Biology subjects

Garg, R.

Publications and source records attributed to Garg, R..

23 records · Page 2Linked to original sources

bioRxiv2021

Weak Task Synchronization of Default Mode Network in Task Based Paradigms

Default mode network (DMN) are the areas of the brain that get deactivated upon the presentation of externally focused, attention demanding tasks. Interestingly, these areas are consistently deactivated irrespective of the nature of the task. Recent evidence shows that the behavior of the DMN may be more nuanced than what was earlier believed. We wanted to investigate the dynamics of DMN further and utilized novel statistical approaches to study the same. We analysed four publicly available datasets (total 223 subjects) across seven tasks related to different cognitive modalities and found out that there is a large amount of variability in the presumed task-negative network across subjects, trials and regions. We designed a method called Inter Trial Temporal Synchronization Analysis (IT-TSA) and Inter Subject TSA (IS-TSA) to analyse variability across trials and subjects respectively. We found out that all task-negative regions and even weak task-positive regions have low synchronization across trials and subjects. We hypothesize that the DMN variability might be more due to neural differences rather than structural or HRF variations. We also investigated the use of non GLM technique like the Inter Subject Correlation (ISC) and found that it may only be suitable to study tightly synchronized task-positive regions. Our study challenges the understanding of DMN as a task-negative region and advances the findings that DMN acts as an active component associated with a unique set of self-referential, autobiographical processes which are deactivated differentially and non linearly across trials and subjects in the presence of extrinsic processes. HighlightsO_LIDefault Mode Network is weakly synchronized across trials and subjects in task paradigms. C_LIO_LIInter Subject Correlation is not suited to detect task-based activations in DMN. C_LIO_LISynchronization Analysis reveals temporal structure in fMRI data. C_LI

neuroscience↗

bioRxiv2020

Bioelectrical Interfaces with Cortical Spheroids in Three-Dimensions

Three-dimensional (3D) neuronal spheroid culture serves as a powerful model system for the investigation of neurological disorders and drug discovery. The success of such a model system requires techniques that enable high-resolution functional readout across the entire spheroid. Conventional microelectrode arrays and implantable neural probes cannot monitor the electrophysiology activity across the entire native 3D geometry of the cellular construct. Here, we demonstrate a 3D self-rolled biosensor array (3D-SR-BA) integrated with a 3D cortical spheroid culture for simultaneous in-vitro electrophysiology recording, functional Ca2+ imaging, and drug effect monitoring. We have also developed a signal processing pipeline to detect neural firings with high spatiotemporal resolution from the electrophysiology recordings based on established spike sorting methods. The 3D-SR-BAs cortical spheroid interface provides a stable, high sensitivity recording of neural action potentials (< 50 V peak-to-peak amplitude). The 3D-SR-BA is demonstrated as a potential drug screening platform through the investigation of the neural response to the excitatory neurotransmitter glutamate. Upon addition of glutamate, the neuronal firing rates increased notably corresponding well with the functional Ca2+ imaging. Our entire system, including the 3D-SR-BA integrated with neural spheroid culture, enables simultaneous electrophysiology recording and functional Ca2+ imaging with high spatiotemporal resolution in conjunction with chemical stimulation. We demonstrate a powerful toolset for future studies of tissue development, disease progression, and drug testing and screening, especially when combined with native spheroid cultures directly extracted from humans.

bioengineering↗

bioRxiv2020

225Ac-labeled CD33-targeting antibody reverses resistance to Bcl-2 inhibitor venetoclax in acute myeloid leukemia models

