Biology subjects

Subramaniam, R.

Publications and source records attributed to Subramaniam, R..

7 recordsLinked to original sources

bioRxiv2026

Harnessing within-cultivar variation to identify hidden genetic resistance using single plant-omics

Fusarium graminearum is a fungal pathogen that causes scab or head blight in small grain cereals and threatens global cereal production. Disease progression varies widely among individual plants of the same cultivar, reflecting both genetic and environmental heterogeneity. This complicates the identification of early host responses, because each individual plant in a population is at a slightly different phase of disease progression. Here we apply single plant-transcriptomics to a population of 121 malt-barley exposed to F. graminearum, enabling us to reconstruct a temporal sequence of regulatory processes during early infection. We identified several disease-resistance associated genetic variants that are already endemic in this high-yielding cultivar, suggesting potential as breeding targets. These variants were within proteins involved in ROS-burst production, a lectin-kinase PRR, and enzymes with DON-detoxification activity. Single plant-transcriptomics offers a novel strategy for characterising early plant-pathogen interactions, turning intra-population heterogeneity from an experimental barrier into an asset.

plant biology↗

bioRxiv2025

Landscapes of missense variant impact for human superoxide dismutase 1

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease for which important subtypes are caused by variation in the Superoxide Dismutase 1 gene SOD1. Diagnosis based on SOD1 sequencing can not only be definitive but also indicate specific therapies available for SOD1-associated ALS (SOD1-ALS). Unfortunately, SOD1-ALS diagnosis is limited by the fact that a substantial fraction (currently 26%) of ClinVar SOD1 missense variants are classified as "variants of uncertain significance" (VUS). Although functional assays can provide strong evidence for clinical variant interpretation, SOD1 assay validation is challenging, given the current incomplete and controversial understanding of SOD1-ALS disease mechanism. Using saturation mutagenesis and multiplexed cell-based assays, we measured the functional impact of over two thousand SOD1 amino acid substitutions on both enzymatic function and protein abundance. The resulting missense variant effect maps not only reflect prior biochemical knowledge of SOD1 but also provide sequence-structure-function insights. Importantly, our variant abundance assay can discriminate pathogenic missense variation and provides new evidence for 41% of missense variants that had been previously reported as VUS, offering the potential to identify additional patients who would benefit from therapy approved for SOD1-ALS.

genetics↗

bioRxiv2024

Coordinated function of paired NLRs confers Yr84 -mediated stripe rust resistance in wheat

Cloning of resistance genes expands our understanding of their function and facilitates their deployment in breeding. Here, we report the cloning of two genes from wild emmer wheat (Triticum turgidum ssp. dicoccoides) underlying Yr84-mediated stripe rust resistance using a combination of fine mapping, long read-sequencing and mutation-induced functional validation. In contrast to all previously cloned stripe rust genes, the incompletely dominant Yr84 phenotype is conferred through the coordinated function of paired nucleotide-binding leucine-rich repeats (NLR) genes CNL and NL. We hypothesize that based on their genomic organization, annotation, expression profiles and predicted protein structure, CNL functions as a sensor NLR (sNLR) responsible for effector recognition, and NL acts as a helper NLR (hNLR) initiating downstream resistance cascades. The CNL and NL lack an integrated domain(s) previously implicated in effector recognition by paired NLRs, therefore these findings contribute new insights into plant paired NLRs structure and molecular mechanisms of function.

genetics↗

bioRxiv2020

Weight and organ specific immune cell profiling of Sleeve Gastrectomy

Sleeve gastrectomy (SG) has profound, immediate weight-loss independent effects on obesity related diabetes (T2D). Our prior studies have shown that immunologic remodeling may play a part in this metabolic improvement. However, to date, little is known about how the major immune cell populations change following SG. Using mass cytometry with time of flight analysis (CyTOF) we aimed to broadly explore the organ-specific immune cell repertoire induced by SG. Surgery was performed on obese, insulin resistant and lean mice in order to understand surgery-specific phenotypes. We identified a shift within the splenic B cell compartment with a reduction in follicular and an increase in innate-like B cell subsets in SG animals. There was a concomitant increase in multiple circulating immunoglobulin classes. Further, SG animals had a conserved increase in splenic neutrophils and a tendency toward M2 macrophage polarization. Others have shown that these, weight-loss independent, surgery-specific changes are linked to improved glucose metabolism and thus, may be a major contributor to post SG physiology. Characterizing the complex immune milieu following SG is an important step toward understanding the physiology of SG and the potential therapies therein.Competing Interest StatementThe authors have declared no competing interest.AbbreviationsSG(Sleeve Gastrectomy)(T2D)Type 2 Diabetes(TNF-α)tumor necrosis factor alpha(VAT)visceral adipose tissuePOD(post-operative Day)GLP-1(glucagon like peptide 1)OGTT(oral glucose tolerance test)ITT(insulin tolerance test)DIO(diet induced obesity)CyTOF(cytometry with time of flight analysis)ARG1(arginase 1)TGR5(Takeda g-protein bile acid receptor)RYGB(Roux-en-Y gastric bypass)View Full Text

