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IntroductionA hexanucleotide repeat expansion (HRE) intronic to chromosome 9 open reading frame 72 (C9orf72) is recognized as the most common genetic cause of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and ALS-FTD. Identifying genes that show similar regional co-expression patterns to C9orf72 may help identify novel gene targets and biological mechanisms that mediate selective vulnerability to ALS and FTD pathogenesis.MethodsWe leveraged mRNA expression data in healthy brain from the Allen Human Brain Atlas to evaluate C9orf72 co-expression patterns. To do this, we correlated average C9orf72 expression values in 51 regions across different anatomical divisions (cortex, subcortex, and cerebellum) with average gene expression values for 15,633 protein-coding genes, including 54 genes known to be associated with ALS, FTD, or ALS-FTD. We then performed imaging transcriptomic analyses to evaluate whether the identified C9orf72 co-expressed genes correlated with patterns of cortical thickness in symptomatic C9orf72 pathogenic HRE carriers (n = 19) compared to controls (n = 23). Lastly, we explored whether genes with significant C9orf72 imaging transcriptomic correlations (i.e., "C9orf72 imaging transcriptomic network") were enriched in specific cell populations in the brain and enriched for specific biological and molecular pathways.ResultsA total of 2,120 genes showed an anatomical distribution of gene expression in the brain similar to C9orf72 and significantly correlated with patterns of cortical thickness in C9orf72 HRE carriers. This C9orf72 imaging transcriptomic network was differentially expressed in cell populations previously implicated in ALS and FTD, including layer 5b cells, cholinergic neurons in the spinal cord and brainstem and medium spiny neurons of the striatum, and was enriched for biological and molecular pathways associated with protein ubiquitination, autophagy, cellular response to DNA damage, endoplasmic reticulum to Golgi vesicle-mediated transport, among others.ConclusionConsidered together, we identified a network of C9orf72 associated genes that may influence selective regional and cell-type-specific vulnerabilities in ALS/FTD.

Despite considerable investigative efforts, the molecular mechanisms of postoperative delirium (POD) remain unresolved. The present investigation employs innovative methodologies for identifying potential primary and secondary metabolic markers of POD by analyzing serum metabolomic profiles utilizing the genetic algorithm and artificial neural networks. The primary metabolomic markers constitute a combination of metabolites that optimally distinguish between POD and non-POD groups of patients. Our analysis revealed L-lactic acid, inositol, and methylcysteine as the most salient primary markers upon which the prediction accuracy of POD manifestation achieved AUC = 99%. The secondary metabolomic markers represent metabolites that exhibit perturbed correlational patterns within the POD group. We identified 54 metabolites as the secondary markers of POD, incorporating neurotransmitters such as gamma-aminobutyric acid (GABA) and serotonin. These findings imply a systemic disruption in metabolic processes in patients with POD. The deployment of gene network reconstruction techniques facilitated the postulation of hypotheses describing the role of established genomic POD markers in the molecular-genetic mechanisms of metabolic pathways dysregulation, and involving the identified primary and secondary metabolomic markers. This study not only expands the understanding of POD pathogenesis but also introduces a novel technology for the bioinformatic analysis of metabolomic data that could aid in uncovering potential primary and secondary markers in diverse research domains. [ABSTRACT FROM AUTHOR]

Summary: Our study utilized genome‐wide association studies (GWAS) to link nucleotide variants to traits in Populus trichocarpa, a species with rapid linkage disequilibrium decay. The aim was to overcome the challenge of interpreting statistical associations at individual loci without sufficient biological context, which often leads to reliance solely on gene annotations from unrelated model organisms.We employed an integrative approach that included GWAS targeting multiple traits using three individual techniques for lignocellulose phenotyping, expression quantitative trait loci (eQTL) analysis to construct transcriptional regulatory networks around each candidate locus and co‐expression analysis to provide biological context for these networks, using lignocellulose biosynthesis in Populus trichocarpa as a case study.The research identified three candidate genes potentially involved in lignocellulose formation, including one previously recognized gene (Potri.005G116800/VND1, a critical regulator of secondary cell wall formation) and two genes (Potri.012G130000/AtSAP9 and Potri.004G202900/BIC1) with newly identified putative roles in lignocellulose biosynthesis.Our integrative approach offers a framework for providing biological context to loci associated with trait variation, facilitating the discovery of new genes and regulatory networks. [ABSTRACT FROM AUTHOR]

Abstract Background The genetic background of cancer remains complex and challenging to integrate. Many somatic mutations within genes are known to cause and drive cancer, while genome-wide association studies (GWAS) of cancer have revealed many germline risk factors associated with cancer. However, the overlap between known somatic driver genes and positional candidate genes from GWAS loci is surprisingly small. We hypothesised that genes from multiple independent cancer GWAS loci should show tissue-specific co-regulation patterns that converge on cancer-specific driver genes. Results We studied recent well-powered GWAS of breast, prostate, colorectal and skin cancer by estimating co-expression between genes and subsequently prioritising genes that show significant co-expression with genes mapping within susceptibility loci from cancer GWAS. We observed that the prioritised genes were strongly enriched for cancer drivers defined by COSMIC, IntOGen and Dietlein et al. The enrichment of known cancer driver genes was most significant when using co-expression networks derived from non-cancer samples of the relevant tissue of origin. Conclusion We show how genes within risk loci identified by cancer GWAS can be linked to known cancer driver genes through tissue-specific co-expression networks. This provides an important explanation for why seemingly unrelated sets of genes that harbour either germline risk factors or somatic mutations can eventually cause the same type of disease.

Abstract Background Soybean establishes a mutualistic interaction with nitrogen-fixing rhizobacteria, acquiring most of its nitrogen requirements through symbiotic nitrogen fixation. This crop is susceptible to water deficit; evidence suggests that its nodulation status—whether it is nodulated or not—can influence how it responds to water deficit. The translational control step of gene expression has proven relevant in plants subjected to water deficit. Results Here, we analyzed soybean roots’ differential responses to water deficit at transcriptional, translational, and mixed (transcriptional + translational) levels. Thus, the transcriptome and translatome of four combined-treated soybean roots were analyzed. We found hormone metabolism-related genes among the differentially expressed genes (DEGs) at the translatome level in nodulated and water-restricted plants. Also, weighted gene co-expression network analysis followed by differential expression analysis identified gene modules associated with nodulation and water deficit conditions. Protein-protein interaction network analysis was performed for subsets of mixed DEGs of the modules associated with the plant responses to nodulation, water deficit, or their combination. Conclusions Our research reveals that the stand-out processes and pathways in the before-mentioned plant responses partially differ; terms related to glutathione metabolism and hormone signal transduction (2 C protein phosphatases) were associated with the response to water deficit, terms related to transmembrane transport, response to abscisic acid, pigment metabolic process were associated with the response to nodulation plus water deficit. Still, two processes were common: galactose metabolism and branched-chain amino acid catabolism. A comprehensive analysis of these processes could lead to identifying new sources of tolerance to drought in soybean.

