Biology subjects

Krishna, V.

Publications and source records attributed to Krishna, V..

11 recordsLinked to original sources

bioRxiv2026

Relaxin-3 neurons of the zebrafish periaqueductal gray mediate behavioral responses evoked by darkness

Ambient illumination influences many aspects of brain function, including responses to threats. One brain region proposed to mediate these effects is the periaqueductal gray (PAG), an evolutionarily conserved midbrain structure that contains multiple subpopulations of peptidergic neurons. Here we ask which cell types in the larval zebrafish PAG respond to changes in ambient illumination. By registering post hoc gene expression to neurons recorded during exposure to sensory stimuli, we show that GABAergic PAG neurons expressing the neuropeptide Relaxin-3 (rln3a+) are persistently activated by darkness, while a neighboring subpopulation of GABAergic PAG neurons expressing penka is not. Zebrafish lacking rln3a show a reduction in locomotion during darkness. We propose that darkness recruits Relaxin-3-releasing PAG neurons to promote vigilance and potentiate defense circuits. These results identify a specific peptidergic population of PAG neurons that are potentially relevant to behavioral state dysregulation associated with excessive darkness.

neuroscience↗

bioRxiv2025

SimulScan and Partial Least Squares: Visualizing swallowing through functional and dynamic imaging correlations

PurposeSwallowing is a complex function involving the precise coordination of muscles, nerves, and brain areas, and can be disrupted in a variety of neurological conditions. Current imaging studies to visualize the central control of swallowing cannot examine both the biomechanics of the swallow and the brain activity associated with swallow events. An updated version of SimulScan is introduced that provides high-quality and high-speed dynamic imaging, together with fMRI acquisitions, to enable data-driven analysis of swallowing function through a partial least squares correlation (PLSC) analysis. MethodsIntegrating updated dynamic imaging approaches, SimulScan can achieve dynamic MRI at 23.75 frames per second and BOLD fMRI at a 1.6 s TR. Five subjects were recruited and scanned with SimulScan twice and with videofluoroscopy to compare the preliminary reliability of measuring swallowing biomechanics and the test-retest relationship in correlated functional and dynamic components of PLSC. ResultsHigh reliability of biomechanical measures of swallowing were achieved across the two SimulScan runs. In addition, these showed moderate correlation with videofluorscopy measures. Correlations between dynamic and functional imaging across runs also showed high reliability indicating that SimulScan with PLSC can extract maps of linked correlations between the brain and the oropharyngeal region. ConclusionThe updated version of SimulScan with PLSC analysis enables the study of central control of swallowing, providing simultaneous biomechanical visualization of the swallow along with brain functional signals.

neuroscience↗

bioRxiv2025

Hydrogen Sulfide Suppresses Keratinocyte Migration in Scratch Assay

Cell migration is crucial for maintaining physiological functions in the body and is driven by mechanical, electrical, or chemical stimuli. Hydrogen sulfide (H2S), a gaseous signaling molecule, has been shown to regulate cellular migration in a cell type and context-dependent manner. Keratinocytes are the predominant cell-type in the epidermis and drive re-epithelialization during wound healing. However, the effect of H2S on keratinocyte migration remains incompletely defined. Here, we demonstrate that H2S suppresses keratinocyte migration in a serum-restricted in vitro scratch assay. Intracellular H2S levels were modulated using fast-releasing donors H2S donors (NaHS or Na2S) to achieve supraphysiological levels or by siRNA knockdown of endogenous H2S-producing enzymes cystathionine-{gamma}-lyase (CGL) and cystathionine-{beta}-synthase (CBS) to obtain infraphysiological levels. Treatment with NaHS or Na2S (10 {micro}M-5 mM, 24 h) reduced gap closure in a dose-dependent fashion, with negligible effects at [≤] 100 {micro}M and progressive suppression at higher concentrations. Conversely, siRNA knockdown of CGL or CBS boosted keratinocyte migration by 30% versus scrambled siRNA control. Supplementation with a slow-release H2S donor rescued the siCGL phenotype, restoring migration to control levels. Across experiments, intracellular H2S level is negatively associated with keratinocyte migration. These findings suggest that H2S can restrain keratinocyte motility under serum-restricted conditions, and that reports of accelerated wound closure with H2S donors in vivo may reflect effects on other cell types and/or inflammatory pathways rather than direct enhancement of keratinocyte migration. Significance StatementDysfunctional wound healing affects millions worldwide. While H2S donors can accelerate wound closure in animal models, the cell-type-specific effects remain unclear. We show that, H2S suppresses keratinocyte migration implicating non-keratinocyte mechanisms (e.g., endothelial, immune, fibroblast) in the in vivo benefit of H2S donors and refining where in the healing cascade H2S is most likely to help.

