Biology subjects

Bhattacharya, A.

Publications and source records attributed to Bhattacharya, A..

At least 55 records · Page 3Linked to original sources

bioRxiv2025

In situ structure of a gap junction - stomatin complex

Gap junctions (GJ) are intercellular channels that mediate electrical signals and the transfer of small molecules. GJs are crucial for the functions of the brain, heart and other organs. While structures of purified homomeric GJs are available, we lack in situ structures. In vivo, GJs can form heteromers with different functionalities, and may associate with other proteins. Here, we analyzed Caenorhabditis elegans GJs by cryo-electron tomography and sub-tomogram averaging. We observed hexagonal arrays of GJs at cellular junctions in primary embryonal cell culture that displayed distinct wide and narrow conformations. Moreover, in about 20% of the observed channels, we found a cap-like, cytosolic protein assembly enclosing the channel pore. We propose that the cap-structure is formed by the stomatin UNC-1, which is known to interact with C. elegans GJs, and strengthen this hypothesis by matching AlphaFold3 models of UNC-1 multimers with our GJ average. Furthermore, expressing UNC-1 and the C. elegans innexin UNC-9 in HEK cells resulted in similar structures at cell-cell contacts. UNC-1/stomatin ring assemblies may affect GJ formation or functions like rectification, that might be evolutionarily conserved. Significance StatementGap junction (GJ) channels connect neighboring cells. Structures of (purified) GJs have been studied in vitro, but not in situ. We identified GJ channels in primary Caenorhabditis elegans cells by cryo-electron tomography, and analyzed their structure by sub-tomogram averaging. The channels transverse the membranes of connected cells, and AlphaFold3 (AF3) models of the GJ subunit UNC-9, assuming dodecamers, fit the experimentally obtained surface map well. We observed a cytosolic cap structure on the GJ channels. The stomatin protein UNC-1 is known to physically interact with UNC-9 GJs. AF3 models of UNC-1 hexadecamers fit the cap structure, indicating that it may be formed by UNC-1, providing a first idea how UNC-1 interacts with, and may functionally influence, GJ channels.

neuroscience↗

bioRxiv2025

Cell type transcriptomics reveal shared genetic mechanisms in Alzheimer's and Parkinson's disease

Historically, Alzheimers disease (AD) and Parkinsons disease (PD) have been investigated as two distinct disorders of the brain. However, a few similarities in neuropathology and clinical symptoms have been documented over the years. Traditional single gene-centric genetic studies, including GWAS and differential gene expression analyses, have struggled to unravel the molecular links between AD and PD. To address this, we tailor a pattern-learning framework to analyze synchronous gene co-expression at sub-cell-type resolution. Utilizing recently published single-nucleus AD (70,634 nuclei) and PD (340,902 nuclei) datasets from postmortem human brains, we systematically extract and juxtapose disease-critical gene modules. Our findings reveal extensive molecular similarities between AD and PD gene cliques. In neurons, disrupted cytoskeletal dynamics and mitochondrial stress highlight convergence in key processes; glial modules share roles in T-cell activation, myelin synthesis, and synapse pruning. This multi-module sub-cell-type approach offers insights into the molecular basis of shared neuropathology in AD and PD.

neuroscience↗

bioRxiv2025

Identification of Evolutionary Trade-Offs Associated with High-Level Colistin Resistance in Acinetobacter baumannii

ABSTRACTColistin (COL) belongs to the polymyxin group of drugs which possesses a positive charge and interacts with lipopolysaccharide (LPS) of Gram-negative bacterial outer membrane. Additionally, it can penetrate the cell membrane and disrupt the integrity of the phospholipid leading to cell death. Resistance against COL has been reported in Acinetobacter baumannii, a bacteria in the ESKAPE group of priority pathogens of the World Health Organization. Multiple and pan-drug-resistant strains of A. baumannii are rising in many medical facilities and they are becoming resistant to last-resort antibiotics including colistin. Though plasmid-encoded acquisition of mcr-1 has been associated with clinical resistance, drug efflux, complete loss of LPS by inactivation of the biosynthetic pathway (lpxACD), and modifications of target LPS by-products of chromosomal pmrCAB genes has been ascribed with resistance evolution against COL. To further delve into the evolutionary dynamics of COL-resistance here we report experimental evolution of extreme COL-resistance by adaptive evolution of the reference strain A. baumannii ATCC19606. Phenotypic characterization has been performed for the evolved strains, which demonstrated hyperbiofilm phenotype and striking decrease in fitness. A comprehensive antibiotic susceptibility profiling has been performed on the evolved strains. Whole genome sequencing of the resistant strains led to the identification of mutations prospectively associated with COL resistance. Phenotypic characterization of three COL-resistant clinical isolates of A. baumannii revealed similarity with experimentally evolved resistant mutants at least in one of the isolates.

