Biology subjects

Roy, T.

Publications and source records attributed to Roy, T..

28 records · Page 2Linked to original sources

bioRxiv2023

Transferrin Receptor 1 is Required for CD4+ T Cell Iron-Dependent Response During Acute Toxoplasma gondii Infection

Elemental iron is an essential nutrient involved in many biological processes including infection and immunity. How iron impacts Toxoplasma gondii (T. gondii) in vivo and development of immunity during infection is unclear. We found that although iron is required for parasite proliferation in vitro, paradoxically, iron restriction in vivo increased parasite burdens during acute and persistent infection stages and decreased survival of mice. Iron restriction lowered IL-12 and IFN{gamma} in spleen and serum, but ratios of myeloid cells and the number and function of Natural Killer cells were unchanged. Iron restriction significantly impaired the development of CD4+ and CD8+ T cell responses to T. gondii during replicating type II and attenuated vaccine strain cps1-1 infection. Low iron conditions reduced the percent and absolute numbers of antigen experienced CD11a+CD49d+, functional IFN{gamma}+, and CD62L-KLRG1+ effector T cells. Iron restriction also decreased vaccine efficacy of cps1-1 strain against secondary lethal challenge. Antigen experienced CD4+ and CD8+ T cells both upregulated their iron transporter Transferrin receptor 1 (CD71) during infection regardless of iron restriction. Mice whose CD4+ T cells were deficient in CD71 had reduced CD4+ T cell antigen experience and polyfunctionality, yet CD8+ T cell responses remained intact, and their long term survival was not affected compared to wild type litter mate controls. This study highlights that iron acquisition by T cells is required for activation and vaccine induced long-term protection against T. gondii. Understanding how iron affects multiple immune compartments will be essential to define iron regulation of immunity to T. gondii.

immunology↗

bioRxiv2023

Precision-engineered biomimetics: the human fallopian tube

The fallopian tube has an essential role in several physiological and pathological processes from pregnancy to ovarian cancer. However, there are no biologically relevant models to study its pathophysiology. The state-of-the-art organoid model has been compared to two-dimensional tissue sections and molecularly assessed providing only cursory analyses of the models accuracy. We developed a novel multi-compartment organoid model of the human fallopian tube that was meticulously tuned to reflect the compartmentalization and heterogeneity of the tissues composition. We validated this organoids molecular expression patterns, cilia-driven transport function, and structural accuracy through a highly iterative platform wherein organoids are compared to a three-dimensional, single-cell resolution reference map of a healthy, transplantation-quality human fallopian tube. This organoid model was precision-engineered to match the human microanatomy. One sentence summaryTunable organoid modeling and CODA architectural quantification in tandem help design a tissue-validated organoid model.

bioengineering↗

bioRxiv2022

In-silico method for predicting infectious strains of Influenza A virus from its genome and protein sequences

Influenza A is a contagious viral disease responsible for four pandemics in the past and a major public health concern. Being zoonotic in nature, the virus can cross the species barrier and transmit from wild aquatic bird reservoirs to humans via intermediate hosts. Virus gradually undergoes host adaptive mutations in their genome and proteins, resulting in different strain s/vari ants which might spread virus from avians/mammals to humans. In this study, we have developed an in-silico models to identify infectious strains of Influenza A virus, which has the potential of getting transmitted to humans, from its whole genome/proteins. Firstly, machine learning based models were developed for predicting infectious strains using composition of 15 proteins of virus. Random Forest based model of protein Hemagglutinin, achieved maximum AUC 0.98 on validation data using dipeptide composition. Secondly, we obtained maximum AUC of 0.99 on validation dataset using one-hot-encoding features of each protein of virus. Thirdly, models build on DNA composition of whole genome of Influenza A, achieved maximum AUC 0.98 on validation dataset. Finally, a web-based service, named "FluSPred"(https://webs.iiitd.edu.in/raghava/fluspred/) has been developed which incorporate best 16 models (15 proteins and one based on genome) for prediction of infectious strains of virus. In addition, we provided standalone software for the prediction and scanning of infectious strains at large-scale (e.g., metagenomics) from genomic/proteomic data. We anticipate this tool will help researchers in prioritize high-risk viral strains of novel influenza virus possesses the capability to spread human to human, thereby being useful for pandemic preparedness and disease surveillance. Key PointsO_LIInfluenza A is a contagious viral disease responsible for four pandemics. C_LIO_LIVirus can cross species barrier and infect human beings. C_LIO_LIIn silico models developed for predicting human infectious strains of virus. C_LIO_LIModels developed were build using 15 proteins and whole genome datasets. C_LIO_LIWebserver and standalone package for predicting and scanning of high-risk viral strains. C_LI

bioinformatics↗

bioRxiv2022

Size-selective mortality fosters evolutionary changes in collective learning across ontogeny and decision-making in zebrafish, Danio rerio

