Biology subjects

Narayanan, H. V.

Publications and source records attributed to Narayanan, H. V..

3 recordsLinked to original sources

bioRxiv2025

Phased epigenetic fragility and stability accelerate the genetic evolution of B-cells

Non-genetic heterogeneity can provide population robustness when responding to threats or making developmental decisions, but when the biological process rests on specific individuals (tissue-resident macrophages or genetic evolution), non-genetic heterogeneity degrades performance. Vaccine responses depend on the Darwinian evolution of B-cells to generate high-affinity, genetically-encoded antibodies, yet B-cell decision-making is non-genetically variable. In fact, B-cell epigenetic states are fragile during selection but stable during the proliferation burst. Here we report that the iterative dynamics of epigenetic fragility and stability of B-cell fate decisions do not impair but accelerate affinity maturation, by modulating the generation and removal of high-affinity outliers on a fitness landscape that is non-monotonic defined not only by survival/proliferation but plasma cell differentiation. These insights reconcile classical B-cell clonal selection theory with experimentally observed dynamics of epigenetic variability. The resulting model correctly predicts emergent vaccine response properties in alternate mouse strains and may contribute to personalized vaccination strategies. HIGHLIGHTSO_LIB-cell epigenetic states are fragile during antigen selection but stable within proliferative bursts C_LIO_LIEpigenetic state fragility allows high affinity cells to escape plasma cell differentiation C_LIO_LIEpigenetic state stability within proliferative bursts maximizes progeny of fittest cells C_LIO_LIPhased epigenetic dynamics of B-cells predicts emergent vaccine response properties C_LI GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/661408v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@1c2af9forg.highwire.dtl.DTLVardef@980003org.highwire.dtl.DTLVardef@128d8c0org.highwire.dtl.DTLVardef@ae48b8_HPS_FORMAT_FIGEXP M_FIG C_FIG

systems biology↗

bioRxiv2024

Systems biology-enabled targeting of NF-κB and BCL2 overcomes microenvironment-mediated BH3-mimetic resistance in DLBCL.

In Diffuse Large B-cell Lymphoma (DLBCL), elevated anti-apoptotic BCL2-family proteins (e.g., MCL1, BCL2, BCLXL) and NF-{kappa}B subunits (RelA, RelB, cRel) confer poor prognosis. Heterogeneous expression, regulatory complexity, and redundancy offsetting the inhibition of individual proteins, complicate the assignment of targeted therapy. We combined flow cytometry fingerprinting, immunofluorescence imaging, and computational modeling to identify therapeutic vulnerabilities in DLBCL. The combined workflow predicted selective responses to BCL2 inhibition (venetoclax) and non-canonical NF-{kappa}B inhibition (Amgen16). Within the U2932 cell line we identified distinct resistance mechanisms to BCL2 inhibition in cellular sub-populations recapitulating intratumoral heterogeneity. Co-cultures with CD40L-expressing stromal cells, mimicking the tumor microenvironment (TME), induced resistance to BCL2 and BCLXL targeting BH3-mimetics via cell-type specific upregulation of BCLXL or MCL1. Computational models, validated experimentally, showed that basal NF-{kappa}B activation determined whether CD40 activation drove BH3-mimetic resistance through upregulation of RelB and BCLXL, or cRel and MCL1. High basal NF-{kappa}B activity could be overcome by inhibiting BTK to resensitize cells to BH3-mimetics in CD40L co-culture. Importantly, non-canonical NF-{kappa}B inhibition overcame heterogeneous compensatory BCL2 upregulation, restoring sensitivity to both BCL2- and BCLXL-targeting BH3-mimetics. Combined molecular fingerprinting and computational modelling provides a strategy for the precision use of BH3-mimetics and NF-{kappa}B inhibitors in DLBCL.

cancer biology↗

bioRxiv2020

Vectorchip: Microfluidic platform for highly parallel bite by bite profiling of mosquito-borne pathogen transmission

Mosquito bites transmit a number of human pathogens resulting in potentially fatal diseases including malaria, dengue, chikungunya, West Nile encephalitis, and Zika. Although female mosquitoes transmit pathogens via salivary droplets deposited during blood feeding on a host, very little is known about the genomic content of these nanoliter scale droplets, including the transmission dynamics of live pathogens. Here we introduce Vectorchip, a low-cost, scalable microfluidic platform for molecular interrogation of individual mosquito bites in a high-throughput fashion. An ultra-thin PDMS membrane coupled to a microfluidic chip acts as a biting interface, through which freely-behaving mosquitoes deposit saliva droplets by biting into isolated arrayed micro-wells enabling molecular interrogation of individual bites. By modulating membrane thickness, the device enables on-chip comparison of biting capacity and provides a mechanical filter allowing selection of a specific mosquito species. Utilizing Vectorchip, we show on-chip simultaneous detection of mosquito DNA as well as viral RNA from Zika infected Aedes aegypti mosquitoes - demonstrating multiplexed high-throughput screening of vectors and pathogens. Focus-forming assays performed on-chip quantify number of infectious viral particles transmitted during mosquito bites, enabling assessment of active virus transmission. The platform presents a promising approach for single-bite-resolution laboratory and field characterization of vector pathogen communities, to reveal the intricate dynamics of pathogen transmission, and could serve as powerful early warning artificial "sentinel" for mosquito-borne diseases.

bioengineering↗