Biology subjects

Sinha, K.

Publications and source records attributed to Sinha, K..

13 recordsLinked to original sources

bioRxiv2026

Warmth shifts rather than speeds transcriptomic ageing in the malaria mosquito Anopheles gambiae

Only older mosquitoes transmit malaria, so how warming changes mosquito ageing matters for disease. Warmer temperatures are known to make mosquitoes age faster, but 'faster' can mean two different things: the ageing clock ticks more quickly, or it is simply set forward. We distinguished these by reanalysing 115 whole-body RNA-sequencing libraries from female Anopheles gambiae kept at 27, 30 or 32 {degrees}C and sampled 1-15 days after emergence. A transcriptomic clock trained on 27 {degrees}C mosquitoes (error {+/-}0.9 days) read 32 {degrees}C mosquitoes as 2.4 days older (95% CI 1.9-2.9) and 30 {degrees}C mosquitoes as 1.1 days older. The gap opened by day 5 and then stopped growing: between days 5 and 15, warmth added 0.01 extra days per day (95% CI -0.16 to 0.19), well below the 0.29-0.45 expected if the clock ran faster. Genome-wide, warmth advanced genes that change late in life, notably melanisation and digestive genes, but moved early-maturation genes the opposite way. Many responses bent at 30 {degrees}C, and immune genes held until 30 {degrees}C before falling. Warmth therefore shifts mosquitoes to an older transcriptional state without accelerating its pace.

bioinformatics↗

bioRxiv2026

Hidden introns and repeated gains shape the heavily interrupted tRNA genes of Asgard archaea

Transfer RNA (tRNA) genes are usually compact, yet in some Asgard archaea-the closest known prokaryotic relatives of eukaryotes-most are interrupted by introns. Studying this has been hampered by circularity: archaeal introns are catalogued by software that finds them partly through the splicing motif later used to explain where they persist. We built a motif-free census that detects intervening sequences by comparing each tRNA gene with compact relatives, and applied it to 90 Asgard genomes and 18 reference archaea. The standard annotator, tRNAscan-SE, had missed 30% of intervening sequences in the three focal families, mostly in the D-arm, but almost none in reference archaea; six independent checks supported the census. After correction, focal tRNA genes carry 2.2 intervening sequences on average, and in 30 genomes chosen before analysis the two focal families ranked first and second of 21 (exact P = 1/210). A reconstruction based on the census rather than on annotated introns placed 129 high-confidence gains at 65 loci on 37 branches of the species tree, 71 of them terminal; the two intron-rich classes are not sister lineages and carry mostly different intron positions, consistent with independent accumulation. Intervening sequences sat at canonical bulge-helix-bulge splicing motifs six to ten times more often than the average of three matched null models, including those the annotator missed and the reconstructed gains. Tests of copying between tRNA genes, mobile elements and reverse transcription found no general route of intron arrival. Asgard tRNA introns were thus gained repeatedly and sit preferentially at sites predicted to allow splicing; how they arrive remains open.

bioinformatics↗

bioRxiv2026

Evolutionary replay of duplicate-gene retention across independent whole-genome duplications

Whole-genome duplication repeatedly exposes ancestral gene lineages to duplicate retention and loss. Although preferential retention is established, whether lineage identity carries transferable information, and which biological properties account for that information, remain separate questions. We compared retention ranks across independent duplications using orthology coordinates constructed independently of target outcomes. Three plant events showed replay (Treplay = 0.210; bootstrap 95% confidence interval, 0.172 to 0.248; permutation P = 1/100,001). A frozen plant score prospectively predicted Apple/Pear retention ({rho} = 0.169; n = 373; 95% confidence interval, 0.069 to 0.262; P = 0.000470). Transfer to yeast was supported, whereas teleost transfer remained unresolved. Independent teleost-Stylommatophora replay was positive but below its prespecified strong-effect threshold; a strict plant-animal scalar comparison remained unresolved. We then prospectively defined tests of dosage-related response, protein-sequence constraint, expression magnitude and expression breadth, followed by a frozen multivariate analysis. Dosage-related proxies, sequence constraint and expression breadth were unsupported under their tested definitions. Conserved expression magnitude was associated with retention across the reference plant events, but its attenuation of replay was unresolved. The multivariate model did not establish reliable prediction of held-out events superior to all single-property models. Thus, gene-lineage identity carries partially transferable retention information, but the tested conserved properties do not demonstrably account for it. Predicting retention and explaining replay are distinct biological problems.