immunology↗

bioRxiv2020

Bariatric surgery reveals a gut-restricted TGR5 agonist that exhibits anti-diabetic effects

Bariatric surgery, the most effective treatment for obesity and type 2 diabetes, is consistently associated with increased levels of the incretin hormone GLP-1 and changes in overall levels of circulating bile acids. The levels of individual bile acids in the GI tract following surgery, however, have remained largely unstudied. Using UPLC-MS-based quantification, we observed an increase in an endogenous bile acid, cholic acid-7-sulfate (CA7S), in the GI tract of both mice and humans after sleeve gastrectomy. We show that CA7S is a TGR5 agonist that induces GLP-1 secretion in vitro and in vivo and that CA7S administration increases glucose tolerance in insulin-resistant mice in a GLP-1 receptor-dependent manner. CA7S remains gut-restricted, minimizing off-target effects previously observed for TGR5 agonists absorbed into circulation. By studying changes in individual metabolites following surgery, this study has revealed a naturally occurring TGR5 agonist that exerts systemic glucoregulatory effects while remaining confined to the gut.

biochemistry↗

bioRxiv2019

Sleeve Gastrectomy enhances glucose utilization and remodels adipose tissue independent of weight loss

ObjectiveSleeve gastrectomy (SG) induces weight-loss independent improvements in glucose homeostasis by unknown mechanisms. We sought to identify the metabolic adaptations responsible for these improvements.\n\nMethodsNon-obese C57Bl6/J mice on standard chow underwent SG or sham surgery. Functional testing and indirect calorimetry were used to capture metabolic phenotypes. Tissue-specific glucose uptake was assessed by 18-FDG PET/CT and RNA sequencing was used for gene expression analysis.\n\nResultsIn this model, SG induced durable improvements in glucose tolerance despite not causing lasting changes in weight, fat/lean mass, or food intake. Indirect calorimetry revealed post-SG animals had respiratory exchange ratios (RER) nearing 1.0 on average and had daily RER excursions above 1.0, indicating preferential glucose utilization and increased energy demand, respectively. Sham operated mice demonstrate normal RER feeding/fasting excursions. PET/CT showed increased avidity within white adipose depots. Finally, SG led to an upregulation in the transcriptional pathways involved in energy metabolism, adipocyte maturation, and adaptive and innate immune cell chemotaxis and differentiation within the visceral adipose tissue.\n\nConclusionsSG induces a rapid, weight-loss independent shift towards glucose utilization and transcriptional remodeling of metabolic and immune pathways in visceral adipose tissue.

physiology↗

bioRxiv2018

Cortical control of kinematic primitives in mice performing a hold-still-center-out reach task

Motor sequences are constructed from primitives, hypothesized building blocks of movement, but mechanisms of primitive generation remain unclear. Using automated homecage training and a novel forelimb sensor, we trained freely-moving mice to initiate forelimb sequences with clearly resolved submillimeter-scale micromovements followed by millimeter-scale reaches to learned spatial targets. Hundreds of thousands of trajectories were decomposed into millions of kinematic primitives, while closed-loop photoinhibition was used to test roles of motor cortical areas. Inactivation of contralateral motor cortex reduced primitive peak speed but, surprisingly, did not substantially affect primitive direction, initiation, termination, or complexity, resulting in isomorphic, spatially contracted trajectories that undershot targets. Our findings demonstrate separable loss of a single kinematic parameter, speed, and identify conditions where loss of cortical drive reduces the gain of motor primitives but does not affect their generation, timing or direction. The combination of high precision forelimb sensing with automated training and neural manipulation provides a system for studying how motor sequences are constructed from elemental building blocks.

neuroscience↗