Background: The genetic background of cancer remains complex and challenging to integrate. Many somatic mutations within genes are known to cause and drive cancer, while genome-wide association studies (GWAS) of cancer have revealed many germline risk factors associated with cancer. However, the overlap between known somatic driver genes and positional candidate genes from GWAS loci is surprisingly small. We hypothesised that genes from multiple independent cancer GWAS loci should show tissue-specific co-regulation patterns that converge on cancer-specific driver genes. Results: We studied recent well-powered GWAS of breast, prostate, colorectal and skin cancer by estimating co-expression between genes and subsequently prioritising genes that show significant co-expression with genes mapping within susceptibility loci from cancer GWAS. We observed that the prioritised genes were strongly enriched for cancer drivers defined by COSMIC, IntOGen and Dietlein et al. The enrichment of known cancer driver genes was most significant when using co-expression networks derived from non-cancer samples of the relevant tissue of origin. Conclusion: We show how genes within risk loci identified by cancer GWAS can be linked to known cancer driver genes through tissue-specific co-expression networks. This provides an important explanation for why seemingly unrelated sets of genes that harbour either germline risk factors or somatic mutations can eventually cause the same type of disease. [ABSTRACT FROM AUTHOR]

Background: Soybean establishes a mutualistic interaction with nitrogen-fixing rhizobacteria, acquiring most of its nitrogen requirements through symbiotic nitrogen fixation. This crop is susceptible to water deficit; evidence suggests that its nodulation status—whether it is nodulated or not—can influence how it responds to water deficit. The translational control step of gene expression has proven relevant in plants subjected to water deficit. Results: Here, we analyzed soybean roots' differential responses to water deficit at transcriptional, translational, and mixed (transcriptional + translational) levels. Thus, the transcriptome and translatome of four combined-treated soybean roots were analyzed. We found hormone metabolism-related genes among the differentially expressed genes (DEGs) at the translatome level in nodulated and water-restricted plants. Also, weighted gene co-expression network analysis followed by differential expression analysis identified gene modules associated with nodulation and water deficit conditions. Protein-protein interaction network analysis was performed for subsets of mixed DEGs of the modules associated with the plant responses to nodulation, water deficit, or their combination. Conclusions: Our research reveals that the stand-out processes and pathways in the before-mentioned plant responses partially differ; terms related to glutathione metabolism and hormone signal transduction (2 C protein phosphatases) were associated with the response to water deficit, terms related to transmembrane transport, response to abscisic acid, pigment metabolic process were associated with the response to nodulation plus water deficit. Still, two processes were common: galactose metabolism and branched-chain amino acid catabolism. A comprehensive analysis of these processes could lead to identifying new sources of tolerance to drought in soybean. [ABSTRACT FROM AUTHOR]

A vexing observation in genome-wide association studies (GWASs) is that parallel analyses in different species may not identify orthologous genes. Here, we demonstrate that cross-species translation of GWASs can be greatly improved by an analysis of co-localization within molecular networks. Using body mass index (BMI) as an example, we show that the genes associated with BMI in humans lack significant agreement with those identified in rats. However, the networks interconnecting these genes show substantial overlap, highlighting common mechanisms including synaptic signaling, epigenetic modification, and hormonal regulation. Genetic perturbations within these networks cause abnormal BMI phenotypes in mice, too, supporting their broad conservation across mammals. Other mechanisms appear species specific, including carbohydrate biosynthesis (humans) and glycerolipid metabolism (rodents). Finally, network co-localization also identifies cross-species convergence for height/body length. This study advances a general paradigm for determining whether and how phenotypes measured in model species recapitulate human biology.

Over the past 2 decades, rapid advances in synthetic biology have enabled the design of increasingly intricate and biologically relevant systems with broad applications in healthcare. A growing area of interest is in designing bacteria that sense and respond to endogenous disease-associated signals, creating engineered theranostics that function as disease surveyors for human health. In particular, engineered cells hold potential in facilitating greatly enhanced temporal and spatial control over the release of a range of therapeutics. Such systems are particularly useful for targeting challenging, under-drugged disease targets in a more nuanced manner than is currently possible. This review provides an overview of the recent advances in the design, delivery, and dynamics of bacterial theranostics to enable safe, robust, and genetically tractable therapies to treat disease. It outlines the primary challenges in theranostic clinical translation, proposes strategies to overcome these issues, and explores promising future avenues for the field.

Thebaine, a vital precursor in the codeine and morphine pathway, shows promise in addiction treatment. We conducted a comprehensive study on the thebaine biosynthesis pathway in opium poppy, utilizing bioinformatics tools. The dataset comprising the thirteen genes associated with the thebaine biosynthesis pathway was compiled from an extensive review of published literature and validated using the NCBI BLAST tool. Utilizing STRING and Cytoscape, we analyzed gene interactions and visualized the molecular interaction network, respectively. To identify hub proteins, CytoHubba was administered. The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) at STRING were used for the enrichment analysis of the hub genes. CytoCluster was used to analyze the network in clusters. Promoter regions of hub genes and potential miRNAs were explored using MEME and the psRNATarget database. Hub genes crucial to thebaine biosynthesis were identified, contributing to essential cellular functions like growth, development, stress response, and signal transduction. Metabolic processes emerged as pivotal for thebaine production, indicating a broader role for the thebaine pathway gene network beyond primary metabolite production. Cell component subnetwork genes demonstrated associations with anatomical units, indicating involvement in plant defense responses. Dominant molecular functions drove plant defense responses. KEGG pathway analysis highlighted the significance of metabolic pathways and biosynthesis of secondary metabolites. Cluster analysis emphasized the relevance of the biosynthesis of amino acids, confirming the link between primary and secondary metabolites. Promoter analysis suggested the potential involvement of signal transduction in thebaine production. Hub genes were targeted by 40 miRNAs, suggesting potential novel biomarkers or target genes within the thebaine biosynthesis pathway. Based on the role of miRNAs identified in connection with the hub genes of the thebaine production process, the secondary metabolite pathway of thebaine appears to be associated with several key plant pathways, e.g. growth, development and stress response. However, these findings, based on bioinformatics analysis, warrant further experimental validation and promise to advance our understanding of the biosynthesis of thebaine and its interactions with other genes and metabolic pathways that influence the production of metabolites.

Background: Studies have shown that cardiovascular health (CVH) is related to depression. We aimed to identify gene networks jointly associated with depressive symptoms and cardiovascular health metrics using the whole blood transcriptome. Materials and methods: We analyzed human blood transcriptomic data to identify gene co-expression networks, termed gene modules, shared by Beck's depression inventory (BDI-II) scores and cardiovascular health (CVH) metrics as markers of depression and cardiovascular health, respectively. The BDI-II scores were derived from Beck's Depression Inventory, a 21-item self-report inventory that measures the characteristics and symptoms of depression. CVH metrics were defined according to the American Heart Association criteria using seven indices: smoking, diet, physical activity, body mass index (BMI), blood pressure, total cholesterol, and fasting glucose. Joint association of the modules, identified with weighted co-expression analysis, as well as the member genes of the modules with the markers of depression and CVH were tested with multivariate analysis of variance (MANOVA). Results: We identified a gene module with 256 genes that were significantly correlated with both the BDI-II score and CVH metrics. Based on the MANOVA test results adjusted for age and sex, the module was associated with both depression and CVH markers. The three most significant member genes in the module were YOD1, RBX1, and LEPR. Genes in the module were enriched with biological pathways involved in brain diseases such as Alzheimer's, Parkinson's, and Huntington's. Conclusions: The identified gene module and its members can provide new joint biomarkers for depression and CVH. [ABSTRACT FROM AUTHOR]

The first hematopoietic stem and progenitor cells (HSPCs) emerge in the Aorta-Gonad-Mesonephros (AGM) region of the mid-gestation mouse embryo. However, the precise nature of their supportive mesenchymal microenvironment remains largely unexplored. Here, we profiled transcriptomes of laser micro-dissected aortic tissues at three developmental stages and individual AGM cells. Computational analyses allowed the identification of several cell subpopulations within the E11.5 AGM mesenchyme, with the presence of a yet unidentified subpopulation characterized by the dual expression of genes implicated in adhesive or neuronal functions.We confirmed the identity of this cell subset as a neuro-mesenchymal population, through morphological and lineage tracing assays. Loss of function in the zebrafish confirmed that Decorin, a characteristic extracellular matrix component of the neuro-mesenchyme, is essential for HSPC development. We further demonstrated that this cell population is not merely derived from the neural crest, and hence, is a bona fide novel subpopulation of the AGM mesenchyme. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) is the most prevalent non-cutaneous cancer in men. Early PCa detection has been made possible by the adoption of screening methods based on the serum prostate-specific antigen and Gleason score (GS). The aim of this study was to correlate gene expression with the differentiation level of prostate adenocarcinomas, as indicated by GS. We used data from The Cancer Genome Atlas (TCGA) and included 497 prostate cancer patients, 52 of which also had normal tissue sample sequencing data. Gene ontology analysis revealed that higher GSs were associated with greater responses to DNA damage, telomere lengthening, and cell division. Positive correlation was found with transcription factor activator of the adenovirus gene E2 (E2F) and avian myelocytomatosis viral homolog (MYC) targets, G2M checkpoints, DNA repair, and mitotic spindles. Immune cell deconvolution revealed high M0 macrophage counts and an increase in M2 macrophages dependent on the GS. The molecular pathways most correlated with GSs were cell cycle, RNA transport, and calcium signaling (depleted). A combinatorial approach identified a set of eight genes able to differentiate by k-Nearest Neighbors (kNN) between normal tissues, low-Gleason tissues, and high-Gleason tissues with high accuracy. In conclusion, our study could be a step forward to better understanding the link between gene expression and PCa progression and aggressiveness. [ABSTRACT FROM AUTHOR]

