Search bioRxiv⌕ Search

Biology subjects

Shah, T.

Publications and source records attributed to Shah, T..

14 recordsLinked to original sources

Machine Learning Identification of Functional Trait Syndromes Associated with Responsiveness to Arbuscular Mycorrhizal Fungi

Arbuscular mycorrhizal fungi (AMF) are widespread plant symbionts that enhance nutrient acquisition, growth, and stress tolerance, yet plant responsiveness to AMF varies substantially and remains difficult to predict. We developed Trait2Myco, a Random Forest based machine-learning framework that integrates plant functional traits and environmental variables to predict mycorrhizal growth response (MGR). The framework was trained using 80 observations spanning four grass species grown under four precipitation regimes. Predictor variables included leaf and root economic traits together with precipitation, while total MGR served as the response variable. A full model incorporating ten functional traits and precipitation was trained using 80% of observations and evaluated on an independent testing dataset (20%, n = 16). The full model explained 41% of variation in MGR (R2 = 0.41), whereas a reduced ecological model containing only specific leaf area, specific root area, root carbon concentration, and precipitation improved predictive performance and explained 51.7% of variation (R2 = 0.517). Ten-fold cross-validation of the full model yielded an R2 of 0.983, RMSE of 0.046, and MAE of 0.036. Variable importance analysis identified specific leaf area, precipitation, root carbon concentration, and specific root area as the strongest predictors of responsiveness. Partial dependence analysis revealed nonlinear relationships between these predictors and MGR, while principal component analysis showed that highly responsive plants occupied distinct regions of functional trait space characterized by resource-acquisitive trait syndromes. Leaf and root traits contributed nearly equally to model performance, accounting for 41.9% and 41.3% of cumulative importance, respectively, while environmental factors contributed 16.8%. An exploratory analysis using an independent AMF colonization dataset produced similarly strong predictive relationships, suggesting that trait-based machine-learning approaches may generalize across multiple AMF-associated responses. Trait2Myco provides a reproducible framework for identifying plant trait syndromes associated with responsiveness to AMF and offers a practical tool for predicting mycorrhizal benefits across environmental gradients.

ecology↗

Spoken Recall Reveals Lexical and Mnemonic Function Differences in Temporal Lobe Epilepsy Patients

Background and Objectives: Word-finding difficulty is common in healthy aging and in neurologic disorders, including temporal lobe epilepsy (TLE) and early Alzheimer disease. Standard language measures have limited sensitivity for detecting subtle or longitudinal changes in spontaneous speech. We examined whether natural language processing and acoustic analysis of spoken biographical recall could identify lexical and temporal speech features associated with language and memory performance in TLE. Methods: We conducted a cross-sectional observational study of spoken recall during a Famous Faces biographical memory task. Adults with TLE and healthy controls (HCs) viewed 20 famous faces and spontaneously recalled biographical details. Speech was transcribed and diarized using automated tools. Lexical measures included word counts and lexical index (ratio of rare to common words). Acoustic measures included utterance and pause duration and pause frequency. Features were compared between groups and correlated with neuropsychological measures, including Montreal Cognitive Assessment (MoCA), Boston Naming Test (BNT), delayed recall, education, and biographical recall accuracy Results: Eighty-one adults participated (51 TLE, 30 HCs). Lexical measures did not differ between groups. In TLE, lexical index correlated with BNT performance (rs=0.62) and MoCA score (rs=0.35). Compared with HCs, participants with TLE produced shorter utterances (5.54 {+/-} 2.50 vs. 6.59 {+/-} 2.63; Cohen's d=0.41, 95% CI -0.05 to 0.86, p=0.041), shorter pauses (0.61 {+/-} 0.21 vs 0.67 {+/-} 0.22, Cohen's d=0.29, 95% CI -0.16 to 0.74, p=0.043), and more frequent pauses (10.81 {+/-} 3.30 vs 9.29 {+/-} 3.59, Cohen's d=-0.45, 95% CI -0.90 to 0.01, p=0.036). Higher education was associated with longer utterances, longer pauses, and lower pause frequency, without evidence of a diagnosis-by-education interaction. Faster utterance rate was associated with better biographical recall in both groups, while higher pause rate was associated with worse recall in TLE. Discussion: Speech-derived lexical and temporal features from naturalistic recall capture clinically relevant variation in language and memory-related performance. Although lexical output did not distinguish TLE from HCs, lexical richness tracked naming and global cognition in TLE, while temporal speech features related to recall performance. These findings support the potential of automated speech analysis as a digital behavioral biomarker for word-finding difficulty in neurologic populations.

