Biology subjects

Bhowmik, A.

Publications and source records attributed to Bhowmik, A..

5 recordsLinked to original sources

bioRxiv2026

HSF1 controls transcriptional programs that establish thalamostriatal shaft synaptic architecture and preserve cognitive flexibility

Cognitive flexibility (CF) declines during aging and is further impaired in neurodegenerative diseases such as Huntingtons disease (HD), yet the molecular mechanisms underlying these deficits remain poorly understood. Thalamostriatal (T-S) synapses are critical for CF, and we previously identified Heat Shock Factor 1 (HSF1) as a regulator of T-S density in HD. However, how HSF1 regulates T-S synapses and whether it modulates cognitive flexibility (CF) remained unclear. Here, we combined HSF1 ChIP-seq, transcriptomics, synapto-proteomics, targeted genetic manipulations and behavioral analyses to study how HSF1 regulates T-S synapses and CF. We found HSF1 directly controls a transcriptional program governing postsynaptic architecture and actin cytoskeletal dynamics, which are disrupted in aging and HD. Loss of HSF1 drives selective destabilization of actin patches at T-S shaft synapses and impaired CF decline. Our results underscore a novel function for HSF1 in the regulation of striatal neural circuits with essential implications in the neurobiology of cognitive flexibility.

neuroscience↗

bioRxiv2024

Dysregulated RNA splicing induces regeneration failure in alcohol-associated liver disease

Individuals with progressive liver failure are at a high risk of mortality without liver transplantation. However, our understanding of derailed regenerative responses in failing livers is limited. Here, we performed comprehensive multi-omic profiling of healthy and diseased human livers using bulk and single-nucleus RNA-plus ATAC-seq. We report that hepatic immune milieu alterations in alcohol-associated liver disease (ALD) prevent hepatocytes from transitioning to a proliferative progenitor-like state, trapping them into an unproductive intermediate state. We discovered striking changes in RNA binding protein (RBP) expression, particularly ESRP, PTBP, and SR families, that cause misregulation of developmentally controlled RNA splicing in ALD. Our data pinpoint ESRP2 as a pivotal disease-sensitive RBP and support a causal role of its deficiency in ALD pathogenesis. Notably, splicing defects in ESRP2-targets Tcf4 and Slk, amongst others, directly alter their nuclear localization and activities, disrupting WNT and Hippo signaling pathways, which are critical for normal liver regeneration. We demonstrate that changes in stromal cell populations enrich failing ALD livers with TGF-{beta}, which suppresses ESRP2-driven epithelial splicing program and replaces functional parenchyma with quasi-progenitor-like cells lacking liver-specific functions. This unprecedented account of transcriptional and post-transcriptional dysregulation in ALD suggests that targeting misspliced RNAs could improve recovery and serve as biomarkers for poor ALD outcomes.

molecular biology↗

bioRxiv2022

Successfully treating biofilms of extensively drug resistant Klebsiella pneumoniae isolates from hospital patients with N-Acetyl Cysteine

Klebsiella pneumoniae is one of the leading causes of community and nosocomial infections. Reduced treatment options against extensively drug resistant (XDR) - K. pneumoniae, is a serious concern in hospital settings, and hence, WHO has categorized it as a "critical priority pathogen". Biofilm forming ability is a common virulence mechanism amongst K. pneumoniae that is associated with antibiotic tolerance up to 1000X MIC and hence, are difficult to treat. N-acetyl cysteine (NAC) is an FDA approved mucolytic drug used to treat acetaminophen-associated toxicity and obstructive pulmonary diseases. In this study, we assessed NACs antibacterial and antibiofilm activity against clinical isolates of XDR K. pneumoniae, obtained from Madras Medical Mission Hospital, India. To assess the biofilm eradication ability of NAC, we grew biofilms in 96 well plates and treated the mature biofilms with different concentrations of NAC. We observed that the biofilms of only 3 isolates of XDR K. pneumoniae could be eradicated at a concentration as low as 20mg/ml. Although increasing the concentration of NAC to 80mg/mL could significantly reduce the biofilms of all the isolates up to 4-5 Log, NAC at a concentration of 100 mg/mL successfully eradicated the mature biofilms of all the isolates of XDR K. pneumoniae. This in vitro study demonstrates the potential of NAC as an efficient agent against the biofilms of clinical isolates of XDR-K. pneumoniae and thus, provides a promising alternative to antibiotics.

