Biology subjects

Srinivas, A.

Publications and source records attributed to Srinivas, A..

6 recordsLinked to original sources

bioRxiv2026

Headbutting goats self-inflict traumatic brain injury

Traumatic brain injury (TBI) is a characteristic feature of neurodegenerative diseases such as Alzheimers disease and chronic traumatic encephalopathy. Small animal models have been used to establish clinically relevant biomarkers of neuropathology, however, they show significant anatomical differences from humans and are affected by artificial experimental manipulations, making them often unsuitable for longitudinal study of repetitive mild TBI. There is a need for more diverse and translationally relevant animal models to better understand disease onset and development. Building on a previous study of neuropathology in headbutting bovids in the wild, this pilot study investigated whether freely headbutting domestic goats, which naturally engage in low-intensity, high-frequency head impacts, accumulate measurable biomarkers of neurodegeneration in cerebrospinal fluid (CSF) and brain tissue. Over a six-month period, three male goats (Capra hircus) were allowed to freely headbutt under continuous video surveillance. Monthly CSF samples were collected, and concentrations of key neurodegeneration biomarkers were measured via multiplex immunoassays, including amyloid-{beta} peptides (A{beta}40, A{beta}42), total and phosphorylated tau (tTau and pTau), glial fibrillary acidic protein (GFAP), S100 calcium-binding protein B (S100B), and neurofilament M (NF-M). Imaging studies were completed for non-invasive assessment of glucose metabolism ([18F]-FDG) and neuroinflammation via translocator protein (TSPO, [18F]DPA-714). Postmortem immunohistochemistry was conducted on prefrontal cortical tissues using antibodies targeting pTau, GFAP, and S100B. Head impact kinematics were quantified using horn-mounted accelerometer and inclinometer sensors that recorded linear acceleration, rotational velocity, and head orientation during naturally occurring headbutting events. Several notable trends were observed. Phosphorylated tau as well as reactive astrocytes were detected in the brain tissue, mirrored by elevated GFAP detected in the CSF. PET TSPO did not illustrate a significant signal, however, PET FDG revealed frontal-dominant activity in all goats, and one with asymmetrical activation. Overall, the goats sustained 5,000-7,000 head impacts each over six months. Accelerometer measurements recorded forces up to 388 N and peak acceleration up to 16.5 g. This multi-modal observational study is the first to characterize neurodegeneration biomarkers and kinematics in headbutting goats. Even at one year old, the combination of pTau and gliosis in both the brain tissue and CSF indicates that the goats repetitive head impacts begin to show neurodegenerative consequences early in life. Likely, the severity of these consequences increases with headbutts and age, eventually resulting in chronic neurodegeneration. This system shows promise as a large-animal model for the longitudinal study of the onset and progression of neurodegenerative disease.

neuroscience↗

bioRxiv2025

Constraints and adaptations in crocodyliform skull evolution

Crocodyliformes display a diverse range of skull morphologies though their evolutionary history. Extant crocodilians possess platyrostral (broad and flat) snouts, thought to be sub-optimal for resisting feeding loads due to the conflicting demands of feeding and hydrodynamic constraints. In contrast, numerous Mesozoic crocodyliformes possessed oreinirostral (dome-shaped) skulls, were terrestrial and hence free from hydrodynamic constraint. This study aims to examine the role of function in determining skull shape in crocodyliformes, and assesses the difference in stress resistance between oreinirostral and platyrostral taxa. We hypothesise that in the absence of hydrodynamic constraints, oreinirostral taxa have skulls that are better suited for resisting feeding induced loads. Using finite element analysis (FEA), we evaluated biomechanical performance in oreinirostral notosuchian taxa Baurusuchus salgadoensis, Montealtosuchus arrudacamposi and Caipirasuchus paulistanus; compared to the extant platyrostral Alligator mississippiensis, Crocodylus niloticus, and Paleosuchus palpebrosus. Results show that oreinirostral morphologies are comparatively better suited for resisting forces generated during feeding, with increased muscular efficiency, supporting the hypothesis that hydrodynamic constraints influence crocodyliform skull evolution.

paleontology↗

bioRxiv2025

GacA regulates symbiosis and mediates lifestyle transitions in Pseudomonas

Through horizontal gene transfer, closely related bacterial strains have assimilated distinct sets of genes, resulting in significantly varied lifestyles. However, it is not clear how strains are able to properly regulate horizontally transferred virulence genes. We hypothesized that strains may use components of the core genome to regulate diverse horizontally acquired genes. To investigate how closely related bacteria assimilate and activate horizontally acquired DNA, we used a model of Pseudomonas fluorescens subspecies brassicacearum strains, N2E2 and N2C3, which exhibit contrasting lifestyles on the model plant Arabidopsis. P. brassicacearum strain N2E2 is a plant commensal and contains the genes that encode biosynthetic enzymes for the anti-fungal compound 2,4-Diacetylphloroglucinol (DAPG). In contrast, N2C3 lacks DAPG biosynthesis and has gained a pathogenic island encoding syringomycin (SYR)-and syringopeptin (SYP)-like toxins from the plant pathogen P. syringae. This causes a transition in lifestyle from plant-protective N2E2 to plant pathogenic N2C3. We found that N2E2 and N2C3 share a highly conserved two-component system GacA/S, a known regulator of DAPG and SYR/SYP. Using knockout mutations, we found that a{Delta} gacA mutation resulted in loss of expression of SYR/SYP virulence genes and returned pathogenic N2C3 to a plant commensal lifestyle. Our study further explored the conservation of regulatory control across strains by demonstrating that GacA genes from both distant and closely related Pseudomonas strains could functionally complement one another across the genus. IMPORTANCEEmerging pathogens represent a significant threat to humans, agriculture, and natural ecosystems. Bacterial horizontal gene transfer aids in the acquisition of novel genes that facilitate bacterial adaptation to new environments. Our work shows a novel role for GacA in orchestrating the regulatory changes necessary for virulence and lifestyle transitions facilitated by HGT. These findings suggest that the GacA/S system plays a key role in mediating transitions across diverse Pseudomonas symbiotic lifestyles. It provides insights into the mechanisms that drive the emergence of pathogenic strains and highlights potential targets for managing bacterial threats to plant health.