evolutionary biology↗

bioRxiv2026

Declines in mRNA synthesis set the rate of organismal aging

The abundance of mRNA sets a ceiling on a cells capacity to produce protein and carry out its functions. Here, we describe a pathological decline in absolute mRNA abundance that occurs in most cell types during invertebrate and mammalian aging, caused by decreases in mRNA synthesis capacity. In C. elegans, decreases in mRNA abundance are tightly coupled to declines in RNA Polymerase II (Pol II) protein abundance. Measuring Pol II abundance dynamics in vivo, we find that individuals enter adulthood with a four-fold excess of Pol II, whose kinetic equilibration towards its homeostatic set point drives reductions in mRNA abundance and, in turn, organismal aging. Briefly accelerating Pol II declines produces permanent, dose-dependent reductions in healthspan and lifespan, whereas deceleration extends both. Although disrupted cellular homeostasis is conventionally seen as a consequence of aging, our results reveal how an out-of-equilibrium state established during development provides a driving force for aging.

systems biology↗

bioRxiv2026

Curli Carrier Burden: a quantitative trait-level microbiome index for amyloidogenic bacterial signals in Parkinsons disease gut metagenomes

BackgroundParkinsons disease (PD) gut metagenomic studies have repeatedly reported disease-associated shifts in microbial taxa, genes, and pathways. However, the field still lacks transparent trait-level indices that summarize biologically coherent microbial exposures. Curli fibres are extracellular bacterial amyloids produced by several Enterobacteriaceae and related taxa, and they provide a plausible microbiological bridge between gut microbial ecology, epithelial/immune interfaces, and alpha-synuclein-centered gut-brain-axis hypotheses. We introduced Curli Carrier Burden (CCB), a mathematically explicit, taxon-informed index that estimates the aggregate abundance of curated curli-carrier bacterial taxa in processed metagenomic profiles. MethodsA curated curli-carrier candidate panel was converted into an evidence-weighted taxon set. For sample s, CCB was defined as [Formula], where ais is the processed relative abundance of matched curli-carrier taxon i and wi is an evidence weight reflecting curli-carrier confidence. We evaluated CCB in five main PD gut metagenomic evidence streams: Wallen 2022, Integrated-US, Mao Central China, Romano non-Wallen, and DuruIC 2024. Results were interpreted cohort-wise rather than as a formal meta-analysis. ResultsThe CCB framework generated a reproducible sample-level microbial trait variable and enabled cohort-wise comparison of amyloidogenic bacterial burden. Wallen showed discovery-stage PD-associated elevation (724 samples; 31 matched curli taxa; Mann-Whitney p = 0.0020). Integrated-US provided supportive independent evidence (244 samples; 18 matched taxa; p = 0.0079). Mao Central China and DuruIC 2024 showed the same PD-greater-than-control direction by mean and median CCB, although their individual comparisons were not nominally significant. Romano non-Wallen provided a large multi-study analysis (600 samples; 29 matched curli-associated mOTUs taxa), with higher PD mean and median CCB in pooled analysis (p = 0.0036, Cliffs{delta} = 0.137) and cohort-sensitive behavior under study-stratified permutation (p = 0.1974). Additional processed-cohort checks indicated that CCB interpretability depends on taxonomic representation and matched curli-candidate coverage, reinforcing the value of explicit compatibility reporting. ConclusionsCCB is a novel, extensible, microbiology-informed index for quantifying amyloidogenic curli-carrier bacterial burden in processed gut metagenomic profiles. The current results support CCB as a useful exploratory trait-level variable for PD microbiome research and provide a principled route toward future raw-read, csg-operon, strain-resolved, and phenotype-aware studies of the curli-vagal PD axis.

neuroscience↗

bioRxiv2026

NeuroFate: endpoint-locked transcriptomic axis scoring for neurodegeneration risk research

MotivationAD and PD transcriptomic cohorts can reveal disease-associated neuronal, glial, mitochondrial, myelin, proteostasis, vascular, and immune programs, but these signals are difficult to compare reproducibly across studies without endpoint-locked, sample-level biological summaries. ResultsWe present NeuroFate, a command-line research package that converts compact transcriptomic cohorts into curated neurodegeneration-axis scores, exploratory research-use risk scores, and conservative evidence reports. The software locks disease-state endpoints before scoring, maps genes or probes onto a 10-axis NeuroFate panel, records axis-gene coverage, and grades external cohort evidence by direction, effect size, nominal/FDR support, and claim-safety rules. Demonstrations across AD and PD resources show nominal independent AD support for a neuronal vulnerability axis, mixed PD convergence, and a PD-divergent synuclein-mitochondrial example while avoiding clinical or mechanism-overstating claims. Availability and implementationNeuroFate is implemented in Python and available at https://github.com/sinhakrishnendu/NeuroFate.git. Contactnabanitaghosh89@gmail.com; dr.krishnendusinha@gmail.com. Supplementary informationDocumentation, examples, tests, and reproducibility notes are included in the repository.

