Although the northern Indian Ocean (IO) is globally one of the most productive regions and receives dissolved iron (DFe) from multiple
sources, there is no comprehensive understanding of how these ...different sources of DFe can impact upper-ocean biogeochemical dynamics. Using
an Earth system model with an ocean biogeochemistry component, this study shows that atmospheric deposition is the most important source of
DFe to the upper 100 m of the northern IO, contributing more than 50 % of the annual DFe concentration. Sedimentary
sources are locally important in the vicinity of the continental shelves and over the southern tropical IO, away from high atmospheric
depositions. While atmospheric depositions contribute more than 10 % (35 %) to 0–100 m (surface-level) chlorophyll
concentrations over large parts of the northern IO, sedimentary sources have a similar contribution to chlorophyll concentrations over the southern
tropical IO. Such increases in chlorophyll are primarily driven by an increase in diatom population over most of the northern IO. The regions that
are susceptible to chlorophyll enhancement following external DFe additions are where low levels of background DFe and high background
nitrate-to-iron values are observed. Analysis of the DFe budget over selected biophysical regimes over the northern IO points to vertical mixing
as the most important mechanism for DFe supply, while the importance of advection (horizontal and vertical) varies seasonally. Apart from
removal of surface DFe by phytoplankton uptake, the subsurface balance between DFe scavenging and regeneration is crucial in replenishing the
DFe pool to be made available to the surface layer by physical processes.
Reproductive failure is still a challenge for beef producers and a significant cause of economic loss. The increased availability of transcriptomic data has shed light on the mechanisms modulating ...pregnancy success. Furthermore, new analytical tools, such as machine learning (ML), provide opportunities for data mining and uncovering new biological events that explain or predict reproductive outcomes. Herein, we identified potential biomarkers underlying pregnancy status and fertility-related networks by integrating gene expression profiles through ML and gene network modeling. We used public transcriptomic data from uterine luminal epithelial cells of cows retrospectively classified as pregnant (P, n = 25) and non-pregnant (NP, n = 18). First, we used a feature selection function from BioDiscML and identified SERPINE3, PDCD1, FNDC1, MRTFA, ARHGEF7, MEF2B, NAA16, ENSBTAG00000019474, and ENSBTAG00000054585 as candidate biomarker predictors of pregnancy status. Then, based on co-expression networks, we identified seven genes significantly rewired (gaining or losing connections) between the P and NP networks. These biomarkers were co-expressed with genes critical for uterine receptivity, including endometrial tissue remodeling, focal adhesion, and embryo development. We provided insights into the regulatory networks of fertility-related processes and demonstrated the potential of combining different analytical tools to prioritize candidate genes.
Overlapping risks for cancer and cardiovascular diseases (CVD), the two leading causes of mortality worldwide, suggest a shared biology between these diseases. The role of senescence in the ...development of cancer and CVD has been established. However, its role as the intersection between these diseases remains unclear. Senescence was originally characterized by an irreversible cell cycle arrest after a high number of divisions, namely replicative senescence (RS). However, it is becoming clear that senescence can also be instigated by cellular stress, so-called stress-induced premature senescence (SIPS). Telomere shortening is a hallmark of RS. The contribution of telomere DNA damage and subsequent DNA damage response/repair to SIPS has also been suggested. Although cellular senescence can mediate cell cycle arrest, senescent cells can also remain metabolically active and secrete cytokines, chemokines, growth factors, and reactive oxygen species (ROS), so-called senescence-associated secretory phenotype (SASP). The involvement of SASP in both cancer and CVD has been established. In patients with cancer or CVD, SASP is induced by various stressors including cancer treatments, pro-inflammatory cytokines, and ROS. Therefore, SASP can be the intersection between cancer and CVD. Importantly, the conventional concept of senescence as the mediator of cell cycle arrest has been challenged, as it was recently reported that chemotherapy-induced senescence can reprogram senescent cancer cells to acquire "stemness" (SAS: senescence-associated stemness). SAS allows senescent cancer cells to escape cell cycle arrest with strongly enhanced clonogenic growth capacity. SAS supports senescent cells to promote both cancer and CVD, particularly in highly stressful conditions such as cancer treatments, myocardial infarction, and heart failure. As therapeutic advances have increased overlapping risk factors for cancer and CVD, to further understand their interaction may provide better prevention, earlier detection, and safer treatment. Thus, it is critical to study the mechanisms by which these senescence pathways (SAS/SASP) are induced and regulated in both cancer and CVD.
