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Gupta, P.

Publications and source records attributed to Gupta, P..

3 recordsLinked to original sources

Functional characterization of retinal ganglion cells using tailored nonlinear modeling

There are 20-50 functionally- and anatomically-distinct ganglion cell types in the mammalian retina; each type encodes a unique feature of the visual world and conveys it via action potentials to the brain. Individual ganglion cells receive input from unique presynaptic retinal circuits, and the characteristic patterns of light-evoked action potentials in each ganglion cell type therefore reflect computations encoded in synaptic input and in postsynaptic signal integration and spike generation. Unfortunately, there is a dearth of tools for characterizing retinal ganglion cell computation. Therefore, we developed a statistical model, the separable Nonlinear Input Model, capable of characterizing the large array of distinct computations reflected in retinal ganglion cell spiking. We recorded ganglion cell responses to a correlated noise (\"cloud\") stimulus designed to accentuate the important features of retinal processing in an in vitro preparation of mouse retina and found that this model accurately predicted ganglion cell responses at high spatiotemporal resolution. It identified multiple receptive fields (RFs) reflecting the main excitatory and suppressive components of the response of each neuron. Most significantly, our model succeeds where others fail, accurately identifying ON-OFF cells and segregating their distinct ON and OFF selectivity and demonstrating the presence of different types of suppressive receptive fields. In total, our computational approach offers rich description of ganglion cell computation and sets a foundation for relating retinal computation to retinal circuitry.

neuroscience

Mycobacterium tuberculosis LprE enhances bacterial persistence by inhibiting cathelicidin and autophagy in macrophages

Mycobacterium tuberculosis(Mtb) lipoproteins are known to facilitate bacterial survival by manipulating the host immune responses. Here, we have characterized a novel Mtb lipoprotein LprE(LprEMtb), and demonstrated its role in mycobacterial survival. LprEMtb acts by down-regulating the expression of cathelicidin, Cyp27B1, VDR and p38-MAPK via TLR-2 signaling pathway. Deletion of lprEMtb resulted in induction of cathelicidin and decreased survival in the host. Interestingly, LprEMtb was also found to inhibit autophagy mechanism to dampen host immune response. Episomal expression of LprEMtb in non-pathogenic Mycobacterium smegmatis(Msm) increased bacillary persistence by down-regulating the expression of cathelicidin and autophagy, while deletion of LprEMtb orthologue in Msm, had no effect on cathelicidin and autophagy expression. Moreover, LprEMtb blocked phago-lysosome fusion by suppressing the expression of EEA1, Rab7 and LAMP-1 endosomal markers by down-regulating IL-12 and IL-22 cytokines. Our results indicate that LprEMtb plays an important role in mycobacterial pathogenesis in the context of innate immunity.

physiology

Mapping The Malaria Parasite Drug-Able Genome Using In Vitro Evolution And Chemogenomics

Chemogenetic characterization through in vitro evolution combined with whole genome analysis is a powerful tool to discover novel antimalarial drug targets and identify drug resistance genes. Our comprehensive genome analysis of 262 Plasmodium falciparum parasites treated with 37 diverse compounds reveals how the parasite evolves to evade the action of small molecule growth inhibitors. This detailed data set revealed 159 gene amplifications and 148 nonsynonymous changes in 83 genes which developed during resistance acquisition. Using a new algorithm, we show that gene amplifications contribute to 1/3 of drug resistance acquisition events. In addition to confirming known multidrug resistance mechanisms, we discovered novel multidrug resistance genes. Furthermore, we identified promising new drug target-inhibitor pairs to advance the malaria elimination campaign, including: thymidylate synthase and a benzoquinazolinone, farnesyltransferase and a pyrimidinedione, and a dipeptidylpeptidase and an arylurea. This deep exploration of the P. falciparum resistome and drug-able genome will guide future drug discovery and structural biology efforts, while also advancing our understanding of resistance mechanisms of the deadliest malaria parasite.\n\nOne Sentence SummaryWhole genome sequencing reveals how Plasmodium falciparum evolves resistance to diverse compounds and identifies new antimalarial drug targets.

genomics