Biology subjects

Bhattacharya, M.

Publications and source records attributed to Bhattacharya, M..

At least 19 recordsLinked to original sources

bioRxiv2025

Non-Optimal Codon Usage Shapes Cell Cycle Regulators: Codon Optimization Studies on CDK1 and NUF2

The expression and functions of genes are largely dependent on genome integrity and stability. Codon usage plays a significant role in maintaining stability and functions of genes. Perturbation in codon sequence can lead to functional and structural dysfunction of a gene. In our study, we performed the codon usage analyses of cell cycle-dependent genes. Various codon usage parameters analyzed using nucleotide compositions like RSCU, ENC, and GC analyses showed that cell cycle dependent genes follow non-optimal codon usage. Genes preferred AT-rich ending over GC-rich ending, thereby suggesting preference for non-optimal codons. Neutrality and parity plot showed that the codon preference is a result of mutation selection pressure. To study the codon usage implications, we optimized the codons of cell cycle dependent genes (CDK1 and NUF2) to study their effects on cell cycle and apoptosis in vitro. We observed that codon optimization alters the cell cycle length in cell cycle-dependent genes impacting cell fate and survival. Our studies revealed that codon usage preferences directly affect the stability of both mRNA and proteins. Specifically, genes and proteins with non-optimal codons exhibited reduced stability compared to their optimized counterparts, suggesting critical implications for cell cycle regulation and apoptosis.

molecular biology↗

bioRxiv2025

Accounting for longitudinal peak quality metrics with MSstats+ enhances differential analysis in proteomic experiments with data-independent acquisition

Mass spectrometry-based proteomics with data-independent acquisition benefits from advanced instrumentation and computational analysis. Despite continued improvements, the quality of quantification may be poor for some measurements. As the scale of proteomic experiments increases, these poor-quality measurements are challenging to characterize by hand, yet they undermine the detection of differentially abundant proteins and the downstream biological conclusions. We introduce MSstats+, a computational workflow that takes as input not only peak intensities reported by tools such as Spectronaut, but also quality metrics such as peak shape and retention time, and longitudinal run order profiles of these metrics. MSstats+ translates these metrics into a single measure of quality, and downweights poor quality measurements when detecting differentially abundant proteins. The method offers a natural treatment of missing values, weighting the imputed values according to the quality metrics in the run. We demonstrate the accuracy of the resulting differential analysis in four experiments: two custom benchmarking studies with intentionally induced anomalies, a controlled mixture of proteomes, and a large-scale clinical investigation. MSstats+ is implemented in the family of open-source R/Bioconductor packages MSstats.

bioinformatics↗

bioRxiv2025

What's next for Indian Ornithology? 101 key research questions

India has a rich history of ornithology, and bird research in this field has expanded considerably in recent decades, spurred by a growing number of birdwatchers and ornithologists. Despite this progress, critical gaps remain. This paper highlights key areas where further research is needed and identifies pressing questions that will shape Indian ornithology in the coming years. Drawing from diverse inputs, we present a curated list of 101 research questions spanning across the various disciplines in ornithology - Natural History, Physiology and Disease Ecology, Behaviour, Population and Community Ecology, Habitat Ecology, Macroecology and Biogeography, Population Genetics and Evolution, Applied/Economic Ornithology and Conservation. The list was compiled through a multi-stage process, starting with a public open call for questions, followed by review and curation by a smaller panel of subject specialists. Each question was independently scored by a panel of experts based on three criteria: generality, novelty, and relevance. To account for variation in scoring styles, scores were normalised using Z-scores. The top 101 research questions were then selected based on these standardised scores. Each question is accompanied by an annotation that describes the significance of the question, and highlights opportunities to address it. While our list of research questions highlights significant research priorities, it is not intended to be exhaustive. Rather, it reflects the perspectives of those involved in its curation, who deemed these questions particularly relevant and impactful towards advancing Indian ornithology. We expect these questions to spark new project ideas among students, researchers, and citizen scientists, while guiding funders, managers, and policymakers toward priority research areas.

ecology↗

bioRxiv2025

Cellular profiling identifies an early profibrotic alveolar type 2 cell signature in lung fibrosis

