Biology subjects

Hazra, S.

Publications and source records attributed to Hazra, S..

8 recordsLinked to original sources

bioRxiv2026

Mechanistic Insights into Adaptive Binding of Vitamins and Hormones at Hotspot-Enriched Interfaces of the Synaptotagmin 1 C2AB Domain

The present in silico study provided the adaptive binding of seven physiologically active molecules, including four non-peptide hormones (cortisol, estradiol, triiodothyronine, melatonin) and three vitamins (methyltetrahydrofolate, pyridoxal phosphate, thiamine), alongside argireline as a benchmark, at hotspot-enriched interfaces of full C2AB-domain of Synaptotagmin 1 (Syt1), using molecular docking study and molecular dynamics (MD) simulations. Linear correlations of MD-features and nonlinear KPCA-IG-based ranking of features and ligands yielded deeper mechanistic insights. All ligands exhibited spontaneous binding with strong negative {Delta}Gbinding values. Fifteen hotspots, clustered across the C2A, C2B, and C2AB-interlink regions, were dominated by hydrophobic and van der Waals interactions. Several hotspots and non-hotspots corresponded to Syt1 residues that are reported to link with Ca2+-dependent phenomena and membrane vesicular fusion. Solvent-excluded volume (VSE) analyses showed that local hotspot burial and global desolvation together influenced protein adaptability, distinguishing ligands with similar hotspots but divergent thermodynamics. Linear correlations established {Delta}Gbinding as an indicator of hydrophobic hotspot burial. KPCA-IG identified {Delta}VSE and RMSD as dominant mechanistic features capturing cooperative induced-fit responses. Pyridoxal phosphate, melatonin and triiodothyronine emerged as mechanistically top adaptive binders, involving adjustable desolvation, hotspot expansion, optimal flexibility and pose retention. Methyltetrahydrofolate and cortisol showed intermediate burial-dominated cooperativity. Argireline, thiamine and estradiol exhibited ligand-specific burial-dominated, pose-locked and adaptability-limited bindings. Overall, our study demonstrates that desolvation control, induced-fit adaptability and structural flexibility, not {Delta}Gbinding alone, govern Syt1-ligand binding, revealing Syt1 as a versatile presynaptic target for modulation by these bioactive molecules.

bioinformatics↗

bioRxiv2026

Peptidyl Protease Inhibitors Block ERM-BP Function and Suppress Entamoeba Encystation

Entamoeba encystation process is a crucial developmental process that support to parasite persistence and disease transmission, yet the molecular mechanisms governing this stage conversion remain poorly understood and represent an attractive opportunity for therapeutic intervention. The Encystation Regulatory Motif-Binding Protein (ERM-BP), a transcription factor and key regulator of encystation, therefore represents a promising target for anti-amoebic drug development to prevent disease transmission. In the present study, we applied a target-based drug discovery approach to screen small molecules that can block the activity of ERM-BP, with a particular focus on the Cys-198 residue of this protein, which is functionally important. A library comprising 100 compounds including broad-spectrum nicotinamidase inhibitors and cysteine-reactive electrophiles were screened against ERM-BP by Protein thermal shift assays (PTSA). Thirty-six compounds bound to wild-type ERM-BP while analysis using the C198A mutant narrowed the candidates to three compounds exhibiting Cys-198-dependent interactions. These three peptidyl protease inhibitors, PFMK (Z-Ala-Phe-FMK), LEK (Z-Leu-EK), and EBLL (Ethylbenzyl-Leu-Lys) binds to ERM-BP-WT and abolishes the DNA-binding activity of ERM-BP in a concentration-dependent way. Cellular evaluation further revealed distinct activity of PFMK, LEK and EBLL on trophozoite growth and PFMK and EBLL reduced encystation efficiency significantly, produced irregular, and structurally defective cysts, which fails to excyst to trophozoites, whereas LEK had no significant effects on encystation efficiency or cyst morphology. Altogether, these findings identify peptidyl protease inhibitors PFMK and EBLL as promising compounds to target ERM-BP and block the Entamoeba encystation, providing a framework for developing therapeutics targeting parasite differentiation and encystation.

microbiology↗

bioRxiv2026

Region-Specific Delta and Alpha2 Relative Power Alterations in Male Adolescent Schizophrenia: Occipital Predominance in Resting-State EEG