neuroscience↗

Comparative transcriptomic analysis of cassava genotypes under extended photoperiodism across flowering stages

Cassava (Manihot esculenta Crantz) is a major staple crop across tropical and subtropical regions. Despite advances in genomic selection, delayed, non-flowering, and asynchronous flowering remain key bottlenecks in breeding programs. To better understand the molecular basis of flowering-time variation, we performed RNA sequencing across three genotypes with contrasting flowering phenotypes (early, late, and non-flowering) sampled at three developmental stages under contrasting light regimes in field conditions (natural light and three-hour night-break with white light). Comparative transcriptomic analysis revealed distinct gene expression patterns associated with flowering responses. Genotype comparisons with no light supplementation revealed stage-specific enrichment of biological processes. Light supplementation was associated with changes in the expression of key components of photoperiodic and circadian regulation, as well as pathways involved in flowering-time integration and hormone and sugar-related signaling. These findings suggest that coordinated changes across multiple biological pathways regulate flowering behavior in cassava. The candidate genes and expression patterns reported provide a foundation for functional studies and advance our understanding of molecular mechanisms governing flowering-time regulation in cassava.

plant biology↗

Small Structural Variations, Large Functional Consequences: Comparative Analysis Reveals Structural Control of Ubiquitylation Site Selection by BRCA1/BARD1

BRCA1/BARD1 is a chromatin-associated E3 ubiquitin ligase that ubiquitylates histone H2A to coordinate DNA damage repair, transcriptional repression, and genome stability. In Caenorhabditis elegans (C. elegans), the orthologous BRC-1/BRD-1 com-plex performs analogous functions but exhibits structural variation, most notably through an additional 11-residue loop in BRD-1 that is absent from human BARD1. Prior exper-iments indicate this worm-specific insertion promotes nucleosome engagement and may alter the preferred lysine target for ubiquitylation. Here, we provide a cross-species comparison by integrating computational and experimental investigation to clarify how a discrete structural variation can tune BRCA1-family ligase behavior and, consequently, chromatin regulation. In vitro ubiquitylation assays and mass spectrometry reveal BRC-1/BRD-1 ubiquitylate the C-terminal tail of histone H2A with less specificity than the human homologs. All-atom molecular dynamics simulations of both the C. elegans BRC-1/BRD-1-LET-70-Ubiquitin assembly and the human BRCA1/BARD1-UbcH5c-Ubiquitin complex in the presence of the nucleosome core particle uncover that the BRD-1 loop makes transient contacts with nucleosomal DNA and histone tails, thereby modulating the positioning and conformational flexibility of the bound E2 (ubiquitin-conjugating enzyme). Together, our results suggest that the BRD-1 loop alters the E3-E2 geometry, thereby altering ubiquitylation-site specificity.

biophysics↗

Decoding the Conformational Dynamics and Hyperactivity of Histone H3K36 N-Methyltransferase in Oncogenic Mutations via tICA and Markov State Modeling

