Biology subjects

Biswas, R.

Publications and source records attributed to Biswas, R..

At least 19 recordsLinked to original sources

bioRxiv2026

14-3-3 Enables β-Adrenergic Regulation of the Cardiac Sodium Channel at the Intercalated Disc

Background: Beta-Adrenergic stimulation enables the heart to adapt electrical activity to increased physiological demand. Although the cardiac sodium channel Nav1.5 is essential for impulse propagation, the mechanisms underlying its acute beta-adrenergic regulation, particularly within distinct cardiomyocyte membrane domains, remain poorly understood. We investigated whether the phosphorylation-sensitive adaptor protein 14-3-3 mediates this regulation. Methods and Results: Using automated patch-clamp electrophysiology in HEK293 cells and human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), we found that isoproterenol rapidly increased sodium current (INa) and promoted channel activation at more hyperpolarized potentials, whereas PKA inhibition reduced INa. Disruption of 14-3-3 function abolished these responses without substantially altering basal sodium current or Nav1.5 surface expression. Macropatch recordings from ventricular myocytes revealed that isoproterenol preferentially enhanced INa at the intercalated disc, an effect prevented by 14-3-3 inhibition. Proximity ligation assays further demonstrated increased Nav1.5/14-3-3 proximity following beta-adrenergic stimulation. Systematic mutagenesis identified S460 in the Nav1.5 DI-DII linker as a critical determinant of acute PKA-dependent regulation. Molecular modeling predicted that S460 phosphorylation stabilizes the Nav1.5/14-3-3 interaction. In CRISPR-engineered S460A iPSC-CMs, acute beta-adrenergic regulation of INa was abolished, whereas the isoproterenol-induced increase in conduction velocity was significantly attenuated. Computational simulations further predicted that enhanced intercalated-disc sodium current supports increased conduction velocity across varying conditions of electrical coupling and pacing rate. Conclusions: Our findings identify 14-3-3 and S460 as critical determinants of spatially selective beta-adrenergic regulation of Nav1.5 at the cardiac intercalated disc. This mechanism provides a molecular link between sympathetic signaling and cardiac sodium current regulation, supporting the concept that localized enhancement of Nav1.5 function contributes to the adaptation of cardiac conduction during increased sympathetic demand.

molecular biology↗

bioRxiv2026

PM2.5 toxin benzopyrene induces life-limiting inflammation and oxidative stress in the airway by up-regulation of TRPC6 and inactivation of β2AR/CFTR signaling

Abstract2O_ST_ABSBackgroundC_ST_ABSSustained exposures to high atmospheric levels of PM2.5 at population scale are associated with increased risks for pulmonary inflammatory diseases. These are marked by activation of the TRPC6 (Transient Receptor Potential Canonical type 6) calcium channel, increased reactive oxygen species (ROS) and oxidative stress. Long term exposures are associated with reduced life span, and increased incidences of cardiovascular diseases, dementia, Parkinsons and Alzheimer disease, and increased risk of autism and autism spectrum disorders. It has been proposed that the PM2.5 toxin is benzo[a]pyrene (B[a]P) that is adsorbed to the surface of the PM2.5 particle.. But the mechanism by which B[a]P might drive pulmonary inflammatory diseases, or any other of the indications above, are not known. HypothesisB[a]P was recently reported to bind irreversibly and destructively to the {beta}2 Adrenergic Receptor ({beta}2AR) in the lung. We have therefore hypothesized that B[a]P is the adsorbed PM2.5 toxin, and that {beta}2AR is the B[a]P receptor responsible for TRPC6 activation in lung epithelial cells. ResultsTo test this hypothesis, we exposed a polarized organoid model of normal human lung epithelia, polarized lung epithelial 16HBE14o-cells, and tracheobronchial slice cultures from ferret lung to either PM2.5 or B[a]P. We found that both PM2.5 and B[a]P: (i) irreversibly activated of {beta}2AR signaling via Gi to PI3K/AKT; (ii) increased NF{kappa}B-activated release of proinflammatory cytokines through IKK{beta} activation by PI3K/AKT, which was suppressed by the PI3K inhibitor LY 294002 (iii) desensitized and destroyed the activated {beta}2AR receptor by endocytic recycling; (iv) also destroyed {beta}2ARs signalplex partner CFTR by the same process; (v) activated the CFTR-bound calcium channel protein TRPC6 due to loss of inhibitory CFTR; leading to (vi) increased cytosolic [Ca2+] concentration; (vii) increased ROS due to mitochondrial uncoupling; and (viii) increased expression of oxidative stress. Treatment with the TRPC6 inhibitor BI 749327 blocked steps (vi-viii), and preserved CFTR from endocytic loss. Treatment of tracheobronchial slice cultures of ferret lung with either PM2.5 or B[a]P resulted in increased secretion of IL-6, increased expression of TRPC6, and reduced expression of {beta}2AR and CFTR. Finally, we found that exposure of lung organoids to B[a]P significantly reduced expression of the same five microRNAs (miR-126a-3p, miR-30b-5p, miR-103a-3p, miR-26a-5p, and miR-766-3p) previously identified in sera from service members exposed to PM2.5 from burn pit emissions during deployment to Iraq and Afghanistan. ConclusionPM2.5 and the PM2.5 toxin benzo[a]pyrene (B[a]P) induce inflammation and oxidative stress in the airway by increased expression of TRPC6 and inactivation of {beta}2AR/CFTR signaling. These discoveries mark the first identification of a mechanism by which exposure to PM2.5 or the PM2.5 toxin B[a]P itself can induce inflammation and TRPC6-dependent oxidative stress in lung epithelia.