Resting-state electroencephalography (EEG) studies consistently report increased slow-wave activity and reduced alpha power in schizophrenia. However, the regional distribution of EEG relative power (RP) across finer frequency bands, particularly in adolescent schizophrenia, remains poorly characterized. We analyzed a publicly available resting-state EEG dataset comprising 45 male adolescents with schizophrenia (SCZ; mean age: 12.3 {+/-} 1.2 years) and 39 age- and sex-matched healthy controls (CON; mean age: 12.3 {+/-} 1.3years), recorded using 16 scalp electrodes (10-20 system). Following band-pass filtering, artefact subspace reconstruction, spline interpolation, average re-referencing and independent component analysis, RP was computed for nine frequency bands across five cortical regions (frontal, central, parietal, temporal, and occipital). Group differences were assessed using three-way repeated-measures analysis of variance (ANOVA), followed by Bonferroni false discovery rate (FDR)-corrected post-hoc pairwise comparisons using estimated marginal means (emmeans). Compared to controls, the SCZ group showed significantly higher delta RP in the frontal, parietal, and occipital regions and significantly lower alpha2 RP, dissociable from alpha1, in the central, parietal, temporal, and occipital regions (all FDR < 0.001). The occipital cortex showed the greatest increase in delta RP (|Cohens d|=0.82) and the greatest reduction in alpha2 RP (|d|=0.73), with moderate-to-large effect sizes. Topographic maps demonstrated widespread delta enhancement and attenuated occipito-parietal alpha2 activity in the SCZ group. These findings demonstrate region-specific alterations in resting-state EEG relative power in adolescent schizophrenia, particularly within the occipital cortex, and suggest that regional RP may serve as a promising neurophysiological feature for early-onset schizophrenia. HighlightsO_LIResting-state EEG relative power was analyzed in adolescent schizophrenia. C_LIO_LIDelta relative power increased (occipital > parietal > frontal). C_LIO_LIAlpha2, but not alpha1, relative power decreased (occipital > parietal > temporal > central). C_LIO_LIOccipital cortex showed the largest EEG spectral abnormalities. C_LIO_LINine-band analysis improved regional spectral characterization. C_LI

neuroscience↗

bioRxiv2025

Structural insights into the mechanism of C3 side chain fragmentation in cephalosporins with SME-1 class A carbapenemase

Cephalosporins remain one of the largest classes of antibiotics used clinically, with a diverse group of dual substituents at C3 and C7 positions. The fragmentation of the C-3 side chain from the C3 position after hydrolysis by Serine or metallo-{beta} lactamase leaving an exo-methylene group has been introduced in the literature recently, but the exact mechnism by which it happens remains unclear until now. Our incrystallo findings suggest that the fragmentation of the C3 side chain will depend on the C3 atom and its hybridization state. A C3 carbon with sp2 hybridization will not allow fragmentation, but a sp3 hybridized carbon will facilitate the detachment of the side chain. Furthermore, heteroatoms like Sulfur, on C3 position, bearing vacant d-orbitals participate in {pi}-cloud delocalization, making the detachment of C3 side chain energetically unfeasible. For the sp3 hybridized carbon at C3, the fragmentation of the bond was independent of the C3 atom. We observed fragmentation of the C3-C3 bond for all three heteroatoms, Nitrogen, Oxygen, and sulfur, at the C3 position. We validated our crystallographic findings with mass spectrometry to confirm the fragmentation of the C3 side chain in sp3 carbon and the unfragmented side chain in sp2 carbon and sulfur at C3 position. QM/MM simulations on three types of enzyme-cephalosporin complexes with different C3 side chains confirm the mechanism of fragmentation. Beyond revealing C3 side chain fragmentation in cephalosporins, useful for inhibitor and diagnostic design, our QM/MM methods are useful on incrystallo complexes to show the enzyme catalysis.

biochemistry↗

bioRxiv2023

Calcitriol impairs the secretion of IL-4 and IL-13 in Th2 cells via modulating the transcription factors Gata3 and Gfi1

Calcitriol, the bioactive form of vitamin D, exerts its biological functions by binding to its cognate receptor VDR. The indicators of the severity of allergies and asthma have been linked to low vitamin D levels. However, the role of calcitriol in regulating IL-4 and IL-13; two cytokines pivotal to allergic inflammation, remained unclear. Our study observed a decrease in IL-4 and IL-13 secretion in murine and human Th2 cells, treated with calcitriol. In murine Th2 cells, Gata3 expression was attenuated by calcitriol. However, the expression of the transcriptional repressor Gfi1, that prevents Th1 fate of activated CD4+ T cells, too was attenuated in the presence of calcitriol. Ectopic expression of either Gfi1 or VDR impaired the secretion of IL-13 in Th2 cells. Gfi1 significantly impaired Il13 promoter activation; which calcitriol failed to restore. Ecr, a conserved region between the two genes, which enhanced the transactivation of Il4 and Il13 promoters; is essential for calcitriol-mediated suppression of both the genes. In murine Th2 cells, VDR interacted with Gata3 but not Gfi1. Calcitriol augmented the recruitment of VDR to the Il13 promoter and Ecr regions. Gata3 recruitment was significantly impaired at Il13 and Ecr locus in the presence of calcitriol but increased at Il4 promoter. However, in the presence of calcitriol, the overall recruitment of Gfi1 remained unchanged at Il4 but increased at Il13 locus in Th2 cells. Together, our study clearly elucidates that calcitriol modulates VDR, Gata3, and Gfi1 to suppress IL-4 and IL-13 production in Th2 cells. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=81 SRC="FIGDIR/small/569823v3_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@1557aaborg.highwire.dtl.DTLVardef@e8b1dcorg.highwire.dtl.DTLVardef@f505dcorg.highwire.dtl.DTLVardef@53b31c_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2022

