Biology subjects

Shinde, S. S.

Publications and source records attributed to Shinde, S. S..

9 recordsLinked to original sources

bioRxiv2026

ST6GAL1 sialyltransferase promotes acinar cell survival and tissue regeneration during pancreatitis

The role of aberrant glycosylation in pancreatitis remains an under-investigated area of research. Here, we determined that the ST6GAL1 sialyltransferase, which adds 2-6-linked sialic acids to N-glycoproteins, was upregulated in pancreatic tissues from patients with acute (AP) and chronic (CP) pancreatitis, and in mice with experimental AP. Within these tissues, ST6GAL1 was selectively expressed in acinar cells undergoing acinar to ductal metaplasia (ADM), a process whereby injured acinar cells de-differentiate and re-enter the cell cycle to enable tissue repair. To study the functional role of ST6GAL1 in pancreatitis, we used HPNE pancreatic epithelial cells with modulated ST6GAL1 expression, along with pancreatic organoids from mice with transgenic expression of ST6GAL1 (SC mice). In these models, ST6GAL1 activity promoted the activation of EGFR (a well-known ADM-driver), ERK, and AKT. ST6GAL1-expressing cells also displayed an ERK-dependent upregulation of the anti-apoptotic proteins, Mcl-1 and Bcl-xL, and impaired apoptotic signaling by the TNFR1 and Fas death receptors. Unbiased kinomics profiling revealed that ST6GAL1 induced the activation of many receptor tyrosine kinases associated with cell survival and proliferation (e.g., EGFR, PDGFR, MET). Furthermore, ST6GAL1 enhanced the survival and proliferation of cells exposed to stress-inducing conditions such as serum withdrawal. Based on these findings, we hypothesized that the pro-survival phenotype imparted by ST6GAL1 would facilitate tissue healing following a bout of pancreatitis. Accordingly, we induced AP in wild type and SC mice via L-arginine injection and found that SC mice had more rapid and efficient tissue repair, evidenced by accelerated restoration of the acini, diminished acinar apoptosis, and reduced immune cell infiltration. Together, these findings highlight a novel glycosylation-dependent mechanism that drives cell survival, positioning ST6GAL1 as a key adaptive mediator of pancreatic regeneration.

cell biology↗

bioRxiv2025

BACH2 dosage establishes the hierarchy of stemness and finetunes antitumor immunity in CAR T cells

Self-renewing stem-like T cells promote the efficacy of cancer immunotherapy and are a heterogeneous population with sub-lineages demonstrating different degrees of stemness. At the apex of this hierarchy is long-term (LT) stem-like T cells with the highest capacity of persistence, repopulation and response to immune checkpoint inhibitors (ICI). However, the pathway that establishes the hierarchy of stemness in chimeric antigen receptor (CAR) T cells and its role in antitumor efficacy of CAR T cells are unclear. Here, we demonstrate that LT stem-like differentiation and antitumor immunity of CAR T cells are dose-dependently regulated by BACH2. Pre-infusion LT stem-like CAR T cells showed epigenetic activation of BACH2 and superior antitumor response in mice and humans. After clearing tumor in vivo, LT stem-like T cells emerged as a CAR subset that transcriptionally and epigenetically upregulated BACH2 and downregulated TOX. Loss-of-function experiments revealed an essential role of BACH2 in the antitumor response of CAR T cells and the transcriptional program of LT stem-like CAR T cells. In exhaustion-prone GD2 CAR T cells with high tonic signaling, we showed that quantitative control of BACH2 protein level by a small molecule drug finetuned the degree of stemness and exhaustion in CAR T cells. Chemically inducing temporal BACH2 activation during manufacture of GD2 CAR T cells imprinted greater antitumor immunity against solid tumor after infusion. Together, we show that BACH2 dosage establishes the hierarchy of stem-like CAR T cells and can be temporally and tunably controlled in CAR T cells to optimize differentiation and antitumor immunity.

cancer biology↗

bioRxiv2025

Gene duplication, translocation and molecular evolution of Dmrt1 and related sex-determining genes in anurans