bioinformatics↗

bioRxiv2025

BABAPPAlign: A Multiple Sequence Alignment Engine with a Learned Residue-Level Scoring Function

Multiple sequence alignment (MSA) underpins comparative genomics, evolutionary analysis, and structural inference. Despite extensive methodological development, most widely used alignment algorithms rely on static amino acid substitution matrices that encode global average substitution tendencies and are inherently context-agnostic. Such models are limited in their ability to capture sequence-specific evolutionary constraints, particularly for divergent or low-signal protein families. BABAPPAlign is a multiple sequence alignment framework that replaces static substitution matrices with a learned, context-aware residue-level scoring function while preserving exact affine-gap dynamic programming. Residue compatibility is inferred using a neural scoring model, BABAPPAScore, operating on fixed contextual embeddings derived from a pretrained protein language model. Neural inference is performed entirely outside the dynamic programming recursion, ensuring that alignment optimization remains exact, deterministic, and reproducible. Evaluation on the BAliBASE benchmark using strict family-wise paired comparisons demonstrates statistically significant improvements in sum-of-pairs and total column scores over ClustalW, MUSCLE, MAFFT, and T-Coffee across 386 reference families.

bioinformatics↗

bioRxiv2025

BABAPPA: An Automated Pipeline for Codeml Mediated Selection Analysis Integrating PRANK and IQ-TREE2

Episodic selection analyses are often assembled from fragmented toolchains in which ortholog discovery, codon alignment, phylogeny, exploratory scans, branch-site testing, and reporting are handled separately, making reproducibility and sensitivity tracking difficult. We introduce BABAPPASnake as an integrated workflow contribution for orthogroup-centered episodic selection analysis. The workflow combines orthogroup construction logic, CDS quality-aware mapping, multi-engine alignment pathways, phylogenetic inference, exploratory nomination, and branch-site follow-up testing in one reproducible execution framework. It also supports optional HyPhy GARD recombination screening as a conservative preprocessing report layer without forcing fragment-level rerouting by default. It generates pathway-level and cross-pathway robustness outputs, including matrix, consensus, narrative, and provenance summaries to support sensitivity-aware interpretation. A four-gene mosquito melanization-associated module is analyzed as a real-data empirical demonstration of end-to-end workflow behavior. In this demonstration, branch/site signals show both recurrent and method-sensitive components across six method-trim pathways, with a directional core-tier tendency in several summaries. These case-study patterns are interpreted as workflow-based empirical evidence and hypothesis-generating asymmetry, not decisive pathway-level confirmation. Overall, BABAPPASnake provides a practical and reproducible framework for episodic selection studies where analytical sensitivity must be explicitly reported.

evolutionary biology↗

bioRxiv2025

Episodic Positive Selection Signatures in Arabidopsis CONSTANS-like Genes COL3 and COL5 Indicating Adaptive Evolution in Red-Light Signaling Pathways

This study investigates the adaptive evolution of the CONSTANS-like (COL) gene family in Arabidopsis thaliana (L) Heynh., focusing on the molecular and structural consequences of episodic positive selection. Using CODEML-based site and branch-site models, I identified statistically significant adaptive substitutions in COL3 and COL5. Ancestral sequence reconstruction revealed that COL3 evolved from serine to alanine at residue 212, while COL5 transitioned from glycine to serine at residue 343. To assess structural impacts, I retrieved modern COL protein structures from the AlphaFold Protein Structure Database, introduced reverse mutations, and generated ancestral models using AlphaFold3. Stability analyses with DynaMut indicated that the G343S mutation in COL5, located within a unique proteomic domain, resulted in slight destabilization and reduced flexibility, with ChimeraX revealing the loss of hydrogen bonding. In contrast, the S212A mutation in COL3, positioned upstream of its CCT domain, showed a stabilizing effect despite reduced flexibility. GO enrichment analysis revealed that positively selected COL genes are significantly associated with red and far-red light signaling and developmental regulation. These findings suggest that episodic positive selection fine-tunes COL protein function, warranting further studies using molecular dynamics simulations and in vivo functional assays.

evolutionary biology↗

bioRxiv2024

Ribosome-inactivation by a class of widely distributed C-tail anchored membrane proteins

