Biology subjects

Pandey, N.

Publications and source records attributed to Pandey, N..

32 records · Page 2Linked to original sources

bioRxiv2022

Density-dependent selection at low food levels leads to the evolution of population stability in Drosophila melanogaster even without a clear r-K trade-off

Density-dependent selection, especially together with r-K trade-offs, has been one of the most plausible suggested mechanisms for the evolution of population stability. However, experimental support for this explanation has been both meagre and mixed. One study with Drosophila melanogaster yielded no evidence for populations adapted to chronic larval crowding having also evolved greater population stability. Another study, on D. ananassae, suggested that populations adapted to larval crowding evolved both greater constancy and persistence stability, and the data also suggested an r-K trade-off in those populations, though the evidence for the latter was not conclusive. Moreover, theoretical work suggested that density-dependent selection could result in the evolution of greater population stability, even in the absence of an r-K trade-off. Here, we show that populations of D. melanogaster, selected for adaptation to larval crowding at very low food amounts per vial, evolve enhanced constancy and persistence stability. The enhanced population stability in the crowding-adapted populations seems to have evolved through the increased equlibrium size (K) and reduced sensitivity of realized population growth rates to density ().There was no clear evidence for reduced intrinsic population growth rate (r) in the more stable crowding-adapted populations. Our study adds to the growing evidence in support of the hypothesis that population stability can evolve in response to density-dependent selection through the evolution of certain life-history traits that are associated with higher K and less negative . We discuss our results in the light of previous work, and suggest that a model-free framework might be of great heuristic value in understanding the evolution of population stability through changes in the density-sensitivity of life-history traits, whether or not these changes result from density-dependent selection.

evolutionary biology↗

bioRxiv2022

Density-dependent selection at high food levels leads to the evolution of persistence but not constancy in Drosophila melanogaster populations

Mechanisms through which population dynamics evolve to be stable have been a subject of considerable interest in population biology. One of the ways through which population stability is likely to evolve is via density-dependent selection with or without an r and K trade-off. In this paper, we test whether the specific combination of egg number and food amount under which density-dependent selection is implemented affects the evolution of population stability attributes in D. melanogaster populations that have evolved under density-dependent selection for 75 generations. Our findings show that these populations have evolved higher persistence stability than controls, although constancy stability did not evolve. Moreover, these populations did not show an r-K trade-off, and evolved persistence largely through a significant decrease in sensitivity of growth rate to population density, especially at densities ranging from medium to the equilibrium population size. Qualitative comparison of these findings with those from another set of crowding-adapted D. melanogaster populations that had evolved both constancy and persistence stability, suggests that the ecology of larval crowding influences the consequent evolution of stability attributes. We discuss previous findings on the evolution of life-history traits to argue that differences in the ecology of density-dependent selection experienced at the larval stage affects population stability differently by altering the sensitivity of population growth rate to population density.

evolutionary biology↗

bioRxiv2022

Effects of larval and adult crowding on fitness components in Drosophila populations adapted to larval crowding experienced under different combinations of food amount and egg number

Since the realization in the 1970s that simple discrete-time population growth models can show complex unstable dynamics of population size, many explanations were proposed for the evolution of enhanced population stability. The most plausible of these was density-dependent selection, suggested to favour greater stability due to r-K trade-offs. However, the first experiment aimed at testing this prediction revealed that Drosophila melanogaster populations adapted to larval crowding did not evolve greater constancy stability than their ancestral controls. A subsequent study showed that D. ananassae populations adapted to larval crowding had evolved greater constancy and persistence than ancestral controls. These D. ananassae populations had experienced chronic larval crowding in conditions of very low amounts of food, whereas the earlier studied D. melanogaster populations had experienced chronic larval crowding at fairly high food amounts. Further theoretical work also suggested that populations adapting to crowding could evolve greater stability even in the absence of r-K trade-offs. Most recently, studies in our laboratory showed that two sets of crowding adapted D. melanogaster populations, derived from a common ancestral lineage, which differed in the food amounts at which they experienced larval crowding, evolved different patterns of constancy and persistence stability. These two sets of populations also differed in the traits, e.g. larval feeding rate, that evolved as they became more competitive. Here, we examine the response of key fitness components to larval and adult densities in these two sets of populations, to see whether differences in their stability attributes can be explained by variation in how their life-histories respond to crowding at different life stages. Of all traits examined, only pre-adult survivorship responded differently to larval density across the two sets of populations. The populations that adapted to larval crowding at low food amounts showed reduced sensitivity of pre-adult survivorship to larval density, compared to those that adapted to larval crowding at high food amounts. We discuss our results in the context of different ways in which density-dependent selection may facilitate the evolution of greater constancy or persistence, depending on the ecological details of how crowding was experienced.

