Biology subjects

Debnath, S.

Publications and source records attributed to Debnath, S..

11 recordsLinked to original sources

bioRxiv2026

Neurogenic colonic motility patterns and gut transit disrupted in a mouse model of Rett Syndrome

Gastrointestinal dysfunction is a prominent feature of neurodevelopmental disorders and contributes significantly to visceral discomfort, but the specific etiology is unclear. In particular, it is unknown which cell types within central, autonomic or enteric nervous systems, gut muscle, epithelium or immune system are the principal drivers of gut dysfunction. We report that the Mecp2 mouse model of Rett syndrome, a neurodevelopmental disorder with profound gut dysmotility, exhibits impaired whole gut transit times and constipation in vivo as well as striking alterations to propagating neurogenic contractions in ex vivo colons. Selective elimination of Mecp2 in neurons, but not glia or smooth muscle, recapitulates these dysmotility phenotypes. Bulk RNA sequencing of colonic external muscle, containing the myenteric compartment of the enteric nervous system, showed significant expression changes in specific neurochemical signaling pathways. Pharmacological modulation of one, the M1 acetylcholine receptor, modified the aberrant neurogenic contractile phenotype in mutant mice and reproduced it in wild-type mice. These results identify disruptions to neuronal muscarinic signaling in the enteric nervous system in a mouse model of Rett syndrome and provide an experimental strategy to identify translationally relevant cellular and molecular pathways underlying gastrointestinal dysmotility in neurodevelopmental disorders.

physiology↗

bioRxiv2026

Systems-level analysis identifies IRF6 as an inhibitor of epithelial-mesenchymal transition

BackgroundEpithelial-mesenchymal transition (EMT) and its reverse process Mesenchymal-Epithelial Transition (MET) are crucial during metastasis and therapy resistance. While the dynamics and master regulators of EMT are well-studied, the transcription factors that can prevent EMT or promote MET are relatively less understood. ResultsHere, by integrating bulk and spatial transcriptomic data analysis from cell lines and patient samples, with mechanism-based dynamical modelling, we identify IRF6 as a factor that strongly associates with an epithelial phenotype and is often inhibited during EMT. In vitro experiments in multiple cancer cell lines demonstrate the progression to a mesenchymal phenotype upon IRF6 knock-down, suggesting a role as an inhibitor of EMT. Finally, we observe that IRF6 expression levels correlates with worse patient survival in a subset of solid tumour types. ConclusionOur integrated computational-experimental systems-level analysis suggests that IRF6 is frequently downregulated during EMT and can also prevent the progression towards a complete EMT, underscoring its role as an MET stabilizing factor.

systems biology↗

bioRxiv2025

A memory-driven model of phenotypic adaptation for anticipating the emergence of enzalutamide resistance in prostate cancer

While contemporary cancer treatment strategies have significantly prolonged the lives of patients, therapeutic resistance remains a predominant cause of disease progression and cancerrelated deaths. Cancer therapy often induces gene regulatory responses that promote cell survival in the face of this therapy. Herein, we sought to develop a stochastic model of the response to repeat therapeutic challenge. This model integrates reinforcement learning to account for environmental history-dependent cellular transitions and growth dynamics. When applied to prostate cancer, this memory-driven adaptive model successfully captures the experimentally-observed dynamics of drugsensitive and drug-resistant LNCaP cells under varying dosing schedules of androgen receptor blockade with enzalutamide (enza), significantly outperforming traditional transition models that lack history dependence. This performance is especially evident in the ability of our approach to robustly predict stochastic fluctuations in cancer cell population sizes across the entire disease trajectory, including subtle, later-emerging responses following initial therapy. The model was further evaluated by predicting the control of resistant cells in an enza environment by modeling inhibition of the p38/MAPK pro-survival stress axis, which was then validated experimentally. Lastly, we developed and applied a patient-calibrated model using prostate-specific antigen (PSA) data from clinical patient cohorts undergoing intermittent androgen deprivation therapy. Our model accurately predicts the PSA dynamics under repeated treatment cycles and effectively distinguishing between patients who respond and those who do not respond to treatment, thereby providing quantitative insight into prostate cancer progression. We anticipate that such adaptive modeling frameworks will be broadly useful for predicting cancer treatment outcomes and developing optimized adaptive therapeutic strategies tailored to patient-specific disease dynamics in additional cancer contexts.

