Biology subjects

Sriram, S.

Publications and source records attributed to Sriram, S..

9 recordsLinked to original sources

bioRxiv2026

Tetravalent dengue mRNA vaccination orchestrates balanced four-serotype immunity with durable memory and protection in mice.

An effective dengue vaccine must establish durable immunity across four dengue virus (DENV) serotypes, evade antibody-dependent enhancement (ADE), and overcome immune imprinting from prior exposure. Here, we developed TetprM-E mRNA-LNP, a tetravalent vaccine comprising LNP-formulated nucleoside-modified mRNAs encoding DENV1-4 precursor membrane-envelope (prM-E) antigens, and evaluated its immunogenicity, durability, protection and breath across serotype-specific immune backgrounds. Three immunization strategies elicited neutralizing titers greater than 1:1500 against each serotype. Passive transfer of immune sera conferred 100% survival and reduced viremia after lethal DENV2 challenge in immunocompromised mice. Vaccination induced DENV envelope (env)-specific CD8+T cells and CD4-dependent germinal-center responses. DENV env-binding antibodies persisted for 34 weeks alongside DENV env-specific memory B cells. Vaccine-elicited sera showed no measurable in vitro ADE. Although monovalent priming initially biased antibody responses, TetprM-E mRNA-LNP vaccination broadened neutralization across DENV1-4 regardless of priming serotype. Together, TetprM-E mRNA-LNP elicits broad, durable, and protective immunity despite serologic constraints from pre-existing immunity.

immunology↗

bioRxiv2026

B cells sustain tumor-specific CD4 T cells to promote response to PD-1 targeted therapy

Immunotherapy transformed cancer treatment, yet precise correlates of response remain to be defined. While intratumoral follicular helper like (Tfhl) CD4 T cells and IgG1+ B cells have been associated with improved outcomes to PD-1 blockade for hepatocellular carcinoma (HCC), their mechanisms contributing to response are unclear. To address this question, we developed a murine model of HCC and examined CD8, CD4 and B cell responses. Increasing CD4-help sensitizes mice to PD-1 blockade, in a CD4- and CD8-dependent manner. Tumor-specific CD4 T cells contained Tfhl and Th1 populations, and both Bcl6 and T-bet were required for efficacy. Antigen-specific B cells were essential for CD4-helper expansion, yet secretion of antibodies was not required for long-term survival. Thus, B cells are critical for effective immunotherapy, but secreted antibodies are not.

immunology↗

bioRxiv2026

Astrocyte regulatory volume decrease is condition-dependent in intact brain tissue and requires the volume regulated anion channel

Multiple lines of evidence point to the volume regulated anion channel (VRAC) as being instrumental for cellular volume regulation in many cell types, including astrocytes. VRAC are thought to open during periods of astrocyte swelling, releasing anions and osmolytes to drive water out of the cell, allowing it to return to baseline volume even under sustained osmotic or ionic challenge, a process called regulatory volume decrease, or RVD. However, the occurrence of RVD and VRACs role in this process has remained controversial, with clear evidence in cultured cells but mixed reports from work in intact brain tissue. In the present study, we aimed to address this gap by generating a transgenic mouse line in which VRAC is conditionally ablated in astrocytes (VRAC cKO) and recording the volume responses of astrocytes in VRAC cKO and control tissue using real-time volume imaging. We found that the effect of VRAC cKO on astrocyte swelling was dependent on whether swelling was evoked by elevated extracellular potassium, or by reduced extracellular osmolarity. We also found that both VRAC and the presence of sufficient intracellular taurine concentration were required to elicit RVD in astrocytes, but only in hypoosmolar conditions. Our findings provide new information on the conditions needed to elicit RVD in intact brain tissue, and that VRAC is required for RVD to occur. Our findings further suggest that reduction of intracellular ion concentration is essential for VRAC to be activated, rather than simply membrane expansion. Future experiments will examine the solute release aspect of VRAC activation upon astrocyte swelling, as well as the contributions of VRAC to pathological volume dysregulation.

neuroscience↗

bioRxiv2026

Distinct macrophage and T cell programs shape pancreatic inflammation during metabolic stress and aging