evolutionary biology↗

bioRxiv2022

Inferring functions of coding and non-coding genes using epigenomic patterns and deciphering the effect of combinatorics of transcription factors binding at promoters

The number of annotated genes in the human genome has increased tremendously, and understanding their biological role is challenging through experimental methods alone. There is a need for a computational approach to infer the function of genes, particularly for non-coding RNAs, with reliable explainability. We have utilized genomic features that are present across both coding and non-coding genes like transcription factor (TF) binding pattern, histone modifications, and DNase hypersensitivity profiles to predict ontology-based functions of genes. Our approach for gene function prediction (GFPred) made reliable predictions (>90% balanced accuracy) for 486 gene-sets. Further analysis revealed that predictability using only TF-binding patterns at promoters is also high, and it paved the way for studying the effect of their combinatorics. The predicted associations between functions and genes were validated for their reliability using PubMed abstract mining. Clustering functions based on shared top predictive TFs revealed many latent groups of gene-sets involved in common major biological processes. Available CRISPR screens also supported the inferred association of genes with the major biological processes of latent groups of gene-sets. For the explainability of our approach, we also made more insights into the effect of combinatorics of TF binding (especially TF-pairs) on association with biological functions.

bioinformatics↗

bioRxiv2021

Cyperus rotundus root extract inhibits progress of lymphedema in mouse tail model

Lymphedema is clinically manifested as swelling due to abnormal accumulation of interstitial fluid attributed to inefficient fluid uptake and reduced lymphatic flow. Here we have evaluated the effect of Cyperus rotundus root (CRR) ethanolic extract in a mouse tail model of lymphedema and hypothesized that Cyperus rotundus plant known for its anti-inflammatory effect through inhibition of TNF alpha will be effective in managing this condition. The skin was removed after leaving 1cm of distance from the base of the trunk. Cut was introduced in sterile condition. The animals were divided into Experimental control(EC) and Cyperus rotundus (CRR) treated groups. A change in tail volume around the wound was monitored upto the 20 days. Kinetics of the swelling was calculated for statistical significance. Further TS of upper part of the wound was stained with H&E stain and documented for histological changes RESULTSIn EC group, gradual rise in swelling was recorded, which peaked on 10th day and continued up to 15th day, followed by gradual decrease. In CR extract treated group, the swelling was significantly low and peak was obtained on 8th day, while in EC group the swelling was significantly higher and peak was obtained 11th day. The histological section show, fibrous band intersection the lobules of adipocyte and lymphatic vascular channel and muscles in the sub epithelium region in the EC group, which was very less in CRR group. CONCLUSIONSPolar fraction of CRR significantly prevents the progress of lymphedema and which lays an important role of this plant as for the drug development in future.

pharmacology and toxicology↗

bioRxiv2021

Interaction of hypoxia and nicotine acetylcholine receptor signaling network reveals a novel mechanism for lung adenocarcinoma progression in never-smokers

High incident of lung cancer among never smokers and their disease pathogenesis is an unexplained phenomenon. We have analyzed 1727 lung cancer patient data to understand the impact of smoking on overall survival of lung cancer patients and have observed a difference of only 47 days between smokers and never smokers in adenocarcinoma patients suggesting that the disease is equally fatal in never-smokers irrespective of gender. In this study, we have investigated the possible collaboration between the nAChR and hypoxia signaling pathway to elucidate a mechanism of disease progression in never-smokers. We report a previously unidentified increase in both acetylcholine and nAChR-7 levels in non small cell lung cancer cells in hypoxia. Similar increase in ubiquitously expressed nAChR-7 transcripts was also observed in other cancer lines. A direct binding of HIF-1 with the hypoxia response element (HRE) present at -48 position preceding the transcriptional start site in nAChR-7 promoter region was established. Significantly, the increased acetylcholine levels in hypoxia drove a feedback loop via modulation of PI3K/AKT pathway to stabilize HIF-1 in hypoxia. Further, Bungarotoxin, an antagonist of nAChR-7 significantly reversed hypoxia mediated metastasis and induction of HIF-1 in these cells. Our study gives a plausible explanation for the equally worse prognosis of lung adenocarcinoma in never-smokers wherein the nAChR signaling is enhanced in hypoxia by acetylcholine, in the absence of nicotine.

cancer biology↗

bioRxiv2021

Extremely rapid development and early reproduction reduces sexual selection in D. melanogaster populations.