bioengineering↗

bioRxiv2024

Decoding scalp health and microbiome dysbiosis in dandruff

A balanced scalp microbiome is crucial for scalp health, yet the mechanisms governing this balance and the etiology of dysbiosis in scalp disorders remain elusive. We conducted a detailed investigation of the scalp and hair follicles, in healthy individuals and those with dandruff/seborrheic dermatitis (D/SD). It was demonstrated that the microbiome inhabiting hair follicles serves as a reservoir for the scalp microbiome, thereby integrating the scalp, follicle, and the hair into one functional unit. Using in vitro models, we further elucidated mechanisms governing the assembly and interactions of the follicular microbiome under healthy and D/SD conditions. We show that propionic acid, produced by C. acnes, plays a pivotal role in maintaining microbiome balance, with implications for scalp health, which was validated through a clinical study.

microbiology↗

bioRxiv2024

Crosstalk of pathogens with human immune system in airway mucus profiled via machine learning-enhanced data-independent acquisition mass spectrometry

Withdrawal StatementThe authors have withdrawn their manuscript owing to Johnson & Johnson publication policies on online archives of unpublished manuscripts in the biological sciences. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

molecular biology↗

bioRxiv2023

Patient phenotypes and their relation to TNFα signaling and immune cell composition in critical illness and autoimmune disease

RationaleTNF inhibitors have shown promise in reducing mortality in hospitalized COVID-19 patients; one hypothesis explaining the limited clinical efficacy is patient heterogeneity in the TNF pathway. MethodsWe evaluated the effect of TNF inhibitors in a mouse model of LPS-induced acute lung injury. Using machine learning we attempted predictive enrichment of TNF signaling in patients with either ARDS or sepsis. We examined biological factors that drive heterogeneity in host responses to critical infection and their relation to clinical outcomes. ResultsIn mice, LPS induced TNF-dependent neutrophilia, alveolar permeability and endothelial injury. In humans, TNF pathway activation was significantly increased in peripheral blood of patients with critical illnesses and associated with the presence of mature neutrophils across critical illnesses and several autoimmune conditions. Machine learning using a gene signature separated patients into 5 phenotypes; one was a hyper-inflammatory, interferon-associated phenotype enriched for increased TNF pathway activation and conserved across critical illnesses and autoimmune diseases. Cell subset profiles segregated severely ill patients into neutrophil-subset-dependent groups that were enriched for disease severity, demonstrating the importance of neutrophils in the immune response in critical illness. ConclusionsTNF signaling and mature neutrophils are associated with a hyper-inflammatory phenotype of patients, shared across critical illness and autoimmune disease. This phenotyping provides a personalized medicine hypothesis to test anti-TNF therapy in severe respiratory illness. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=103 SRC="FIGDIR/small/564631v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@1e25724org.highwire.dtl.DTLVardef@c708bcorg.highwire.dtl.DTLVardef@10e7531org.highwire.dtl.DTLVardef@3014b8_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2023

Sustained liver HBsAg loss and clonal T and B cell expansion upon therapeutic DNA vaccination require low HBsAg levels