RationaleIdiopathic pulmonary fibrosis (IPF) is a progressive, age-associated, lung disease characterized by short telomeres in alveolar type 2 (AT2) cells, epithelial remodeling, and fibrosis. ObjectivesThis study investigated how telomere dysfunction in AT2 cells lacking Telomere Repeat Binding Factor 1 (TRF1) drives lung remodeling in SPC-creTRF1flox/flox mice and its relevance to IPF. MethodsMouse model of telomere dysfunction was used to conditionally delete TRF1 in AT2 cells. SPC-creTRF1flox/flox mouse lung epithelial cells were used to perform single cell RNA sequencing. AT2 cells from IPF lungs were analyzed by single cell RNA sequencing in an organoid model. Measurements and Main ResultsSingle cell RNA-sequencing revealed distinct pathological AT2 cells enriched in DNA damage, senescence, oxidative stress, and pro-fibrotic genes, along with fewer "normal" AT2 cells and increased club cells in SPC-creTRF1flox/flox mice. Pathological AT2 cells showed different early and late-stage gene signatures, with a prominent p53 signature at both time-points. Genetic deletion of p53 in SPC-creTRF1flox/flox AT2 cells improved survival and prevented lung fibrosis. p53 deletion or inhibition improved organoid formation, surfactant protein C expression, and reduced pro-fibrotic gene expression in AT2 cells isolated from SPC-creTRF1flox/flox mice or IPF lungs. ConclusionsThese data suggest that the DNA damage response to AT2 cell telomere dysfunction, driven by enhanced p53 activity, mediates early AT2 cell transdifferentiation and senescence, leading to epithelial cell remodeling and fibrosis and that reversing this reprogramming is a potential therapeutic approach for managing IPF.

cell biology↗

bioRxiv2024

Matrix porosity is associated with Staphylococcus aureus biofilm survival during prosthetic joint infection

Biofilms are a cause of chronic, non-healing infections. Staphylococcus aureus is a proficient biofilm forming pathogen commonly isolated from prosthetic joint infections that develop following primary arthroplasty. Extracellular adhesion protein (Eap), previously characterized in planktonic or non-biofilm populations as being an adhesin and immune evasion factor, was recently identified in the exoproteome of S. aureus biofilms. This work demonstrates that Eap and its two functionally orphaned homologs EapH1 and EapH2, contribute to biofilm structure and prevent macrophage invasion and phagocytosis into these communities. Biofilms unable to express Eap proteins demonstrated increased porosity and reduced biomass. We describe a role for Eap proteins in vivo using a mouse model of S. aureus prosthetic joint infection. Results suggest that the protection conferred to biofilms by Eap proteins is a function of biofilm structural stability that interferes with the leukocyte response to biofilm-associated bacteria.

microbiology↗

bioRxiv2024

Polymicrobial interactions between Staphylococcus aureus and Pseudomonas aeruginosa promote biofilm formation and persistence in chronic wound infections

Chronic, non-healing wounds are a leading cause of prolonged patient morbidity and mortality due to biofilm-associated, polymicrobial infections. Staphylococcus aureus and Pseudomonas aeruginosa are the most frequently co-isolated pathogens from chronic wound infections. Competitive interactions between these pathogens contribute to enhanced virulence, persistence, and antimicrobial tolerance. P. aeruginosa utilizes the extracellular proteases LasB, LasA, and AprA to degrade S. aureus surface structures, disrupt cellular physiology, and induce cell lysis, gaining a competitive advantage during co-infection. S. aureus evades P. aeruginosa by employing aggregation mechanisms to form biofilms. The cell wall protein SasG is implicated in S. aureus biofilm formation by facilitating intercellular aggregation upon cleavage by an extracellular protease. We have previously shown that proteolysis by a host protease can induce aggregation. In this study, we report that P. aeruginosa proteases LasA, LasB, and AprA cleave SasG to induce S. aureus aggregation. We demonstrate that SasG contributes to S. aureus biofilm formation in response to interactions with P. aeruginosa proteases by quantifying aggregation, SasG degradation, and proteolytic kinetics. Additionally, we assess the role of SasG in influencing S. aureus biofilm architecture during co-infection in vivo, chronic wound co-infections. This work provides further knowledge of some of the principal interactions that contribute to S. aureus persistence within chronic wounds co-infected with P. aeruginosa, and their impact on healing and infection outcomes.