The role of sexual selection in mediating levels of sexual conflict has been demonstrated in many experimental evolution studies on Drosophila spp. where competition among males for mating was the target of selection. Sexual selection has also been shown to affect the evolution of life-histories. However, the influence of divergent life-histories on reproductive strategies and, therefore, sexual selection and possibly sexual conflict, has been less well studied. We examined D. melanogaster populations selected for a short development time and early age at reproduction for changes in reproductive behaviour and traits that are proxies of sexual selection. We report a large reduction in reproductive competition experienced by the males of these populations, compared to ancestral populations that are not consciously selected for rapid development or early reproduction, potentially leading to reduced sexual selection. We show that rapidly developing and early reproducing populations have very low levels of mating in their lifetime (females are more or less monandrous), low courtship levels, shorter copulation duration, and longer time from eclosion to first mating, compared to the controls. These results are discussed in the context of the previously demonstrated reduction of inter-locus sexual conflict in these populations. We show that life-history strategies might have a large and significant impact on sexual selection, with each influencing the other and contributing to the complexities of adaptation. Significance statementSexual conflict, often manifested as an arms-race between males and females trying to enhance their own reproductive success at some cost to the other, is of great evolutionary interest because it can maintain genetic variation in populations, prevent the independent optimization of male and female traits, and also promote speciation. Sexual selection, or variation in mating success, is well known to affect levels of sexual conflict. However, it is not so clear whether, and how, the regular evolution of life-histories also affects sexual selection. Here, we show that life-history evolution in fruit fly populations selected for traits not directly related to sexual conflict might, nevertheless, mediate the possible evolution of altered sexual conflict levels through effects on sexual selection. Populations that evolved to develop to adulthood fast, and reproduce relatively early in life, are shown to potentially experience less sexual selection, which can explain the low sexual conflict levels earlier observed in them.

evolutionary biology↗

bioRxiv2021

A search-engine for single-cell epigenome profiles for multi-purpose applications

The true benefits of large datasets of the single-cell transcriptome and epigenome profiles can be availed only with their inclusion and search for annotating individual cells. Matching a single cell epigenome profile to a large pool of reference cells remains a major challenge. We developed a method (scEpiSearch) to resolve the challenges of searching and comparing single-cell open-chromatin profiles against large pools of single-cell expression and open chromatin datasets. scEpiSearch is more accurate than other methods when comparing single cell open-chromatin profiles to single-cell transcriptomes and epigenomes. scEpiSearch also provides a robust method for reference-supported co-embedding of single-cell open chromatin profiles. In performance benchmarks, scEpiSearch outperformed multiple methods for the low dimensional co-embedding of single-cell open-chromatin profiles irrespective of platforms and species. scEpiSearch works with both reference single-cell expression and epigenome profiles, enabling classification of single-cell open-chromatin profiles. Here we demonstrate the unconventional utilities of scEpiSearch by applying it on single-cell epigenome profiles of K562 cells and samples from patients with acute leukaemia to reveal different aspects of their heterogeneity, multipotent behaviour and de-differentiated states. Applying scEpiSearch on our single-cell open-chromatin profiles from embryonic stem cells(ESCs), we identified ESC subpopulations with more activity and poising for endoplasmic reticulum stress and unfolded protein response. Thus, scEpiSearch solves the non-trivial problem of amalgamating information from a large pool of single-cells to identify and study the regulatory states of cells using their single-cell epigenomes.The true benefits of large datasets of the single-cell transcriptome and epigenome profiles can be availed only with their inclusion and search for annotating individual cells.

systems biology↗

bioRxiv2020

Improving chromatin-interaction prediction using single-cell open-chromatin profile and making insight about the cis-regulatory landscape of the human brain