Ribosome hibernation is a commonly used strategy that protects ribosomes under unfavorable conditions and regulates developmental processes. Multiple ribosome-hibernation factors have been identified in all domains of life, but due to their structural diversity and the lack of a common inactivation mechanism, it is currently unknown how many different hibernation factors exist. Here, we show that the YqjD/ElaB/YgaM paralogs, initially discovered as membrane-bound ribosome binding proteins in E. coli, constitute an abundant class of ribosome-hibernating proteins, which are conserved across all proteobacteria and some other bacterial phyla. Our data demonstrate that they inhibit in vitro protein synthesis by interacting with the 50S ribosomal subunit. In vivo cross-linking combined with mass spectrometry reveals their specific interactions with proteins surrounding the ribosomal tunnel exit and even their penetration into the ribosomal tunnel. Thus, YqjD/ElaB/YgaM inhibit translation by blocking the ribosomal tunnel and thus mimic the activity of antimicrobial peptides and macrolide antibiotics.

biochemistry↗

bioRxiv2023

Molecular Mechanism of Regulation of RhoA GTPase by Phosphorylation of RhoGDI

Rho-specific guanine dissociation inhibitors (RhoGDIs) play a crucial role in the regulation of Rho family GTPases. They act as negative regulators that prevent the activation of Rho GTPases by forming complexes with the inactive GDP-bound state of GTPase. Release of Rho GTPase from the RhoGDI-bound complex is necessary for Rho GTPase activation. Biochemical studies provide evidence of a "phosphorylation code", where phosphorylation of some specific residues of RhoGDI selectively releases its GTPase partner (RhoA, Rac1, Cdc42 etc.). This work attempts to understand the molecular mechanism behind this phosphorylation code. Using several microseconds long atomistic molecular dynamics (MD) simulations of the wild-type and phosphorylated states of the RhoA-RhoGDI complex, we propose a molecular-interaction-based mechanistic model for the dissociation of the complex. Phosphorylation induces major structural changes, particularly in the positively charged polybasic region (PBR) of RhoA and the negatively charged N-terminal region of RhoGDI that contribute most to the binding affinity. MM-PBSA binding free energy calculations show a significant weakening of interaction on phosphorylation at the RhoA-specific site of RhoGDI. In contrast, phosphorylation at a Rac1-specific site leads to the strengthening of the interaction confirming the presence of a phosphorylation code. RhoA-specific phosphorylation leads to a reduction in the number of contacts between the PBR of RhoA and the N-terminal region of RhoGDI, which manifests reduction of the binding affinity. Using hydrogen bond occupancy analysis and energetic perturbation network, we propose a mechanistic model for the allosteric response, i.e., long range signal propagation from the site of phosphorylation to the PBR and buried geranylgeranyl group in the form of rearrangement and rewiring of hydrogen bonds and salt bridges. Our results highlight the crucial role of specific electrostatic interactions in manifestation of the phosphorylation code.

biophysics↗

bioRxiv2023

Histone modifications regulate pioneer transcription factor cooperativity

Pioneer transcription factors have the ability to access DNA in compacted chromatin. Multiple transcription factors can bind together to a regulatory element in a cooperative way and cooperation between pioneer transcription factors Oct4 and Sox2 is important for pluripotency and reprogramming. However, the molecular mechanisms by which pioneer transcription factors function and cooperate remain unclear. Here we present cryo-EM structures of human Oct4 bound to a nucleosome containing human Lin28B and nMatn1 DNA sequences, which bear multiple binding sites for Oct4. Our structural and biochemistry data reveal that Oct4 binding induces changes to the nucleosome structure, repositions the nucleosomal DNA and facilitates cooperative binding of additional Oct4 and of Sox2 to their internal binding sites. The flexible activation domain of Oct4 contacts the histone H4 N-terminal tail, altering its conformation and thus promoting chromatin decompaction. Moreover, the DNA binding domain of Oct4 engages with histone H3 N-terminal tail, and posttranslational modifications at H3K27 modulate DNA positioning and affect transcription factor cooperativity. Thus, our data show that the epigenetic landscape can regulate Oct4 activity to ensure proper cell reprogramming.

biophysics↗

bioRxiv2019

Renal Localization of Plasmodium vivax and Zoonotic Monkey Parasite Plasmodium knowlesi in Malaria Associated Acute Kidney Injury

Acute kidney injury (AKI) is a frequent presentation in Plasmodium vivax (P. vivax) associated severe malaria. However, tissue presence of P. vivax parasites in the kidney has never been demonstrated. In the present study, we show that renal biopsies from malaria associated AKI patients harbor the human malaria parasite P. vivax and, in several cases, the zoonotic monkey malaria parasite P. knowlesi in addition to P. vivax. Presence of microvascular injury in a majority of the malaria associated AKI cases suggests vascular involvement of P. vivax and P. knowlesi. This study implicates Plasmodium species as a possible pathogenic mechanism for AKI, and suggests host renal tissue interaction of P. vivax and P. knowlesi.

microbiology↗