Background & AimsSuppression of HBV DNA, inhibition of HBsAg production and therapeutic vaccination to reverse HBV-specific T-cell exhaustion in chronic HBV patients are likely required to achieve functional cure. In the AAV-HBV mouse model, therapeutic vaccination can be effective in clearing HBsAg when hepatitis B surface (HBsAg) levels are low. The factor(s) required for mounting an effective immune control of HBV infection are unclear. Using a single-cell approach, we investigated the liver immune environment in the context of different levels of HBsAg as well as upon sustained HBsAg loss through treatment with an HBV specific GalNAc-siRNA followed by therapeutic vaccination. MethodsC57BL/6 mice were transduced with a range of rAAV-HBV DNA to express different HBsAg levels. Mice were treated with GalNAc-siRNA targeting HBV transcripts to lower the HBsAg levels and then vaccinated 4 times with a DNA vaccine encoding HBV Core, Pol and Surface. We used single-cell RNA-sequencing on homogenised liver resident cells, paired with single-cell V(D)J receptor sequencing to understand the changes in the liver immune microenvironment. ResultsTreatment with GalNAc-HBV siRNA followed by therapeutic vaccination, achieved a sustained HBsAg loss in all mice. This was accompanied by an induction of CD4 follicular helper T-cell responses, polyclonal activation of CD8 T-cells in the liver and clonal expansion of plasma cells that were responsible for antibody production. ConclusionsThis study provides novel insight into the immune changes in the liver at the single-cell level, highlighting the correlation between the induced reduction in HBsAg levels and the clonal expansion of CD4 follicular helper T-cells, CD8 cytotoxic T-cells, plasma cells, and ISG-producing neutrophils in the liver upon HBV siRNA and subsequent therapeutic vaccine treatment. Lay SummaryChronic hepatitis B infection is characterized by a complex interplay between immune responses and viral replication in the liver. To achieve functional cure a combination of different treatments is likely required. In this study single-cell approach was used to understand the liver microenvironment in the context of different HBsAg levels followed by therapeutic vaccination in AAV-HBV mouse model and to identify key factors required to achieve functional cure. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=93 SRC="FIGDIR/small/556204v1_ufig1.gif" ALT="Figure 1"> View larger version (15K): org.highwire.dtl.DTLVardef@5776a4org.highwire.dtl.DTLVardef@2e1b9forg.highwire.dtl.DTLVardef@1179a2eorg.highwire.dtl.DTLVardef@8b801d_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIAAV-HBV transduced mice sequentially treated with GalNAc-siRNA and therapeutic vaccine showed sustained HBsAg loss. C_LIO_LIThe sustained HBsAg loss correlates with increased proportion and clonal expansion of CD4 follicular helper T-cells, CD8 cytotoxic T-cells, plasma cells, and ISG producing neutrophils in the liver. C_LIO_LIBaseline levels of HBsAg are important to determine outcome of therapeutic vaccination in mice. C_LI

immunology↗

bioRxiv2023

Multi-omic Profiling Reveals Early Immunological Indicators for Identifying COVID-19 Progressors

The pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to a rapid response by the scientific community to further understand and combat its associated pathologic etiology. A focal point has been on the immune responses mounted during the acute and post-acute phases of infection, but the immediate post-diagnosis phase remains relatively understudied. We sought to better understand the immediate post-diagnosis phase by collecting blood from study participants soon after a positive test and identifying molecular associations with longitudinal disease outcomes. Multi-omic analyses identified differences in immune cell composition, cytokine levels, and cell subset-specific transcriptomic and epigenomic signatures between individuals on a more serious disease trajectory (Progressors) as compared to those on a milder course (Non-progressors). Higher levels of multiple cytokines were observed in Progressors, with IL-6 showing the largest difference. Blood monocyte cell subsets were also skewed, showing a comparative decrease in non-classical CD14-CD16+ and intermediate CD14+CD16+ monocytes. Additionally, in the lymphocyte compartment, CD8+ T effector memory cells displayed a gene expression signature consistent with stronger T cell activation in Progressors. Importantly, the identification of these cellular and molecular immune changes occurred at the early stages of COVID-19 disease. These observations could serve as the basis for the development of prognostic biomarkers of disease risk and interventional strategies to improve the management of severe COVID-19. One Sentence SummaryImmunological changes associated with COVID-19 progression can be detected during the early stages of infection.