microbiology↗

bioRxiv2024

Nonuple atg8 mutant provides genetic evidence for functional specialization of ATG8 isoforms in Arabidopsis thaliana

Autophagy sustains cellular health by recycling damaged or excess components through autophagosomes. It is mediated by conserved ATG proteins, which coordinate autophagosome biogenesis and selective cargo degradation. Among these, the ubiquitin-like ATG8 protein plays a central role by linking cargo to the growing autophagosomes through interacting with selective autophagy receptors. Unlike most ATG proteins, the ATG8 gene family is significantly expanded in vascular plants, but its functional specialization remains poorly understood. Using transcriptional and translational reporters in Arabidopsis thaliana, we revealed that ATG8 isoforms are differentially expressed across tissues and form distinct autophagosomes within the same cell. To explore ATG8 specialization, we generated the nonuple{Delta} atg8 mutant lacking all nine ATG8 isoforms. The mutant displayed hypersensitivity to carbon and nitrogen starvation, coupled with defects in bulk and selective autophagy as shown by biochemical and ultrastructural analyses. Complementation experiments demonstrated that ATG8A could rescue both carbon and nitrogen starvation phenotypes, whereas ATG8H could only complement carbon starvation. Proximity labeling proteomics further identified isoform-specific interactors under nitrogen starvation, underscoring their functional divergence. These findings provide genetic evidence for functional specialization of ATG8 isoforms in plants and lay the foundation for investigating their roles in diverse cell types and stress conditions.

plant biology↗

bioRxiv2024

Mechanism-based approach in designing patient-specific combination therapies for nonsense mutation diseases

Premature termination codon (PTC) diseases, arising as a consequence of nonsense mutations in a patients DNA, account for approximately 12% of all human disease mutations. Currently there are no FDA approved treatments for increasing PTC readthrough in nonsense mutation diseases, although one translational readthrough inducing drug, ataluren, has had conditional approval for treatment of Duchenne muscular dystrophy in Europe and elsewhere for 10 years. Ataluren displays consistent low toxicity in clinical trials for treatment of several different PTC diseases, but its therapeutic effects on such diseases are inconsistent. The identity of the stop codon and its sequence context are major determinants of PTC readthrough efficiency in both the absence and presence of nonsense suppressors. Previously we have shown that ataluren stimulates readthrough exclusively by competitively inhibiting release factor complex (RFC, eRF1.eRF3.GTP)-dependent catalysis of translation termination. Here, using an in vitro reconstituted system (PURE-LITE) and both ensemble and single molecule assays, we demonstrate that PTC identity and the immediately adjacent mRNA sequence contexts modulate the catalytic activity of RFC in terminating peptide elongation. Such modulation largely determines the effectiveness of ataluren in stimulating readthrough, whether added alone or in combination with either the aminoglycoside G418 or an anticodon edited aa-tRNA, each of which stimulate readthrough by mechanisms orthogonal to that of ataluren. Our results provide an attractive rationale for the variability of ataluren effectiveness in stimulating readthrough in clinical trials. Patients harboring a PTC mutation with a sequence context promoting strong interaction with RFC are predicted to be resistant to ataluren, whereas ataluren treatment should be more effective for patient sequences conferring weaker interaction with RFC.

biochemistry↗

bioRxiv2024

Transcriptional pattern enriched for synaptic signaling is associated with shorter survival of patients with high-grade serous ovarian cancer