Single-cell open-chromatin profiles have the potential to reveal the pattern of chromatin-interaction in a cell-type. However, currently available cis-regulatory network prediction methods using single-cell open-chromatin profiles focus more on local chromatin-interactions despite the fact that long-range interaction among genomic sites plays a significant role in gene regulation. Here, we propose a method that predicts both local and long-range interactions among genomic sites using single-cell open chromatin profiles. Using our methods better sensitivity, we could predict almost 0.7 million interactions among genomic sites across 7 cell-types in the human brain. The chromatin-interactions estimated in the human brain revealed surprising but useful insight about target genes of human-accelerated-elements and disease-associated mutations.

bioinformatics↗

bioRxiv2020

FITs: Forest of imputation trees for recovering true signals in single-cell open chromatin profiles

The advent of single-cell open-chromatin profiling technology has facilitated the analysis of heterogeneity of activity of regulatory regions at single-cell resolution. However, stochasticity and availability of low amount of relevant DNA cause high drop-out rate and noise in single-cell open-chromatin profiles. We introduce here a robust method called as Forest of Imputation Trees (FITs) to recover original signals from highly sparse and noisy single-cell open-chromatin profiles. FITs makes a forest of imputation trees to avoid bias during the restoration of read-count matrices. It resolves the challenging issue of recovering open chromatin signals without blurring out information at genomic sites with cell-type-specific activity. FITs is generalized for wider applicability, especially for highly sparse read-count matrices. The superiority of FITs in recovering signals of minority cells also makes it highly useful for single-cell open-chromatin profile from in vivo samples. First made online as thesis work at https://repository.iiitd.edu.in/xmlui/handle/123456789/807

bioinformatics↗

bioRxiv2020

PICH translocase activity is required for proper distribution of SUMOylated proteins on mitotic chromosomes

Proper chromosome segregation is essential for faithful cell division and if not maintained results in defective cell function caused by abnormal distribution of genetic information. Polo-like kinase 1 interacting checkpoint helicase (PICH) is a DNA translocase essential in chromosome bridge resolution during mitosis. Its function in resolving chromosome bridges requires both DNA translocase activity and ability to bind chromosomal proteins modified by Small Ubiquitin-like modifier (SUMO). However, it is unclear how these activities are cooperating to resolve chromosome bridges. Here, we show that PICH specifically promotes the organization of SUMOylated proteins like SUMOylated TopoisomeraseIIα (TopoIIα) on mitotic chromosomes. Conditional depletion of PICH using the Auxin Inducible Degron (AID) system resulted in the retention of SUMOylated chromosomal proteins, including TopoIIα, indicating that PICH functions to control proper association of these proteins with chromosomes. Replacement of PICH with its mutants showed that PICH is required for the proper organization of SUMOylated proteins on chromosomes. In vitro assays showed that PICH specifically attenuates SUMOylated TopoIIα activity using its SUMO-binding ability. Taken together, we propose a novel function of PICH in remodeling SUMOylated proteins to ensure faithful chromosome segregation.Summary Statement Polo-like kinase interacting checkpoint helicase (PICH) interacts with SUMOylated proteins to mediate proper chromosome segregation during mitosis. The results demonstrate that PICH controls association of SUMOylated chromosomal proteins, including Topoisomerase IIα, and that function requires PICH translocase activity and SUMO binding ability.Competing Interest StatementThe authors have declared no competing interest.AbbreviationsTopoIIαTopoisomerase IIαPICHPolo-like kinase interacting checkpoint helicaseSPRStrand passage reactionSUMOSmall ubiquitin-like modifierXEEXenopus egg extractCSFCytostatic factordnUbc9dominant negative E2 SUMO-conjugating enzymeSENPSentrin-specific proteasePIASProtein inhibitor of activated STATSIMSUMO-interacting-motifView Full Text

cell biology↗

bioRxiv2019

Interactions of helices on interdomain interface couple the chemistry of intermediate formation with allostery in Plasmodium falciparum GMP synthetase