immunology↗

bioRxiv2023

How random is the review outcome? A systematic study of the impact of external factors on eLife peer review

The advance of science rests on a robust peer review process. However whether or not a paper is accepted can depend on random external factors--e.g. the timing of the submission, the matching of editors and reviewers--that are beyond the quality of the work. This article systematically investigates the impact of these random factors independent of the papers quality on peer review outcomes in a major biomedical journal, eLife. We analyzed all of the submissions to eLife between 2016 to 2018, with 23,190 total submissions. We examined the effects of random factors at each decision point in the review process, from the gatekeeping senior editors who may desk-reject papers to review editors and reviewers who recommend the final outcome. Our results suggest that the peer-review process in eLife is robust overall and that random external factors have relatively little quantifiable bias.

bioinformatics↗

bioRxiv2022

Single neurons in thalamus and subthalamic nucleus process cardiac and respiratory signals in humans

Visceral signals are constantly processed by our central nervous system, enable homeostatic regulation, and influence perception, emotion, and cognition. While visceral processes at cortical level have been extensively studied using non-invasive imaging techniques, very few studies have investigated how this information is processed at the single neuron level, both in humans and animals. Subcortical regions, relaying signals from peripheral interoceptors to cortical structures, are particularly understudied and how visceral information is processed in thalamic and subthalamic structures remains largely unknown. Here, we took advantage of intraoperative microelectrode recordings in patients undergoing surgery for deep brain stimulation (DBS) to investigate the activity of single neurons related to cardiac and respiratory functions in three subcortical regions: Ventral Intermedius nucleus (Vim) and Ventral caudalis nucleus (Vc) of the thalamus, and subthalamic nucleus (STN). We report that the activity of a large portion of the recorded neurons (about 70%) was modulated by either the heartbeat, the cardiac inter-beat interval, or the respiration. These cardiac and respiratory response patterns varied largely across neurons both in terms of timing and their kind of modulation. We observed neurons with increases or decreases in firing rate in response to either the heartbeat or the inter-beat interval. Peaks of neural activity were found at different phases of the cardiac and respiratory cycles. Whereas most neurons only responded to one of the tested signals, a substantial proportion of these visceral neurons (30%) was responsive to more than one of the tested signals, underlining specialization and integration of cardiac and respiratory signals in STN and thalamic neurons. By extensively describing for the first time single unit activity related to cardiorespiratory function in thalamic and subthalamic neurons, our results highlight the major role of these subcortical regions in the processing of visceral signals.

neuroscience↗

bioRxiv2019

Non-motor effects of subthalamic nucleus stimulation in Parkinson's patients

IntroductionThe existing white matter connectivity analyses of the subthalamic region have mainly included the motor effects of deep brain stimulation. We investigate white matter connectivity associated with the stimulation-induced non-motor acute clinical effects in three domains: mood changes, dizziness and sweating. MethodsUsing whole brain probabilistic tractography and seeding from the volumes of tissue activation, connectivity maps were generated and statistically compared across patients. The cortical voxels associated with each non-motor domain were compared with stimulation-induced motor improvements in a multivariate model. The resulting voxels maps were thresholded for false discovery (FDR q<0.05) and clustered using a multimodal atlas. To understand the role of local pathways in the subthalamic region, a group level parcellation was performed for each non-motor domain. ResultsThe non-motor effects are rarely observed during stimulation titration: from 1100 acute clinical effects, mood change was observed in 14, dizziness in 23, and sweating in 20. Distinct cortical clusters were associated with each domain, notably mood change was associated with voxels in salience network and dizziness with voxels in visual association cortex. The subthalamic parcellation yielded a medio-lateral gradient with motor parcel being lateral and the non-motor parcels being medial. We also observed an antero-posterior organization in the medial non-motor clusters with mood changes (anterior), dizziness and sweating (posterior). ConclusionWe interpret these findings based on the literature and foresee these to be useful for shaping the electrical field with the imminent use of steerable DBS electrodes.

neuroscience↗