microbiology↗

bioRxiv2024

Collagen binding adhesin restricts Staphylococcus aureus skin infection

Staphylococcus aureus causes approximately 80% of skin and soft tissue infections (SSTIs). Collagen is the most abundant human extracellular matrix protein with critical roles in wound healing, and S. aureus encodes a collagen binding adhesin (Cna). The role of this protein during skin infections is unknown. Here we report that inability to bind collagen results in worsened pathology of intradermal {Delta}cna S. aureus infection. WT/Cna+ S. aureus showed reduced infection severity, aggregate formation, and significantly improved clearance of bacteria. Cna binds to the collagen-like domain of serum C1q protein to reduce its opsonophagocytic functions. We demonstrate that infection of C1qKO mice with WT bacteria show results similar to the {Delta}cna group. Conversely, inability to bind collagen resulted in an amplified inflammatory response caused in part by macrophage and neutrophil small molecule mediators released at the infection site (MMP-9, MMP-12, LTB4), resulting in increased immune cell infiltration and death.

microbiology↗

bioRxiv2024

Deep Profiling of Plasma Proteoforms with Engineered Nanoparticles for Top-down Proteomics

The dynamic range challenge for detection of proteins and their proteoforms in human plasma has been well documented. Here, we use the nanoparticle protein corona approach to enrich low-abundant proteins selectively and reproducibly from human plasma and use top-down proteomics to quantify differential enrichment for the 2841 detected proteoforms from 114 proteins. Furthermore, nanoparticle enrichment allowed top-down detection of proteoforms between [~]1 {micro}g/mL and [~]10 pg/mL in absolute abundance, providing up to 105-fold increase in proteome depth over neat plasma in which only proteoforms from abundant proteins (>1 {micro}g/mL) were detected. The ability to monitor medium and some low abundant proteoforms through reproducible enrichment significantly extends the applicability of proteoform research by adding depth beyond albumin, immunoglobins and apolipoproteins to uncover many involved in immunity and cell signaling. As proteoforms carry unique information content relative to peptides, this report opens the door to deeper proteoform sequencing in clinical proteomics of disease or aging cohorts.

biochemistry↗

bioRxiv2024

Improving allele-specific epigenomic signal coverage by 10-fold using Hidden Markov Modeling and Machine Learning

Allele-specific epigenomic signals refer to differences in epigenomic patterns between the two copies, or "alleles," of a DNA region inherited from each parent. Epigenomic patterns are defined as alterations of the DNA sequence (e.g., chemical) without modifying the underlying DNA sequence (which would be referred to as "mutations"). Mapping allele-specific epigenomic signals across a genome is crucial, as some can influence gene expression, disease susceptibility, and developmental processes. However, identifying allele-specific epigenomic patterns across an entire genome is limited by the average read length (50-150 nucleotides) of short-read sequencing technologies, which are the most widely-used and affordable whole genome sequencing methods, and by the 99.9% similarity in the DNA sequences inherited from each parent. These limitations restrict the assessment of allele-specific signals to approximately 10% of the genome, potentially overlooking critical regulatory regions. In this paper, we present a highly effective machine-learning approach based on variational hidden Markov modeling, which enables the detection of allele-specific epigenomic signals across the entire genome, resulting in a 10-fold improvement in genomic coverage compared to state-of-the-art methods. We demonstrate our method on DNA methylation, a critical epigenomic regulatory signal.

genomics↗

bioRxiv2024

Androgens at the skin surface regulate S. aureus pathogenesis through the activation of agr quorum sensing

Staphylococcus aureus, the most frequent cause of skin infections, is more common in men than women and selectively colonizes the skin during inflammation. Yet, the specific cues that drive infection in these settings remain unclear. Here we show that the host androgens testosterone and dihydrotestosterone promote S. aureus pathogenesis and skin infection. Without the secretion of these hormones, skin infection in vivo is limited. Testosterone activates S. aureus virulence in a concentration dependent manner through stimulation of the agr quorum sensing system, with the capacity to circumvent other inhibitory signals in the environment. Taken together, our work defines a previously uncharacterized inter-kingdom signal between the skin and the opportunistic pathogen S. aureus and identifies the mechanism of sex-dependent differences in S. aureus skin infection. One-Sentence SummaryTestosterone promotes S. aureus pathogenesis through activation of the agr quorum sensing system.