pharmacology and toxicology↗

bioRxiv2026

State-Dependent Organization of Microscale Functional Circuitry in Visual Cortex

How the cortex organizes directed functional interactions among individual neurons and how this microscale circuitry maps onto cell types and the underlying anatomy remains poorly understood. Here, we construct one of the largest single-neuron-resolution directed functional circuit maps in mouse visual cortex from calcium imaging of more than 57,000 active neurons across four visual areas and five cortical layers. We infer directed connections with a time-aware causal-inference method (CITS) that is specifically designed for neural time-series. In the co-registered electron-microscopy connectome, CITS-inferred pairs are 3.6-fold more likely to be synaptically connected than unconnected pairs, which is significantly more than Granger causality (1.1-fold) or lagged correlation (1.6-fold). We found that our inferred functional circuits organization aligns with synaptic connectivity at areal, laminar, and cell-type levels. Among intra-areal connections, anterolateral area (AL) had the highest density, and among inter-areal connections, the AL{leftrightarrow}rostrolateral area (RL) axis formed the strongest pathway. At the cell-type level, layer 6 recurrence dominated the aggregate network in low arousal, whereas layer 6-to-layer 5 output connections dominated in high arousal. Spatial extent expanded with inter-neuron distance in high arousal, for both excitatory-to-excitatory and excitatory-to-inhibitory connections. Finally, in stimulusdriven response prediction, neuron pairs with stronger functional connections exhibited more similar predictive performance in both high-arousal and low-arousal states, with performance varying by layer and cell type. Overall, our findings establish, at single-neuron resolution, the multi-scale organization of directed functional circuitry in mouse visual cortex across brain states.

neuroscience↗

bioRxiv2025

Conformational Diversity and Allosteric Network Enable Multi-Substrate Recognition in Laccase Enzyme

Laccase is a multicopper oxidase with remarkable potential for environmental remediation due to its ability to degrade a wide range of pollutants. However, the molecular origins of its broad substrate scope have remained elusive. Here, through extensive molecular dynamics (MD) simulations coupled with machine learning (ML) based Markov State Model (MSM), we uncover a previously uncharacterized allosteric pathway that governs laccases catalytic activity. This pathway functionally couples the dynamics of two key loops at the active site, and its integrity is crucial for enzymatic efficiency. Our analysis of the apo enzymes conformational free energy landscape reveals that this allostery is part of a cooperative global network, leading to distinct, slowly interconverting conformational states. We demonstrate that different dye substrates bind by selectively recognising these pre-existing states, confirming a conformational selection mechanism. Collectively, these findings provide a dynamic blueprint for laccases functional versatility and offer a general framework for understanding and engineering other multi-substrate enzymes.

