Omics A Journal of Integrative Biology最新文献

The COVID-19 pandemic phase caused by the SARS-CoV-2 has ended, but the emergence of new variants continues to threaten public health. The public health toolbox for COVID-19 is in need of not only vaccines but also drug discovery against the SARS-CoV-2 virus, the causative agent for the ongoing COVID-19 infections. We report here an in silico molecular docking and dynamics study that uncovered the interactions of 26 flexible heteroarotinoids (FHT18), which are a class of anti-cancer compounds, as potential inhibitors against all 24 SARS-CoV-2 proteins. Of the 624 docked complexes, 69 displayed binding energies between -9.0 and -11.6 kcal/mol, indicating good to strong binding affinities. At least five of these compounds displayed excellent binding affinities against the nonstructural protein 2, papain-like protease, nonstructural protein 4 (Nsp4), proof-reading exoribonuclease, membrane protein, and nucleocapsid protein. Structure-activity relationship (SAR) analyses of these results revealed that a urea linker in place of a thiourea linker, enhanced the hydrophobic side chains attached to the chromane unit, and a CF₃ or OCF₃ functional group attached to the benzene ring contributed to increased binding affinities. Further, the molecular dynamics simulation study of the best-docked complex FHT18-6c with Nsp4 remained stable for at least 200 ns, leading to decreased structural fluctuations and increased compactness of the binding site. In conclusion, FHT18-6c deserves further translational research to explore its potential for repurposing as a potent drug candidate to combat COVID-19. We also call for continued drug discovery efforts to enrich the public health toolbox for COVID-19.

Camellia sinensis L., commonly known as the tea plant, produces derivatives such as green tea, which are among the most extensively consumed beverages worldwide. Green tea is rich in polyphenolic compounds, such as epigallocatechin-3-gallate (EGCG) and gallocatechin gallate. These phytochemicals have drawn particular attention as antioxidants, especially in relation to their potential to reduce the risks for prostate cancer (PC) among other common human diseases. However, the molecular evidence base needs to be strengthened before large-scale controlled clinical trials with C. sinensis L. and/or specific phytochemicals are pursued. We investigated cytochrome P45017A1 (CYP17A1), a key enzyme in androgen biosynthesis, as a molecular target for the green tea phytochemicals. In this study, molecular docking, pharmacokinetic and toxicity evaluations, molecular dynamics (MD) simulations, and post-MD simulation analyses were performed to assess the binding potential of green tea phytochemicals with the CYP17A1 enzyme. A library of 92 green tea-derived phytochemicals, along with the reference inhibitor abiraterone, was docked against the CYP17A1 enzyme. MD simulations validated the stability and enhanced binding affinity of the CYP17A1-EGCG complex compared with the abiraterone complex, as further confirmed by post-MD simulation analyses. Collectively, these findings suggest that EGCG inhibits CYP17A1, potentially reducing androgen biosynthesis and thereby highlighting green tea as a promising natural source for PC therapeutics. Further preclinical and translational studies are warranted to substantiate the clinical applicability of green tea phytochemicals.

Amyloid deposits formed by misfolding and aggregation of human islet amyloid polypeptide (hIAPP) are one of the key pathophysiological features of type 2 diabetes mellitus (T2DM) and have been associated with the loss of function and viability of the pancreatic β-cells. The molecular processes by which hIAPP induces cytotoxicity in these cells are not well understood. To the best of our knowledge, this is the first report describing findings from the combined analysis of Affymetrix microarray and high-throughput sequencing (HTS) Gene Expression Omnibus (GEO) datasets of hIAPP-transgenic (Tg) mice islets. In brief, using GEO data, we compared in silico the pancreatic islets obtained from hIAPP-Tg and wild-type mice. Affymetrix microarray datasets (GSE84423, GSE85380, and GSE94672) and HTS datasets (GSE135276 and GSE148809) were chosen. Weighted gene coexpression network analysis was performed using GSE135276 to identify the coexpressed gene networks and establish a correlation pattern between gene modules and hIAPP overexpression under hyperglycemic conditions. Subsequently, we analyzed differential gene expression with the remaining datasets. Network analysis was performed to identify hub genes and the associated pathways using Cytoscape. Key findings from the present study include identification of seven hub genes, namely, Ins2, Agt, Jun, Fos, CD44, Igf1, and Ppar-γ, significantly involved in the process(es) of insulin synthesis and secretion, development of insulin resistance, oxidative stress, inflammation, mitophagy, and apoptosis. In conclusion, we propose that these hub genes can help explain T2DM pathogenesis and can be potentially utilized to develop therapeutic interventions targeting hIAPP for clinical management of T2DM.