microbiology↗

bioRxiv2023

Reciprocal inflammatory signals establish profibrotic cross-feeding metabolism

Idiopathic pulmonary fibrosis (IPF) is a disease of progressive lung remodeling and collagen deposition that leads to respiratory failure. Myeloid cells are abundant in IPF lung and in murine lung fibrosis, but their functional effects are incompletely understood. Using mouse and human lung models, we show that ornithine produced by myeloid cells expressing Arg1 serves as a substrate for proline and collagen synthesis by lung fibroblasts. The predominant Arg1-expressing myeloid cells in mouse lung were macrophages, but in IPF lung, high-dimensional imaging revealed ARG1 to be expressed mainly in neutrophils. Arg1 inhibition suppressed both ornithine levels and collagen expression in cultured, precision-cut IPF lung slices and in murine lung fibrosis. These results were confirmed in macrophage-specific Arg1 KO mice. Furthermore, we find that this pathway is regulated by cell-to-cell crosstalk, starting with purinergic signaling: Fibroblast eATP receptor P2rx4 was necessary for fibroblast IL-6 expression, which in turn was necessary for Arg1 expression by myeloid cells. Taken together, our findings define an immune-mesenchymal circuit that governs profibrotic metabolism in lung fibrosis.

immunology↗

bioRxiv2022

Human endometrial KISS1R inhibits stromal cell decidualization in a manner associated with a reduction in ESR1 levels

Defective endometrial stromal cell decidualization is a major cause of recurrent implantation failure (RIF), a condition with a prevalence of [~]15%. To treat RIF, a stronger understanding of the endometrial factors that regulate decidualization is required. Here we studied the role of the kisspeptin receptor (KISS1R) in regulating human endometrial stromal cell (HESC) decidualization. Our data revealed KISS1R inhibits HESC decidualization in vitro in a manner associated with a striking reduction in ESR1 protein levels. To determine whether KISSR inhibition of decidualization results from reduced ESR1 levels we expressed the dominant negative ESR1-46 isoform in decidualizing HESCs. We found that expression of ESR1-46 in decidualizing HESCs ablated the expression of ESR1-66 and ESR1-54 isomers, and blocked decidualization. Interestingly, when ESR1-64 was co-expressed with ESR1-46, ESR1-66 and ESR1-54 expression was restored and decidualization was rescued. Taken together, these results suggest that KISS1R inhibits HESC decidualization by downregulating ESR1 levels. Based on our findings, we suggest that by inhibiting HESC decidualization, KISS1R regulates the depth of embryo invasion of the stroma, a requirement for a successful pregnancy.

cell biology↗

bioRxiv2022

Rewiring Dynamics of Functional Connectome in Motor Cortex during Motor Skill Learning

The brains connectome continually rewires throughout the life of an organism. In this study, we sought to elucidate the operational principles of such rewiring by analyzing the functional connectomes in mouse primary motor cortex (M1) during a 14-session (day) lever-press task learning in response to an auditory cue. Specifically, we employed Calcium imaging recordings of L2/3 and L5 of M1 in awake mice to reconstruct and analyze functional connectomes across learning sessions. Our results show that functional connectomes in L2/3 and L5 follow a similar learning-induced rewiring trajectory. More specifically, the connectomes rewire in a biphasic manner, where functional connectivity increases over the first few learning sessions, and then, it is gradually pruned to return to a homeostatic level of network density. We demonstrated that the increase of network connectivity in L2/3 connectomes, but not in L5, generates neuronal co-firing activity that correlates with higher motor performance (shorter cue-to-reward time), while motor performance remains relatively stable throughout the pruning phase. The results show a biphasic rewiring principle that involves the maximization of reward / performance and maintenance of network density. Finally, we demonstrated that the connectome rewiring in L2/3 is clustered around a core set of movement-associated neurons that form a highly interconnected hub in the connectomes, and that the activity of these core neurons stably encodes movement throughout learning. Significance StatementConnectomes in the motor cortex rewire during motor skill learning, but the operational principle behind this rewiring is yet to be determined. Here, we characterized the rewiring dynamics of functional connectomes in L2/3 and L5 of M1 in mice engaging in a lever-press learning, using two-photon fluorescence microscopy data. We identified a universal biphasic rewiring trajectory across animals and layers in the motor cortex that reflects two objectives: an exploratory phase that increases functional connectivity and optimizes motor performance, and a pruning phase that brings connectivity back to a homeostatic level while maintaining motor performance. We found further that connectome rewiring during motor skill learning concentrates around a core set of highly interconnected neurons in L2/3 that reliably encode movements.