biophysics↗

bioRxiv2025

Fibroblast orchestration of inflammaging via NF-kB activation

Aged tissue is characterized by chronic inflammation known as "inflammaging". While this aging immune phenotype supposedly drives some of the most common diseases affecting the elderly, little is known about the structural drivers of inflammaging. In this study, we demonstrate that age-dependent activation of NF-kB in tissue fibroblasts remodels the immune architecture, promoting the emergence of an exhausted T cell population (GZMK+/CD8+) recently identified in normal aging, as well as autoimmunity and cancer. Fibroblast-specific NF-kB activation triggered a fibroblast-macrophage-T cell circuit to form tertiary lymphoid structures in the lung and promoted the emergence of exhausted GZMK+ T cells. Fibroblastic activation of NF-kB increased host susceptibility to acute lung injury and mimics severe pneumonia commonly seen in elderly patients, which was alleviated by deletion of GZMK+ T cells. Our data provide a structural basis for inflammaging, where fibroblasts orchestrate the complex immune aging phenotype in non-immune tissues, increasing susceptibility to age-related diseases. Highlights- Bronchus-associated lymphoid tissue (BALT) enriched for GZMK+ T cells develop with age - Lung adventitial fibroblasts demonstrate increased NF-kB activation with age. - Fibroblast activation of NF-kB in young animals recapitulates multiple features of normal lung immune aging - Depletion of GZMK+ cells decreases lung inflammation in a mouse model of acute respiratory distress syndrome (ARDS)

immunology↗

bioRxiv2025

Integrated Stress Response and Necroptosis Drive Epithelial Dysfunction in Crohn's Disease: Repurposing Cancer drugs for Permeability Barrier Healing.

Background and AimsEpithelial permeability barrier dysfunction is a central pathogenic driver of Crohns disease (CD), fueling microbial translocation, chronic inflammation, and progressive tissue injury. While current therapies suppress inflammation, none directly restore epithelial barrier function. Importantly, in CD patients, permeability barrier healing (BH) rather than mucosal healing is associated with long-term remission and a reduced risk of disease complications. Yet BH remains an unaddressed therapeutic target in CD. Here, we investigated whether pharmacologic inhibition of the integrated stress response (ISR) and RIPK3-mediated necroptosis, two convergent pathways of epithelial injury, can promote epithelial viability, regeneration, and barrier integrity in CD. MethodsWe employed villin-1/gelsolin double knockout (DKO) mice with epithelial-intrinsic ISR activation, TNF{Delta}ARE/+ mice with chronic inflammation, and CD patient-derived enteroids (PDEs). Animals and PDE were treated with ISR inhibitor ISRIB, RIPK3 inhibitor Necrostatin-1 (Nec-1), or FDA-approved cancer drugs pazopanib and ponatinib, repurposed as potent RIPK3 inhibitors. Epithelial survival, regenerative growth (enteroid formation, budding), and barrier function (transepithelial electrical resistance, TEER) were assessed. ResultsChronic ISR activation and necroptosis were prominent in both murine models and CD PDEs, causing epithelial death, Paneth cell expansion, impaired enteroid survival, and regenerative failure. Pharmacologic inhibition with ISRIB, Nec-1, pazopanib, or ponatinib restored villus architecture, reduced inflammation, enhanced epithelial survival and regeneration, and significantly improved TEER. ConclusionsISR activation and RIPK3-mediated necroptosis converge to drive epithelial injury and barrier dysfunction in CD. Repurposing pazopanib and ponatinib restored epithelial regeneration and BH, offering an immediately translatable therapeutic strategy for sustained remission in CD. SynopsisISR activation and RIPK3-mediated necroptosis drive epithelial injury in Crohns disease. Repurposed RIPK3 inhibitors, pazopanib and ponatinib, restore epithelial homeostasis and permeability barrier function, providing a translational strategy to achieve sustained remission in CD.

