Biology subjects

Kashyap, S.

Publications and source records attributed to Kashyap, S..

24 records · Page 2Linked to original sources

bioRxiv2023

Novel insights into hippocampal perfusion using high-resolution, multi-modal 7T MRI

We present a comprehensive study on the non-invasive measurement of hippocampal perfusion. Using high-resolution 7 Tesla arterial spin labelling data, we generated robust perfusion maps and observed significant variations in perfusion among hippocampal subfields, with CA1 exhibiting the lowest perfusion levels. Notably, these perfusion differences were robust and detectable even within five minutes and just fifty perfusion-weighted images per subject. To understand the underlying factors, we examined the influence of image quality metrics, various tissue microstructure and morphometry properties, macrovasculature and cytoarchitecture. We observed higher perfusion in regions located closer to arteries, demonstrating the influence of vascular proximity on hippocampal perfusion. Moreover, ex vivo cytoarchitectonic features based on neuronal density differences appeared to correlate stronger with hippocampal perfusion than morphometric measures like gray matter thickness. These findings emphasize the interplay between microvasculature, macrovasculature, and metabolic demand in shaping hippocampal perfusion. Our study expands the current understanding of hippocampal physiology and its relevance to neurological disorders. By providing in vivo evidence of perfusion differences between hippocampal subfields, our findings have implications for diagnosis and potential therapeutic interventions. In conclusion, our study provides a valuable resource for extensively characterising hippocampal perfusion.

neuroscience↗

bioRxiv2022

Novel Peptide Inhibitor of Human Tumor Necrosis Factor-α has Antiarthritic Activity

The inhibition of tumor necrosis factor- (TNF) trimer formation renders it inactive for binding to its receptors thus mitigating the vicious cycle of inflammation. We designed a peptide (PIYLGGVFQ) that simulates a sequence strand of human TNF monomer using a series of in silico methods, such as active site finding (Acsite), protein-protein interaction (PPI), docking studies (GOLD and Modeller) followed by molecular dynamics (MD) simulation studies. The MD studies confirmed the intermolecular interaction of the peptide with the TNF. Fluorescence-activated cell sorting (FACS) and fluorescence microscopy revealed that the peptide effectively inhibited the binding of TNF to the cell surface receptors. The cell culture assays showed that the peptide significantly inhibited the TNF-mediated cell death. In addition, the nuclear translocation of the nuclear factor kappa B (NF{kappa}B) was significantly suppressed in the peptide-treated A549 cells as observed in immunofluorescence and gel mobility-shift assays. Furthermore, peptide protected against joint damage in collagen-induced arthritis (CIA) mouse model as revealed in the microfocal-CT scans. In conclusion, this TNF antagonist would be useful for the prevention and repair of inflammatory bone destruction and subsequent loss in the mouse model of CIA as well as human rheumatoid arthritis (RA) patients. This calls upon further clinical investigation to utilize its potential effect as an anti-arthritic drug.

immunology↗

bioRxiv2022

DrDimont: Explainable drug response predictionfrom differential analysis of multi-omics networks

MotivationWhile it has been well established that drugs affect and help patients differently, personalized drug response predictions remain challenging. Solutions based on single omics measurements have been proposed, and networks provide means to incorporate molecular interactions into reasoning. However, how to integrate the wealth of information contained in multiple omics layers still poses a complex problem. ResultsWe present DrDimont, Drug response prediction from Differential analysis of multi-omics networks. It allows for comparative conclusions between two conditions and translates them into differential drug response predictions. DrDimont focuses on molecular interactions. It establishes condition-specific networks from correlation within an omics layer that are then reduced and combined into heterogeneous, multi-omics molecular networks. A novel semi-local, path-based integration step ensures integrative conclusions. Differential predictions are derived from comparing the condition-specific integrated networks. DrDimonts predictions are explainable, i.e., molecular differences that are the source of high differential drug scores can be retrieved. We predict differential drug response in breast cancer using transcriptomics, proteomics, phosphosite, and metabolomics measurements and contrast estrogen receptor positive and receptor negative patients. DrDimont performs better than drug prediction based on differential protein expression or PageRank when evaluating it on ground truth data from cancer cell lines. We find proteomic and phosphosite layers to carry most information for distinguishing drug response. AvailabilityDrDimont is available on CRAN: https://cran.r-project.org/package=DrDimont. Contactkatharina.baum@hpi.de

bioinformatics↗

bioRxiv2021

Chimeric chromosome landscapes of human somatic cell cultures show dependence on stress and regulation of genomic repeats by CGGBP1.