evolutionary biology↗

bioRxiv2025

Quinolinic acid metabolism may mitigate AKI to CKD transition

The transition from acute kidney injury (AKI) to chronic kidney disease (CKD) remains a significant clinical problem with unclear underlying mechanisms. Emerging evidence suggests that alterations in tryptophan metabolism, particularly in the production of downstream metabolites such as quinolinic acid (QA), play a role in renal pathophysiology. QA is a NAD biosynthesis intermediate metabolized by the enzyme quinolinate phosphoribosyltransferase (QPRT). In this study, we investigated the role of QA in the AKI-to-CKD transition using experimental mouse models and clinical observations and leveraging multiple omics approaches. Systematic metabolomic profiling identified endogenous QA as one of the most significantly elevated metabolites following folic acid-(FA) induced injury. Exogenous QA exacerbated FA-induced kidney dysfunction. Conversely, aged mice deficient in QPRT showed worsened expression of kidney fibrosis markers even in absence of kidney injury, while younger littermates exhibited worsened induced kidney injury. Mice lacking QA-producing enzymes resisted experimental AKI and AKI-to-CKD progression. Multimodal spatial metabolomics analysis of human AKI kidney biopsies revealed QA accumulation in regions of inflammatory infiltration. Finally, children with CKD exhibited higher urinary QA levels compared to healthy controls. These findings underscore QA as a potential mediator of kidney injury and a therapeutic target for preventing the progression from AKI to CKD. One Sentence SummaryQuinolinic acid promotes kidney damage and fibrosis, suggesting it as a contributor of AKI-to-CKD progression and a potential therapeutic target.

pathology↗

bioRxiv2025

Longitudinal Characterization of Compound Action Potentials in Chronic Vagus Nerve Recordings in Mice

The vagus nerve (VN) mediates bidirectional communication between the body and brain to maintain physiological homeostasis; likewise, alterations in ongoing vagal signaling may be indicators of disease and/or contribute to disease pathogenesis. Even though extensively documented in acute experiments, ongoing vagal activity has not been characterized longitudinally, over days or weeks, in mice, a preferred preclinical model. In addition, even though many VN recordings in mice occur during anesthesia, the effects of anesthesia on vagal signaling are unknown. This study uses a chronic implant mouse model to record vagal activity in anesthetized and awake, behaving animals for an average of 10 weeks and up to 6 months. Individual compound action potentials (CAPs) are tracked across multiple days by quantifying comparisons in features, including firing rates, waveform shape, inter-CAP interval histograms, and phase-locking to cardiac and respiratory signals while demonstrating long-term electrode-nerve interface viability and stable signal-to-noise ratios. Additionally, cytokine challenge experiments produced detectable CAP responses up to 3 months after electrode implantation. Lastly, awake recordings incorporated video analysis to identify and remove motion artifacts to preserve and extract neural and cardiac recordings during behavior. Results reveal diverse CAP populations with diverse physiological coupling and firing rates modulated by anesthesia. This work highlights the potential of chronic VN recordings to assess long-term changes in vagal activity in health and disease, with implications in discovery of autonomic markers of disease and closed-loop VNS stimulation strategies.