BackgroundBulk transcriptomic analyses of high-grade serous ovarian cancer (HGSOC) so far have not uncovered potential drug targets, possibly because subtle, disease-relevant transcriptional patterns are overshadowed by dominant, non-relevant ones. Our aim was to uncover disease-outcome-related patterns in HGSOC transcriptomes that may reveal novel drug targets. MethodUsing consensus-independent component analysis, we dissected 678 HGSOC transcriptomes of systemic therapy naive patients--sourced from public repositories--into statistically independent transcriptional components (TCs). To enhance c-ICAs robustness, we added 447 transcriptomes from non-serous histotypes, low-grade serous, and non- cancerous ovarian tissues. Cox regression and survival tree analysis were performed to determine the association between TC activity and overall survival (OS). Finally, we determined the activity of the OS-associated TCs in 11 publicly available spatially resolved ovarian cancer transcriptomes. ResultsWe identified 374 TCs, capturing prominent and subtle transcriptional patterns linked to specific biological processes. Six TCs, age, and tumor stage stratified patients with HGSOC receiving platinum-based chemotherapy into ten distinct OS groups. Three TCs were linked to copy-number alterations affecting expression levels of genes involved in replication, apoptosis, proliferation, immune activity, and replication stress. Notably, the TC identifying patients with the shortest OS captured a novel transcriptional pattern linked to synaptic signaling, which was active in tumor regions within all spatially resolved transcriptomes. ConclusionThe association between a synaptic signaling-related TC and OS supports the emerging role of neurons and their axons as cancer hallmark-inducing constituents of the tumor microenvironment. These constituents might offer a novel drug target for patients with HGSOC.

cancer biology↗

bioRxiv2024

Subtractive proteomics unravel the potency of D-Alanine-D-Alanine Ligase as the drug target for Burkholderia pseudomallei

Melioidosis, also known as Whitmores disease, is caused by the deadly pathogen Burkholderia pseudomallei and remains a significant global health concern, particularly in South Asia. The disease is contracted through exposure to contaminated soil, water, air, and food. Infected individuals often present with abscesses in internal organs such as the lungs, spleen, and liver, and in soft tissues, with severe cases leading to septic shock and acute pneumonia. The rising incidence and mortality rates, coupled with B. pseudomalleis ability to form biofilms and develop resistance to antibiotics like cephalosporins, make treatment increasingly challenging. This highlights the urgent need for novel therapeutic approaches. D-Alanine-D-Alanine ligase (Ddl), a crucial enzyme involved in the final stage of bacterial cell wall synthesis, which protects the pathogen from the hostile cellular environment of the host. While many bacteria have two isoforms of this enzyme, B. pseudomallei possesses only the DdlB isoform, presenting a significant vulnerability. Our study represents the first successful attempt to target DdlB through a combination of molecular docking and molecular dynamics simulations. These investigations provide strong evidence that Conivaptan acts as an effective inhibitor of DdlB, offering a novel therapeutic approach for combating melioidosis.

bioinformatics↗

bioRxiv2024

Single-Molecule Studies of Cognate and Near-Cognate Elongation in an in vitro Eukaryotic Translation System

The ribosome plays a central role in translation of the genetic code into amino acid sequences during synthesis of polypeptides. During each cycle of peptide elongation, the ribosome must discriminate between correct and incorrect aminoacyl-tRNAs according to the codon present in its A-site. Ribosomes rely on a complex sequence of proofreading mechanisms to minimize erroneous selection of incorrect aminoacyl-tRNAs that would lead to mistakes in translation. These mechanisms have been studied extensively in prokaryotic organisms, but eukaryotic elongation is less well understood. Here, we use single-molecule fluorescence resonance energy transfer (smFRET) with an in vitro eukaryotic translation system to investigate tRNA selection and subsequent steps during peptide elongation. We compared accommodation of a tryptophan-aminoacyl-tRNA into the ribosomal A-site containing either a cognate or near-cognate codon and unexpectedly found that, following an initial slow sampling event, subsequent near-cognate sampling events proceeded more rapidly than the initial event. Further, we found a strong negative correlation between the concentration of near-cognate aminoacyl-tRNA and the efficiency of tRNA accommodation. These novel characteristics of near-cognate interaction with the eukaryotic ribosome suggest that rejection of a near-cognate tRNAs leads to formation of an altered ribosomal conformation that assists in rejecting subsequent incorrect tRNA interactions.