GMP synthetase catalyzes the substitution of the C2 oxo-group of the purine base in XMP with an amino-group generating GMP, the last step in the biosynthesis of GMP. This reaction involves a series of catalytic events that include hydrolysis of Gln generating ammonia in the glutamine amidotransferase (GATase) domain, activation of XMP to adenyl-XMP intermediate in the ATP pyrophosphatase (ATPPase) domain and reaction of ammonia with the intermediate to generate GMP. Inherent to the functioning of GMP synthetases is bidirectional domain crosstalk, which leads to allosteric activation of the GATase domain by substrates binding to the ATPPase domain, synchronization of the two catalytic events and tunnelling of ammonia from the GATase to the ATPPase domain. Herein, we have taken recourse to the analysis of structures of GMP synthetases, site-directed mutagenesis and, steady-state and transient kinetic assays on the Plasmodium falciparum enzyme to decipher the molecular basis of catalysis in the ATPPase domain and domain crosstalk. The results map the residues critical for catalysis in the ATPPase domain to the helices 11 and 12 that are located at the interdomain interface, and the lid-loop that follows 11. This apart, perturbing interdomain interactions involving residues on 11 and 12 impairs GATase activation. These results imply that this arrangement of helices at the domain interface with residues that play roles in ATPPase catalysis as well as domain crosstalk enables coupling ATPPase catalysis with GATase activation. Overall, the study enhances our understanding of GMP synthetases, which are drug targets in many infectious pathogens.

biochemistry↗

bioRxiv2019

PICH promotes SUMOylated TopoisomeraseIIα dissociation from mitotic centromeres for proper chromosome segregation

Polo-like kinase interacting checkpoint helicase (PICH) is a SNF2 family DNA translocase and is a Small Ubiquitin-like modifier (SUMO) binding protein. Despite that both translocase activity and SUMO-binding activity are required for proper chromosome segregation, how these two activities function to mediate chromosome segregation remains unknown. Here, we show that PICH specifically promotes dissociation of SUMOylated TopoisomeraseII (TopoII) from mitotic chromosomes. When TopoII is stalled by treatment of cells with a potent TopoII inhibitor, ICRF-193, TopoII becomes SUMOylated, and this promotes its interaction with PICH. Conditional depletion of PICH using the Auxin Inducible Degron (AID) system resulted in retention of SUMOylated TopoII on chromosomes, indicating that PICH removes stalled SUMOylated TopoII from chromosomes. In vitro assays showed that PICH specifically regulates SUMOylated TopoII activity using its SUMO-binding and translocase activities. Taken together, we propose a novel mechanism for how PICH acts on stalled SUMOylated TopoII for proper chromosome segregation.\n\nSummary StatementPolo-like kinase interacting checkpoint helicase (PICH) interacts with SUMOylated proteins to mediate proper chromosome segregation during mitosis. The results demonstrate that PICH promotes dissociation of SUMOylated TopoisomeraseII from chromosomes and that function leads to proper chromosome segregation.

cell biology↗

bioRxiv2018

Detection of Leishmania DNA in saliva among patients with HIV/AIDS in Trang Province, southern Thailand

Leishmaniasis is a neglected tropical disease causing opportunistic infection among patients with HIV/AIDS. The fatal form of this disease is visceral leishmaniasis (VL). DNA of Leishmania can be detected in saliva, for which the collection is noninvasive and requires little expertise. This study aimed to evaluate the sensitivity and specificity of a nested-PCR to amplify the Internal Transcribed Spacer 1 (ITS1) to detect Leishmania DNA in paired saliva and buffy coat samples of 305 Thai patients with HIV/AIDS in Trang Hospital, Trang Province, southern Thailand. For asymptomatic Leishmania infection among Thai patients with HIV/AIDS, the sensitivity and specificity of the nested-PCR-ITS1 in buffy coat were 73.9 and 100%, respectively. However, the sensitivity in saliva was 26.1% and specificity was 100%. Using the nested-PCR-ITS1, saliva and buffy coat samples showed positive agreement in only 52.0% of patients. Saliva tested results with the nested-PCR-ITS1 showed positive agreement with the Direct Agglutination Test (DAT) in 46.5% of patients. Only 12.1% of the samples showed positive agreement for Leishmania infection among all the three tests: saliva, buffy coat and DAT results. Using nucleotide sequencing, at least three species of Leishmania infection were identified in saliva, i.e., L. siamensis (n=28), L. martiniquensis (n=9), and L. donovani complex (n=1). As a result, buffy coat still appears to be a better specimen to diagnose asymptomatic VL infection among individuals with HIV. However, the use of both buffy coat and saliva together as clinical specimens would increase the sensitivity of Leishmania detection.

microbiology↗