pathology↗

bioRxiv2025

Furrow tillage reduces soil carbon loss and enhances microbial metabolism

With increasing global carbon loss from agricultural fields, agricultural practices should be monitored with proper regulatory measures. To address three problems of minimising carbon loss, optimising soil fertility and enhancing soil microbiota together, this study has developed a new innovative "Furrow tillage" approach that affords a balance between conventional and conservative tillage. Based on two years of trials in rice fields at multiple sites, this practice has justifications from agronomy, geochemistry, crop physiology, and molecular microbiology. Furrow tillage illustrated low carbon loss, similar to no-tillage, while retaining high nutrient bioavailability, similar to deep tillage. Microbial diversity, molecular responses and metabolic activities showed that furrow tillage induced microbial interactions while allowing a better entrapment of carbon dioxide in the soil. The study used CO2 flux, spatial distribution, total and available elemental analysis, plant ultra-structural observations, microbial metagenomics, high-throughput sequencing and molecular modelling to establish an optimal soil-crop quality, microbial maintenance and reduce carbon loss through furrow tillage practice.

ecology↗

bioRxiv2025

Structural and Functional Mechanisms Underlying Activation Gate Dynamics and IFM Motif Accessibility in Human Nav1.5

Voltage-gated sodium channels are vital for regulating excitability in muscle and nerve cells, and their dysregulation is linked to a range of diseases. However, therapeutic targeting of Nav channels remains challenging due to a limited understanding of their gating mechanisms. Here, we present a cryo-EM structure of human Nav1.5 in an intermediate open state, stabilized by interactions between the N-terminal domain and the S6I segment. This structure reveals a previously uncharacterized Na+ binding site adjacent to the conserved inactivation (IFM) motif. Molecular dynamics simulations demonstrate that monovalent cations stably occupy this site, while electrophysiological recordings demonstrate that ion binding modulates IFM motif docking and fast inactivation kinetics. Our findings reveal that IFM accessibility is dynamically regulated in this intermediate state, challenging the canonical hinged-lid model of fast inactivation. Collectively, our study provides a revised structural framework for Nav1.5 gating mechanisms, suggesting an alternative pathway for ion accessibility that may inform better mechanistic and therapeutic strategies for treating Nav1.5-related cardiac arrhythmias.

biophysics↗

bioRxiv2025

Cryo-EM reveals the structural heterogeneity and conformational flexibility of multidrug efflux pumps MdtB and MdtF

RND efflux pumps are a major cause of multidrug resistance in bacteria, particularly in Gram-negative bacteria. They are complex molecular machines forming tripartite assemblies that actively pump out a wide range of antimicrobial agents, including antibiotics, biocides and host defence molecules. However, the presence of multiple RND pumps with overlapping functions in a single bacterium raises questions about their individual functional relevance. In this study, we determined the Cryo-EM structures of two distinct HAE-RND pumps from E.coli., MdtB and MdtF. MdtF is a unique class of RND pump whose expression is regulated by oxygen availability and is crucial for the survival of E.coli in anaerobic growth conditions. Surprisingly, homotrimeric MdtB, previously reported to be inactive, exhibited activity in our experiments. Cryo-EM structure determination of MdtF at 2.8 [A] resolution revealed the flexible transmembrane domain with significant conformational changes in the core helixes, leading to the closure of the central pore. While the MdtB structure adopts a resting state, MdtF displays structural dynamics in the presence of DDM. The apo structures of both pumps unveil novel conformational states of HAE-RND efflux transporters. Our findings highlight significant structural and functional divergence among closely related HAE-RND proteins. Despite 71% sequence similarity and phylogenetic proximity to AcrB, the structure of MdtF differs from the solved AcrB structures. In contrast, the MdtB structure exhibits greater resemblance to AcrB, regardless of 32% sequence similarity. Furthermore, our structural analysis provides insights into drug-binding sites and the transport mechanism of these important transporters.

biophysics↗

bioRxiv2025

Impact of Soil Salinity on Microbial Community Composition in Coastal Agricultural lands of Bangladesh: A Metagenomic Approach