Size-selective harvesting evolutionary alters the life-history, behavioural and physiological traits in exploited fish populations. Changes in these traits may cause alteration in learning and decision-making abilities, either due to energetic trade-offs with brain investment that may vary across development or via correlations with boldness, sociability or other personality traits. Whether size-selective harvesting evolutionarily alters learning and decision-making abilities in fish remains unexplored, despite the global scale of fisheries. We tested the hypothesis that persistent removal of large-bodied individuals typical of many fisheries reduces learning ability in adults but not in juveniles, increases cognitive flexibility but reduces decision-making ability in adults. We examined associative learning through ontogeny, and reversal learning and collective decision-making in adults in three selection lines of zebrafish (Danio rerio) generated through positive, negative and random size-selective harvesting for five generations. Fish groups of each selection line were tested across ontogeny using a colour-discrimination paradigm with a food reward. The associative reversal task was conducted with a social reward, and the propensity to make group decisions was tested in an associative task. All selection lines showed significant learning ability and improved performance across ontogeny. Consistent with our hypothesis, the large-harvested line fish revealed a significantly reduced learning speed as subadults and adults, while the small-harvested line fish showed slower error rate compared to controls as 4-month old adults. We found no evidence of memory decay, and the selection lines did not vary in associative reversal ability. Decision-making speed did not vary across lines, but the large-harvested line made faster decisions during the probe trial. We conclude that size-selective harvesting typical of many fisheries evolutionarily alters learning and decision making. As this is likely to negatively and persistently affect resource acquisition and survival in exploited populations, we suggest that the cognition-related mechanism we identify may increase natural mortality.

ecology↗

bioRxiv2022

Identification of potential inhibitors of cutaneous Melanoma and Non-Melanoma skin cancer cells through in vitro and in silico screening of a small library of Phenolic compounds

Melanoma and non-melanoma skin cancers are the most-lethal and commonest forms of skin cancers, that affecting one-fifth of the US population. With the aim of identifying new lead compounds as starting point for attaining cost-effective therapies, a small library of about 90 molecules was screened in vitro against A375, SKMEL-28, A431, SCC-12 skin cancer cell lines. About 35 of them, mainly dihydroquinolines, C-C and C-N linked biphenyls, and substituted methylgallate or aniline derivatives, displayed low-micromolar range activities, primarily against the A431 and SCC-12 squamous carcinoma cell lines, with only a handful of these compounds displaying any activity against the A375 and SKMEL-28 melanoma cell lines. Compounds 11 (A431: IC50 = 5.0 {micro}M, SCC-12: IC50 = 2.9 {micro}M, SKMEL-28: IC50 = 4.9 {micro}M, A375: IC50 = 6.7 {micro}M) and 13 (A431: IC50 = 5.0 {micro}M, SCC-12: IC50 = 3.3 {micro}M, SKMEL-28: IC50 = 13.8 {micro}M, A375: IC50 = 17.1 {micro}M) were the most active across all these cell lines. Furthermore, many of the hit compounds showed little to no activity against mammalian nontumorigenic immortalized HaCaT cells, with a far better selectivity index than cisplatin (a well-known anticancer agent used as a positive control). Compounds 11 and 13 significantly and dose-dependently induced apoptosis of SCC-12 and SK-MEL-28 cells as evidenced by the downregulation of Bcl-2 and upregulation of Bax protein expression levels, and by cleaved caspase-3, caspase-9 and PARP levels. Both agents also significantly reduced scratch wound healing, colony formation, and activated expression levels of major cancer molecular targets such as RSK/AKT/ERK1/2 and S6K1. To provide a better attribute profile for each of the hit molecules, in-silico target(s) prediction, pharmacokinetic and ADMET studies are also reported, together with some preliminary structure-activity relationship outlines. The SwissTargetPrediction web-based tool identified CDK8, CLK4, nuclear receptor ROR, tyrosine protein-kinase Fyn/LCK, ROCK1/2, and PARP, all of which are dysregulated in skin cancers, as likely targets for these hit compounds. Furthermore, the SwissADME web_tool predicted these compounds to exhibit high GI tract absorption, good skin permeation, and a viable biodegradability profile. To summarize, these data highlight the promising anticancer potential of these small molecules leads, warranting further investigation and/or optimization towards obtaining clinical candidates for combatting both melanoma and non-melanoma skin cancers.