Genomes of somatic cells in culture are prone to spontaneous mutations due to errors in replication and DNA repair. Some of these errors, such as chromosomal fusions, are not rectifiable and subject to selection or elimination in growing cultures. Somatic cell cultures are thus expected to generate background levels of potentially stable chromosomal chimeras. A description of the landscape of such spontaneously generated chromosomal chimeras in cultured cells will help us understand the factors affecting somatic mosaicism. Here we show that short homology-associated non-homologous chromosomal chimeras occur in normal human fibroblasts and HEK293T cells at genomic repeats. The occurrence of chromosomal chimeras is enhanced by heat stress and depletion of a repeat regulatory protein CGGBP1. We also present evidence of homologous chromosomal chimeras between allelic copies in repeat-rich DNA obtained by methylcytosine immunoprecipitation. The formation of homologous chromosomal chimeras at Alu and L1 repeats increases upon depletion of CGGBP1. Our data are derived from de novo sequencing from three different cell lines under different experimental conditions and our chromosomal chimera detection pipeline is applicable to long read as well as short read sequencing platforms. These findings present significant information about the generation, sensitivity and regulation of somatic mosaicism in human cell cultures.

genomics↗

bioRxiv2020

Sub-millimetre resolution laminar fMRI using Arterial Spin Labelling in humans at 7T

Laminar fMRI at ultra-high magnetic field strength is typically carried out using the Blood Oxygenation Level-Dependent (BOLD) contrast. Despite its unrivalled sensitivity to detecting activation, the BOLD contrast is limited in its spatial specificity due to signals stemming from intra-cortical ascending and pial veins. Alternatively, regional changes in perfusion (i.e., cerebral blood flow through tissue) are colocalised to neuronal activation, which can be non-invasively measured using arterial spin labelling (ASL) MRI. In addition, ASL provides a quantitative marker of neuronal activation in terms of perfusion signal, which is simultaneously acquired along with the BOLD signal. However, ASL for laminar imaging is challenging due to the lower SNR of the perfusion signal and higher RF power deposition i.e., specific absorption rate (SAR) of ASL sequences. In the present study, we present for the first time in humans, isotropic sub-millimetre spatial resolution functional perfusion images using Flow-sensitive Alternating Inversion Recovery (FAIR) ASL with a 3D-EPI readout at 7T. We show that robust statistical activation maps can be obtained with perfusion-weighting in a single session. We observed the characteristic BOLD amplitude increase towards the superficial laminae, and, in apparent discrepancy, the relative perfusion profile shows a decrease of the amplitude and the absolute perfusion profile a much smaller increase towards the cortical surface. Considering the draining vein effect on the BOLD signal using model-based spatial convolution, we show that the empirically measured perfusion and BOLD profiles are, in fact, consistent with each other. This study demonstrates that laminar perfusion fMRI in humans is feasible at 7T and that caution must be exercised when interpreting BOLD signal laminar profiles as direct representation of the cortical distribution of neuronal activity.

neuroscience↗

bioRxiv2018

Sub-millimeter fMRI reveals multiple topographical digit representations that form action maps in human motor cortex

The human brain coordinates a wide variety of motor activities. On a large scale, the cortical motor system is topographically organized such that neighboring body parts are represented by neighboring brain areas. This homunculus-like somatotopic organization along the central sulcus has been observed using neuroimaging for large body parts such as the face, hands and feet. However, on a finer scale, invasive electrical stimulation studies show deviations from this somatotopic organization that suggest an organizing principle based on motor actions rather than body part moved. It has not been clear how the action-map organization principle of the motor cortex in the mesoscopic (sub-millimeter) regime integrates into a body map organization principle on a macroscopic scale (cm). Here we developed and applied advanced mesoscopic (sub-millimeter) fMRI and analysis methodology to non-invasively investigate the functional organization topography across columnar and laminar structures in humans. We find that individual fingers have multiple mirrored representations in the primary motor cortex depending on the movements they are involved in. We find that individual digits have cortical representations up to 3 mm apart from each other arranged in a column-like fashion. These representations are differentially engaged depending on whether the digits muscles are used for different motor actions such as flexion movements like grasping a ball or retraction movements like releasing a ball. This research provides a starting point for noninvasive investigation of mesoscale topography across layers and columns of the human cortex and bridges the gap between invasive electrophysiological investigations and large coverage non-invasive neuroimaging.

neuroscience↗