NSD2 is a histone methyltransferase that modifies lysine 36 in histone H3 (H3K36), playing a central role in chromatin organization and transcriptional regulation. Oncogenic mutations, such as E1099K and T1150A in NSD2, have been associated with hyperactive methylation, but the molecular mechanisms underlying this gain of function remain poorly understood. In this study, we performed all-atom molecular dynamics simulations on models of NSD2 bound to the nucleosome for the wild type (WT), E1099K, T1150A, and the E1099K/T1150A double mutant. Analysis of MD simulations reveals that the global dynamics of the enzymes remain unaltered upon mutations. The time-lagged independent component analysis (tICA) and Markov state modeling uncovered fundamental differences in free-energy landscapes among the variants. The WT NSD2 exhibited energetically and kinetically unfavorable transitions between the macrostates along with extended enzyme-substrate distances. On the other hand, the mutant systems demonstrate reduced SAM-H3K36 distances with modified energy landscapes that facilitate transitions or favor prolonged occupancy of catalytically competent states. Importantly, the mutations reorganize the network of intramolecular contacts around the catalytic site, SAM-binding pocket, and histone-binding interface, optimizing substance engagement geometry. These findings demonstrate that oncogenic mutations achieve hyperactivity through strategic reorganization of conformational dynamics rather than simple destabilization, balancing local flexibility with global stability to enhance catalytic efficiency. Our results provide mechanistic insights into NSD2 dysregulation in cancer and establish a framework to develop allosteric inhibitors that target the enzymes dynamic landscape.

biochemistry↗

Complement modulation synergizes with therapeutic hypothermia in a rat model of neonatal HIE

BackgroundNeurodevelopmental impairment remains common in neonatal hypoxic-ischemic encephalopathy (HIE) despite treatment with the standard of care, therapeutic hypothermia (TH). The complement response activates at reperfusion and is known to exacerbate neuroinflammation and injury, though its full role and interaction with hypothermia are incompletely defined. We hypothesized that modulating the complement response could improve structural and functional outcomes in HIE, and tested a novel complement therapy (CT), consisting of C3a peptides and the C5a-receptor antagonist PMX205, as both a stand-alone treatment and as an adjuvant to TH. MethodsWistar rat pups were randomized to the following treatment groups: Sham (uninjured control), NT (uninjured, normothermia/not treated control), or injured and treated with either TH, CT, or CT+TH. At term-equivalence, mild-moderate hypoxic-ischemic injury was induced by Vannuccis method. To capture the short and long-term effects of the treatments, cohorts were harvested 3 or 66-72 days post-injury, respectively. Cerebral injury was measured by quantifying levels of inflammatory markers and cerebral tissue loss, and functional outcomes were assessed in a series of behavioral tests. The data were stratified to detect sexual dimorphisms. ResultsCT and TH treatments demonstrated test and sex-dependent differences in improvement compared to untreated, injured rats. In male rats, TH treatment worsened long-term hippocampal and thalamic brain injury and functional measures of ataxia and attention. CT-treatment worsened long-term thalamic loss in females. Combining the two treatments (CT+TH) demonstrated additive improvement in both sexes, including short and long-term cortical loss and ataxia. ConclusionsComplement modulation enhances the neuroprotective effects of TH after neonatal hypoxic-ischemic injury, with sex-specific effects on inflammation and behavior. Combining complement modulation with the standard of care often demonstrated synergistic improvement in both sexes, supporting complement-targeted therapy as a promising adjunct to hypothermia in neonatal HIE. Graphical abstract. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/717097v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@1025d1forg.highwire.dtl.DTLVardef@2fa4e5org.highwire.dtl.DTLVardef@1f2c1c4org.highwire.dtl.DTLVardef@8f3410_HPS_FORMAT_FIGEXP M_FIG C_FIG Created with BioRender. Saadat, A. (2026) https://BioRender.com/siwm825.

