprising 26 HCC specimens to assess the efficacy of the ARL-6 gene. To unravel the mechanistic intricacies, we employed diverse assays such as the cell counting kit 8 (CCK8), flow cytometry, and transwell invasion assessment. Results: Our findings demonstrated the mRNA expression of ARL-6 was significantly upregulated in HCC compared to normal tissue, as evidenced by comprehensive database analysis. Immunohistochemistry further revealed that ARL-6 expression was remarkably higher in HCC than in para-carcinoma tissues. Moreover, ARL-6 expression exhibited noteworthy variations across diverse LIHC characteristics, including sample type, histological subtype, TP53 mutation status, nodal metastatic status, and cancer stage. In addition, high transcriptional levels of ARL-6 were correlated with diminished overall survival (OS) and disease-free survival (DFS) in HCC patients. Furthermore, our study indicated positive correlations between ARL-6 expression levels and the activities of tumor-infiltrating immune cells such as B cells, myeloid dendritic cells, macrophages, neutrophils, CD8+T cells, and CD4+T cells. Substantiating our findings, database analysis uncovered additional evidence of ARL-6 gene co-expression and its functional significance in HCC cases. Finally, we demonstrated the involvement of the ARL-6 gene in HCC cell invasion, proliferation, and apoptosis. Conclusions: In conclusion, our investigation sheds light on the pivotal role of ARL-6 in influencing HCC prognosis and treatment by modulating the biological activities of tumor cells. These discoveries hold promise for the development of predictive biomarkers and novel therapeutic avenues for affected patients.

Intrahepatic neutrophil accumulation and extracellular trap formation are associated with posthepatectomy liver failure.

Posthepatectomy liver failure (PHLF) represents a life-threatening complication with limited therapeutic options. Neutrophils play a critical and dynamic role during regeneratory processes, but their role in human liver regeneration is incompletely understood, especially as underlying liver disease, detectable in the majority of patients, critically affects hepatic regeneration. Here we explored intrahepatic neutrophil accumulation and neutrophil extracellular traps (NETs) in patients with PHLF and validated the functional relevance of NETs in a murine partial hepatectomy (PHx) model. We investigated the influx of neutrophils, macrophages, eosinophils, and mast cells and the presence of their respective extracellular traps in liver biopsies of 35 patients undergoing hepatectomy (10 patients with PHLF) before and after the initiation of liver regeneration by fluorescence microscopy. In addition, NET formation and neutrophil activation were confirmed by plasma analysis of 99 patients (24 patients with PHLF) before and up to 5 days after surgery. Furthermore, we inhibited NETs via DNase I in a murine PHx model of mice with metabolically induced liver disease. We detected rapid intrahepatic neutrophil accumulation, elevated levels of myeloperoxidase release, and NET formation in regenerating human livers, with a significantly higher increase of infiltrating neutrophils and NETs in patients with PHLF. Circulating markers of neutrophil activation, including elastase, myeloperoxidase, and citrullinated histone H3, correlated with markers of liver injury. In a murine PHx model, we showed that the inhibition of NET accelerated hepatocyte proliferation and liver regeneration. Patients with PHLF showed accelerated intrahepatic neutrophil infiltration and NET formation, which were associated with liver damage. Further, we identified postsurgical myeloperoxidase levels as predictive markers for adverse outcomes and observed that blocking NETs in a murine PHx model accelerated tissue regeneration.

Evaluating the secondary bioactive metabolites in Geodia corticostylifera.

Ophiactis savignyi could be discovered all over the world in tropical marine environments. People could have aided in the spread of O. savignyi, particularly in the western and eastern populations of Panama's Isthmus. The brittle star Ophiactis savignyi, often known as savigny's brittle star, coexists alongside the sponge Geodia corticostylifera. The focus of this research has been to assess the functional relevance of G. corticostylifera secondary metabolites as antifoulant against mussels, protection against generalist fish, and chemical cues to affiliated brittle stars. Both in flow-through and static seawater laboratory studies, O. savignyi which has previously been connected with sponges, was given both treated and control mimics at the same time. The sponge extract was also tested for its ability to protect fish against predators and fouling. Deterrence test using chemicals indicated that the normal level of the sponge extract may also suppress generalist fish predation in the field as well as the mussel Perna perna's normal attachment in clinical contexts. According to the findings, G. corticostylifera crude extract has many roles in the aquatic environments, apparently being accountable for this sponge's tighter relationship with O. savignyi, which protects the ophiuroid and inhibits epibionts on itself.