The rapidly developing pandemic, known as coronavirus disease 2019 (COVID-19) and caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has recently spread across 213 countries ...and territories. This pandemic is a dire public health threat-particularly for those suffering from hypertension, cardiovascular diseases, pulmonary diseases, or diabetes; without approved treatments, it is likely to persist or recur. To facilitate the rapid discovery of inhibitors with clinical potential, we have applied ligand- and structure-based computational approaches to develop a virtual screening methodology that allows us to predict potential inhibitors. In this work, virtual screening was performed against two natural products databases, Super Natural II and Traditional Chinese Medicine. Additionally, we have used an integrated drug repurposing approach to computationally identify potential inhibitors of the main protease of SARS-CoV-2 in databases of drugs (both approved and withdrawn). Roughly 360,000 compounds were screened using various molecular fingerprints and molecular docking methods; of these, 80 docked compounds were evaluated in detail, and the 12 best hits from four datasets were further inspected
molecular dynamics simulations. Finally, toxicity and cytochrome inhibition profiles were computationally analyzed for the selected candidate compounds.
Taste of a chemical compound present in food stimulates us to take in nutrients and avoid poisons. However, the perception of taste greatly depends on the genetic as well as evolutionary ...perspectives. The aim of this work was the development and validation of a machine learning model based on molecular fingerprints to discriminate between sweet and bitter taste of molecules. BitterSweetForest is the first open access model based on KNIME workflow that provides platform for prediction of bitter and sweet taste of chemical compounds using molecular fingerprints and Random Forest based classifier. The constructed model yielded an accuracy of 95% and an AUC of 0.98 in cross-validation. In independent test set, BitterSweetForest achieved an accuracy of 96% and an AUC of 0.98 for bitter and sweet taste prediction. The constructed model was further applied to predict the bitter and sweet taste of natural compounds, approved drugs as well as on an acute toxicity compound data set. BitterSweetForest suggests 70% of the natural product space, as bitter and 10% of the natural product space as sweet with confidence score of 0.60 and above. 77% of the approved drug set was predicted as bitter and 2% as sweet with a confidence score of 0.75 and above. Similarly, 75% of the total compounds from acute oral toxicity class were predicted only as bitter with a minimum confidence score of 0.75, revealing toxic compounds are mostly bitter. Furthermore, we applied a Bayesian based feature analysis method to discriminate the most occurring chemical features between sweet and bitter compounds using the feature space of a circular fingerprint.
Type 2 diabetes is the most prominent of all diabetes types, contributing to global morbidity and mortality. Availability and cost of treatment with little or no side effect especially in developing ...countries, remains a huge burden. This has led to the search of affordable alternative therapies especially from medicinal plants. In this study, the antidiabetic effect of the methanolic extract, dichloromethane (DCM), butanol (BuOH) and aqueous fractions of
leaves were investigated in type 2 diabetic rats for their effect on glucose homeostasis, serum insulin level and hepatic biomarkers, lipid profile, pancreatic redox balance and Ca
levels, and β-cell distribution and function. The DCM was further fractionated to isolate the active compounds, biochanin and 5,7,4'-trimethoxykaempferol. They were investigated for their toxicity and ADMET properties, α-glucosidase and angiotensin I converting enzyme (ACE) inhibitory activities
. There were significant (
< 0.05) decrease in blood glucose, cholesterol, LDL-C, vLDL-C, triglyceride, AST and ALT levels in all treated groups, with DCM fraction showing the best activity. All treated rats showed significantly (
< 0.05) improved anti-oxidative activities. Treatment with the DCM fraction led to significant (
< 0.05) increased serum insulin and pancreatic Ca
levels, as well as improved β-cell distribution and function. DCM fraction also showed improved glucose tolerance. DCM fraction dose-dependently inhibited ACE activity. The toxicity class of the isolated compounds was predicted to be 5. They were also predicted to be potent inhibitors of cytochrome P (CYPs) 1A2, 2D6 and 3A4. They docked well with α-glucosidase and ACE. These results indicate the therapeutic potential of the plant against type 2 diabetes, with the DCM fraction being the most potent which may be attributed to the isolated flavones. It further suggests antihypertensive potentials of the DCM fraction. However, inhibition of CYPs by the flavones may suggest caution in usage with other prescribed drugs metabolized by these enzymes.