A significant obstacle to agricultural productivity is soil salinity, especially in coastal areas where the problem is made worse by climate change and rising sea levels. This study investigates the impact of salinity on microbial community structure and function in agricultural soils from Kuakata, Bangladesh, using 16S rRNA metagenomic sequencing technique. Both saline (EC > 4 dS/m) and non-saline (EC < 1.5 dS/m) areas had soil samples taken; saline soils showed symptoms of crop stress, such as yellowing and blackish discoloration. In comparison to their non-saline counterparts, our investigation showed that saline soils had much reduced microbial diversity and different community compositions. Both soil types were dominated by Proteobacteria and Chloroflexi, while saline soils displayed an enrichment of anaerobic texa (e.g., Desulfobacterota, Pseudomonas) and sulfate-reducing bacteria (e.g., Desulfobacterota, Deferrisomatota). Interestingly, saline soils had a much larger percentage of anaerobic microorganisms (36.4%) than non-saline soils (29.3%) which might results in enhanced denitrification, sulphate reduction, and hydrogen sulphide buildup. These processes disrupt nutrient cycling, lower organic matter decomposition and create toxic conditions for plant growth, ultimately contributing to crop failure. This study provides an insight into the distinct microbial composition in saline and non-saline samples, which can assist in understanding the role of microbial populations in agriculture in saline environments.

microbiology↗

bioRxiv2024

Alterations in Causal Functional Brain Networks in Alzheimer's Disease: A resting-state fMRI study

BackgroundAlterations in functional connectivity (FC) of the brain is known to predate the onset of clinical symptoms of Alzheimers disease (AD) by several decades. Identifying the altered functional brain networks in AD can help in its prognosis and diagnosis. ObjectiveFC analysis is predominantly correlational. However, correlation does not necessarily imply causation. This study aims to infer causal functional connectivity (CFC) from functional magnetic resonance imaging (fMRI) data and obtain the sub-networks of CFC that are altered in AD compared to cognitively normal (CN) subjects. MethodsWe used the recently developed Time-aware PC algorithm to infer CFC between brain regions. The CFC outcome was compared with correlation-based functional connectivity obtained by sparse partial correlation. Then, Network-based Statistics (NBS) was used to obtain CFC sub-networks that altered in AD subjects compared to healthy controls while correcting for multiple comparisons at 5% level of significance. ResultsOur findings identified causal brain networks involving the inferior frontal gyrus, superior temporal gyrus (temporal pole), middle temporal gyrus (temporal pole), and different lobes of the cerebellum to be significantly reduced in strength in AD compared to CN group (p-value = 0.0299; NBS corrected). In the sample dataset that has been analysed, no brain networks were found to exhibit significant increase in strength in AD compared to CN group at 5% level of significance with NBS correction. ConclusionsOur findings provide insights into disruptions in causal brain networks in AD. The corresponding brain regions are in agreement with published medical literature on brain regions impacted by AD. Our work establishes a methodology for finding causal brain networks that are affected by AD using TPC algorithm to compute subject-specific CFC and then using NBS for finding CFC subnetworks that alter between AD and CN groups. Larger datasets are expected to identify further subnetworks affected by AD.

neuroscience↗

bioRxiv2024

Atomically accurate de novo design of single-domain antibodies

Despite the central role that antibodies play in modern medicine, there is currently no method to design novel antibodies that bind a specific epitope entirely in silico. Instead, antibody discovery currently relies on animal immunization or random library screening approaches. Here, we demonstrate that combining computational protein design using a fine-tuned RFdiffusion network alongside yeast display screening enables the generation of antibody variable heavy chains (VHHs) and single chain variable fragments (scFvs) that bind user-specified epitopes with atomic-level precision. To verify this, we experimentally characterized VHH binders to four disease-relevant epitopes using multiple orthogonal biophysical methods, including cryo-EM, which confirmed the proper Ig fold and binding pose of designed VHHs targeting influenza hemagglutinin and Clostridium difficile toxin B (TcdB). For the influenza-targeting VHH, high-resolution structural data further confirmed the accuracy of CDR loop conformations. While initial computational designs exhibit modest affinity, affinity maturation using OrthoRep enables production of single-digit nanomolar binders that maintain the intended epitope selectivity. We further demonstrate the de novo design of single-chain variable fragments (scFvs), creating binders to TcdB and a Phox2b peptide-MHC complex by combining designed heavy and light chain CDRs. Cryo-EM structural data confirmed the proper Ig fold and binding pose for two distinct TcdB scFvs, with high-resolution data for one design additionally verifying the atomically accurate conformations of all six CDR loops. Our approach establishes a framework for the rational computational design, screening, isolation, and characterization of fully de novo antibodies with atomic-level precision in both structure and epitope targeting.