biophysics↗

bioRxiv2024

Accelerated Missense Mutation Identification in Intrinsically Disordered Proteins using Deep Learning

We use a combination of Brownian dynamics (BD) simulation results and Deep Learning (DL) strategies for rapid identification of large structural changes caused by missense mutations in intrinsically disordered proteins (IDPs). We used [~] 6500 IDP sequences from MobiDB database of length 20 - 300 to obtain gyration radii from BD simulation on a coarse-grained single bead amino acid model (HPS2 model) used by us and others [Seth et al. J. Chem. Phys. 160, 014902 (2024), Dignon et al. PLOS Comp. Biology, 14, 2018, Tesei et al. PNAS, 118, 2021] to generate the training sets for the DL algorithm. Using the gyration radii [<]Rg[>] of the simulated IDPs as the training set, we develop a multilayer perceptron neural net (NN) architecture that predicts the gyration radii of 33 IDPs previously studied using BD simulation with 97% accuracy from the sequence and the corresponding parameters from the HPS model. We now utilize this NN to predict gyration radii of every permutation of missense mutations in IDPs. Our approach successfully identifies mutation-prone regions that induce significant alterations in the radius of gyration when compared to the wild-type IDP sequence. We further validate the prediction by running BD simulations on the subset of identified mutants. The neural network yields a (104 - 106)-fold faster computation in the search space for potentially harmful mutations. Our findings have substantial implications for rapid identification and understanding diseases related to missense mutations in IDPs and for the development of potential therapeutic interventions. The method can be extended to accurate predictions of other mutation effects in disordered proteins.

bioinformatics↗

bioRxiv2024

Heat-killed probiotic Levilactobacillus brevis MKAK9 and its exopolysaccharide promote longevity by modulating aging hallmarks and enhancing immune responses in Caenorhabditis elegans

BackgroundProteostasis is a critical aging hallmark responsible for removing damaged or misfolded proteins and their aggregates by improving proteasomal degradation through the autophagy-lysosome pathway (ALP) and the ubiquitin-proteasome system (UPS). Research on the impact of heat-killed probiotic bacteria and their structural components on aging hallmarks and innate immune responses is scarce, yet enhancing these effects could potentially delay age- related diseases. ResultsThis study introduces a novel heat-killed Levilactobacillus brevis strain MKAK9 (HK MKAK9), along with its exopolysaccharide (EPS), demonstrating their ability to extend longevity by improving proteostasis and immune responses in wild-type Caenorhabditis elegans. We elucidate the underlying mechanisms through a comprehensive approach involving mRNA- and small RNA sequencing, proteomic analysis, lifespan assays on loss-of- function mutants, and quantitative RT-PCR. Mechanistically, HK MKAK9 and its EPS resulted in downregulation of the insulin-like signaling pathway in a DAF-16-dependent manner, enhancing protein ubiquitination and subsequent proteasomal degradation through activation of the ALP pathway, which is partially mediated by microRNA mir-243. Importantly, autophagosomes engulf ubiquitinylated proteins, as evidenced by increased expression of the autophagy receptor sqst-3, and subsequently fuse with lysosomes, facilitated by increased levels of the lysosome-associated membrane protein (LAMP) lmp-1, suggesting the formation of autolysosomes for degradation of the selected cargo. Moreover, HK MKAK9 and its EPS activated the p38 MAPK pathway and its downstream SKN-1 transcription factor, which are known to regulate genes involved in innate immune response (thn-1, ilys-1, cnc-2, spp-9, spp-21, clec-47, and clec-266) and antioxidation (sod-3 and gst-44), thereby reducing the accumulation of reactive oxygen species (ROS) at both cellular and mitochondrial levels. Notably, SOD-3 emerged as a transcriptional target of both DAF-16 and SKN-1 transcription factors. ConclusionOur research sets a benchmark for future investigations by demonstrating that heat-killed probiotic and its specific cellular component, EPS, can downregulate the insulin- signaling pathway, potentially improving the autophagy-lysosome pathway (ALP) for degrading ubiquitinylated proteins and promoting organismal longevity. Additionally, we discovered that increased expression of microRNA mir-243 regulates insulin-like signaling and its downstream ALP pathway. Our findings also indicate that postbiotic treatment may bolster antioxidative and innate immune responses, offering a promising avenue for interventions in aging-related diseases.