microbiology↗

bioRxiv2024

In mouse and gut-on-a-chip models, pre-colonoscopy bowel preparation promotes pathogen colonization of the gut and translocation to other organs

In the United States an estimated 14 million colonoscopies are performed yearly, each requiring patients to undergo bowel preparation, a laxative cleansing of the intestines luminal contents. Despite its widespread use, the effects of bowel preparation on gut physiology and susceptibility to pathogens remains poorly understood, particularly in individuals with compromised gut health. Using mouse and in vitro models, we found that bowel preparation with the laxative polyethylene glycol (PEG) rapidly disrupts, transiently increasing susceptibility to infection by Salmonella Typhimurium, including a non-motile mutant, and by gut pathobionts derived from ulcerative colitis microbiota. Bowel preparation also facilitated bacterial translocation to extraintestinal sites (mesenteric lymph nodes, liver, and spleen) and exacerbated inflammation in a chemically-induced colitis model. Although these findings are preclinical, they suggest that bowel preparation may have underappreciated risks in vulnerable populations, and warrant further clinical investigation.

microbiology↗

bioRxiv2021

Uncovering natural variation in root system architecture and growth dynamics using a robotics-assisted phenomics platform

The plant kingdom contains a stunning array of complex morphologies easily observed above ground, but largely unexplored below-ground. Understanding the magnitude of diversity in root distribution within the soil, termed root system architecture (RSA), is fundamental to determining how this trait contributes to species adaptation in local environments. Roots are the interface between the soil environment and the shoot system and therefore play a key role in anchorage, resource uptake, and stress resilience. Previously, we presented the GLO-Roots (Growth and Luminescence Observatory for Roots) system to study the RSA of soil-grown Arabidopsis thaliana plants from germination to maturity (Rellan-Alvarez et al. 2015). In this study, we present the automation of GLO-Roots using robotics and the development of image analysis pipelines in order to examine the natural variation of RSA in Arabidopsis over time. This dataset describes the developmental dynamics of 93 accessions and reveals highly complex and polygenic RSA traits that show significant correlation with climate variables.

plant biology↗

bioRxiv2020

ST6GAL1-mediated heterogeneity in sialic acid levels potentiates invasion of breast cancer epithelia

Heterogeneity in phenotypes of malignantly transformed cells and aberrant glycan expression on their surface are two prominent hallmarks of cancers that have hitherto not been linked to each other. In this paper, we identify heterogeneity in a specific glycan linkage: 2,6-linked sialic acids within breast cancer cells in vivo and in culture. Upon sorting out two populations with moderate and relatively higher cell surface 2,6-linked sialic acid levels from the triple negative breast cancer cell line MDA-MB-231, both populations (denoted as medium and high-2,6-Sial cells respectively) stably retained their levels in early passages. Upon continuous culturing, medium 2,6-Sial cells recapitulated the heterogeneity of the unsorted line whereas high 2,6-Sial cells showed no such tendency. Compared with the high 2,6-Sial, the medium 2,6-Sial cells showed greater adhesion to reconstituted extracellular matrices (ECM) as well as invaded faster as single cells. The level of 2,6-linked sialic acids in the two sublines was found to be consistent with the expression of a specific glycosyl transferase, ST6GAL1. Stably knocking down ST6GAL1 in the high 2,6-Sial cells, enhanced their invasiveness. When cultured together, medium 2,6-Sial cells differentially migrated to the edge of growing tumoroid-like cultures, whereas high 2,6-Sial cells formed the central bulk. Simulations in a Cellular Potts model-based computational environment that is calibrated to our experimental findings suggest that the heterogeneity of cell-ECM adhesion, likely regulated by 2,6-linked sialic acids facilitates niches of highly invasive cells to efficiently migrate centrifugally as the invasive front of a malignant tumor. Significance StatementCell-surface sugars are aberrantly expressed in cancer but their contributions to tumor heterogeneity are not known. In this study, we uncover and separate breast cancer populations with distinct 2,6-linked sialic acid levels. The moderately expressing population shows stronger adhesion to extracellular matrix than the high expressing population. It also invades faster through the matrix as single cells. Combining experiments with computational modelling, we show that the heterogeneity in matrix adhesion is vital to accentuating cell invasion. In some conditions, invasion of heterogeneous populations may compare with, or exceed that of, homogeneous moderately expressing populations. Our findings are vital to furthering our understanding of how cancers spread and potentially qualify efforts to manage the disease through glycan-editing or immunotherapeutic approaches.

cancer biology↗