Feed efficiency (FE) is an economically important trait. Thus, reliable predictors would help to reduce the production cost and provide sustainability to the pig industry. We carried out ...metabolome-transcriptome integration analysis on 40 purebred Duroc and Landrace uncastrated male pigs to identify potential gene-metabolite interactions and explore the molecular mechanisms underlying FE. To this end, we applied untargeted metabolomics and RNA-seq approaches to the same animals. After data quality control, we used a linear model approach to integrate the data and find significant differently correlated gene-metabolite pairs separately for the breeds (Duroc and Landrace) and FE groups (low and high FE) followed by a pathway over-representation analysis. We identified 21 and 12 significant gene-metabolite pairs for each group. The valine-leucine-isoleucine biosynthesis/degradation and arginine-proline metabolism pathways were associated with unique metabolites. The unique genes obtained from significant metabolite-gene pairs were associated with sphingolipid catabolism, multicellular organismal process, cGMP, and purine metabolic processes. While some of the genes and metabolites identified were known for their association with FE, others are novel and provide new avenues for further research. Further validation of genes, metabolites, and gene-metabolite interactions in larger cohorts will elucidate the regulatory mechanisms and pathways underlying FE.
India confines more than 17% of the world’s population and has a diverse genetic makeup with several clinically relevant rare mutations belonging to many sub-group which are undervalued in global ...sequencing datasets like the 1000 Genome data (1KG) containing limited samples for Indian ethnicity. Such databases are critical for the pharmaceutical and drug development industry where diversity plays a crucial role in identifying genetic disposition towards adverse drug reactions. A qualitative and comparative sequence and structural study utilizing variant information present in the recently published, largest curated Indian genome database (IndiGen) and the 1000 Genome data was performed for variants belonging to the kinase coding genes, the second most targeted group of drug targets. The sequence-level analysis identified similarities and differences among different populations based on the nsSNVs and amino acid exchange frequencies whereas a comparative structural analysis of IndiGen variants was performed with pathogenic variants reported in UniProtKB Humsavar data. The influence of these variations on structural features of the protein, such as structural stability, solvent accessibility, hydrophobicity, and the hydrogen-bond network was investigated. In-silico screening of the known drugs to these Indian variation-containing proteins reveals critical differences imparted in the strength of binding due to the variations present in the Indian population. In conclusion, this study constitutes a comprehensive investigation into the understanding of common variations present in the second largest population in the world and investigating its implications in the sequence, structural and pharmacogenomic landscape. The preliminary investigation reported in this paper, supporting the screening and detection of ADRs specific to the Indian population could aid in the development of techniques for pre-clinical and post-market screening of drug-related adverse events in the Indian population.
Reproductive failure is a major contributor to inefficiency within the cow-calf industry. Particularly problematic is the inability to diagnose heifer reproductive issues prior to pregnancy diagnosis ...following their first breeding season. Therefore, we hypothesized that gene expression from the peripheral white blood cells at weaning could predict the future reproductive potential of beef heifers. To investigate this, the gene expression was measured using RNA-Seq in Angus-Simmental crossbred heifers sampled at weaning and retrospectively classified as fertile (FH,
= 8) or subfertile (SFH,
= 7) after pregnancy diagnosis. We identified 92 differentially expressed genes between the groups. Network co-expression analysis identified 14 and 52 hub targets. ENSBTAG00000052659,
,
, and
were exclusive hubs to the FH group, while 42 hubs were exclusive to the SFH group. The differential connectivity between the networks of each group revealed a gain in connectivity due to the rewiring of major regulators in the SFH group. The exclusive hub targets from FH were over-represented for the CXCR chemokine receptor pathway and inflammasome complex, while for the SFH, they were over-represented for immune response and cytokine production pathways. These multiple interactions revealed novel targets and pathways predicting reproductive potential at an early stage of heifer development.
Conjugated bile acids (BA) are significantly elevated in several liver pathologies and in the metastatic lymph node (LN). However, the effects of BAs on pathological lymphangiogenesis remains ...unknown. The current study explores the effects of BAs on lymphangiogenesis. BA levels were elevated in the LN and serum of Mdr2
mice (model of sclerosing cholangitis) compared to control mice. Liver and LN tissue sections showed a clear expansion of the lymphatic network in Mdr2
mice, indicating activated lymphangiogenic pathways. Human lymphatic endothelial cells (LECs) expressed BA receptors and a direct treatment with conjugated BAs enhanced invasion, migration, and tube formation. BAs also altered the LEC metabolism and upregulated key metabolic genes. Further, BAs induced the production of reactive oxygen species (ROS), that in turn phosphorylated the redox-sensitive kinase p90RSK, an essential regulator of endothelial cell dysfunction and oxidative stress. Activated p90RSK increased the SUMOylation of the Prox1 transcription factor and enhanced
expression and 3-D LEC invasion. BA-induced ROS in the LECs, which led to increased levels of Yes-associated protein (YAP), a lymphangiogenesis regulator. The suppression of cellular YAP inhibited BA-induced VEGFR3 upregulation and lymphangiogenic mechanism. Overall, our data shows the expansion of the lymphatic network in presclerotic liver disease and establishes a novel mechanism whereby BAs promote lymphangiogenesis.
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