This study explores the genetic risk associations with autism spectrum disorder (ASD) using graph neural networks (GNNs), leveraging the Sfari dataset and protein interaction network (PIN) data. We built a gene network with genes as nodes, chromosome band location as node features, and gene interactions as edges. Graph models were employed to classify the autism risk associated with newly introduced genes (test set). Three classification tasks were undertaken to test the ability of our models: binary risk association, multi-class risk association, and syndromic gene association. We tested graph convolutional networks, Graph Sage, graph transformer, and Multi-Layer Perceptron (Baseline) architectures on this problem. The Graph Sage model consistently outperformed the other models, showcasing its utility in classifying ASD-related genes. Our ablation studies show that the chromosome band location and protein interactions contain useful information for this problem. The models achieved 85.80% accuracy on the binary risk classification, 81.68% accuracy on the multi-class risk classification, and 90.22% on the syndromic classification. [ABSTRACT FROM AUTHOR]

Key developmental pathways and gene networks underlie the formation of sensory cell types and structures involved in chemosensation, vision and mechanosensation, and of the efferents these sensory inputs can activate. We describe similarities and differences in these pathways and gene networks in selected species of the three main chordate groups, lancelets, tunicates, and vertebrates, leading to divergent development of olfactory receptors, eyes, hair cells and motoneurons. The lack of appropriately posited expression of certain transcription factors in lancelets and tunicates prevents them from developing vertebrate-like olfactory receptors and eyes, although they generate alternative structures for chemosensation and vision. Lancelets and tunicates lack mechanosensory cells associated with the sensation of acoustic stimuli, but have gravisensitive organs and ciliated epidermal sensory cells that may (and in some cases clearly do) provide mechanosensation and thus the capacity to respond to movement relative to surrounding water. Although functionally analogous to the vertebrate vestibular apparatus and lateral line, homology is questionable due to differences in the expression of the key transcription factors Neurog and Atoh1/7, on which development of vertebrate hair cells depends. The vertebrate hair cell-bearing inner ear and lateral line thus likely represent major evolutionary advances specific to vertebrates. Motoneurons develop in vertebrates under the control of the ventral signaling molecule hedgehog/sonic hedgehog (Hh,Shh), against an opposing inhibitory effect mediated by dorsal signaling molecules. Many elements of Shh-signaling and downstream genes involved in specifying and differentiating motoneurons are also exhibited by lancelets and tunicates, but the repertoire of MNs in vertebrates is broader, indicating greater diversity in motoneuron differentiation programs. [ABSTRACT FROM AUTHOR]

Introduction: A hexanucleotide repeat expansion (HRE) intronic to chromosome 9 open reading frame 72 (C9orf72) is recognized as the most common genetic cause of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and ALS-FTD. Identifying genes that show similar regional co-expression patterns to C9orf72 may help identify novel gene targets and biological mechanisms that mediate selective vulnerability to ALS and FTD pathogenesis. Methods: We leveraged mRNA expression data in healthy brain from the Allen Human Brain Atlas to evaluate C9orf72 co-expression patterns. To do this, we correlated average C9orf72 expression values in 51 regions across different anatomical divisions (cortex, subcortex, and cerebellum) with average gene expression values for 15,633 protein-coding genes, including 54 genes known to be associated with ALS, FTD, or ALS-FTD. We then performed imaging transcriptomic analyses to evaluate whether the identified C9orf72 coexpressed genes correlated with patterns of cortical thickness in symptomatic C9orf72 pathogenic HRE carriers (n = 19) compared to controls (n = 23). Lastly, we explored whether genes with significant C9orf72 imaging transcriptomic correlations (i.e., "C9orf72 imaging transcriptomic network") were enriched in specific cell populations in the brain and enriched for specific biological and molecular pathways. Results: A total of 2,120 genes showed an anatomical distribution of gene expression in the brain similar to C9orf72 and significantly correlated with patterns of cortical thickness in C9orf72 HRE carriers. This C9orf72 imaging transcriptomic network was differentially expressed in cell populations previously implicated in ALS and FTD, including layer 5b cells, cholinergic neurons in the spinal cord and brainstem and medium spiny neurons of the striatum, and was enriched for biological and molecular pathways associated with protein ubiquitination, autophagy, cellular response to DNA damage, endoplasmic reticulum to Golgi vesicle-mediated transport, among others. Conclusion: Considered together, we identified a network of C9orf72 associated genes that may influence selective regional and cell-type-specific vulnerabilities in ALS/FTD. [ABSTRACT FROM AUTHOR]

A significant limitation of numerous current genetic engineering therapy approaches is their limited control over the strength, timing, or cellular context of their therapeutic effect. Synthetic gene/genetic circuits are synthetic biology approaches that can control the generation, transformation, or depletion of a specific DNA, RNA, or protein and provide precise control over gene expression and cellular behavior. They can be designed to perform logical operations by carefully selecting promoters, repressors, and other genetic components. Patent search was performed in Espacenet, resulting in 38 selected patents with 15 most frequent international classifications. Patent embodiments were categorized into applications for the delivery of therapeutic molecules, treatment of infectious diseases, treatment of cancer, treatment of bleeding, and treatment of metabolic disorders. The logic gates of selected genetic circuits are described to comprehensively demonstrate their therapeutic applications. Synthetic gene circuits can be customized for precise control of therapeutic interventions, leading to personalized therapies that respond specifically to individual patient needs, enhancing treatment efficacy and minimizing side effects. They can be highly sensitive biosensors that provide real-time therapy by accurate monitoring various biomarkers or pathogens and appropriately synthesizing a therapeutic molecule. Synthetic gene circuits may also lead to the development of advanced regenerative therapies and to implantable biodevices that produce on-demand bioactive molecules. However, this technology faces challenges for commercial profitability. The genetic circuit designs need adjustments for specific applications, and may have disadvantages like toxicity from multiple regulators, homologous recombination, context dependency, resource overuse, and environmental variability.

Abstract Diabetes cell replacement therapy has the potential to be transformed by human pluripotent stem cell-derived β cells (SC-β cells). However, the precise identity of SC-β cells in relationship to primary fetal and adult β-cells remains unclear. Here, we used single-cell sequencing datasets to characterize the transcriptional identity of islets from in vitro differentiation, fetal islets, and adult islets. Our analysis revealed that SC-β cells share a core β-cell transcriptional identity with human adult and fetal β-cells, however SC-β cells possess a unique transcriptional profile characterized by the persistent expression and activation of progenitor and neural-biased gene networks. These networks are present in SC-β cells, irrespective of the derivation protocol used. Notably, fetal β-cells also exhibit this neural signature at the transcriptional level. Our findings offer insights into the transcriptional identity of SC-β cells and underscore the need for further investigation of the role of neural transcriptional networks in their development.