microbiology↗

bioRxiv2019

Dillenia indica fruit extract has Glucose and Cholesterol Lowering effects

BackgroundDillenia indica (D. indica) can suppress carbohydrates hydrolysis by inhibiting -amylase and -glucosidase. However, there is a lack of understanding of its therapeutic potential as an antidiabetic and anti-hyperlipidemic agent. Methods and findingsType 2 diabetes (T2D) was induced by a single intraperitoneal injection of Streptozotocin (STZ; 90mg/kg) and hyperlipidemia by feeding with 1% cholesterol, 5% coconut oil and 5% cow fat diet. Administration of D. indica extracts in water for four weeks triggered a significant (p[≤]0.05) reduction in fasting serum glucose (FSG) levels with concomitant improvement in serum insulin levels. Both the water- and ethanol-extract of D. indica treated groups showed significant (p[≤]0.01) reduction in total cholesterol levels by 25% and 19%, respectively. HDL-cholesterol was also augmented (by 14%) in ethanol-extract treated group. Liver glycogen content was higher in the water-extract treated group. Histopathological examination revealed that there was no tubular epithelial cell degeneration or necrosis in the renal tissues or hepatocyte degeneration and sinusoidal dilation in liver tissues in animals that received the water-extract. On the other hand, consumption of D. indica extract with 1% cholesterol, 5% coconut oil diet or with a 5% cow fat diet for 14 days significantly reduced serum cholesterol levels in group-lll (60[->]45 mg/dl; p[≥]0.05) and -IV (85[->]66 mg/dl; p[≥]0.05) hypercholesterolemic model rats. D. indica fruit extract also reduced serum TG levels (Group-III: 87[->]65 mg/dl; Group-IV: 40[->]90 mg/dl; p[≥]0.05). Interestingly, treatment with D. indica prevented a reduction in serum HDL levels in those hypercholesterolemic model rats. Serum LDL levels were significantly lower in group-III (47[->]39 mg/dl; p[≥]0.05) and group-IV (57[->]44 mg/dl; p[≥]0.05) hypercholesterolemic model rats after D. indica treatment. ConclusionD. indica fruit ameliorates FSG, insulin secretion, glycogen synthesis, and serum lipid profile. Therefore, D. indica fruit can be a potential therapeutic agent for diabetic and hyperlipidemia. Graphical AbstractExtract of D. indica in water reduces FSG, serum insulin levels, and ameliorates the serum lipid profile in diabetic model rats without any adverse effects on kidney and liver tissues. Extract of D. indica in ethanol significantly reduces serum cholesterol, TG, LDL with no reduction in HDL levels in hyper-lipidemic model rats. HighlightsO_LID. indica fruit extracts diminished fasting serum glucose (FSG) levels in STZ-induced type 2 diabetic model rats C_LIO_LID. indica fruit extracts boosted insulin secretion C_LIO_LID. indica fruit extracts showed no toxic effects on the kidney and the liver functions C_LIO_LIExtract in water was more effective in reducing FSG levels than extract in ethanol C_LIO_LIChronic consumption of 1% cholesterol, 5% coconut oil and 5% cow fat diet was sufficient to make the rat hypercholesterolemic C_LIO_LID. indica fruit extract has the potential to reduce serum cholesterol, TG, LDL with prevention in reduction in serum HDL levels. C_LI

pharmacology and toxicology↗

bioRxiv2018

Rapid Whole Cell Imaging Reveals An APPL1-Dynein Nexus That Regulates Stimulated EGFR Trafficking

Multicellular life processes such as proliferation and differentiation depend on cell surface signaling receptors that bind ligands generally referred to as growth factors. Recently, it has emerged that the endosomal system provides rich signal processing capabilities for responses elicited by these factors [1-3]. At the single cell level, endosomal trafficking becomes a critical component of signal processing, as exemplified by the epidermal growth factor (EGF) receptors of the receptor tyrosine kinase family. EGFRs, once activated by EGF, are robustly trafficked to the phosphatase-enriched peri-nuclear region (PNR), where they are dephosphorylated [4-8]. However, the details of the mechanisms regulating the movements of stimulated EGFR in time and space, i.e., towards the PNR, are not known. What endosomal regulators provide specificity to EGFR? Do modifications to the receptor upon stimulation regulate its trafficking? To understand the events leading to EGFR translocation, and especially the early endosomal dynamics that immediately follow EGFR internalization, requires the real-time, long-term, whole-cell imaging of multiple elements. Here, exploiting the advantages of lattice light-sheet microscopy [9], we show that the binding of EGF by its receptor, EGFR, triggers a transient calcium increase that peaks by 30 s, causing the desorption of APPL1 from pre-existing endosomes within one minute, the rebinding of liberated APPL1 to EGFR within three minutes, and the dynein-dependent translocation of APPL1-EGF-bearing endosomes to the PNR within five minutes. The novel, cell spanning, fast acting network that we reveal integrates a cascade of events dedicated to the cohort movement of activated EGFR receptors. Our findings support the intriguing proposal that certain endosomal pathways have shed some of the stochastic strategies of traditional trafficking, and have evolved behaviors whose predictability is better suited to signaling [10, 11]. Work presented here demonstrates that our whole cell imaging approach can be a powerful tool in revealing critical transient interactions in key cellular processes such as receptor trafficking.

cell biology↗