PurposeDespite the availability of new drugs, many patients with acute myeloid leukemia (AML) do not achieve remission and outcomes remain poor. Venetoclax is a promising new therapy approved for use in combination with a hypomethylating agent or with low dose cytarabine for the treatment of newly diagnosed older AML patients or those ineligible for intensive chemotherapy. 225Actinium-lintuzumab (225Ac-lintuzumab) is a clinical stage radioimmunotherapy targeting CD33 that has shown evidence of single agent activity in relapsed/refractory AML. Increased expression of MCL-1 is a mediator of resistance to venetoclax in cancer. Experimental designHere we investigated the potential for 225Ac-lintuzumab-directed DNA damage to suppress MCL-1 levels as a possible mechanism of reversing resistance to venetoclax in two preclinical in vivo models of AML. ResultsWe demonstrated that 225Ac-lintuzumab in combination with venetoclax induced a synergistic increase in tumor cell killing compared to treatment with either drug alone in venetoclax-resistant AML cell lines through both an induction of double-stranded DNA breaks (DSBs) and depletion of MCL-1 protein levels. Further, this combination led to significant tumor growth control and prolonged survival benefit in venetoclax-resistant in vivo AML models. ConclusionsThere results suggest that the combination of 225Ac-lintuzumab with venetoclax may be a promising therapeutic strategy for the treatment of patients with venetoclax-resistant AML.

cancer biology↗

bioRxiv2020

Requirement for PKC epsilon in KRAS-driven lung tumorigenesis

ABSTRACTNon-small cell lung cancer (NSCLC), the most frequent subtype of lung cancer, remains a highly lethal malignancy and one of the leading causes of cancer deaths worldwide. Mutant KRAS is the prevailing oncogenic driver of lung adenocarcinoma, the most common histological form of NSCLC. In this study, we examined the role of PKCε, an oncogenic kinase highly expressed in NSCLC and other cancers, in KRAS-driven tumorigenesis. Notably, database analysis revealed an association between PKCε expression and poor outcome in lung adenocarcinoma patients specifically having KRAS mutation. By generating a PKCε-deficient, conditionally activatable allele of oncogenic Kras (LSL-KrasG12D;PKCε−/− mice) we were able to demonstrate the requirement of PKCε for Kras-driven lung tumorigenesis in vivo, which is consistent with the impaired transformed growth observed in PKCε-deficient KRAS-dependent NSCLC cells. Moreover, PKCε-knockout mice were found to be less susceptible to lung tumorigenesis induced by benzo[a]pyrene, a carcinogen that induces mutations in Kras. Mechanistic analysis using RNA-Seq revealed little overlapping for PKCε and KRAS in the control of genes/biological pathways relevant in NSCLC, suggesting that a permissive role of PKCε in KRAS-driven lung tumorigenesis may involve non-redundant mechanisms. Our results thus highlight the relevance and potential of targeting PKCε for lung cancer therapeutics.Competing Interest StatementThe authors have declared no competing interest.View Full Text

cancer biology↗

bioRxiv2019

Role of DNA methylation dynamics in desiccation and salinity stress responses in rice cultivars

DNA methylation is an epigenetic mark that controls gene expression in response to internal and environmental cues. In this study, we sought to understand the role of DNA methylation in response to desiccation and salinity stresses in three rice cultivars (IR64, stress-sensitive; Nagina 22, drought-tolerant and Pokkali, salinity-tolerant) via bisulphite sequencing. We identified DNA methylation patterns in different genomic/genic regions and analysed their correlation with gene expression. Methylation in CG context within gene body and methylation in CHH context in distal promoter regions were positively correlated with gene expression. However, methylation in other sequence contexts and genic regions was negatively correlated with gene expression. DNA methylation was found to be most dynamic in CHH context under stress condition(s) in the rice cultivars. The expression profiles of genes involved in de-novo methylation were correlated with methylation dynamics. Hypomethylation in Nagina 22 and hypermethylation in Pokkali in response to desiccation and salinity stress, respectively, were correlated with higher expression of abiotic stress response related genes. Our results suggest an important role of DNA methylation in abiotic stress responses in rice in cultivar-specific manner. This study provides useful resource of DNA methylomes that can be integrated with other data to understand abiotic stress response in rice. HighlightBisulphite sequencing revealed single base resolution DNA methylation, and cultivar-specific differential methylation patterns and correlation with gene expression that control desiccation and salinity stress response in the rice cultivars.

genomics↗