The participants of Hepatitis C virus (HCV) replication are both viral and host proteins. Therapeutic approaches based on activity inhibition of viral non-structural proteins NS3, NS5A, and NS5B are undergoing clinical trials. However, rapid mutation processes in the viral genome and acquisition of drug resistance to the existing drugs remain the main obstacles to fighting HCV. Identifying the host factors, exploring their role in HCV RNA replication, and studying viral effects on their expression is essential for understanding the mechanisms of viral replication and developing novel, effective curative approaches. It is known that the host factors PREB (prolactin regulatory element binding) and PLA2G4C (cytosolic phospholipase A2 gamma) are important for the functioning of the viral replicase complex and the formation of the platforms of HCV genome replication. The expression of PREB and PLA2G4C was significantly elevated in the presence of the HCV genome. However, the mechanisms of its regulation by HCV remain unknown. In this paper, using a text-mining technology provided by ANDSystem, we reconstructed and analyzed gene networks describing regulatory effects on the expression of PREB and PLA2G4C by HCV proteins. On the basis of the gene network analysis performed, we put forward hypotheses about the modulation of the host factors functions resulting from protein-protein interaction with HCV proteins. Among the viral proteins, NS3 showed the greatest number of regulatory linkages. We assumed that NS3 could inhibit the function of host transcription factor (TF) NOTCH1 by protein-protein interaction, leading to upregulation of PREB and PLA2G4C. Analysis of the gene networks and data on differential gene expression in HCV-infected cells allowed us to hypothesize further how HCV could regulate the expression of TFs, the binding sites of which are localized within PREB and PLA2G4C gene regions. The results obtained can be used for planning studies of the molecular-genetic mechanisms of viral-host interaction and searching for potential targets for anti-HCV therapy.

Postoperative delirium (POD) is considered one of the most severe complications, resulting in impaired cognitive function, extended hospitalization, and higher treatment costs. The challenge of early POD diagnosis becomes particularly significant in cardiac surgery cases, as the incidence of this complication exceeds 50 % in certain patient categories. While it is known that neuroinflammation, neurotransmitter imbalances, disruptions in neuroendocrine regulation, and interneuronal connections contribute significantly to the development of POD, the molecular, genetic mechanisms of POD in cardiac surgery patients, along with potential metabolomic diagnostic markers, remain in adequately understood. In this study, blood plasma was collected from a group of patients over 65 years old after cardiac surgery involving artificial circulation. The collected samples were analyzed for sphingomyelin content and quantity using high-performance liquid chromatography coupled with mass spectrometry (HPLC-MS/MS) me thods. The analysis revealed four significantly different sphingomyelin contents in patients with POD compared to those who did not develop POD (control group). Employing gene network reconstruction, we perceived a set of 82 regulatory enzymes affiliated with the genetic coordination of the sphingolipid metabolism pathway. Within this set, 47 are assumed to be regulators of gene expression, governing the transcription of enzymes pivotal to the metabolic cascade. Complementing this, an additional assembly of 35 regulators are considered to be regulators of activity, degradation, and translocation dynamics of enzymes integral to the aforementioned pathway. Analysis of the overrepresentation of diseases with which these regulatory proteins are associated showed that the regulators can be categorized into two groups, associated with cardiovascular pathologies (CVP) and neuropsychiatric diseases (NPD), respectively. The regulators associated with CVP are expectedly related to the effects on myocardial tissue during surgery. It is hypothesized that dysfunction of NPD-associated regulators may specifically account for the development of POD after cardiac surgery. Thus, the identified regulatory genes may provide a basis for planning further experiments, in order to study disorders at the level of expression of these genes, as well as impaired function of proteins encoded by them in patients with POD. The identified significant sphingolipids can be considered as potential markers of POD.

Hepatocellular carcinoma (HCC) is a common severe type of liver cancer characterized by an extremely aggressive course and low survival rates. It is known that disruptions in the regulation of apoptosis activation are some of the key features inherent in most cancer cells, which determines the pharmacological induction of apoptosis as an important strategy for cancer therapy. The computer design of chemical compounds capable of specifically regulating the external signaling pathway of apoptosis induction represents a promising approach for creating new effective ways of therapy for liver cancer and other oncological diseases. However, at present, most of the studies are devoted to pharmacological effects on the internal (mitochondrial) apoptosis pathway. In contrast, the external pathway induced via cell death receptors remains out of focus. Aberrant gene methylation, along with hepatitis C virus (HCV) infection, are important risk factors for the development of hepatocellular carcinoma. The reconstruction of gene networks describing the molecular mechanisms of interaction of aberrantly methylated genes with key participants of the extrinsic apoptosis pathway and their regulation by HCV proteins can provide important information when searching for pharmacological targets. In the present study, 13 criteria were proposed for prioritizing potential pharmacological targets for developing anti-hepatocarcinoma drugs modulating the extrinsic apoptosis pathway. The criteria are based on indicators of the structural and functional organization of reconstructed gene networks of hepatocarcinoma, the extrinsic apoptosis pathway, and regulatory pathways of virus-extrinsic apoptosis pathway interaction and aberrant gene methylation-extrinsic apoptosis pathway interaction using ANDSystem. The list of the top 100 gene targets ranked according to the prioritization rating was statistically significantly (p-value = 0.0002) enriched for known pharmacological targets approved by the FDA, indicating the correctness of the prioritization method. Among the promising potential pharmacological targets, six highly ranked genes (JUN, IL10, STAT3, MYC, TLR4, and KHDRBS1) are likely to deserve close attention.

Background: Human papillomavirus (HPV)-induced cervical cancer progresses through a series of steps. Despite our limited understanding of the mechanisms driving this progression, identifying the key genes involved could significantly improve early detection and treatment. Materials and Methods: Two gene expression profiles of GSE9750 and GSE6791, which included cervical cancer HPV-positive and -negative samples, were evaluated using the R limma package with established cut-off criteria of P value < 0.05 and | fold change| ≥ 1. KEGG pathway enrichment was performed to identify potential pathways. Weighted gene co-expression network analysis (WGCNA) was used to discover co-expressed gene modules and trait–module connections. Results: Considering the defined criteria, 115 differentially expressed genes (DEGs) were identified. The DEG’s KEGG pathway enrichment analysis revealed enrichment in highly relevant pathways to the HPV infection, including cell cycle, viral carcinogenesis, autophagy-animal, Epstein-Barr virus infection, human T-cell leukemia virus 1 infection, and microRNAs in cancer. WGCNA results in 13 co-expression modules, and the magenta module is identified with significant relations to HPV, cervical cancer stage, and metastasis traits. The survival analysis identified BEX1 and CDC45 as potential prognostic factors in HPV-associated cervical cancer. Conclusion: The innovation of our work lies in identifying essential genes associated with the multi-step process of cervical carcinogenesis. In fact, the current study has the potential to give a distinct viewpoint on the molecular pathways linked to cervical cancer. Considering the potential importance of the hub genes, we recommend conducting in-depth wet lab research to determine their impact on the biological mechanisms of cervical cancer.

An intrinsic and genetically determined ripening program of tomato fruits often depends upon the appropriate activation of tissue- and stage-specific transcription factors in space and time. The past two decades have yielded considerable progress in detailing these complex transcriptional as well as hormonal regulatory circuits paramount to fleshy fruit ripening. This non-linear ripening process is strongly controlled by the MADS-box and NOR family of proteins, triggering a transcriptional response associated with the progression of fruit ripening. Deepening insights into the connection between MADS-RIN and plant hormones related transcription factors, such as ERFs and ARFs, further conjugates the idea that several signaling units work in parallel to define an output fruit ripening transcriptome. Besides these TFs, the role of other families of transcription factors such as MYB, GLK, WRKY, GRAS and bHLH have also emerged as important ripening regulators. Other regulators such as EIN and EIL proteins also determine the transcriptional landscape of ripening fruits. Despite the abundant knowledge of the complex spectrum of ripening networks in the scientific domain, identifying more ripening effectors would pave the way for a better understanding of fleshy fruit ripening at the molecular level. This review provides an update on the transcriptional regulators of tomato fruit ripening. [ABSTRACT FROM AUTHOR]

Diabetes cell replacement therapy has the potential to be transformed by human pluripotent stem cell-derived β cells (SC-β cells). However, the precise identity of SC-β cells in relationship to primary fetal and adult β-cells remains unclear. Here, we used single-cell sequencing datasets to characterize the transcriptional identity of islets from in vitro differentiation, fetal islets, and adult islets. Our analysis revealed that SC-β cells share a core β-cell transcriptional identity with human adult and fetal β-cells, however SC-β cells possess a unique transcriptional profile characterized by the persistent expression and activation of progenitor and neural-biased gene networks. These networks are present in SC-β cells, irrespective of the derivation protocol used. Notably, fetal β-cells also exhibit this neural signature at the transcriptional level. Our findings offer insights into the transcriptional identity of SC-β cells and underscore the need for further investigation of the role of neural transcriptional networks in their development. [ABSTRACT FROM AUTHOR]