microbiology↗

bioRxiv2024

Exploring the probiotic potential, antioxidant capacity, and healthy aging based on whole genome analysis of Lactiplantibacillus plantarum LPJBC5 isolated from fermented milk product

AbstractLactiplantibacillus plantarum is a beneficial bacterium commonly found in fermented foods, including fermented milk products. In the present study, we reported the whole genome sequence of L. plantarum LPJBC5. The complete genome sequence of LPJBC5 was 3.23Mb, and the average GC% was found to be 44.55% encoding a total of 3016 genes. A comprehensive analysis of the LPJBC5 genome detected major carbohydrate-active enzymes, exopolysaccharide synthesis genes (eps), and the presence of genes related to stress response and antioxidant activity. Longevity regulating genes including katE, CAT (chloramphenicol acetyltransferase), catB and their regulating pathways (MAPK signaling pathway) were detected in the LPJBC5 genome. The genome was found to contain plantaracin (pln) operon for the production of antimicrobial bacteriocin and various regions of secondary metabolite biosynthetic gene clusters, including the type III polyketide synthases (T3PKS), Ribosomally synthesized and post- translationally modified peptide product (Ripp-Like), which exhibit specific antimicrobial activity. A comparative pangenome analysis was performed to further evaluate the metabolic framework of L. plantarum JBC5, including the complete L. plantarum genome (N=30) retrieved from publicly available repositories. The core/soft-core genome was found to harbor probiotic associated marker genes. Functional analysis revealed the presence of genes majorly enriched in cell wall/membrane/envelop biogenesis, carbohydrate metabolism and transport, amino acid metabolism and transport, translational mechanism, and transcription processes. Identification of probiotic and longevity associated genes suggests that LPJBC5 holds potential as a probiotic candidate with multifaceted applications in the food industries. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=92 SRC="FIGDIR/small/584937v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@1a0299dorg.highwire.dtl.DTLVardef@c347dorg.highwire.dtl.DTLVardef@14a28baorg.highwire.dtl.DTLVardef@1b7f81b_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2024

Designing Combinatorial Multiepitope Vaccine Candidates against Scrub Typus by a Proteome-wide Immunoinfomatics Approach.

Scrub typhus (ST) is a mite-borne infection caused by the bacteria Orientia tsutsugamushi and a major public health concern in eastern and south eastern Asia. Early diagnosis and immediate intervention with antibiotics are required to limit the severity of the infection. Prophylaxis is compromised by the absence of an effective vaccine against O. tsutsugamushi. Development an effective vaccine is impeded due to extreme divergence of major surface antigens limiting cross-protectivity. Adopting a proteome-wide immunoinformatic approach, here, immunodominant outer membrane proteins are identified and conserved regions enriched in B-cell, Tc-cell, and Th-cell epitopes were mapped. Similarly, immunodominant stretches from salivary proteins of the vector were identified. Fifteen independent MEVs were designed by combining such segments and were analysed for physicochemical and immunological properties. Tertiary structure of the prioritized MEV was modelled, and interaction with TLR2, 4, and 5 was profiled through molecular docking and MD simulation. A glycosylation-deficient version of the MEV was also designed and analysed similarly. Both the MEVs were immune-simulated, which indicated elicitation of effective immune response. In silico cloning and expression were performed for bacterial and mammalian expression systems. Though the proteome-wide combinatorial approach with immunodominant segments demonstrated prospect, experimental validation for its efficacy against ST is warranted.

bioinformatics↗

bioRxiv2024

PDE4 inhibitor Rolipram represses hedgehog signaling via ubiquitin-mediated proteolysis of GLI transcription factors to regress breast cancer