neuroscience↗

bioRxiv2021

Molecular programs of fibrotic change in aging human lung

Aging is associated with both overt and subclinical lung fibrosis, which increases risk for mortality from viruses and other respiratory pathogens. The molecular programs that induce fibrosis in the aging lung are not well understood. To overcome this knowledge gap, we undertook multimodal profiling of distal lung samples from healthy human donors across the lifespan. Telomere shortening, a cause of cell senescence and fibrosis, was progressive with age in a sample of 86 lungs and was associated with foci of DNA damage. Bulk RNA sequencing confirmed activation of cellular senescence and pro-fibrotic pathways as well as genes necessary for collagen processing with increasing age. These findings were validated in independent datasets for lung and sun-exposed skin, but not other organs including heart, liver and kidney. Cell type deconvolution analysis revealed a progressive loss of lung epithelial cells and an increasing proportion of fibroblasts. Consistent with the observed pro-fibrotic transcriptional profile, second harmonic imaging demonstrated increased density of interstitial collagen in aged human lungs. Furthermore, regions of parenchymal fibrosis were associated with decreased alveolar expansion and surfactant secretion. These findings reveal the transcriptional and structural features of fibrosis and associated physiologic impairments in normal lung aging.

genomics↗

bioRxiv2020

In silico analyses on the comparative sensing of SARS-CoV-2 mRNA by intracellular TLRs of human

The worldwide outbreak of COVID-19 pandemic caused by SARS-CoV-2 leads to loss of mankind and global economic stability. The continuous spreading of the disease and its pathogenesis takes millions of lives of peoples and the unavailability of appropriate therapeutic strategy makes it much more severe. Toll-like receptors (TLRs) are the crucial mediators and regulators of host immunity. The role of several TLRs in immunomodulation of host by SARS-CoV-2 is recently demonstrated. However, the functionality of human intracellular TLRs including TLR3,7,8 and 9 is still being untested for sensing of viral RNA. This study is hoped to rationalize the comparative binding and sensing of SARS-CoV-2 mRNA towards the intracellular TLRs, considering the solvent-based force-fields operational in the cytosolic aqueous microenvironment that predominantly drive these reactions. Our in-silico study on the binding of all mRNAs with the intracellular TLRs shown that the mRNA of NSP10, S2, and E proteins of SARS-CoV-2 are potent enough to bind with TLR3, TLR9, and TLR7 and trigger downstream cascade reactions, and may be used as an option for validation of therapeutic option and immunomodulation against COVID-19.

bioinformatics↗

bioRxiv2020

FARCI: Fast and Robust Connectome Inference

The inference of neuronal connectome from large-scale neuronal activity recordings, such as two-photon Calcium imaging, represents an active area of research in computational neuroscience. In this work, we developed FARCI (Fast and Robust Connectome Inference), a MATLAB package for neuronal connectome inference from high-dimensional two-photon Calcium fluorescence data. We employed partial correlations as a measure of the functional association strength between pairs of neurons to reconstruct a neuronal connectome. We demonstrated using gold standard datasets from the Neural Connectomics Challenge (NCC) that FARCI provides an accurate connectome and its performance is robust to network sizes, missing neurons, and noise levels. Moreover, FARCI is computationally efficient and highly scalable to large networks. In comparison to the best performing algorithm in the NCC, FARCI produces more accurate networks over different network sizes and subsampling, while providing over two orders of magnitude faster computational speed.