During future space missions, astronauts will be exposed to cosmic radiation and microgravity (μG), which are known to be health risk factors. To examine the differentially expressed genes (DEG) and their prevalent biological processes and pathways as a response to these two risk factors simultaneously, 1BR-hTERT human fibroblast cells were cultured under 1 gravity (1G) or simulated μG for 48 h in total and collected at 0 (sham irradiated), 3 or 24 h after 1 Gy of X-ray or Carbon-ion (C-ion) irradiation. A three-dimensional clinostat was used for the simulation of μG and the simultaneous radiation exposure of the samples. The RNA-seq method was used to produce lists of differentially expressed genes between different environmental conditions. Over-representation analyses were performed and the enriched biological pathways and targeting transcription factors were identified. Comparing sham-irradiated cells under simulated μG and 1G conditions, terms related to response to oxygen levels and muscle contraction were identified. After irradiation with X-rays or C-ions under 1G, identified DEGs were found to be involved in DNA damage repair, signal transduction by p53 class mediator, cell cycle arrest and apoptosis pathways. The same enriched pathways emerged when cells were irradiated under simulated μG condition. Nevertheless, the combined effect attenuated the transcriptional response to irradiation which may pose a subtle risk in space flights. [ABSTRACT FROM AUTHOR]

In many plant species, flowering is promoted by the cold treatment or vernalization. The mechanism of vernalization-induced flowering has been extensively studied in Arabidopsis but remains largely unknown in legumes. The orthologs of the FLC gene, a major regulator of vernalization response in Arabidopsis, are absent or non-functional in the vernalization-sensitive legume species. Nevertheless, the legume integrator genes FT and SOC1 are involved in the transition of the vernalization signal to meristem identity genes, including PIM (AP1 ortholog). However, the regulatory contribution of these genes to PIM activation in legumes remains elusive. Here, we presented the theoretical and data-driven analyses of a feed-forward regulatory motif that includes a vernalization-responsive FT gene and several SOC1 genes, which independently activate PIM and thereby mediate floral transition. Our theoretical model showed that the multiple regulatory branches in this regulatory motif facilitated the elimination of no-sense signals and amplified useful signals from the upstream regulator. We further developed and analyzed four data-driven models of PIM activation in Medicago trancatula in vernalized and non-vernalized conditions in wild-type and fta1-1 mutants. The model with FTa1 providing both direct activation and indirect activation via three intermediate activators, SOC1a, SOC1b, and SOC1c, resulted in the most relevant PIM dynamics. In this model, the difference between regulatory inputs of SOC1 genes was nonessential. As a result, in the M. trancatula model, the cumulative action of SOC1a, SOC1b, and SOC1c was favored. Overall, in this study, we first presented the in silico analysis of vernalization-induced flowering in legumes. The considered vernalization network motif can be supplemented with additional regulatory branches as new experimental data become available. [ABSTRACT FROM AUTHOR]

Simple Summary: The study of the innate immune system's (IIS) properties is one of the key tasks of modern immunology, since it could help enhance the quality of therapy and drug discovery. This system remains understudied for nonmammalians, and teleost fish are promising model organisms for fundamental studies of IIS organization. The recent single-cell transcriptomics (scRNAseq) experiments carried out on zebrafish and other teleosts brought fundamental knowledge about their innate immunity organization. The aim of this review is to summarize information about the available IIS-related scRNAseq experiments for teleosts and outline further perspectives for studies in this field. We found 89 scRNAseq datasets for zebrafish in different stages and organs suitable for the further meta-analysis of IIS properties and six experiments for other teleosts. Therefore, the obtained data for zebrafish could be further generalized and compared with that of mammals, while for other teleosts, we still have a large gap in knowledge. We believe that in the coming years, new scRNAseq data obtained for nonmodel teleosts will be of particular value and interest in the context of animal immunology. The innate immune system is the first line of defense in multicellular organisms. Danio rerio is widely considered a promising model for IIS-related research, with the most amount of scRNAseq data available among Teleostei. We summarized the scRNAseq and spatial transcriptomics experiments related to the IIS for zebrafish and other Teleostei from the GEO NCBI and the Single-Cell Expression Atlas. We found a considerable number of scRNAseq experiments at different stages of zebrafish development in organs such as the kidney, liver, stomach, heart, and brain. These datasets could be further used to conduct large-scale meta-analyses and to compare the IIS of zebrafish with the mammalian one. However, only a small number of scRNAseq datasets are available for other fish (turbot, salmon, cavefish, and dark sleeper). Since fish biology is very diverse, it would be a major mistake to use zebrafish alone in fish immunology studies. In particular, there is a special need for new scRNAseq experiments involving nonmodel Teleostei, e.g., long-lived species, cancer-resistant fish, and various fish ecotypes. [ABSTRACT FROM AUTHOR]

BackgroundStudies have shown that cardiovascular health (CVH) is related to depression. We aimed to identify gene networks jointly associated with depressive symptoms and cardiovascular health metrics using the whole blood transcriptome.Materials and methodsWe analyzed human blood transcriptomic data to identify gene co-expression networks, termed gene modules, shared by Beck’s depression inventory (BDI-II) scores and cardiovascular health (CVH) metrics as markers of depression and cardiovascular health, respectively. The BDI-II scores were derived from Beck’s Depression Inventory, a 21-item self-report inventory that measures the characteristics and symptoms of depression. CVH metrics were defined according to the American Heart Association criteria using seven indices: smoking, diet, physical activity, body mass index (BMI), blood pressure, total cholesterol, and fasting glucose. Joint association of the modules, identified with weighted co-expression analysis, as well as the member genes of the modules with the markers of depression and CVH were tested with multivariate analysis of variance (MANOVA).ResultsWe identified a gene module with 256 genes that were significantly correlated with both the BDI-II score and CVH metrics. Based on the MANOVA test results adjusted for age and sex, the module was associated with both depression and CVH markers. The three most significant member genes in the module were YOD1, RBX1, and LEPR. Genes in the module were enriched with biological pathways involved in brain diseases such as Alzheimer’s, Parkinson’s, and Huntington’s.ConclusionsThe identified gene module and its members can provide new joint biomarkers for depression and CVH.

Key developmental pathways and gene networks underlie the formation of sensory cell types and structures involved in chemosensation, vision and mechanosensation, and of the efferents these sensory inputs can activate. We describe similarities and differences in these pathways and gene networks in selected species of the three main chordate groups, lancelets, tunicates, and vertebrates, leading to divergent development of olfactory receptors, eyes, hair cells and motoneurons. The lack of appropriately posited expression of certain transcription factors in lancelets and tunicates prevents them from developing vertebrate-like olfactory receptors and eyes, although they generate alternative structures for chemosensation and vision. Lancelets and tunicates lack mechanosensory cells associated with the sensation of acoustic stimuli, but have gravisensitive organs and ciliated epidermal sensory cells that may (and in some cases clearly do) provide mechanosensation and thus the capacity to respond to movement relative to surrounding water. Although functionally analogous to the vertebrate vestibular apparatus and lateral line, homology is questionable due to differences in the expression of the key transcription factors Neurog and Atoh1/7, on which development of vertebrate hair cells depends. The vertebrate hair cell-bearing inner ear and lateral line thus likely represent major evolutionary advances specific to vertebrates. Motoneurons develop in vertebrates under the control of the ventral signaling molecule hedgehog/sonic hedgehog (Hh,Shh), against an opposing inhibitory effect mediated by dorsal signaling molecules. Many elements of Shh-signaling and downstream genes involved in specifying and differentiating motoneurons are also exhibited by lancelets and tunicates, but the repertoire of MNs in vertebrates is broader, indicating greater diversity in motoneuron differentiation programs.