neuroscience↗

Structure and conformational dynamics of the Pseudomonas CbrA transceptor

The CbrA protein is a central regulator of carbon metabolism, biofilm formation, and virulence in Pseudomonas species, but the molecular mechanisms by which CbrA links nutrient sensing to downstream signaling has remained unclear. CbrA is a rare "transceptor" that combines membrane transporter and histidine kinase domains into a single functional polypeptide. The structural basis for histidine recognition and membrane transport, as well as signaling through intracellular histidine kinase domains has remained elusive. Here we determined a cryo-EM structure of CbrA which provides key molecular details of the SLC5-STAC domains in this unusual system. Unexpectedly, the small peptide CbrX encoded upstream of CbrA formed a stable complex with the SLC5 transporter domain. The structure reveals how histidine binds within the transporter, and molecular dynamics simulations provide insight into proton gradient driven conformational changes that enable histidine transport. These findings define the molecular architecture of key CbrA functional domains, and pave a path toward developing a comprehensive understanding of coupling between membrane transport and downstream signaling pathways that guide essential physiological traits in Pseudomonas. Significance StatementCbrA is a key regulator of carbon-nitrogen metabolism in Pseudomonas and is essential for successful host infection. The molecular basis for CbrAs dual role in membrane transport and downstream signaling has remained elusive. Here we determined a cryo-EM structure that defines the organization of the CbrA SLC5 and STAC domains, and reveals that the small peptide CbrX encoded upstream of CbrA forms a stable complex with the SLC5 transporter region. A structure with histidine trapped in the binding cavity, together with molecular dynamics simulations, identifies protonation dependent transitions that guide the transport cycle. This work establishes a mechanistic foundation for understanding how CbrA and related transceptors integrate substrate sensing and transport with regulatory control of signaling.

biophysics↗

KGBN: Augmenting and optimizing logical gene regulatory networks using knowledge graphs

Logical gene regulatory network (GRN) models provide interpretable, mechanistic representations of cellular regulation and are widely used in systems biology. However, most existing models remain incomplete, context-specific, and difficult to extend to comprehensive GRNs, limiting their broader applicability to tasks such as drug-response prediction and precision medicine. Here, add some ideas about virtual twins: With AML patients, we can use comprehensive GRNs to predict drug response. We present KGBN (Knowledge Graph-augmented Boolean Network modeling), a computational workflow for systematically augmenting logical GRN models. KGBN incorporates regulatory interactions derived from curated knowledge graphs as alternative logical rules while preserving the validated structure of existing models. Rule probabilities are optimized against experimental data to represent regulatory uncertainty and achieve data-driven calibration. Applying KGBN to acute myeloid leukemia, we show that extending an existing GRN with drug-target pathways and training against ex vivo drug-response data yields mutation-specific models that recapitulate known therapeutic sensitivities and signaling dependencies, demonstrating the utility of KGBN for interpretable, context-aware GRN modeling. (Should be predict)

systems biology↗

Backyard proteomics: A case study with the black widow spider

Nearly all methods of mass spectrometry-based proteomics rely on knowing the proteome of the species. In less studied organisms without annotated genomes, it can seem impossible to perform proteomic analysis. In this study we sought to answer the question - does enough information exist to do proteomics on any organism we want? As a case study we started with material available due to an infestation of a home with black widow spiders. Thanks to the recent publication of an annotated genome for one species of black widow spider, we were able to identify 5502 protein groups and assign putative annotations using ortholog mapping. We also demonstrate that had we not had this resource, over 2000 proteins could be identified using other available spider genome annotations, despite their unrelatedness. Moreover, regardless of spider proteome used, proteins annotated as toxins were almost exclusively observed in the main body of the mature female black widow spider. Overall, these results provide a draft proteome map for the black widow spider and valuable data for validating machine learning models, while also suggesting that the door to insightful quantitative proteomics may already be open for millions of less studied organisms. All raw and processed proteomic data are available through the ProteomeXchange repository as accession PXD051601. TOC Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=138 SRC="FIGDIR/small/648442v1_ufig1.gif" ALT="Figure 1"> View larger version (16K): org.highwire.dtl.DTLVardef@7e4c7eorg.highwire.dtl.DTLVardef@1cfeba1org.highwire.dtl.DTLVardef@1769a02org.highwire.dtl.DTLVardef@1790450_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