Lung adenocarcinoma (LUAD) is one of the leading global health challenges wherein novel therapeutic targets are much needed. In this systems bioinformatics study, we report that disruption of the long noncoding RNA (lncRNA) SFTA1P-centered network, respiratory gaseous exchange and surfactant-associated Biological Network (rgsBNet), is consistent with impairing surfactant homeostasis and respiratory function, and thus warrants attention for future drug discovery and development. We analyzed data from The Cancer Genome Atlas LUAD cohort to identify differentially expressed mRNAs, lncRNAs, and microRNAs (miRNAs), followed by correlational analysis to examine the coexpression network of lncRNA SFTA1P and its potential role in LUAD pathogenesis. We observed the downregulation of lncRNA SFTA1P and its coexpressed network in LUAD. Intriguingly, this network appears to be associated with disrupting surfactant homeostasis and perturbing respiratory function, suggesting a potential role in LUAD progression. Additionally, we identified key transcription factors that correlate with the expression of genes crucial for respiratory gaseous exchange and surfactant homeostasis. The attendant regulatory mechanisms suggested that SFTA1P may act as a "sponge" for certain miRNAs, sequestering them away from their mRNA targets. In conclusion, this work uncovers novel insights into the molecular mechanisms governing surfactant homeostasis in LUAD and offers a possible avenue for therapeutic interventions aimed at ameliorating lung function and improving disease management. The downregulation of lncRNA SFTA1P and its coexpressed network highlights their potential as regulators of lung function and opens doors for further investigation into their role in LUAD progression and as potential therapeutic targets.

Next-generation sequencing technology has revolutionized all fields of living systems, and its applications almost reinvented some research areas including metagenomics. The microbiotas in our body, including those of the oral, nasal, ocular, alveolar, skin regions, and particularly gut microbiota, have close linkages with our health status. Maturation of experimental techniques for metagenomics has been followed by other related omics platforms, for example, metatranscriptomics, metaproteomics, and all possible metacounterparts of multiomics studies. Now, we are on the eve of a meta-multi-omics era for the analysis of human holobiome in medical research. This era will help buttress the current efforts for systems medicine by illuminating the relationships between human holobiome and health or all human diseases including not only cancers but also infectious diseases, autoimmune diseases, obesity, aging, genetic disorders, and psychiatric conditions. Equally important, meta-multi-omics era is also poised to inform the determinants of human health and, by extension, help build individually tailored precision medicine interventions.

Climate emergency and ecological sustainability call for new ways of thinking livestock health, including the dairy cattle. This study unpacks the genetic diversity and selection sweeps of Sahiwal cattle in relation to adaptability, production, and disease resistance. Using nucleotide diversity (π) calculated from 10 kb windows across the genome with VCFtools, 716 regions of genetic diversity were identified across 29 chromosomes, and importantly, with chromosome 15 showing the highest density. A total of 92 quantitative trait loci (QTL) linked genes were analyzed, with chromosome 1 harboring the highest number. Trait association analysis using the Cattle QTL database showed that 14 genes were linked to production traits, 10 to reproduction traits, and 8 to disease susceptibility. Notable genes included CSMD2 and EFNA1, which influence milk production traits such as fat percentage and yield, and PCBP3 and SGCD, which affect reproductive traits. Additionally, the genes TBXAS1 and ASTN2 were associated with disease traits such as bovine respiratory disease and sole ulcers. Selection sweeps, identified using Tajima's D, revealed 728 sweeps across the genome, with chromosomes 6 and 8 showing the highest frequencies. These sweeps indicate regions under strong selective pressure, likely due to the breed's adaptation to arid environments and specific trait selection. The present study highlights how genetic diversity and selection sweeps contribute to Sahiwal cattle's adaptability, production efficiency, and disease resistance. The insights reported here provide a foundation for livestock health and targeted breeding strategies in the case of Sahiwal cattle under diverse ecological conditions such as tropical climate.

Riverine buffalo domestication likely occurred around 6300 years ago in Northwestern India. Murrah and Surti are important buffalo breeds that originated in this region and the gene flow from these buffaloes to Mehsana buffalo has long been proposed. However, the extent to which Murrah and Surti ancestry diffused across Mehsana has not been investigated thoroughly. Therefore, we investigated the global and local ancestry of Indian Mehsana buffalo using double digest restriction-site associated DNA sequencing data. Principal component analysis, global ancestry analysis, admixture dating, and three population tests revealed with statistical significance that Mehsana is a unique population. Hence, the hypothesis that Mehsana is a crossbreed between Murrah and Surti is not supported by these findings. However, we noticed that some individuals of Mehsana, 6 out 15, were admixed having 41% Murrah-specific ancestry and 11% Surti-specific ancestry. Local ancestry and post-admixture selection signatures (PASS) in admixed Mehsana individuals revealed PASS in the Mehsana genome, that is, on Bubalus bubalis autosomes (BBA), 1-23 linked from Surti and on BBA, 24 linked from Murrah. Interestingly, upon functional enrichment of these signatures, several adaptation-related genes and pathways were ascertained to Surti, while Murrah-derived regions featured genes involved in fatty acid synthesis (Acyl-CoA Synthetase Short-Chain Family Member 2 (ACSS2)) and milk production. Based on local ancestry analysis, we infer that the introgression of the Murrah genome into Mehsana happened in recent times and that of the Surti genome happened in ancient generations. The finding that Mehsana is an independent population highlights the importance of recognizing distinct genetic lineages in domesticated species. This has global implications for reevaluating the origins and uniqueness of other livestock breeds often assumed to be hybrids. Practically, these findings open up new avenues for selective breeding to preserve traits such as disease resistance, adaptability, and production efficiency. Further studies in larger samples are called for.