Type 2 diabetes is linked to systemic inflammation driven by metabolic stress and aging. Although pancreatic inflammation associated with these factors is well documented, the dynamics of immune cell populations and their molecular changes remain poorly understood. We characterized immune cell alterations in the pancreas and pancreatic islets during Western diet (WD) feeding and aging using imaging mass cytometry (IMC) and single-cell RNA sequencing (scRNA-seq). Spatial and transcriptional analyses were performed to define immune cell subtype composition, activation states, and inferred cell-cell communication programs under metabolic and age-related stress conditions. Our analyses identified expansion of an F4/80low macrophage subtype and activated effector-like CD8+ T cells throughout the pancreas during WD feeding and aging. Within pancreatic islets, single-cell RNA sequencing identified a type I interferon-responsive macrophage population with low F4/80 expression that expanded during overnutrition. Notably, the type I interferon responses elicited by these stressors diverged: aging was associated with a more canonical type I interferon response, whereas overnutrition induced a broader response that included STAT3-associated transcriptional programs. We further provide evidence for enhanced cytokine-mediated communication between macrophages and a CD8+ cytotoxic T-cell population under overnutrition and aging. These findings show that metabolic stress and aging remodel pancreatic inflammation through overlapping but distinct immune mechanisms, involving expansion of F4/80low macrophages, activation of divergent type I interferon programs, and enhanced macrophage-CD8+ T-cell communication. Together, these findings suggest that distinct therapeutic approaches may be required to preserve islet function in type 2 diabetes driven by metabolic stress versus aging. Article HighlightsO_LIMetabolic stress and aging remodel pancreatic inflammation through overlapping but distinct immune mechanisms. C_LIO_LISpatial and single-cell analyses identified conserved remodeling of pancreatic macrophage populations accompanied by activation of cytotoxic T-cell responses during metabolic stress and aging. C_LIO_LIIn pancreatic islets, macrophages exhibited distinct type I interferon-associated transcriptional programs, with aging showing a more canonical interferon response and metabolic stress eliciting a broader inflammatory program that included STAT3-associated transcriptional signatures. C_LIO_LIThese findings provide a framework for understanding how metabolic stress and aging differentially shape pancreatic inflammation. C_LI

cell biology↗

bioRxiv2025

GlycoEnzDB: A database of enzymes involved in human glycosylation

The glycan distribution on cells is governed by the stochastic activity of different families of enzymes that are together called glycoEnzymes. These include ~400 gene products or 2% of the proteome, that have recently been curated in an ontology called GlycoEnzOnto. With the goal of making this ontology more accessible to the larger biomedical and biotechnology community, we organized a web resource called GlycoEnzDB, presenting this enzyme classification both in terms of enzyme function and the pathways that they participate in. This information is linked to i) Figures from the "Essentials of Glycobiology" textbook, ii) General gene, enzyme and pathway data appearing in external databases, iii) Manual and generative-artificial intelligence (AI) based text describing the function and pathways regulated by these entities, iv) Single-cell expression data across cell lines, normal human cell-types and tissue, and v) CRISPR-knockout/activation/inactivation and Transcription factor activity predictions. Whereas these data are curated for human glycoEnzymes, the knowledge framework may be extended to other species also. The user-friendly web interface is accessible at www.virtualglycome.org/glycoenzdb.

biochemistry↗

bioRxiv2025

Transformer-based Deep Learning for Glycan Structure Inference from Tandem Mass Spectrometry

Glycans play critical roles in diverse biological processes, but their structural analysis by tandem mass spectrometry (MS/MS) remains a major challenge due to their branched structure and stereochemistry. Traditional computational methods, such as database searching, are constrained by the scope of existing libraries and can be computationally intensive. While recent deep learning models have advanced the field, they often struggle to capture the complex, long-range dependencies within MS/MS spectra required for accurate inference. To address these challenges, we present GlycoBERT and GlycoBART, novel transformer-based models for glycan structure prediction from MS/MS data. GlycoBERT, a sequence classifier, achieves 95.1% structural accuracy on test data, surpassing the current state-of-the-art deep learning model, CandyCrunch. However, classification-based methods are inherently limited to predicting structures present in the training data. To overcome this, we developed GlycoBART, a generative sequence-to-sequence model capable of de novo glycan inference. On independent validation datasets, both models demonstrate robust performance. Critically, when applied to an MS/MS dataset from human embryonic kidney cells, GlycoBART generated two de novo glycan structures absent from the training set, one of which is a novel structure not catalogued in major glycan databases. Together, GlycoBERT and GlycoBART establish a new benchmark for glycan analysis, offering a powerful framework that enables more accurate and comprehensive exploration of glycan diversity and discovery.