A pan-cancer characterization of immune-related NFIL3 identifies potential predictive biomarker.

Background: Nuclear factor interleukin 3 (NFIL3) mainly focuses on the regulation of the circadian rhythm and immune system. However, the potential role of NFIL3 in human cancers has not been studied extensively. Methods: We retrieved original data from the TCGA, TARGET, and GTEx datasets via the UCSC Xena browser (http://genome.ucsc.edu/) and integrated them using R version 3.6.4. NFIL3 expression was assessed using resources such as UCSC, GEPIA (http://gepia.cancer-pku.cn/), Kaplan-Meier Plotter (KM Plotter; https://kmplot.com/), and the Human Protein Atlas (HPA; https://www.proteinatlas.org/) databases. To investigate the prognostic implications of NFIL3, we utilized GEPIA, Kaplan-Meier Plotter, and PrognoScan (http://www.abren.net/PrognoScan/) datasets. For a comprehensive analysis across multiple cancer types, we employed pan-cancer data from UCSC, examining associations between NFIL3 expression and genomic heterogeneity, tumor mutational burden (TMB), microsatellite instability (MSI), tumor purity, and neoantigens. Furthermore, we explored the relationships between NFIL3 expression and the infiltration of immune cells and the expression of immune checkpoint genes. In the context of ovarian cancer, we validated the expression and functional relevance of NFIL3. Cell Counting Kit 8 (CCK8) assays were conducted to assess cell proliferation, while scratch and transwell assays were employed to evaluate cell migration capabilities. We further examined the interaction between NFIL3 and the p53 signaling pathway through quantitative real-time polymerase chain reaction (qRT-PCR), Western blot analysis, immunofluorescence confocal, and Coimmunoprecipitation (Co-IP) assays. Results: In general, NFIL3 expression in cancerous tissues exhibited diminished levels when compared to normal tissue samples. Notably, NFIL3 expression demonstrated a robust correlation with several pivotal aspects, including prognosis, immune cell infiltration, immune checkpoint-related genes, TMB, MSI, tumor purity, and the presence of neoantigens. Experimental investigations involving scratch assays, transwell assays, and assessments of cell proliferation in ovarian cancer cells have provided indications that NFIL3 may exert influence over cell migration and proliferation processes. Moreover, a substantial association between NFIL3 and the p53 signaling pathway was discerned through Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, with subsequent validation through qRT-PCR, Western blot analysis, immunofluorescence confocal, and co-immunoprecipitation (Co-IP) assays. Conclusions: Therefore, we concluded NFIL3 may serve as a possible prognostic and immunological pan-cancer biomarker.

GLIS1, Correlated with Immune Infiltrates, Is a Potential Prognostic Biomarker in Prostate Cancer.

Prostate cancer (PCa) is a prevalent malignant disease and the primary reason for cancer-related mortality among men globally. GLIS1 (GLIS family zinc finger 1) is a key regulator in various pathologies. However, the expression pattern, clinical relevance, and immunomodulatory function of GLIS1 in PCa remain unclear. In this study, GLIS1 was discovered to serve as a key gene in PCa by integrating mRNA and miRNA expression profiles from GEO database. We systematically explored the expression and prognostic values of GLIS1 in cancers using multiple databases. Additionally, we examined the functions of GLIS1 and the relationship between GLIS1 expression levels and immune infiltration in PCa. Results showed that GLIS1 was differentially expressed between normal and tumor tissues in various cancer types and was significantly low-expressed in PCa. Low GLIS1 expression was associated with poor PCa prognosis. GLIS1 was also involved in the activation, proliferation, differentiation, and migration of immune cells, and its expression showed a positive correlation with the infiltration of various immune cells. Moreover, GLIS1 expression was positively associated with various chemokines/chemokine receptors, indicating the involvement in regulating immune cell migration. In summary, GLIS1 is a potential prognostic biomarker and a therapeutic target to modulate anti-tumor immune response in PCa.

