Biology subjects

Kumar, M. R.

Publications and source records attributed to Kumar, M. R..

3 recordsLinked to original sources

bioRxiv2026

A Kidney Stone Associated CLDN4 Variant Impairs Tight Junction Stability and Paracellular Ion Permeability

Claudin-4 (CLDN4) is a key determinant of paracellular ion transport in the distal nephron, where it contributes to chloride permeability and transepithelial resistance. Although CLDN4 knockout mice exhibit hypercalciuria, the epithelial mechanism linking CLDN4 to calcium permeability and kidney stone disease remains unclear. We examined the molecular and functional effects of a kidney stone-associated CLDN4 variant P74L which was identified in two unrelated individuals with nephrolithiasis from the Bern Kidney Stone Registry. Using doxycycline-inducible epithelial cell models expressing human wild-type (WT) or mutant CLDN4, we show that the P74L variant displayed reduced protein stability, impaired junctional incorporation, and decreased surface expression. In contrast to WT CLDN4, whose overexpression increased transepithelial electrical resistance and restricted paracellular sodium, chloride, and calcium permeability, P74L CLDN4 failed to confer these effects. Expression of P74L CLDN4 was associated with reduced CLDN3 and CLDN7 messenger abundance without significant changes in CLDN8 or transcriptional regulation of other distal calcium (and other ion) transport genes. Together, these findings identify CLDN4 P74L as a loss-of-function variant that increases epithelial calcium permeability, possibly leading to increased calcium back-flux in the distal nephron relevant to nephrolithiasis.

physiology↗

bioRxiv2024

Yeast Knowledge Graphs Database for Exploring Saccharomyces cerevisiae and Schizosaccharomyces pombe

Biomedical literature contains an extensive wealth of information on gene and protein function across various biological processes and diseases. However, navigating this vast and often restricted-access data can be challenging, making it difficult to extract specific insights efficiently. In this study, we introduce a high-throughput pipeline that leverages OpenAIs Generative Pre-Trained Transformer Model (GPT) to automate the extraction and analysis of gene function information. We applied this approach to 84,427 publications on Saccharomyces cerevisiae and 6,452 publications on Schizosaccharomyces pombe, identifying 3,432,749 relationships for budding yeast and 421,198 relationships for S. pombe. This resulted in a comprehensive, searchable online Knowledge Graph database, available at yeast.connectome.tools and spombe.connectome.tools, which offers users extensive access to various interactions and pathways. Our analysis underscores the power of integrating artificial intelligence with bioinformatics, as demonstrated through key insights into important nodes like Hsp104 and Atg8 proteins. This work not only facilitates efficient data extraction in yeast research but also presents a scalable model for similar studies in other biological systems. HIGHLIGHTSO_LIGenerated Yeast Knowledge Graphs from full-text research articles. C_LIO_LIAnalyzed over 90,000 publications for Saccharomyces and Schizosaccharomyces species. C_LIO_LIExtracted millions of relationships using GPT-based natural language processing. C_LIO_LIYeast Knowledge Graphs accessible through interactive web platforms and APIs. C_LIO_LIAdvanced tool enabling insights into gene networks and functional interactions. C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=76 SRC="FIGDIR/small/626523v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@15afd5corg.highwire.dtl.DTLVardef@afa4bcorg.highwire.dtl.DTLVardef@16858f2org.highwire.dtl.DTLVardef@1a7a19f_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2023

Assessing the effect of antibody responses on viral rebound dynamics in postnatally SHIV-infected infant Rhesus macaques

AO_SCPLOWBSTRACTC_SCPLOWWhile the benefits of early antiretroviral therapy (ART) initiation in perinatally infected infants are well documented, early ART initiation is not always possible in postnatal pediatric HIV infections, which account for the majority of pediatric HIV cases worldwide. The timing of onset of ART initiation is likely to affect the size of the latent viral reservoir established, as well as the development of adaptive immune responses, such as the generation of neutralizing antibody responses against the virus. How these parameters impact the ability of infants to control viremia and the time to viral rebound after ART interruption is unclear. To gain insight into the dynamics, we utilized mathematical models to investigate the effect of time of ART initiation via latent reservoir size and autologous virus neutralizing antibody responses in delaying viral rebound when treatment is interrupted. We used an infant nonhuman primate Simian/Human Immunodeficiency Virus (SHIV) infection model that mimics breast milk HIV transmission in human infants. Infant Rhesus macaques (RMs) were orally challenged with SHIV.C.CH505 375H dCT and either given ART at 4-7 days post-infection (early ART condition), at 2 weeks post-infection (intermediate ART condition), or at 8 weeks post-infection (late ART condition). These infants were then monitored for up to 60 months post-infection with serial viral load and immune measurements. We develop a stochastic mathematical model to investigate the joint effect of latent reservoir size, the autologous neutralizing antibody potency, and CD4+ T cell levels on the time to viral rebound and control of post-rebound viral loads. We find that the latent reservoir size is an important determinant in explaining time to viral rebound by affecting the growth rate of the virus. The presence of neutralizing antibodies also can delay rebound, but we find this effect for high potency antibody responses only.

immunology↗