bioengineering↗

bioRxiv2023

Robust discovery of causal gene networks via measurement error estimation and correction

Discovering causal relations among genes from observational data is a fundamental problem in systems biology, especially in humans where direct gene interventions or perturbations are unethical/infeasible. Furthermore, causality is emerging as an integral factor for building interpretable and generalizable machine-learning models of complex phenotypes. Existing methods can discover causal relations from observed gene expression and matched genetic data using the well-established framework of Mendelian Randomization. But, the prevalence of expression measurement errors can mislead most existing methods into making wrong causal discoveries, especially among genes transcribed at low to moderate levels and using data with large sample size (say thousands as in modern genomic or GWAS studies). In this study, we propose a new framework for causal discovery that is robust against measurement noise by extending an established statistical approach CIT (Causal Inference Test). We specifically developed a two-stage approach called RCD (Robust Causal Discovery), wherein we first estimate measurement error from gene expression data and then incorporate it to get consistent parameter estimates that could be used with appropriately extended statistical tests of correlation or mediation done in the original CIT. By quantifying and accounting for noise in the data, our RCD method is able to significantly outperform the baseline method in recovering ground-truth causal relations among simulated noisy genes and transcription factor to target gene relations among noisy yeast genes using data on 1012 yeast segregants. Encouraged by these results, we applied our RCD to a human setting where perturbations are infeasible and identified several causal relations, including ones involving transcriptional regulators in the skeletal muscle tissue. Data and Code AvailabilityThe code that implements our two-stage RCD framework is available here: https://github.com/BIRDSgroup/RCD; code for reproducing the figures/tables in this manuscript is also provided in this link.

bioinformatics↗

bioRxiv2023

Rapid resistance profiling of SARS-CoV-2 protease inhibitors

Resistance to nirmatrelvir (Paxlovid) has been shown by multiple groups and may already exist in clinical SARS-CoV-2 isolates. Here a panel of SARS-CoV-2 main protease (Mpro) variants and a robust cell-based assay are used to compare the resistance profiles of nirmatrelvir, ensitrelvir, and FB2001. The results reveal distinct resistance mechanisms ("fingerprints") and indicate that these next-generation drugs have the potential to be effective against nirmatrelvir-resistant variants and vice versa.

microbiology↗

bioRxiv2022

MicroRNA-205 promotes hair regeneration by modulating mechanical properties of hair follicle stem cells

Stiffness and actomyosin contractility are intrinsic mechanical properties of animal cells required for the shaping of tissues. However, whether tissue stem cells (SCs) and progenitors located within SC niche have different mechanical properties that govern their size and functions remains unclear. We show that hair follicle SCs in the bulge are stiff with high actomyosin contractility and resistant to size change, whereas hair germ (HG) progenitors are soft and periodically enlarge and contract during quiescence. During activation, HGs reduce contraction and more frequently enlarge, a process that is associated with weakening of the actomyosin network, nuclear YAP accumulation and cell cycle re-entry. Induction of miR-205, a novel regulator of the actomyosin cytoskeleton, reduces actin contractility, decreases the stiffness of the bulge and HG, and activates hair regeneration in young and old mice. This study reveals the control of tissue SC size and activities by spatiotemporally compartmentalized mechanical properties and demonstrates the possibility to stimulate tissue regeneration by fine-tuning cell mechanics.

genetics↗

bioRxiv2022

The Arabidopsis ARID-HMG protein AtHMGB15 modulates JA signalling by regulating MYC2 during pollen development

In flowering plants, jasmonic acid (JA) signalling regulates the complex process of male gametophyte development. JA signalling initiates with the activation of MYC2 transcription factor, for the expression of several JA responsive genes throughout stamen development and pollen maturation. However, the regulation of JA signalling during different developmental stages of male gametophytes is still less understood. In this study we have characterized T-DNA insertion line of AtHMGB15. Phenotypic characterization of athmgb15-4 mutant plants showed delayed bolting, shorter siliques and reduced seed set compared to wildtype. Moreover, deletion of AtHMGB15 resulted in defective pollen morphology, delayed pollen germination, abberant pollen tube growth and a higher percentage of non-viable pollen population in athmgb15-4 compared to wildtype. Molecular analysis indicated down-regulation of JA-biosynthesis and JA-signalling genes viz MYC2, MYB21 and MYB24 in athmgb15-4 mutant. Furthermore, jasmonic acid and its derivatives were found almost ten-fold lower in athmgb15-4 flowers. However, exogenous application of jasmonate could restore pollen morphology and pollen germination, suggesting that impaired JA signalling is responsible for the pollen phenotype in athmgb15 mutant. AtHMGB15 physically interacts with MYC2 protein to form the transcription activation complex for promoting transcription of genes responsible for JA signalling during stamen and pollen development. Collectively, our findings indicate that AtHMGB15, a plant specific DNA binding protein of the ARID-HMG group, acts as a positive regulator of JA signalling to control the spatiotemporal expression of key regulators responsible for stamen and pollen development.