Hepatocellular carcinoma (HCC) has been associated with hepatitis C viral (HCV) infection as a potential risk factor. Nonetheless, the precise genetic regulatory mechanisms triggered by the virus, leading to virus-induced hepatocarcinogenesis, remain unclear. We hypothesized that HCV proteins might modulate the activity of aberrantly methylated HCC genes through regulatory pathways. Virus-host regulatory pathways, interactions between proteins, gene expression, transport, and stability regulation, were reconstructed using the ANDSystem. Gene expression regulation was statistically significant. Gene network analysis identified four out of 70 HCC marker genes whose expression regulation by viral proteins may be associated with HCC: DNA-binding protein inhibitor ID – 1 (ID1), flap endonuclease 1 (FEN1), cyclin-dependent kinase inhibitor 2A (CDKN2A), and telomerase reverse transcriptase (TERT). It suggested the following viral protein effects in HCV/human protein heterocomplexes: HCV NS3(p70) protein activates human STAT3 and NOTC1; NS2-3(p23), NS5B(p68), NS1(E2), and core(p21) activate SETD2; NS5A inhibits SMYD3; and NS3 inhibits CCN2. Interestingly, NS3 and E1(gp32) activate c-Jun when it positively regulates CDKN2A and inhibit it when it represses TERT. The discovered regulatory mechanisms might be key areas of focus for creating medications and preventative therapies to decrease the likelihood of HCC development during HCV infection.

Abstract Rice is more vulnerable to drought than maize, wheat, and sorghum because its water requirements remain high throughout the rice life cycle. The effects of drought vary depending on the timing, intensity, and duration of the events, as well as on the rice genotype and developmental stage. It can affect all levels of organization, from genes to the cells, tissues, and/or organs. In this study, a moderate water deficit was applied to two contrasting rice genotypes, IAC 25 and CIRAD 409, during their reproductive stage. Multi‐level transcriptomic, metabolomic, physiological, and morphological analyses were performed to investigate the complex traits involved in their response to drought. Weighted gene network correlation analysis was used to identify the specific molecular mechanisms regulated by each genotype, and the correlations between gene networks and phenotypic traits. A holistic analysis of all the data provided a deeper understanding of the specific mechanisms regulated by each genotype, and enabled the identification of gene markers. Under non‐limiting water conditions, CIRAD 409 had a denser shoot, but shoot growth was slower despite better photosynthetic performance. Under water deficit, CIRAD 409 was weakly affected regardless of the plant level analyzed. In contrast, IAC 25 had reduced growth and reproductive development. It regulated transcriptomic and metabolic activities at a high level, and activated a complex gene regulatory network involved in growth‐limiting processes. By comparing two contrasting genotypes, the present study identified the regulation of some fundamental processes and gene markers, that drive rice development, and influence its response to water deficit, in particular, the importance of the biosynthetic and regulatory pathways for cell wall metabolism. These key processes determine the biological and mechanical properties of the cell wall and thus influence plant development, organ expansion, and turgor maintenance under water deficit. Our results also question the genericity of the antagonism between morphogenesis and organogenesis observed in the two genotypes.

ABSTRACT: Staphylococcus aureus is one of the most prevalent contagious bacterial pathogen of bovine mastitis. The subclinical mastitis it causes has long-term economic implications and it is difficult to control. To further understanding of the genetic basis of mammary gland defense against S. aureus infection, the transcriptomes of milk somatic cells from 15 cows with persistent natural S. aureus infection (S. aureus-positive, SAP) and 10 healthy control cows (HC) were studied by deep RNA-sequencing technology. Comparing the transcriptomes of SAP to HC group revealed 4,077 differentially expressed genes (DEG; 1,616 up- and 2,461 downregulated). Functional annotation indicated enrichment of DEG in 94 Gene Ontology (GO) and 47 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Terms related to the immune response and disease processes were mostly enriched for by upregulated DEG, whereas biological process terms related to cell adhesion, cell movement and localization, and tissue development were mostly enriched for by downregulated DEG. Weighted gene co-expression network analysis grouped DEG into 7 modules, the most important module (colored turquoise by software and here referred to as Turquoise module) was positively significantly correlated with S. aureus subclinical mastitis. The 1,546 genes in the Turquoise module were significantly enriched in 48 GO terms and 72 KEGG pathways, with 80% of them being disease- and immune-related terms [e.g., immune system process (GO:0002376), cytokine-cytokine receptor interaction (bta04060) and S. aureus infection (bta05150)]. Some DEG such as IFNG, IL18, IL1B, NFKB1, CXCL8, and IL12B were enriched in immune and disease pathways suggesting their possible involvement in the regulation of the host response to S. aureus infection. Four modules (Yellow, Brown, Blue, and Red) were negatively correlated (significantly) with S. aureus subclinical mastitis, and were enriched in functional annotations involved in the regulation of cell migration, cell communication, metabolic process, and blood circulatory system development, respectively. Application of sparse partial least squares discriminant analysis to genes of the Turquoise module identified 5 genes (NR2F6, PDLIM5, RAB11FIP5, ACOT4, and TMEM53) capable of explaining the majority of the differences in the expression patterns between SAP and HC cows. In conclusion, this study has furthered understanding of the genetic changes in the mammary gland and the molecular mechanisms underlying S. aureus mastitis, as well as revealed a list of candidate discriminant genes with potential regulatory roles in response to S. aureus infection.

BACKGROUND: Retinoblastoma is a common neoplasia that affects the visual organ in young children. The mortality rate is approximately 15%. In 91% of cases, surgery with enucleation is required, which significantly reduces the patients quality of life. Early diagnosis of the disease may help to correct approaches to treatment of retinoblastoma, significantly increasing the chances of preserving vision. This is important since approximately 95% of retinoblastoma cases are diagnosed before the age of 5. Using bioinformatic methods, a comprehensive analysis of the patterns and connections between the retinoblastoma-associated genes was conducted, which may further form the basis of molecular genetic testing for diagnosing this oncology. AIM: The study aimed to comprehensively analyze the genes and their products associated with retinoblastoma to reveal patterns of oncologic development. METHODS: Obtaining and sorting the list of genes using the OMIM and COSMIC databases (https://omim.org/; https://cancer.sanger.ac.uk/cosmic). Calculating gene ontology categories using DAVID and PANTHER services (https://david.ncifcrf.gov/; http://pantherdb.org/). Reconstructing the gene network using the GeneMANIA service (https://genemania.org/). Analyzing the three-dimensional (3D) structure of proteins using the PDB (RCSB) database (https://www.rcsb.org/). RESULTS: After sorting retinoblastoma-associated genes, the OMIM.org database generated a list of 139 elements. After sorting and comparison with the results of a similar query in the COSMIC database, RB1, KRAS, SYK, MYCN, and BCOR retinoblastoma-associated key genes were identified. The resulting list was analyzed for gene ontology categories using DAVID and PATHER services. The most significant categories for retinoblastoma genes were cell cycle regulators, in particular regulators of the transition from G to S phase and regulators of transcription from the RNA polymerase II promoter. Gene network structure analysis for retinoblastoma genes using the GeneMANIA service showed the existence of dense and linked gene clusters with cell cycle and transcriptional regulator genes at the center. Using the PDB database, 3D structures of key gene expression products were obtained. CONCLUSIONS: The development of molecular genetic testing of retinoblastoma for the activity of expression of associated genes and their products in the prenatal and/or postnatal period is required to improve the retinoblastoma monitoring system. The results of the study may serve as input data for this testing.

The construction of gene co-expression networks is an essential tool in Bioinformatics for discovering useful biological knowledge. There are a multitude of methodologies related to the construction of this type of network, and one of them is EnGNet, which carries out a joint and greedy approach to the reconstruction of large gene coexpression networks. This work introduces CyEnGNet-App, a Cytoscape application designed to integrate and leverage the EnGNet algorithm. The application allows dynamic interaction and visualisation of gene networks and integration with other Cytoscape applications. CyEnGNet-App is a valuable addition to the field of Bioinformatics, improving the reconstruction of genetic networks and providing a more accessible and efficient user experience in Cytoscape.