neuroscience↗

bioRxiv2025

Future flooding tolerant rice germplasm: resilience afforded beyond Sub1A gene

Developing high-yielding, flood-tolerant rice varieties is essential for enhancing productivity and livelihoods in flood-prone ecologies. We explored genetic avenues beyond the well-known SUB1A gene to improve flood resilience in rice. We screened a collection of 6,274 elite genotypes from IRRIs germplasm repository for submergence and stagnant flooding tolerance over multiple seasons and years. This rigorous screening identified 89 outstanding elite genotypes, among which thirty-seven exhibited high submergence tolerance, surpassing the survival rate of SUB1A introgression genotypes by 40-50%. Thirty-five genotypes showed significant tolerance to stagnant flooding, and 17 demonstrated dual tolerance capabilities, highlighting their adaptability to varying flood conditions. The genotypes identified have a broader genetic diversity and harbor 86 key QTLs and genes related to traits such as grain quality, grain yield, herbicide resistance, and various biotic and abiotic traits, highlighting the richness of the identified elite collection. Besides germplasm, we introduce an innovative breeding approach called Transition from Trait to Environment (TTE). TTE leverages a parental pool of high-performing genotypes with complete submergence tolerance to drive population improvement and enable genomic selection in the flood breeding program. Our approach of TTE achieved a remarkable 65% increase in genetic gain for submergence tolerance, with the resulting fixed breeding genotypes demonstrating exceptional performance in flood-prone environments of India and Bangladesh. The elite genotypes identified herein represent invaluable genetic resources for the global rice research community. By adopting the TTE approach, which is trait agonistic, we establish a robust framework for developing more resilient genotypes using advanced breeding tools. Plain Language SummaryTo address climate challenges, an urgent focus is necessary to identify and develop flood-tolerant rice varieties, particularly for flood-prone ecosystems across Asia and Africa. We screened 6,274 elite genotypes from IRRIs germplasm and identified 89 promising lines with improved tolerance to submergence and stagnant flooding. Among these, 37 demonstrated 40-50% greater submergence tolerance than SUB1A introgression lines, 35 exhibited stagnant flooding tolerance, and 17 showed dual tolerance. These genotypes contain 86 key QTLs and genes associated with yield, grain quality, and biotic and abiotic tolerance traits. A new breeding strategy, the Transition from Trait to Environment (TTE) approach, was developed. We achieved a genetic gain of 65% for submergence tolerance in rice using this method. The newly identified germplasm provides invaluable genetic resources for the global rice research community to develop flood-tolerant rice genotypes. Core ideas The SUB1A gene, enabling rice to survive underwater for 14 days, marked a significant breakthrough. We have identified elite genotypes with submergence tolerance significantly surpassing the SUB1A gene-mediated tolerance. The diverse elite genotypes identified harbor 86 key genes and QTLs that affect various traits positively. Developed a unique breeding strategy for implementing population improvement in challenging environments. The new breeding strategy demonstrated a genetic gain of 65% for submergence tolerance.

plant biology↗

bioRxiv2024

H105A peptide eye drops promote photoreceptor survival in murine and human models of retinal degeneration

Photoreceptor death causes blinding inheritable retinal diseases, such as retinitis pigmentosa (RP). As disease progression often outpaces therapeutic advances, finding effective treatments is urgent. This study focuses on developing a targeted approach by evaluating the efficacy of small peptides derived from pigment epithelium-derived factor (PEDF), known to restrict common cell death pathways associated with retinal diseases. Peptides with affinity for the PEDF receptor, PEDF-R, (17-mer and H105A) delivered via eye drops reached the retina, efficiently promoted photoreceptor survival, and improved retinal function in RP mouse models based on both the rd10 mutation and the rhodopsin P23H mutation. Additionally, intravitreal delivery of AAV-H105A vectors delayed photoreceptor degeneration in the latter RP mouse model. Furthermore, peptide H105A specifically prevented photoreceptor death induced by oxidative stress, a contributing factor to RP progression, in human retinal organoids. This promising approach for peptide eye drop delivery holds significant potential as a therapeutic for preventing photoreceptor death in retinal disorders, offering a high safety profile, low invasiveness and multiple delivery options. One Sentence SummaryNeurotrophic PEDF peptides delivered as eye drops preserve photoreceptor viability, morphology, and function in models of human retinal diseases.

neuroscience↗

bioRxiv2024

Quinolinic acid links kidney injury to brain toxicity

Kidney dysfunction often leads to neurological impairment, yet the complex kidney-brain relationship remains elusive. We employed spatial and bulk metabolomics to investigate a mouse model of rapid kidney failure induced by mouse double minute 2 (Mdm2) conditional deletion in the kidney tubules to interrogate kidney and brain metabolism. Pathway enrichment analysis of focused plasma metabolomics panel pinpointed tryptophan metabolism as the most altered pathway with kidney failure. Spatial metabolomics showed toxic tryptophan metabolites in the kidneys and brains, revealing a novel connection between advanced kidney disease and accelerated kynurenine degradation. In particular, the excitotoxic metabolite quinolinic acid was localized in ependymal cells adjacent to the ventricle in the setting of kidney failure. These findings were associated with brain inflammation and cell death. A separate mouse model of acute kidney injury also had an increase in circulating toxic tryptophan metabolites along with altered brain inflammation. Patients with advanced CKD similarly demonstrated elevated plasma kynurenine metabolites and quinolinic acid was uniquely correlated with fatigue and reduced quality of life in humans. Overall, our study identifies the kynurenine pathway as a bridge between kidney decline, systemic inflammation, and brain toxicity, offering potential avenues for diagnosis and treatment of neurological issues in kidney disease.