developmental biology↗

bioRxiv2021

Neural epidermal growth factor-like 1 protein variant increases survival and modulates the inflammatory and immune responses in human ACE-2 transgenic mice infected with SARS-CoV-2

Coronavirus disease 2019 (COVID-19) is a viral illness caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is a worsening global pandemic. COVID-19 has caused at least 1.7 million deaths worldwide and over 300,000 in the United States. Recently, two promising vaccines are being administered in several countries. However, there remains an urgent need for a therapeutic treatment for COVID-19 patients with severe respiratory damage that can lead to intensive care, prolonged hospitalization, or mortality. Moreover, an increasing population of patients manifest lingering disabling symptoms (called Long Haulers). Here, we tested the efficacy of a recombinant neural epidermal growth factor like 1 protein variant (NELL1-NV1) in a COVID-19 mouse model, transgenic mice expressing the human angiotensin I-converting enzyme 2 (ACE2) receptor (tg-mice hACE2) infected with SARS-CoV-2. The administration of NELL1-NV1 to SARS-CoV-2-infected tg-mice hACE2 significantly improved clinical health score and increased survival. Analyses of bronchoalveolar (BAL) fluid demonstrated decreased levels of several cytokines and chemokines (IFN-{gamma}, IL-10, IL-12 p70, CXCL-10/IP-10, MIG and Rantes), in NV1-treated treated mice compared to controls. Cytokines including IL-1, IL-9, IL-6, LIX/CXCL5, KC/CXCL1, MIP-2/CXCL2, MIP-1/CCL3, and G-CSF, critical to immune responses such as neutrophil recruitment, viral clearance and vascularization, were increased compared to controls. Our data suggest the potential of NELL1-NV1-based therapy to mitigate the cytokine storm, modulate the abnormal immune response and repair respiratory tissue damage in COVID-19 patients.

immunology↗

bioRxiv2020

Suppression of miR-155 attenuates lung cytokine storm induced by SARS-CoV-2 infection in human ACE2-transgenic mice

Coronavirus disease 2019 (COVID-19) is a recent global pandemic. It is a deadly human viral disease, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with a high rate of infection, morbidity and mortality. Therefore, there is a great urgency to develop new therapies to control, treat and prevent this disease. Endogenous microRNAs (miRNAs, miRs) of the viral host are key molecules in preventing viral entry and replication, and building an antiviral cellular defense. Here, we have analyzed the role of miR-155, one of the most powerful drivers of host antiviral responses including immune and inflammatory responses, in the pathogenicity of SARS-CoV-2 infection. Subsequently, we have analyzed the potency of anti-miR-155 therapy in a COVID-19 mouse model (mice transgenic for human angiotensin I-converting enzyme 2 receptor (tg-mice hACE2)). We report for the first time that miR-155 expression is elevated in COVID-19 patients. Further, our data indicate that the viral load as well as miR-155 levels are higher in male relative to female patients. Moreover, we find that the delivery of anti-miR-155 to SARS-CoV-2-infected tg-mice hACE2 effectively suppresses miR-155 expression, and leads to improved survival and clinical scores. Importantly, anti-miR-155-treated tg-mice hACE2 infected with SARS-CoV-2 not only exhibit reduced levels of pro-inflammatory cytokines, but also have increased anti-viral and anti-inflammatory cytokine responses in the lungs. Thus, our study suggests anti-miR-155 as a novel therapy for mitigating the lung cytokine storm induced by SARS-CoV-2 infection.

immunology↗