Traditional paradigms of pharmaceutical innovation have long relied on the "one drug, one disease" premise. However, a network mindset in unpacking disease mechanisms can be fruitful to move toward a "one drug, polydisease" paradigm of drug discovery and development. A case in point is obstructive sleep apnea (OSA) and lung cancer, which are two prevalent respiratory disorders that share common risk factors and may potentially exhibit overlapping molecular mechanisms. The putative mechanistic linkages between OSA and lung cancer remain underexplored; however, this study offers new evidence on overlapping genetic signatures between OSA and lung cancer with an in-silico approach. Bioinformatics analysis of the publicly available datasets (GSE135917 and GSE268175) identified 123 upregulated and 13 downregulated genes in OSA and 3175 upregulated and 2272 downregulated genes in lung cancer. A total of four genes (C1GALT1, TMEM106B, ZNF117, and ZNF486) were significantly upregulated with both disorders, highlighting potentially shared genetic and molecular mechanisms. Pathway and cell enrichment analysis indicated that mucin type O-glycan biosynthesis pathway and endothelial cells are strongly associated with these shared genes, lending support for their potential roles in both diseases. Moreover, hsa-miR-34a-5p, hsa-let-7g-5p, and hsa-miR-19a-3p were found to be associated with these common genes. Validation using the GEPIA2 tool confirmed the consistent expression patterns of these four genes in lung cancer. Machine learning analysis highlighted TMEM106B as the most significant biomarker candidate for distinguishing OSA and lung cancer from controls. In summary, this study supports the overarching concept that human diseases can have shared mechanistic pathways in the specific example of OSA and lung cancer. While these findings call for further research and validation, they invite rethinking the current pharmaceutical innovation paradigms to move beyond the "one drug, one disease" concept.

Anophthalmia is the most severe ocular malformation inherited in an autosomal, X-linked, recessive, or dominant form. We report here the use of whole exome sequencing (WES) to help the clinical diagnosis of familial anophthalmia in Harare, Zimbabwe. A mother presented her two sons, who are half-brothers, at the Eye, Ear, Nose, and Throat Institute, Ophthalmology Unit in Harare, Zimbabwe. Upon clinical examination, half-brothers were diagnosed with clinical bilateral anophthalmia. The mother requested a genetic diagnosis for her two sons. To segregate the phenotype with genotype, whole blood was collected from two half-brothers, their mother, maternal aunt, and maternal uncle to the half-brothers, and an unrelated healthy control. Genetic characterization was done, first, through a candidate gene approach screening of putative genes SOX2, OTX2, VSX2, PAX6, and RAX. When no causative variants were identified, the next step employed WES. Variants in 80 genes associated with anophthalmia were prioritized and subjected to pathogenicity testing. One pathogenic variant, BCOR c.254C>T (rs121434618, p. Pro85Leu), segregated with the mother and her two sons. The present clinical genomics study of a family and a healthy control sample underscores WES as a valuable tool that can help clinical diagnosis of anophthalmia in the Zimbabwean clinical setting. In this article, we also offer a reasoned discussion and call from the field, to fund clinical genomics and omics research and development in planetary health, especially in the current era of uncertainties in international aid and funding of innovative technologies. The findings reported herein encourage further research on the clinical utility of WES as a diagnostic tool in Africa and around the world as well, given that the candidate gene approach might miss the important genes or variants of relevance to disease pathophysiology.

Intracellular calcium signaling is a cornerstone in cell biology and a key molecular target for human health and disease. Calcium/calmodulin dependent protein kinase kinases, CAMKK1 and CAMKK2 are serine/threonine kinases that contribute to the regulation of intracellular calcium signals in response to diverse stimuli. CAMKK1 generally has stable dynamics, whereas CAMKK2 dysregulation triggers oncogenicity and neurological disorders. To differentiate the phosphosignaling hierarchy associated with predominant phosphosites of CAMKK1 and CAMKK2, we assembled and analyzed the global cellular phosphoproteome datasets. We found that predominant phosphosites in CAMKK1 and CAMKK2 are located outside the kinase domain, and their phosphomotifs are highly homologous. Further, we employed a coregulation analysis approach to these predominant phosphosites, to infer the co-occurrence patterns of phosphorylations within CAMKKs and the coregulation patterns of other protein phosphosites with CAMKK sites. We report herein that independent phosphorylations at CAMKK2 S100 and S511 increase their enzymatic activity in the presence of calcium/calmodulin. In addition, the study unveils kinase-substrate associations such as RPS6KB1 as a novel high-confidence upstream kinase of both CAMKK1 S74 and CAMKK2 S100. Further, CAMKK2 was identified as a primary orchestrator in mediating intracellular calcium signaling cascades compared to CAMKK1 based on coregulation patterns of phosphosites from proteins involved in the calcium signaling pathway. These molecular details shed promising insights into the pathophysiology of several diseases such as cancers and psychiatric disorders associated with kinase activity dysregulations of CAMKK2 and further open the avenue for novel PTM-directed therapeutic strategies to regulate CAMKK2.