Aberrant activation of the hedgehog signaling pathway positively correlates with progression, invasion and metastasis of several cancers, including breast cancer. Although numerous inhibitors of the Hedgehog signaling pathway are available, several oncogenic mutations of key components of the pathway, including Smoothened (Smo), have limited their capability to be developed as putative anti-cancer drugs. In this study, we have modulated the Hedgehog signaling pathway in breast cancer cell lines and tumor-bearing BALB/c mice, using a specific phosphodiesterase 4 (PDE4) inhibitor rolipram. The results indicated that increased levels of cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA), due to the treatment with rolipram on MCF-7 and MDA-MB-231 cells, induced PKA-mediated ubiquitination of Glioma-associated oncogene homolog 2 full length (GLI2FL) and GLI3FL, leading to their transformation to respective repressor forms. This in turn reduced the level of Glioma-associated oncogene homolog 1 (GLI1) transcription factor in a time-dependent manner. We have also shown that elevated level of PKA reduced the level of phosphorylated glycogen synthase kinase 3{beta} (GSK3{beta}), which is known to augment PKA-mediated phosphorylation of GLI2FL and GLI3FL. Rolipram also significantly altered the wound healing capability as well as key markers of wound healing in MCF-7 and MDA-MB-231 cells. Moreover, rolipram caused significant reduction in tumor weight and volume in tumor-bearing mice model. The histological analysis revealed significant reduction in the number of multi-nucleated cells in tumor tissue and substantially reduced levels of cellular infiltration in the lung of rolipram treated tumor-bearing mice. Rolipram also reduced the levels of GLI1 in tumor-bearing mice by enhancing the PKA levels. Therefore, it may be concluded that rolipram can be used as an effective inhibitor of Hedgehog signaling pathway downstream of Smo to control breast cancer progression and metastasis in both hormone-responsive and triple negative breast cancers.

cancer biology↗

bioRxiv2024

Repurposing approved protein kinase inhibitors as potent anti-leishmanials targeting Leishmania MAP kinases

Leishmaniasis is a vast array of chronic diseases caused by the protozoan parasite of the genus Leishmania transmitted by the sandfly belonging to the genus Phlebotomus (Old World) and Lutzomyia (New World). Among the various factors that contribute to the virulence and pathogenesis of the disease, protein kinases play crucial role in modulating the parasites biology in the host system. There are no specific drugs identified to treat the disease specifically. Moreover, resistance against approved anti-leishmanials has made it important to look for a few pre-clinical candidates against visceral leishmaniasis. MAP kinase is one such candidate of protein kinase family that regulates cell proliferation in eukaryotes. In this study, we have identified 23 MAPKs from Leishmania genome and have screened 12 FDA approved protein kinase inhibitors against those MAPKs in search of a potential lead for new drug exploration. Among the inhibitors, sorafenib and imatinib have been identified as potential drug candidates based on multiple criteria including binding affinity, ADME scores, absorption and their ability to cross blood-brain barrier. Furthermore, these drugs showed excellent anti-proliferative effects in Leishmania promastigotes, resulted in change of cell morphology, flagellar length, promoted cell cycle arrest through ROS generation and reduced intra-macrophage parasitic burden. Collectively, these results imply involvement of MAP kinases in infectivity and survival of the parasite and can pave the avenue for repurposing sorafenib and imatinib as anti-leishmanial agents.

bioinformatics↗

bioRxiv2023

The colocatome as a spatial -omic reveals shared microenvironment features between tumour-stroma assembloids and lung cancer specimens

Computational frameworks to quantify and compare microenvironment spatial features of in-vitro patient-derived models and clinical specimens are needed. Here, we acquired and analysed multiplexed immunofluorescence images of human lung adenocarcinoma (LUAD) alongside tumour- stroma assembloids constructed with organoids and fibroblasts harvested from the leading edge (Tumour-Adjacent Fibroblasts;TAFs) or core (Tumour Core Fibroblasts;TCFs) of human LUAD. We introduce the concept of the "colocatome" as a spatial -omic dimension to catalogue all proximate and distant colocalisations between malignant and fibroblast subpopulations in both the assembloids and clinical specimens. The colocatome expands upon the colocalisation quotient (CLQ) through a nomalisation strategy that involves permutation analysis and thereby allows comparisons of CLQs under different conditions. Using colocatome analysis, we report that both TAFs and TCFs protected cancer cells from targeted oncogene treatment by uniquely reorganising the tumour-stroma cytoarchitecture, rather than by promoting cellular heterogeneity or selection. Moreover, we show that the assembloids colocatome recapitulates the tumour-stroma cytoarchitecture defining the tumour microenvironment of LUAD clinical samples and thereby can serve as a functional spatial readout to guide translational discoveries. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=190 SRC="FIGDIR/small/557278v1_ufig1.gif" ALT="Figure 1"> View larger version (60K): org.highwire.dtl.DTLVardef@a79aa3org.highwire.dtl.DTLVardef@199582forg.highwire.dtl.DTLVardef@6c7fb6org.highwire.dtl.DTLVardef@134a2aa_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2023