neuroscience↗

bioRxiv2020

'Phase Zero' clinical study platform combining broadband Vis/near-infrared spectroscopy and electrophysiology to study human brain organoid models of neurodevelopmental disorders

Homeostatic control of neuronal excitability by modulation of synaptic inhibition (I) and excitation (E) of the principal neurons is important during brain maturation. The fundamental features of in-utero brain developmental, including local synaptic E-I ratio and bioenergetics, can be modeled by cerebral organoids (CO) that have exhibited highly regular nested oscillatory network events. Therefore, we evaluated a Phase Zero clinical study platform combining broadband Vis/near-infrared(NIR) spectroscopy and electrophysiology to study E-I ratio based on the spectral exponent of local field potentials and bioenergetics based on the activity of mitochondrial Cytochrome-C Oxidase (CCO). We found a significant effect of the age of the healthy controls iPSC CO from 23 days to 3 months on the CCO activity ({chi}2(2,N=10)=20,p=4.5400e-05), and spectral exponent between 30-50Hz ({chi}2(2,N=16)=13.88,p=0.001). Also, a significant effect of drugs, choline (CHO), idebenone (IDB), R-alpha-lipoic acid plus acetyl-L-carnitine (LCLA), was found on the CCO activity ({chi}2(3,N=10)=25.44,p = 1.2492e-05), spectral exponent between 1-20Hz ({chi}2(3,N=16)=43.5,p=1.9273e-09) and 30-50Hz ({chi}2(3,N=16)=23.47, p=3.2148e-05) in 34 days old CO from schizophrenia (SCZ) patients iPSC. We present a multidimensional approach combining electrophysiology and Vis-NIR spectroscopy to complement traditional drug design approaches that can advance the system towards a normative parameter space.

bioengineering↗

bioRxiv2020

Functional near-infrared spectroscopy in conjunction with electroencephalography of cerebellar transcranial direct current stimulation responses in the latent neurovascular coupling space a chronic stroke study

Cerebellar transcranial direct current stimulation (ctDCS) can facilitate motor learning; however, ctDCS effects have not been investigated using portable neuroimaging vis-a-vis lobular electric field strength. This is important since the subject-specific residual architecture for cerebellar interconnections with the cerebral cortex, including the prefrontal cortex (PFC) and the sensorimotor cortex (SMC), can influence the ctDCS effects on the cerebral functional activation. In this study, we investigated functional near-infrared spectroscopy (fNIRS) in conjunction with electroencephalography (EEG) to measure the changes in the brain activation at the PFC and the SMC following virtual reality (VR)-based Balance Training (VBaT), before and after ctDCS treatment in 12 hemiparetic chronic stroke survivors. Furthermore, we performed general linear modeling (GLM) that can putatively associate the lobular electric field strength due to ctDCS priming with the changes in the fNIRS-EEG measures in the chronic stroke survivors. Here, fNIRS-EEG based measures were investigated in their latent space found using canonical correlation analysis (CCA) that is postulated to capture neurovascular coupling. We found that the ctDCS electrode montage, as well as the state (pre-intervention, during intervention, post-intervention), had a significant (p<0.05) effect on the changes in the canonical scores of oxy-hemoglobin (O2Hb) signal measured with fNIRS. Also, skill acquisition during first exposure to VBaT decreased the activation (canonical score of O2Hb) of PFC of the non-lesioned hemisphere in the novices at their first exposure before the ctDCS intervention. Moreover, ctDCS intervention targeting the leg representation in the cerebellum led to a decrease in the canonical scores of O2Hb at the lesioned SMC, which is postulated to be related to the cerebellar brain inhibition. Furthermore, ctDCS electrode montage, as well as the state, had a significant (p<0.05) interaction effect on the canonical scores of log10-transformed EEG bandpower. Our current study showed the feasibility of fNIRS-EEG imaging of the ctDCS responses in the latent neurovascular coupling space that can not only be used for monitoring the dynamical changes in the brain activation associated with ctDCS-facilitated VBaT, but may also be useful in subject-specific current steering for tDCS to target the cerebral fNIRS-EEG sources to reduce inter-individual variability.

neuroscience↗