Eco‐physiological arguments on the functional impact of Lepus timidus mitochondrial DNA introgression in Iberian hares (Lepus granatensis)

AbstractGenetic exchanges between species provide valuable opportunities to dissect the relative importance of neutral and selective processes driving introgression events and to test their functional relevance. In the northern half of the Iberian Peninsula, the Iberian hare, Lepus granatensis, presents extensive patterns of mitochondrial DNA (mtDNA) introgression from the mountain hare, L. timidus, a species that disappeared from the region after the Last Glacial Maximum. Here, we test whether mtDNA introgression affects reproductive success and body condition of Iberian hare individuals. For that end, hares (n = 149) were sampled from populations along the mtDNA introgression gradient during the 2013–2014 and 2014–2015 hunting seasons. Reproductive performance indicators, including pregnancy status and testicular weight, were recorded, while body condition was measured as kidney fat (our response variables). Predictors included individual traits (sex and age), sampling period (month and hunting season), mtDNA introgression, occurrence or burden of different endoparasites and environmental factors. Our results showed that mtDNA introgression was negatively associated with pregnancy in females and body condition in males, while a positive association was found with body condition in females. These results suggest that carrying the mountain hare mtDNA has physiological effects in Iberian hares, but that the allospecific mtDNA type may not always be beneficial for the individual. This study shows that the patterns of mtDNA introgression seen in the Iberian hare today may result from a complex balance between deleterious and beneficial individual effects.

Hypobaric hypoxia drives selection of altitude-associated adaptative alleles in the Himalayan population

Genetic variants play a crucial role in shaping the adaptive phenotypes associated with high-altitude populations. Nevertheless, a comprehensive understanding of the specific impacts of different environments associated with increasing altitudes on the natural selection of these genetic variants remains undetermined. Hence, this study aimed to identify genetic markers responsible for high-altitude adaptation with specific reference to different altitudes, majorly focussing on an altitude elevation range of ∼1500 m and a corresponding decrease of ≥5 % in ambient oxygen availability. We conducted a comprehensive genome-wide investigation (n = 192) followed by a validation study (n = 514) in low-altitude and three high-altitude populations (>2400 m) of Nubra village (NU) (3048 m), Sakti village (SKT) (3812 m), and Tso Moriri village (TK) (4522 m). Extensive genetic analysis identified 86 SNPs that showed significant associations with high-altitude adaptation. Frequency mapping of these SNPs revealed 38 adaptive alleles and specific haplotypes that exhibited a strong linear correlation with increasing altitude. Notably, these SNPs spanned crucial genes, such as ADH6 and NAPG along with the vastly studied genes like EGLN1 and EPAS1, involved in oxygen sensing, metabolism, and vascular homeostasis. Correlation analyses between these adaptive alleles and relevant clinical and biochemical markers provided evidence of their functional relevance in physiological adaptation to hypobaric hypoxia. High-altitude population showed a significant increase in plasma 8-isoPGF2α levels as compared to low-altitude population. Similar observation showcased increased blood pressure in NU as compared to TK (P < 0.0001). In silico analyses further confirmed that these alleles regulate gene expression of EGLN1, EPAS1, COQ7, NAPG, ADH6, DUOXA1 etc. This study provides genetic insights into the effects of hypobaric-hypoxia on the clinico-physiological characteristics of natives living in increasing high-altitude regions. Overall, our findings highlight the synergistic relationship between environment and evolutionary processes, showcasing physiological implications of genetic variants in oxygen sensing and metabolic pathway genes in increasing high-altitude environments.

EGFR-activated myofibroblasts promote metastasis of pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis. Cancer-associated fibroblasts (CAFs) are recognized potential therapeutic targets, but poor understanding of these heterogeneous cell populations has limited the development of effective treatment strategies. We previously identified transforming growth factor beta (TGF-β) as a main driver of myofibroblastic CAFs (myCAFs). Here, we show that epidermal growth factor receptor/Erb-B2 receptor (EGFR/ERBB2) signaling is induced by TGF-β in myCAFs through an autocrine process mediated by amphiregulin. Inhibition of this EGFR/ERBB2-signaling network in PDAC organoid-derived cultures and mouse models differentially impacts distinct CAF subtypes, providing insights into mechanisms underpinning their heterogeneity. Remarkably, EGFR-activated myCAFs promote PDAC metastasis in mice, unmasking functional significance in myCAF heterogeneity. Finally, analyses of other cancer datasets suggest that these processes might operate in other malignancies. These data provide functional relevance to myCAF heterogeneity and identify a candidate target for preventing tumor invasion in PDAC.