molecular biology↗

bioRxiv2024

Effects of Feed Processing Type, Protein Source, and Environmental Salinity on Litopenaeus vannamei Feeding Behaviour

In an 8-week trial, the effects of feed processing types (extruded vs. steamed pellets) and protein source (soya/pea vs. fish meal) on Litopenaeus vannamei were studied under 30 ppt (first 30 days) and 5 ppt (last 15 days) salinity conditions. Diets included D1-SE soya/pea extruded, D2-SS soya/pea steamed, D3-FE fishmeal extruded, and D4 (FS) fishmeal steamed pellets. No significant weight differences were observed. Survival rates (80-97% at 30 ppt) decreased at reduced salinity and were significantly higher for shrimp fed steamed pellets (D2:80.00%, D4:76.67%) compared to extruded (D1: 50.00%, p<0.05). Shrimp fed D2-SS and D4-FS diets had increased lipid content (6.79%, 6.36%, p<0.05). Significantly lower lysine and isoleucine were noted in D2-SS. Behaviourally, at 30 ppt, D3-FE attracted significantly more shrimp (84.72%) than D1-SE (74.49%) and D2-SS (75.70%, p<0.05). Click analysis showed D1-SE and D2-SS with the shortest durations (17.97, 17.24ms, respectively), and D3-FE and D4-FS the longest (20.10, 23.89ms, respectively, p<0.05). Click frequency was also significantly higher in fishmeal-based diets, whereas the number of clicks was higher in shrimp fed extruded feed. Overall, extruded pellets and fishmeal diets were more favourable. These findings emphasize the importance of tailored feed strategies that consider nutritional content, feed physical properties and environmental factors for optimal shrimp feeding.

zoology↗

bioRxiv2020

A method to quantify autonomic nervous system function in healthy, able-bodied individuals

The autonomic nervous system (ANS), which maintains physiological homeostasis in various organ systems via parasympathetic and sympathetic branches, is altered in common diffuse and focal conditions. Sensitive, quantitative biomarkers could detect changes in ANS function, first here in healthy participants and eventually in patients displaying dysautonomia. This framework combines controlled autonomic testing with feature extraction from physiological responses. Twenty-one individuals were assessed in two morning and two afternoon sessions over two weeks. Each session included five standard clinical tests probing autonomic function: squat test, cold pressor test, diving reflex test, deep breathing, and Valsalva maneuver. Noninvasive sensors captured continuous electrocardiography, blood pressure, breathing, electrodermal activity, and pupil diameter. Heart rate, heart rate variability, mean arterial pressure, electrodermal activity, and pupil diameter responses to the perturbations were extracted, and averages across participants were computed. A template matching algorithm calculated scaling and stretching features that optimally fit the average to an individual response. These features were grouped based on test and modality to derive sympathetic and parasympathetic indices for this healthy population. A significant positive correlation (p = 0.000377) was found between sympathetic amplitude response and body mass index. Additionally, longer duration and larger amplitude sympathetic and longer duration parasympathetic responses occurred in afternoon testing sessions; larger amplitude parasympathetic responses occurred in morning sessions. These results demonstrate the robustness and sensitivity of an algorithmic approach to extract multimodal responses from standard tests. This novel method of quantifying ANS function can be used for early diagnosis, measurement of disease progression, or treatment evaluation.

bioengineering↗

bioRxiv2020

COVID19: Exploring uncommon epitopes for a stable immune response through MHC1 binding

The COVID19 pandemic has resulted in 1,092,342 deaths as of 14th October 2020, indicating the urgent need for a vaccine. This study highlights novel protein sequences generated by shot gun sequencing protocols that could serve as potential antigens in the development of novel subunit vaccines and through a stringent inclusion criterion, we characterized these protein sequences and predicted their 3D structures. We found distinctly antigenic sequences from the SARS-CoV-2 that have led to identification of 4 proteins that demonstrate an advantageous binding with Human leukocyte antigen-1 molecules. Results show how previously unexplored proteins may serve as better candidates for subunit vaccine development due to their high stability and immunogenicity, reinforce by their HLA-1 binding propensities and low global binding energies. This study thus takes a unique approach towards furthering the development of vaccines by employing multiple consensus strategies involved in immuno-informatics technique.

bioinformatics↗