pharmacology and toxicology↗

bioRxiv2021

Size-selective mortality fosters ontogenetic changes in collective risk-taking behaviour in zebrafish, Danio rerio

Size-selective mortality is common in fish populations and can operate either in a positive size-selective fashion or be negatively size-selective. Through various mechanisms (like genetic correlations among behaviour and life-history traits or direct selection on behaviour co-varying with growth rate or size-at-maturation), both positive- and negative size-selection can result in evolutionary changes in behavioural traits. Theory suggests that size-selection alone favours boldness, but little experimental evidence exists about whether and to what extent size-selection can trigger its evolution. Here we investigated the impact of size-selective mortality on boldness across ontogeny using three experimental lines of zebrafish (Danio rerio) generated through positive (large-harvested), negative (small-harvested) and random (control line) size-selective mortality for five generations. We measured risk-taking during feeding (boldness) under simulated aerial predation threat and in presence of a live cichlid. We found that boldness decreased with ontogenetic age under aerial predation threat, and the small-harvested line was consistently bolder than controls. Collective personality emerged post larval stages among the selection lines. In presence of a cichlid, the large-harvested line was bolder at the highest risk of predation. The large-harvested line showed higher variability and plasticity in boldness across life stages and predation risks. Collectively, our results demonstrate that size-selective harvesting may evolutionarily alter risk-taking tendency. Size-selection alone favours boldness when selection acts on small fish. Selection typical of fisheries operating on large fish favours boldness at the highest risk of predation and increases behavioural variability and plasticity. There was no evidence for positive size-selection favouring evolution of shyness.

ecology↗

bioRxiv2020

Genetic Variation Regulates Opioid-Induced Respiratory Depression in Mice

In the U.S., opioid prescription for treatment of pain nearly quadrupled from 1999 to 2014, leading to an epidemic in addiction and overdose deaths. The most common cause of opioid overdose and death is opioid-induced respiratory depression (OIRD), a life-threatening depression in respiratory rate thought to be caused by stimulation of opioid receptors in the inspiratory-generating regions of the brain. Studies in mice have revealed that variation in opiate lethality is associated with strain differences, suggesting that sensitivity to OIRD is genetically determined. We first tested the hypothesis that genetic variation in inbred strains of mice influences the innate variability in opioid-induced responses in respiratory depression, recovery time and survival time. Using the founders of the advanced, high-diversity mouse populations, the Collaborative Cross (CC) and Diversity Outbred (DO), we found substantial sex and genetic effects on respiratory sensitivity and opiate lethality. To define genetic modifiers of OIRD, we then used the high precision DO population treated with morphine to map and identify quantitative trait loci (QTL) for respiratory depression, recovery time and survival time. Trait mapping and integrative functional genomic analysis in GeneWeaver has allowed us to implicate Galnt11, an N-acetylgalactosaminyltransferase, as a candidate gene that regulates OIRD.

genetics↗

bioRxiv2020

Evidence for a growth zone for deep subsurface microbial clades in near-surface anoxic sediments