The role of hippocampal CaMKII in resilience to trauma-related psychopathology

Traumatic stress exposure can form persistent trauma-related memories. However, only a minority of individuals develop post-traumatic stress disorder (PTSD) symptoms upon exposure. We employed a rat model of PTSD, which enables differentiating between exposed-affected and exposed-unaffected individuals. Two weeks after the end of exposure, animals were tested behaviorally, following an exposure to a trauma reminder, identifying them as trauma affected or unaffected. In light of the established role of hippocampal synaptic plasticity in stress and the essential role of Ca2+/calmodulin-dependent protein kinase II (CaMKII) in hippocampal based synaptic plasticity, in two separate experiments, we pharmacologically inhibited CaMKII or knocked-down CaMKII in the dorsal dentate gyrus of the hippocampus (dDG) following exposure to the same trauma paradigm. Both manipulations brought down the prevalence of affected individuals in the trauma- exposed population. A day after the last behavioral test, long-term potentiation (LTP) was examined in the dDG as a measure of synaptic plasticity. Trauma exposure reduced the ability to induce LTP, whereas, contrary to expectation, CaMKII-kd reversed this effect. Further examination revealed that reducing CaMKII expression, enables the formation of CaMKII-independent LTP, which may enable increased resilience in the face of a traumatic experience. The current findings further emphasize the pivotal role dDG has in stress resilience.

neuroscience↗

bioRxiv2022

Candidate genes associated with neurological manifestations of COVID-19: Meta-analysis using multiple computational approaches

COVID-19 develops certain neurological symptoms, the molecular pathophysiology of which is obscure. In the present study, two networks were constructed and their hub-bottleneck and driver nodes were evaluated to consider them as target genes followed by identifying candidate genes and their associations with neurological phenotypes of COVID-19. A tripartite network was first constructed using literature-based neurological symptoms of COVID-19 as input. The target genes evaluated therefrom were then used as query genes to identify the co-expressed genes from the RNA-sequence data of the frontal cortex of COVID-19 patients using pair-wise mutual information to genes. A combined gene network (CGN) was constructed with 189 genes selected from TN and 225 genes co-expressed in COVID-19. Total 44 target genes evaluated from both networks and their connecting genes in respective networks were analyzed functionally by measuring pair-wise semantic similarity scores (SSS) and finding Enrichr annotation terms against a set of genes. A new integrated weighted harmonic mean score was formulated using SSS and STRING-based combined score to select 21 gene-pairs among target genes that provided 21 candidate genes with their properties as indispensable driver nodes of CGN. Finally, six pairs providing seven prevalent candidate genes (ADAM10, ADAM17, AKT1, CTNNB1, ESR1, PIK3CA, FGFR1) exhibited direct linkage with the neurological phenotypes under tumour/cancer, cellular signalling, neurodegeneration and neurodevelopmental diseases. The other phenotypes under behaviour/cognitive and motor dysfunctions showed indirect associations with the former genes through other candidate genes. The pathophysiology of prevalent candidate genes has been discussed for better interpretation of neurological manifestation in COVID-19.

systems biology↗

bioRxiv2019

Parsers, Data Structures and Algorithms for Macromolecular Analysis Toolkit (MAT): Design and Implementation

The structural information of biological macromolecules are stored in .pdb, .mm-cif and lately mmtf files and thus it requires accurate and efficient biological tools for various utilities. Here, we describe Macromolecular Analysis Toolkit (MAT) that parses .pdb, .mmcif and .mmtf files; and builds data structures from the input. This original program is written in C++ programming language to ensure efficiency and consistency to organize structural information in an integral way. The novelty of the program lies in the addition of new structure-based biological algorithms and applications. This package also stands out from other similar libraries by being 1) faster and 2) accurate. We also provide detailed comparison of available parsers on the whole PDB database. The parser of MAT is designed in such a way that it allows quick extraction and organized loading of the core data structure. The same data structure is extended to accommodate information from the .mmcif and .mmtf file parsers. Tokenization of the data allows the extraction of information from disordered text, making it compatible for accurate identification of the entities present in the .pdb file. Additionally, we add a new approach of performance optimization by creating a few derived data structures, namely kD-Tree, Octree and graphs, for certain applications that need spatial coordinate calculations. MAT provides advanced data structure which is time efficient and is designed to avail reusability and consistency in a systematic framework. MAT parser can be accessed online through bitbucket at https://bitbucket.org/gazalk/pdb_parser/.

bioinformatics↗