Sex determination, the developmental process that directs embryos toward male or female fates, is controlled by master sex-determining genes whose origins and evolutionary dynamics remain poorly understood outside of a few model systems. In contrast to the highly differentiated sex chromosomes of mammals, birds, and Drosophila, most anurans (frogs and toads) maintain homomorphic sex chromosomes that exhibit a rapid turnover, even among closely related species. To uncover the mechanisms underlying the emergence of new master sex-determining genes and sex chromosome turnover, we analysed 53 published anurans and one caecilian genome (>200 Ma divergence) and available transcriptomes. We asked how often new master sex-determining genes arise by gene duplication, whether and how often gene translocation associates with sex chromosome turnover, and if new master sex-determining genes evolve under positive selection. We find that chromosome-level synteny is remarkably conserved, with only a few fusions or fissions and no evidence for translocation of four candidate master sex-determining genes (Dmrt1, Foxl2, Bod1l, Sox3). Only Dmrt1 duplicated in 3 out of 50 species (excluding tetraploid Xenopus), and it showed strong testis-biased expression in all 8 species with available gonadal expression data. While Dmrt1 has evolved under purifying selection, Dmrt1 duplicates exhibit elevated nonsynonymous substitution rates and a tendency towards positive selection. Lineage-specific amino acid changes were observed in the conserved DM domain of Dmrt1. These results demonstrate that, in anurans, master sex-determining genes arise rarely via gene duplication, and more likely evolve via allelic diversification. Sex chromosome turnover is not associated with gene translocation, and is more likely driven by mutations on genes involved in sexual developmental pathway. All candidate sex-determining genes were under strong purifying selection, with the exception of duplications which are linked to positive selection. Our results suggest future research on anuran sex determination and sex chromosome evolution should focus on identifying allelic diversification and novel mutations on genes involved in sexual developmental pathway.

evolutionary biology↗

bioRxiv2023

Hundreds of independent midsize deletions mediate DNA loss in wild relatives of Red Jungle Fowl

Small and midsize deletions and insertions (InDels) are major events that play a crucial role in the evolution of genome size and contribute to the genetic and phenotypic diversity of species. In recent years, considerable attention has been given to studying small indels associated with various developmental, growth, and production traits in domestic chicken breeds. Additionally, small and midsize indels have been studied between chicken and phylogenetically more distant species such as duck, turkey, rock pigeon, and other passerine birds. However, the investigation of small and midsize deletions in the wild relatives of chickens has been relatively overlooked until now. To address this gap, our study aimed to identify the presence and distribution of midsize deletions (> 1 Kb) in the wild relatives of chickens. We conducted a comparative genomic analysis using high-quality genomic data from four species belonging to the Gallus genus. Our analysis revealed the existence of more than 125 midsize deletions in the three other species compared to Gallus gallus (red junglefowl). These midsize deletions were found to be distributed in intergenic regions and within introns of various protein-coding genes but not in the exonic regions of protein-coding genes. Furthermore, we observed a trend between the number of midsize deletions and the phylogenetic distance in the phylogeny of the Gallus genus. The most ancestral species, Gallus varius (green junglefowl), exhibited the highest deletions, followed by Gallus lafayettii (Ceylon junglefowl) and Gallus sonneratii (grey junglefowl). Some protein-coding genes harboring deletions in their introns and upstream regions were associated with body development, production, growth traits, abdominal fat deposition, behavioral patterns such as stress, fear, anxiety, plumage color, and adaptation to extreme climatic conditions. Our study finds that the midsize deletions identified in wild relatives of red junglefowl contribute less than 1% of DNA loss with a rate of 8-44 Kb/My during the evolution of the Gallus genus.

genomics↗

bioRxiv2022

Kadaknath chicken specific hitchhiking of BPIL with the FM locus

Black-bone-chicken (BBC) meat is popular for its distinctive taste and texture. A complex chromosomal rearrangement at the fibromelanosis (Fm) locus on the 20th chromosome results in increased expression of the endothelin-3 (EDN3) gene and is responsible for melanin hyperpigmentation in BBC. We use public long-read sequencing data of the silkie breed to resolve high-confidence haplotypes at the Fm locus spanning both Dup1 and Dup2 regions and establish that the Fm_2 scenario is correct of the three possible scenarios of the complex chromosomal rearrangement. The relationship between Chinese and Korean BBC breeds with Kadaknath native to India is underexplored. Our data from whole-genome re-sequencing establishes that all BBC breeds, including Kadaknath, share the complex chromosomal rearrangement junctions at the fibromelanosis (Fm) locus. We also identify two Fm locus proximal regions ([~]70Kb and [~]300 Kb) with signatures of selection unique to Kadaknath. These regions harbor several genes with protein-coding changes, with the Bactericidal/permeability-increasing-protein-like (BPIL) gene having two Kadaknath-specific changes within protein domains. Our results indicate that protein-coding changes in the BPIL gene hitchhiked with the Fm locus in Kadaknath due to close physical linkage. Identifying this Fm locus proximal selective sweep sheds light on the genetic distinctiveness of Kadaknath compared to other BBC.

evolutionary biology↗

bioRxiv2021

Recurrent erosion of COA1/MITRAC15 demonstrates gene dispensability in oxidative phosphorylation