Histone H3 Orchestrates the Ubiquitination of Nucleosomal H2A by BRCA1/BARD1-UbcH5c Complex

The Breast Cancer Associated Protein 1 (BRCA1) is a human tumor suppressor protein that commonly functions as ubiquitin ligase enzyme (E3) in the ubiquitination of the C-terminal H2A. BRCA1 enhances ubiquitin ligase activity by forming a heterodimeric complex with the BRCA1 Associated Ring Domain Protein (BARD1). The BRCA1/BARD1 complex works in concert with the ubiquitin-conjugating enzyme (UbcH5c or E2) to ubiquitinate one of the five lysines of the H2A C-terminal, ultimately promoting the repair of double-stranded DNA breaks. The mutations in the BRCA1-UbcH5c portion of the E3-E2 complex have been linked to breast and ovarian cancer. However, the mechanism of BRCA1/BARD1-UbcH5c complex ubiquitination at H2A is poorly understood, and the ubiquitination of exact lysine is debated. In this study, we sought to expand on the current research on H2A ubiquitination by using all-atom molecular dynamics simulations to model the BRCA1/BARD1-UbcH5c complex with the human ubiquitin protein (Ub). The Ub protein covalently bonds to the active site of E2, resulting in diminished flexibility of the E3-E2 complex with respect to the nucleosome core particle. The results of this study suggest a possible contribution of H3 in determining the preferred orientation of E2-Ub with respect to the H2A C-terminal lysines.

biochemistry↗

Plastid phylogenomics of the Sansevieria clade (Dracaena; Asparagaceae) resolves a rapid evolutionary radiation

Sansevierias are a diverse group of flowering plants native to Africa, Madagascar, the Arabian Peninsula and the Indian subcontinent, popular outside their native range as low maintenance houseplants. Traditionally recognized as a distinct genus, Sansevieria was recently merged with the larger genus Dracaena based on molecular phylogenetic data. Within the Sansevieria clade, taxonomic uncertainties remain despite numerous attempts to classify the species. We aim to arrive at a robust phylogeny using a plastid phylogenomic approach, and estimate a time-frame of diversification to infer the evolutionary history of the group, including geographical and morphological evolution. Molecular data was obtained using genome skimming for 50 Sansevieria, representing all informal groups previously instated based on morphology, and two Dracaena sensu stricto species. The resulting Maximum Likelihood phylogenetic hypotheses are generally well supported, except for some very short branches along the backbone of the tree. The time-calibrated phylogeny indicates a recent rapid radiation with the main clades emerging in the Pliocene. Two well-supported clades align with previously defined informal groups, i.e., Sansevieria section Dracomima, characterised by the Dracomima-type inflorescence, and the Zeylanica group, native to the Indian subcontinent. Other morphologically defined informal groups are shown to be polyphyletic: a pattern due to convergent evolution of the identifying characters. Cylindrical leaves arose multiple times independently in the evolution of the Sansevieria clade and similarly, the Cephalantha-type inflorescence has originated multiple times from an ancestor with a Sansevieria-type inflorescence. To provide a more accessible tool for species identification and delimitation, genes and spacer regions were screened for variability and phylogenetic informativeness to investigate their potential as chloroplast DNA barcodes. Candidate chloroplast DNA barcodes include the trnH-rpl12, ndhH-rps15, psbE-petL, psbT-psbN, rps18-rpl20 intergenic spacers, the chloroplast gene rps8 and the first intron of ycf3.

evolutionary biology↗

Validation of lipid-related therapeutic targets for coronary heart disease prevention using human genetics

