Biology subjects

Paliwal, S.

Publications and source records attributed to Paliwal, S..

6 recordsLinked to original sources

bioRxiv2025

DINOcell: Learning Generalizable Perturbation Effects through Self-Distillation

AO_SCPLOWBSTRACTC_SCPLOWPredicting cellular responses to therapeutics is a promising approach for novel target discovery. However, state-of-the-art computational models designed to predict perturbation effects struggle to generalize and outperform simple baselines. We present DINOcell, a weakly supervised framework that adapts self-distillation to single-cell transcriptomics for predicting perturbation effects. We demonstrate that DINOcell outperforms baselines in predicting the effects of single gene perturbations. Furthermore, DINOcell accurately predicts non-additive effects of combination perturbations, indicating its capacity to model complex genetic interactions. Finally, we show that DINOcell learns representations that capture biological signals and is a promising, generalizable approach for in silico perturbation modeling, providing a valuable tool for accelerating therapeutic target discovery.

bioinformatics↗

bioRxiv2023

Cerebellar Activity in Hemi-Parkinsonian Rats during Volitional Gait and Freezing

Parkinsons disease is a neurodegenerative disease characterized by gait dysfunction in the advanced stages of the disease. The unilateral 6-OHDA toxin-induced model is the most studied animal model of Parkinsons disease, which reproduces gait dysfunction after greater than 68% dopamine (DA) loss in the substantia nigra pars compacta (SNc). The extent to which the neural activity in hemi-parkinsonian rats correlates to gait dysfunction and DAergic cell loss is not clear. In this paper we report the effects of unilateral DA depletion on cerebellar vermis activity using micro-electrocorticography (ECoG) during walking and freezing on a runway. Gait and neural activity were measured in 6-OHDA lesioned and sham lesioned rats at 14d, 21d, and 28d after infusion of 6-OHDA or control vehicle into the medial forebrain bundle (MFB) (n=20). Gait deficits in 6-OHDA rats were different from sham rats at 14d (p<0.05). Gait deficits in 6-OHDA rats improved at 21d and 28d except for run speed, which decreased at 28d (p=0.018). No differences in gait deficits were observed in sham lesioned rats at any time points. Hemiparkinsonian rats showed hyperactivity in the cerebellar vermis at 21d (p<0.05), but not at 14d and 28d, and the activity was reduced during freezing epochs in lobules VIa, VIb, and VIc (p<0.05). These results suggest that DAergic cell loss causes pathological cerebellar activity at 21d postlesion and suggests that compensatory mechanisms from the intact hemisphere contribute to normalized cerebellar activity at 28d. The decrease in cerebellar oscillatory activity during freezing may be indicative of neurological changes during freezing of gait in Parkinsons disease patients making this region a potential location for biomarker detection. Although the unilateral 6-OHDA model presents gait deficits that parallel clinical presentations of Parkinsons disease, further studies in animal models of bilateral DA loss are needed to understand the role of the cerebellar vermis in Parkinsons disease.

neuroscience↗

bioRxiv2021

NFIC regulates ribosomal biology and ER stress in pancreatic acinar cells and suppresses PDAC initiation

Tissue-specific differentiation is driven by specialized transcriptional networks. Pancreatic acinar cells crucially rely on the PTF1 complex, and on additional transcription factors, to deploy their transcriptional program. Here, we identify NFIC as a novel regulator of acinar differentiation using a variety of methodological strategies. NFIC binding sites are found at very short distances from NR5A2-bound genomic regions and both proteins co-occur in the same complex. Nfic knockout mice show reduced expression of acinar genes and, in ChIP-seq experiments, NFIC binds the promoters of acinar genes. In addition, NFIC binds to the promoter of, and regulates, genes involved in RNA and protein metabolism; in Nfic knockout mice, p-RS6K1 and p-IEF4E are down-regulated indicating reduced activity of the mTOR pathway. In 266-6 acinar cells, NFIC dampens the ER stress program through its binding to ER stress gene promoters and is required for complete resolution of Tunicamycin-mediated ER stress. Normal human pancreata from subjects with low NFIC mRNA levels display reduced epxression of genes down-regulated in Nfic knockout mice. Consistently, NFIC displays reduced expression upon induced acute pancreatitis and is required for proper recovery after damage. Finally, expression of NFIC is lower in samples of mouse and human pancreatic ductal adenocarcinoma and Nfic knockout mice develop an increased number of mutant Kras-driven pre-neoplastic lesions.

cell biology↗

bioRxiv2019

High accuracy DNA sequencing on a small, scalable platform via electrical detection of single base incorporations