IntroductionA hexanucleotide repeat expansion (HRE) intronic to chromosome 9 open reading frame 72 (C9orf72) is recognized as the most common genetic cause of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and ALS-FTD. Identifying genes that show similar regional co-expression patterns to C9orf72 may help identify novel gene targets and biological mechanisms that mediate selective vulnerability to ALS and FTD pathogenesis.MethodsWe leveraged mRNA expression data in healthy brain from the Allen Human Brain Atlas to evaluate C9orf72 co-expression patterns. To do this, we correlated average C9orf72 expression values in 51 regions across different anatomical divisions (cortex, subcortex, and cerebellum) with average gene expression values for 15,633 protein-coding genes, including 54 genes known to be associated with ALS, FTD, or ALS-FTD. We then performed imaging transcriptomic analyses to evaluate whether the identified C9orf72 co-expressed genes correlated with patterns of cortical thickness in symptomatic C9orf72 pathogenic HRE carriers (n = 19) compared to controls (n = 23). Lastly, we explored whether genes with significant C9orf72 imaging transcriptomic correlations (i.e., “C9orf72 imaging transcriptomic network”) were enriched in specific cell populations in the brain and enriched for specific biological and molecular pathways.ResultsA total of 2,120 genes showed an anatomical distribution of gene expression in the brain similar to C9orf72 and significantly correlated with patterns of cortical thickness in C9orf72 HRE carriers. This C9orf72 imaging transcriptomic network was differentially expressed in cell populations previously implicated in ALS and FTD, including layer 5b cells, cholinergic neurons in the spinal cord and brainstem and medium spiny neurons of the striatum, and was enriched for biological and molecular pathways associated with protein ubiquitination, autophagy, cellular response to DNA damage, endoplasmic reticulum to Golgi vesicle-mediated transport, among others.ConclusionConsidered together, we identified a network of C9orf72 associated genes that may influence selective regional and cell-type-specific vulnerabilities in ALS/FTD.

Sugar beet is an important root crop with a biennial life cycle. In the first year of its life cycle, it produces huge amounts of leaf and root mass used for the production of sugar and bioethanol, livestock feed, confectionery and pharmaceuticals, fertilizers, and soil restoration. Normally, after exposure to cold temperatures during winter storage, in the second year of its life cycle, it enters its reproductive phase. However, during the first year of growth, sugar beet plants may be susceptible to producing flowering shoots, or "bolting", due to vernalization and long-day conditions. Bolting reduces both the yield and the sugar content of roots. Here, we review the published research works that study the environmental factors influencing bolting, the genetic (including epigenetic) and physiological mechanisms that regulate the transition to the reproductive phase, and the agrotechnical and breeding practices used to prevent bolting. Models of gene networks that regulate the transition to flowering are presented. Methods for selecting non-bolting plants using conventional, marker-assisted, and genomic breeding are demonstrated. Attention is also paid to the speed breeding technology that stimulates bolting and flowering sugar beet plants in an artificial climate. Growing sugar beet plants "from seed to seed" can potentially accelerate the breeding and seed production of sugar beet. This review compares different conditions for inducing bolting in sugar beet in climatic chambers and greenhouses. It examines parameters such as temperature, duration of light exposure, and light intensity during the pre-vernalization, post-vernalization, and vernalization periods. The present review may be useful for specialists in sugar beet cultivation, breeders working on developing cultivars and hybrids that are resistant to bolting, and molecular biologists studying the genetic and physiological mechanisms underlying the transition of plants into the flowering stage. [ABSTRACT FROM AUTHOR]

Although it is well known that epistasis plays an important role in many evolutionary processes (e.g., speciation, evolution of sex), our knowledge on the frequency and prevalent sign of epistatic interactions is mainly limited to unicellular organisms or cell cultures of multicellular organisms. This is even more pronounced in regard to how the environment can influence genetic interactions. To broaden our knowledge in that respect we studied gene–gene interactions in a whole multicellular organism, Caenorhabditis elegans. We screened over one thousand gene interactions, each one in standard laboratory conditions, and under three different stressors: heat shock, oxidative stress, and genotoxic stress. Depending on the condition, between 7% and 22% of gene pairs showed significant genetic interactions and an overall sign of epistasis changed depending on the condition. Sign epistasis was quite common, but reciprocal sign epistasis was extremally rare. One interaction was common to all conditions, whereas 78% of interactions were specific to only one environment. Although epistatic interactions are quite common, their impact on evolutionary processes will strongly depend on environmental factors. [ABSTRACT FROM AUTHOR]

Complex diseases are heterogenous due to variation in their genetic and environmental underpinnings, leading to varied treatment responses. Genome‐wide association studies (GWAS) integrated with single‐cell expression quantitative trait loci analyses (eQTL) can pinpoint cell‐type specific candidate disease‐relevant genes and pathways. This knowledge can be applied to patient stratification and novel therapeutic target identification. Here, we describe the translational potential of cell‐type specific genetic regulation, using Crohn's disease as an example. [ABSTRACT FROM AUTHOR]

Rice is more vulnerable to drought than maize, wheat, and sorghum because its water requirements remain high throughout the rice life cycle. The effects of drought vary depending on the timing, intensity, and duration of the events, as well as on the rice genotype and developmental stage. It can affect all levels of organization, from genes to the cells, tissues, and/or organs. In this study, a moderate water deficit was applied to two contrasting rice genotypes, IAC 25 and CIRAD 409, during their reproductive stage. Multi‐level transcriptomic, metabolomic, physiological, and morphological analyses were performed to investigate the complex traits involved in their response to drought. Weighted gene network correlation analysis was used to identify the specific molecular mechanisms regulated by each genotype, and the correlations between gene networks and phenotypic traits. A holistic analysis of all the data provided a deeper understanding of the specific mechanisms regulated by each genotype, and enabled the identification of gene markers. Under non‐limiting water conditions, CIRAD 409 had a denser shoot, but shoot growth was slower despite better photosynthetic performance. Under water deficit, CIRAD 409 was weakly affected regardless of the plant level analyzed. In contrast, IAC 25 had reduced growth and reproductive development. It regulated transcriptomic and metabolic activities at a high level, and activated a complex gene regulatory network involved in growth‐limiting processes. By comparing two contrasting genotypes, the present study identified the regulation of some fundamental processes and gene markers, that drive rice development, and influence its response to water deficit, in particular, the importance of the biosynthetic and regulatory pathways for cell wall metabolism. These key processes determine the biological and mechanical properties of the cell wall and thus influence plant development, organ expansion, and turgor maintenance under water deficit. Our results also question the genericity of the antagonism between morphogenesis and organogenesis observed in the two genotypes. [ABSTRACT FROM AUTHOR]

Genome-wide association meta-analysis (GWAMA) by the Cortisol Network (CORNET) consortium identified genetic variants spanning the SERPINA6/SERPINA1 locus on chromosome 14 associated with morning plasma cortisol, cardiovascular disease (CVD), and SERPINA6 mRNA expression encoding corticosteroid-binding globulin (CBG) in the liver. These and other findings indicate that higher plasma cortisol levels are causally associated with CVD; however, the mechanisms by which variations in CBG lead to CVD are undetermined. Using genomic and transcriptomic data from The Stockholm Tartu Atherosclerosis Reverse Networks Engineering Task (STARNET) study, we identified plasma cortisol-linked single-nucleotide polymorphisms (SNPs) that are trans-associated with genes from seven different vascular and metabolic tissues, finding the highest representation of trans-genes in the liver, subcutaneous fat, and visceral abdominal fat, [false discovery rate (FDR) = 15%]. We identified a subset of cortisol-associated trans-genes that are putatively regulated by the glucocorticoid receptor (GR), the primary transcription factor activated by cortisol. Using causal inference, we identified GR-regulated trans-genes that are responsible for the regulation of tissuespecific gene networks. Cis-expression Quantitative Trait Loci (eQTLs) were used as genetic instruments for identification of pairwise causal relationships from which gene networks could be reconstructed. Gene networks were identified in the liver, subcutaneous fat, and visceral abdominal fat, including a high confidence gene network specific to subcutaneous adipose (FDR = 10%) under the regulation of the interferon regulatory transcription factor, IRF2. These data identify a plausible pathway through which variation in the liver CBG production perturbs cortisol-regulated gene networks in peripheral tissues and thereby promote CVD. [ABSTRACT FROM AUTHOR]