bioinformatics↗

bioRxiv2024

Antiviral immunity within neural stem cells distinguishes viral strain differences in forebrain organoids

Neural stem cells have intact innate immune responses that protect them from virus infection and cell death. Yet, viruses can antagonize such responses to establish neuropathogenesis. Using a forebrain organoid model system at two developmental time points, we identified that neural stem cells, in particular radial glia, are basally primed to respond to virus infection by upregulating several antiviral interferon-stimulated genes. Infection of these organoids with a neuropathogenic Enterovirus-D68 strain, demonstrated the ability of this virus to impede immune activation by blocking interferon responses. Together, our data highlight immune gene signatures present in different types of neural stem cells and differential viral capacity to block neural-specific immune induction.

immunology↗

bioRxiv2023

Influence of preprocessing, distortion correction and cardiac triggering on the quality of diffusion MR images of spinal cord

Diffusion MRI of the spinal cord (SC) is susceptible to geometric distortion caused by field inhomogeneities, and prone to misalignment across time series and signal dropout caused by biological motion. Several modifications of image acquisition and image processing techniques have been introduced to overcome these artifacts, but their specific benefits are largely unproven and warrant further investigations. We aim to evaluate two specific aspects of image acquisition and processing that address image quality in diffusion studies of the spinal cord: susceptibility corrections to reduce geometric distortions, and cardiac triggering to minimize motion artifacts. First, we evaluate 4 distortion preprocessing strategies on 7 datasets of the cervical and lumbar SC and find that while distortion correction techniques increase geometric similarity to structural images, they are largely driven by the high-contrast cerebrospinal fluid, and do not consistently improve the geometry within the cord nor improve white-to-gray matter contrast. We recommend at a minimum to perform bulk-motion correction in preprocessing and posit that improvements/adaptations are needed for spinal cord distortion preprocessing algorithms, which are currently optimized and designed for brain imaging. Second, we design experiments to evaluate the impact of removing cardiac triggering. We show that when triggering is foregone, images are qualitatively similar to triggered sequences, do not have increased prevalence of artifacts, and result in similar diffusion tensor indices with similar reproducibility to triggered acquisitions. When triggering is removed, much shorter acquisitions are possible, which are also qualitatively and quantitatively similar to triggered sequences. We suggest that removing cardiac triggering for cervical SC diffusion can be a reasonable option to save time with minimal sacrifice to image quality.

neuroscience↗

bioRxiv2022

On the Interaction of Biopotential Sensing and Right Leg Drive System with Electro-Quasistatic Human Body Communication

Continuous long-term sensing of biopotential signals is vital to facilitate accurate diagnosis. The current state of the art in wearable health monitoring relies on radiative technology for communication. Due to their radiative nature, these systems result in lossy and inefficient transmission, limiting the devices life span. Human Body Communication has emerged as an energy-efficient secure communication modality, and literature has shown body communication to transmit biopotential signals at 100x lower power than traditional radiative technologies. Unlike radiative communication that uses airwaves, HBC, specifically Capacitive Electro-Quasistatic HBC (EQS-HBC), couple signals and confine them within the human body. In Capacitive EQS-HBC, the transmitter uses an electrode to modulate the body potential to transmit data. The modulation of body potential by HBC raises the following concerns. Will HBC transmissions affect the quality of biopotential signals sensed from the body? Additionally, since biopotential sensing systems commonly use Right Leg Drive (RLD) to bias body potential, there is also a concern if RLD can affect the quality of HBC transmissions. For the first time, our work studies the interactions between EQS-HBC and biopotential sensing. Our work is important since understanding HBC-RLD interactions is integral to developing EQS-HBC-based biosensors for Body Area Networks (BANs). For the studies, we conducted lab experiments and developed circuit theoretic models to back the experimental outcomes. We show that due to their higher frequency content and common-mode nature, HBC transmissions do not affect the differential sensing of low-frequency biopotential signals. We show that biopotential sensing using RLD affects HBC. RLD deteriorates the signal strength of HBC transmissions. We thus propose not to use RLD with HBC. We demonstrate our proposed solution by transmitting ECG signals using HBC with 96% correlation compared to the traditional wireless system at a fraction of the power.

bioengineering↗