Gestures Of Hunger: Uncovering Intentional Gestural Communication In Free-Ranging Hanuman Langurs

Contrary to previous beliefs, intentional gestural communication (IGC) is not exclusive to the hominoid lineage but is also present in other non-human primates. Here, we report the presence of IGC among free-ranging Hanuman langur troop in Dakshineswar, West Bengal, India. These langurs exhibit a food-requesting behaviour wherein they use several gestures to communicate with the humans nearby. Moreover, they can also assess the recipients mental state and persistently check if the signal (food request) has been received, waiting until they receive the desired food item. We have identified eight begging gestures used by langurs of all ages, except infants. The most common gesture is by holding cloth (BGc), but provocation-initiated begging (BGpi) and begging by embracing legs (BGe) efficiently direct these events to its success. The frequency of successful begging events is higher in the evening due to increased human interactions. Our findings suggest that ontogenetic ritualization might be at play here among these troop members as this gestural communication has been learned through imitation and reinforced by the reward of receiving food. Moreover, these successful begging events serve as an effective foraging strategy for urban-adapted langurs, allowing them to acquire high-calorie processed food items within a human-modified urban ecosystem.

animal behavior and cognition↗

bioRxiv2023

Serine ubiquitination of p62 regulates Nrf2 dependent redox homeostasis

The KEAP1-Nrf2 axis is essential for the cellular response against metabolic and oxidative stress. KEAP1 is an adaptor protein of Cullin-3 ubiquitin ligase that controls the cellular levels of Nrf2, a critical transcription factor of several cytoprotective genes. Oxidative stress, defective autophagy and pathogenic infections activate Nrf2 signaling through phosphorylation of the adaptor protein p62, which competes with Nrf2 for binding to KEAP1. Here we show that phosphoribosyl-linked serine ubiquitination of p62 catalyzed by SidE effectors of Legionella pneumophila controls Nrf2 signaling and cell metabolism upon Legionella infection. Serine ubiquitination of p62 sterically blocks its binding to KEAP1, resulting in Nrf2 ubiquitination and degradation. This reduces Nrf2-dependent antioxidant synthesis in the early phase of infection. Levels of serine ubiquitinated p62 diminish in the later stage of infection allowing the expression of Nrf2-target genes; resulting in a differential regulation of the host metabolome and proteome in a Nrf2 dependent manner.

cell biology↗

bioRxiv2023

Impact of cross-ancestry genetic architecture on GWAS in admixed populations

Genome-wide association studies (GWAS) have identified thousands of variants for disease risk. These studies have predominantly been conducted in individuals of European ancestries, which raises questions about their transferability to individuals of other ancestries. Of particular interest are admixed populations, usually defined as populations with recent ancestry from two or more continental sources. Admixed genomes contain segments of distinct ancestries that vary in composition across individuals in the population, allowing for the same allele to induce risk for disease on different ancestral backgrounds. This mosaicism raises unique challenges for GWAS in admixed populations, such as the need to correctly adjust for population stratification to balance type I error with statistical power. In this work we quantify the impact of differences in estimated allelic effect sizes for risk variants between ancestry backgrounds on association statistics. Specifically, while the possibility of estimated allelic effect-size heterogeneity by ancestry (HetLanc) can be modeled when performing GWAS in admixed populations, the extent of HetLanc needed to overcome the penalty from an additional degree of freedom in the association statistic has not been thoroughly quantified. Using extensive simulations of admixed genotypes and phenotypes we find that modeling HetLanc in its absence reduces statistical power by up to 72%. This finding is especially pronounced in the presence of allele frequency differentiation. We replicate simulation results using 4,327 African-European admixed genomes from the UK Biobank for 12 traits to find that for most significant SNPs HetLanc is not large enough for GWAS to benefit from modeling heterogeneity.

bioinformatics↗