Skeletal muscle fibers rely upon either oxidative phosphorylation or glycolytic pathway to achieve muscular contractions that power mechanical movements. Species with energy-intensive adaptive traits that require sudden bursts of energy have a greater dependency on fibers that use the glycolytic pathway. Glycolytic fibers have decreased reliance on OXPHOS and lower mitochondrial content compared to oxidative fibers. Hence, we hypothesized that adaptive gene loss might have occurred within the OXPHOS pathway in lineages that largely depend on glycolytic fibers. The protein encoded by the COA1/MITRAC15 gene with conserved orthologs found in budding yeast to humans promotes mitochondrial translation. We show that gene disrupting mutations have accumulated within the COA1/MITRAC15 gene in the cheetah, several species of galliforms, and rodents. The genomic region containing COA1/MITRAC15 is a well-established evolutionary breakpoint region in mammals. Careful inspection of genome assemblies of closely related species of rodents and marsupials suggests two independent COA1/MITRAC15 gene loss events co-occurring with chromosomal rearrangements. Besides recurrent gene loss events, we document changes in COA1/MITRAC15 exon structure in primates and felids. The detailed evolutionary history presented in this study reveals the intricate link between skeletal muscle fiber composition and dispensability of the chaperone-like role of the COA1/MITRAC15 gene.

evolutionary biology↗

bioRxiv2020

The ratio versus difference optimization and its implications for optimality theory

Among the classical models of optimization, some models maximize the ratio of returns per investment, others maximize the difference between returns and investment. However, the question under what conditions use of the ratio model is appropriate and under what conditions a difference model should be used remained unaddressed until recently. The question is important because the strategies indicated by ratio optimum can be substantially different than the ones suggested by difference optimum. We make a general case here for the set of conditions for appropriate use of ratio versus difference optimum. When the investable amount is perceived as limiting but not the investment opportunities a ratio optimum is appropriate and when the investment opportunities are perceived to be limiting but not the investable amount, difference optimum is appropriate. Taking examples of Concorde fallacy, parental investment, r and K selection, nectar production, pollinator behavior, protein synthesis and stability, viral burst size and human economic behavior we show that the ratiodifference distinction in optimization models resolves many long standing debates and conundrums in evolution, behavior and economics.

evolutionary biology↗

bioRxiv2020

CoalQC - Quality control while inferring demographic histories from genomic data: Application to forest tree genomes

Estimating demographic histories using genomic datasets has proven to be useful in addressing diverse evolutionary questions. Despite improvements in inference methods and availability of large genomic datasets, quality control steps to be performed prior to the use of sequentially Markovian coalescent (SMC) based methods remains understudied. While various filtering and masking steps have been used by previous studies, the rationale for such filtering and its consequences have not been assessed systematically. In this study, we have developed a reusable pipeline called "CoalQC", to investigate potential sources of bias (such as repeat regions, heterogeneous coverage, and callability). First, we demonstrate that genome assembly quality can affect the estimation of demographic history using the genomes of several species. We then use the CoalQC pipeline to evaluate how different repeat classes affect the inference of demographic history in the plant species Populus trichocarpa. Next, we assemble a draft genome by generating whole-genome sequencing data for Mesua ferrea (sampled from Western Ghats, India), a multipurpose forest plant distributed across tropical south-east Asia and use it as an example to evaluate several technical (sequencing technology, PSMC parameter settings) and biological aspects that need to be considered while comparing demographic histories. Finally, we collate the genomic datasets of 14 additional forest tree species to compare the temporal dynamics of Ne and find evidence of a strong bottleneck in all tropical forest plants during Mid-Pleistocene glaciations. Our findings suggest that quality control prior to the use of SMC based methods is important and needs to be standardised.

evolutionary biology↗

bioRxiv2019

Signatures of relaxed selection in the CYP8B1 gene of birds and mammals

The CYP8B1 gene is known to catalyse reactions that determine the ratio of primary bile salts and the loss of this gene has recently been linked to lack of cholic acid in the bile of naked-mole rats, elephants and manatees using forward genomics approaches. We screened the CYP8B1 gene sequence of more than 200 species and test for relaxation of selection along each terminal branch. The need for retaining a functional copy of the CYP8B1 gene is established by the presence of a conserved open reading frame across most species screened in this study. Interestingly, the dietary switch from bovid to cetacean species is accompanied by an exceptional ten amino-acid extension at the C-terminal end through a single base frame-shift deletion. We also verify that the coding frame disrupting mutations previously reported in the elephant are correct, are shared by extinct Elephantimorpha species and coincide with the dietary switch to herbivory. Relaxation of selection in the CYP8B1 gene of the wombat (Vombatus ursinus) also corresponds to drastic change in diet. In summary, our forward genomics based screen of bird and mammal species identifies recurrent changes in the selection landscape of the CYP8B1 gene concomitant with a change in dietary lipid content.

evolutionary biology↗