Global marine sediments harbor a large and highly diverse microbial biosphere, but the mechanism by which this biosphere is established during sediment burial is largely unknown. During burial in marine sediments, concentrations of easily-metabolized organic compounds and total microbial cell abundance decrease steadily. However, it is unknown whether some microbial clades increase with depth, despite the overall trend of abundance decrease. We show total population increases in 38 microbial families over 3 cm of sediment depth in the upper 7.5 cm of White Oak River (WOR) estuary sediments. Clades that increased with depth were more often anaerobic, uncultured, or common in deep marine sediments relative to those that decreased. Minimum turnover times (which are minimum in situ doubling times of growth rates) were estimated to be 2-25 years by combining sedimentation rate with either quantitative PCR (qPCR) or the product of the Fraction Read Abundance of 16S rRNA genes and total Cell counts (FRAxC). Turnover times were within an order of magnitude of each other in two adjacent cores, as well as in two laboratory enrichments of Cape Lookout Bight (CLB), NC, sediments (average difference of 28 {+/-} 19%). qPCR and FRAxC in WOR cores and FRAxC in CLB incubations produced similar turnover times for key deep subsurface uncultured clades Bathyarchaeota (8.7 {+/-} 1.9 years) and Thermoprofundales/MBG-D (4.1 {+/-} 0.7 years). We conclude that common deep subsurface microbial clades experience a narrow zone of growth in shallow sediments, offering an opportunity for natural selection of traits for long-term subsistence after resuspension events. Significance statementThe current dogma is that the deeply-branching uncultured microbes that dominate global marine sediments do not actually increase in population size as they are buried in marine sediments - rather they exist in a sort of prolonged torpor for thousands of years. This is because no evidence has ever been found that these clades actually increase population sizes, or grow, as they are gradually buried. We discovered that they actually do increase population sizes during burial, but only in the upper few centimeters. This changes our dogma about marine sediments as a vast repository of non-growing microbes, to a vast repository of non-growing microbes with a thin and relatively rapid area of growth in the upper 10 centimeters.

microbiology↗

bioRxiv2020

Genetic variation and sex differences are missed opportunities for addiction biology.

Concerns about external validity of rodent models and translation of findings across species are often based on narrow investigations of populations with limited diversity. Sources of individual variation - including genetics and sex - are only infrequently encompassed in model organism studies. As with most complex diseases, risk for cocaine use disorder is subject to considerable inter-individual variation. Explicit inclusion of individual differences in rodent research may reveal conserved phenotypes and molecular systems relevant to human addiction. We surveyed cocaine-related traits in both males and females of eight inbred mouse strains whose genomes collectively capture 90% of the genetic diversity of the mouse species. Across these strains, individual differences explained a substantial proportion of variance in cocaine-responsive or cocaine response-predictive behavioral and physiological phenotypes. Wild-derived mouse strains often extended the phenotypic ranges of these behaviors beyond what is observed in conventional laboratory strains. Striatum transcriptional responses to cocaine were also highly dependent upon strain and sex differences; most cocaine-responsive genes were differentially expressed in a manner moderated by strain, sex, or their combination. We compared the strain- and sex-mediated transcriptional responses to cocaine in mice to transcriptomic analysis of people with cocaine use disorder and found that mouse similarity to humans was highly dependent upon mouse genetic background and sex. Specifically, male WSB/EiJ mice and female NOD/ShiLtJ mice exhibited the greatest degree of neural transcriptional consilience with humans with cocaine use disorder. Model organism diversity thus represents a crucial source of biological information that can substantially improve external validity of neuropsychiatric research. Significance StatementLaboratory mice are widely used in research on neurobiological mechanisms of addiction, but most studies use a single strain and often sex of mice. To assess how individual differences in mice modulate addiction-related traits and how this impacts comparative analysis with humans, we studied cocaine-relevant behaviors and brain molecular correlates in both males and females of genetically diverse mouse strains. In this population, individual differences related to sex and/or genetics explain large proportions of differences in cocaine-related traits. Importantly, brain gene expression data demonstrated that some strains mimic human genomic states more readily than others. Individual differences thus represent a crucial and underdeveloped source of biological information about addiction mechanisms that may influence the translational utility of such studies.

neuroscience↗

bioRxiv2018

Ensemble projections of global ocean animal biomass with climate change

Climate change is shifting the abundance and distribution of marine species with consequences for ecosystem functioning, seafood supply, management and conservation. Several approaches for future projection exist but these have never been compared systematically to assess their variability. We conducted standardized ensemble projections including 6 global fisheries and marine ecosystem models, forced with 2 Earth-system models and 4 emission scenarios in a fished and unfished ocean, to derive average trends and associated uncertainties. Without fishing, mean global animal biomass decreased by 5% ({+/-}4%) under low and 17% ({+/-}11%) under high emissions by 2100, primarily driven by increasing temperature and decreasing primary production. These climate-change effects were slightly weaker for larger animals and in a fished ocean. Considerable regional variation ranged from strong biomass increases in high latitudes to strong decreases in mid-low latitudes, with good model agreement on the direction of change but variable magnitude. Uncertainties due to differences among ecosystem or Earth-system models were similar, suggesting equal need for model improvement. Our ensemble projections provide the most comprehensive outlook on potential climate-driven ecological changes in the ocean to date. Realized future trends will largely depend on how fisheries and management adapt to these changes in a changing climate.

ecology↗