Drug target Mendelian randomization (MR) studies use DNA sequence variants in or near a gene encoding a drug target, that alter its expression or function, as a tool to anticipate the effect of drug action on the same target. Here, we applied MR to prioritize drug targets for their causal relevance for coronary heart disease (CHD). The targets were further prioritized using genetic co-localization, protein expression profiles from the Human Protein Atlas and, for targets with a licensed drug or an agent in clinical development, by sourcing data from the British National Formulary and clinicaltrials.gov. Out of the 341 drug targets identified through their association with circulating blood lipids (HDL-C, LDL-C and triglycerides), we were able to robustly prioritize 30 targets that might elicit beneficial treatment effects in the prevention or treatment of CHD. The prioritized list included NPC1L1 and PCSK9, the targets of licensed drugs whose efficacy has been already proven in clinical trials. To conclude, we discuss how this approach can be generalized to other targets, disease biomarkers and clinical end-points to help prioritize and validate targets during the drug development process. One Sentence SummaryWe provide genetic support for lipid-modifying drug targets for coronary heart disease prevention using drug target Mendelian randomization and further prioritization based on clinical and biological evidence.

genetics↗

Identification of unique mutations in SARS-CoV-2 strains isolated from India suggests its attenuated pathotype

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), which was first reported in Wuhan, China in November 2019 has developed into a pandemic since March 2020, causing substantial human casualties and economic losses. Studies on SARS-CoV-2 are being carried out at an unprecedented rate to tackle this threat. Genomics studies, in particular, are indispensable to elucidate the dynamic nature of the RNA genome of SARS-CoV-2. RNA viruses are marked by their unique ability to undergo high rates of mutation in their genome, much more frequently than their hosts, which diversifies their strengths qualifying them to elude host immune response and amplify drug resistance. In this study, we sequenced and analyzed the genomic information of the SARS-CoV-2 isolates from two infected Indian patients and explored the possible implications of point mutations in its biology. In addition to multiple point mutations, we found a remarkable similarity between relatively common mutations of 36-nucleotide deletion in ORF8 of SARS-CoV-2. Our results corroborate with the earlier reported 29-nucleotide deletion in SARS, which was frequent during the early stage of human-to-human transmission. The results will be useful to understand the biology of SARS-CoV-2 and itsattenuation for vaccine development.

microbiology↗

Enhancer Reprogramming Confers Dependence on Glycolysis and IGF signaling in KMT2D Mutant Melanoma

Epigenetic modifiers have emerged as important regulators of tumor progression. We identified histone methyltransferase KMT2D as a potent tumor-suppressor through an in vivo epigenome-focused pooled RNAi screen in melanoma. KMT2D harbors frequent somatic point mutations in multiple tumor types. How these events contribute to tumorigenesis and whether they impart therapeutic vulnerability are poorly understood. To address these questions, we generated a genetically engineered mouse model of melanoma based on conditional and melanocyte-specific deletion of KMT2D. We demonstrate KMT2D as a bona fide tumor suppressor which cooperates with activated BRAF. KMT2D-deficient tumors showed substantial reprogramming of key metabolic pathways including glycolysis. Glycolysis enzymes, intermediate metabolites and glucose consumption rate were aberrantly upregulated in KMT2D mutant cells. The pharmacological inhibition of glycolysis reduced proliferation and tumorigenesis preferentially in KMT2D mutant cells. Mechanistically, KMT2D loss caused drastic reduction of H3K4me1-marked active enhancer states. Loss of distal enhancer and subsequent reduction in expression of IGFBP5 activated IGF1R-AKT to increase glycolysis in KMT2D-deficient cells. We conclude that KMT2D loss promotes tumorigenesis by facilitating increased usage of glycolysis pathway for enhanced biomass needs via enhancer reprogramming. Our data imply that inhibition of glycolysis or IGFR pathway could be a potential therapeutic strategy in KMT2D mutant tumors.

cancer biology↗