The present hypothesis tries to explain animal regeneration in relation to the life cycles and environment of different animals. Regeneration is a basic phenomenon present since the origin of life in the sea, as testimonial in lower or more complex extant marine animals. Aquatic animals that evolved an indirect development, forming larvae and transiting into the adult stage through metamorphosis, use gene networks present in their genome for these transformations. In case of injury or organ loss as adults, they can re-utilize most or part of the gene networks previously activated during larval growth and metamorphosis. In contrast, terrestrial animals that evolved life cycles with the elimination of larvae and metamorphosis for the adaptation to land conditions lost some of the genes implicated in these post-developmental processes and consequently also the ability to regenerate. Few arthropods and lizards are capable to form hydrated regenerative blastemas with a similar consistence of embryonic tissues. The present hypothesis submits that regeneration cannot be activated in the dry land environment and consequently was largely or completely abolished in terrestrial animals. After injury or organ loss, nematodes, most arthropods and terrestrial vertebrates can only form scars or a limited healing or regengrow in juveniles. This is a process where somatic growth is superimposed to wound healing so that the apparent regeneration derives from the combination from both processes. When full growth is terminated these terrestrial animals can only heal by scarring. • A new hypothesis on animal regeneration is here formulated. • Regeneration is related to the aquatic environment, larvae and metamorphosis. • It is the re-utilization of developmental-metamorphic processes in adults that allows animal regeneration. • Land colonization determined loss of the above developmental phases and of regeneration. [ABSTRACT FROM AUTHOR]

Deep transfer learning improves the inference of gene regulatory networks in human cells, reveals disease-associated genes, and identifies network-based druggable targets in human heart disease. [ABSTRACT FROM AUTHOR]

Abstract Complex diseases are heterogenous due to variation in their genetic and environmental underpinnings, leading to varied treatment responses. Genome‐wide association studies (GWAS) integrated with single‐cell expression quantitative trait loci analyses (eQTL) can pinpoint cell‐type specific candidate disease‐relevant genes and pathways. This knowledge can be applied to patient stratification and novel therapeutic target identification. Here, we describe the translational potential of cell‐type specific genetic regulation, using Crohn's disease as an example.

Broflanilide is a novel pesticide that can antagonize ion channels and disrupt neurotransmitter systems in the brain. Zebrafish larvae were exposed to either 0, 1 or 10- µg/L broflanilide in the water for a period of 7 days during early development. RNA extraction was conducted on larval zebrafish for RNA-seq analysis using the Illumina NovoSeq 6000. Raw sequence data were processed through fastp and clean reads obtained by removing adapter and poly-N sequences. Alignment and differential gene expression analysis was conducted using HISAT2, StringTie assembler, and FPKM (Fragments Per Kilobase of transcript sequence per Millions base pairs sequenced). Subnetwork enrichment analysis (SNEA) revealed that exposure to 1 µg/L broflanilide altered gene networks associated with axonal injury, depression, neuroinflammation, and traumatic brain injury while exposure to 10- µg/L broflanilide resulted in changes in gene networks associated with brain infarction and ischemia, excitotoxicity, and neurogenic inflammation. In addition, genes related to MPTP-induced neurotoxicity were altered by broflanilide which has relevance for Parkinson's disease. Several transcripts were identified as being associated with a disease network link to neurodegeneration and included phospholipase A2 activating protein, calpain 1, ATPase Na+/K+ transporting subunit alpha 2, glia maturation factor beta, sphingomyelin phosphodiesterase 1, leucine rich repeat kinase 2, glutamate ionotropic receptor NMDA type subunit 2C, lysosomal associated membrane protein, and calcium/calmodulin dependent protein kinase II alpha among others. Data presented here include disease biomarkers for a novel pesticide and can be reused to refine models that describe adverse outcome pathways for neurotoxicity.

Genome-wide association meta-analysis (GWAMA) by the Cortisol Network (CORNET) consortium identified genetic variants spanning the SERPINA6/SERPINA1 locus on chromosome 14 associated with morning plasma cortisol, cardiovascular disease (CVD), and SERPINA6 mRNA expression encoding corticosteroid-binding globulin (CBG) in the liver. These and other findings indicate that higher plasma cortisol levels are causally associated with CVD; however, the mechanisms by which variations in CBG lead to CVD are undetermined. Using genomic and transcriptomic data from The Stockholm Tartu Atherosclerosis Reverse Networks Engineering Task (STARNET) study, we identified plasma cortisol-linked single-nucleotide polymorphisms (SNPs) that are trans-associated with genes from seven different vascular and metabolic tissues, finding the highest representation of trans-genes in the liver, subcutaneous fat, and visceral abdominal fat, [false discovery rate (FDR) = 15%]. We identified a subset of cortisol-associated trans-genes that are putatively regulated by the glucocorticoid receptor (GR), the primary transcription factor activated by cortisol. Using causal inference, we identified GR-regulated trans-genes that are responsible for the regulation of tissue-specific gene networks. Cis-expression Quantitative Trait Loci (eQTLs) were used as genetic instruments for identification of pairwise causal relationships from which gene networks could be reconstructed. Gene networks were identified in the liver, subcutaneous fat, and visceral abdominal fat, including a high confidence gene network specific to subcutaneous adipose (FDR = 10%) under the regulation of the interferon regulatory transcription factor, IRF2. These data identify a plausible pathway through which variation in the liver CBG production perturbs cortisol-regulated gene networks in peripheral tissues and thereby promote CVD.

Staphylococcus aureus is one of the most prevalent contagious bacterial pathogen of bovine mastitis. The subclinical mastitis it causes has long-term economic implications and it is difficult to control. To further understanding of the genetic basis of mammary gland defense against S. aureus infection, the transcriptomes of milk somatic cells from 15 cows with persistent natural S. aureus infection (S. aureus -positive, SAP) and 10 healthy control cows (HC) were studied by deep RNA-sequencing technology. Comparing the transcriptomes of SAP to HC group revealed 4,077 differentially expressed genes (DEG; 1,616 up- and 2,461 downregulated). Functional annotation indicated enrichment of DEG in 94 Gene Ontology (GO) and 47 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Terms related to the immune response and disease processes were mostly enriched for by upregulated DEG, whereas biological process terms related to cell adhesion, cell movement and localization, and tissue development were mostly enriched for by downregulated DEG. Weighted gene co-expression network analysis grouped DEG into 7 modules, the most important module (colored turquoise by software and here referred to as Turquoise module) was positively significantly correlated with S. aureus subclinical mastitis. The 1,546 genes in the Turquoise module were significantly enriched in 48 GO terms and 72 KEGG pathways, with 80% of them being disease- and immune-related terms [e.g., immune system process (GO:0002376), cytokine-cytokine receptor interaction (bta04060) and S. aureus infection (bta05150)]. Some DEG such as IFNG , IL18 , IL1B , NFKB1 , CXCL8 , and IL12B were enriched in immune and disease pathways suggesting their possible involvement in the regulation of the host response to S. aureus infection. Four modules (Yellow, Brown, Blue, and Red) were negatively correlated (significantly) with S. aureus subclinical mastitis, and were enriched in functional annotations involved in the regulation of cell migration, cell communication, metabolic process, and blood circulatory system development, respectively. Application of sparse partial least squares discriminant analysis to genes of the Turquoise module identified 5 genes (NR2F6 , PDLIM5 , RAB11FIP5 , ACOT4 , and TMEM53) capable of explaining the majority of the differences in the expression patterns between SAP and HC cows. In conclusion, this study has furthered understanding of the genetic changes in the mammary gland and the molecular mechanisms underlying S. aureus mastitis, as well as revealed a list of candidate discriminant genes with potential regulatory roles in response to S. aureus infection. [ABSTRACT FROM AUTHOR]