High throughput DNA sequencing technologies have undergone tremendous development over the past decade. Although optical detection-based sequencing has constituted the majority of data output, it requires a large capital investment and aggregation of samples to achieve optimal cost per sample. We have developed a novel electronic detection-based platform capable of accurately detecting single base incorporations. The GenapSys technology with its electronic detection modality allows the system to be compact, accessible, and affordable. We demonstrate the performance of the system by sequencing several different microbial genomes with varying GC content. The platform is capable of generating up to 2 Gb of high-quality nucleic acid sequence in a single run. We routinely generate sequence data that exceeds 99% raw accuracy with read lengths of up to 175 bp. Average quality scores remain above Q30 (99.9% raw sequencing accuracy) beyond 150 bp, with more than 85% of total bases at or above Q30. The utility of the platform is highlighted by targeted sequencing of the human genome. We show high concordance of SNP detection on the human NA12878 HapMap cell line with data generated on the Illumina sequencing platform. In addition, we sequenced a targeted panel of cancer-associated genes in a well characterized reference standard. With multiple library preparation approaches on this sample, we were able to identify low frequency mutations at expected allele frequencies.

genomics↗

bioRxiv2018

Subjective estimates of uncertainty and volatility during gambling predict impulsivity after subthalamic deep brain stimulation for Parkinson’s disease

1Subthalamic deep brain stimulation (STN-DBS) for Parkinsons disease may modulate chronometric and instrumental aspects of choice behaviour, including motor inhibition, decisional slowing, and value sensitivity. However, it is not well known whether STN-DBS affects more complex aspects of decision-making, such as the influence of subjective estimates of uncertainty on choices. In this study, thirty-eight participants with Parkinsons disease played a virtual casino prior to subthalamic DBS (whilst on medication) and again, three-months postoperatively (whilst on stimulation). At the group level, there was a small but statistically significant postoperative decrease in impulsivity, as quantified by the Barratt Impulsiveness Scale (BIS). The gambling behaviour of participants (bet increases, slot machine switches and double or nothing gambles) was associated with this self-reported measure of impulsivity. However, there was a large variance in outcome amongst participants, and we were interested in whether individual differences in subjective estimates of uncertainty (specifically, volatility) were related to differences in pre- and postoperative impulsivity. To examine these individual differences, we fit a computational model (the Hierarchical Gaussian Filter, HGF), to choices made during slot machine game play as well as a simpler reinforcement learning model based on the Rescorla-Wagner formalism. The HGF was superior in accounting for the behaviour of our participants, suggesting that participants incorporated beliefs about environmental uncertainty when updating their beliefs about gambling outcome and translating these beliefs into action. A specific aspect of subjective uncertainty, the participants estimate of the tendency of the slot machines winning probability to change (volatility), increased subsequent to DBS. Additionally, the decision temperature of the response model decreased post-operatively, implying greater stochasticity in the belief-to-choice mapping of participants. Model parameter estimates were significantly associated with impulsivity; specifically, increased uncertainty was related to increased postoperative impulsivity. Moreover, changes in these parameter estimates were significantly associated with the maximum post-operative change in impulsivity over a six month follow up period. Our findings suggest that impulsivity in persons with Parkinsons disease may be influenced by subjective estimates of uncertainty (environmental volatility) and implicate a role for the subthalamic nucleus in the modulation of outcome certainty. Furthermore, our work outlines a possible approach to characterising those persons who become more impulsive after subthalamic DBS, an intervention in which non-motor outcomes can be highly variable.

neuroscience↗

bioRxiv2018

Pharmacophore-driven Identification of N-Methyl-D-Receptor Antagonists as Potent Neuroprotective Agents Validated Using In-Vivo Studies

Alzheimers disease (AD), the most widespread cause of dementia is delineated by progressive cognitive impairment in the elderly people. During its progression, N-Methyl-D-Aspartate receptor antagonists are known to play a key role in the mechanisms of learning and memory. Extensive side effects alongside other effects on learning and memory have limited the therapeutic significance of various blockers and antagonists of the NMDA receptor. In this study, we identify potential compounds targeted against NMDA. In order to reveal the essential structural features for NMDA receptor, three-dimensional pharmacophore models are constructed based on a set of known NMDA inhibitors. This is followed by virtual screening which results in novel chemical compounds having the potential to inhibit NMDA. The lead compounds are then subjected to molecular docking and assessed by a scoring function, which results in two compounds with high Libdock scores. These compounds also show interactions with important residues at the active site. The compounds are shortlisted on the basis of high estimated activity, fit values, LibDock score, no violation to Lipinskis and availability for procuring.\n\nOf the shortlisted compounds, one compound satisfying the entire aforementioned criterion is further tested using in-vivo studies on mice with the help of an eight-arm radial maze. The pharmacophore-based virtual screening protocol presented in this study pave the way forward to address the unmet medical need of Alzheimer disease.

bioinformatics↗