Biology subjects

Chopra, V.

Publications and source records attributed to Chopra, V..

4 recordsLinked to original sources

bioRxiv2025

Utilizing Genomics to Identify Novel Immunotherapeutic Targets in Multiple Myeloma High-Risk Subgroups

Immunotherapy is now standard of care for multiple myeloma, where the most common targets are B cell maturation antigen, CD38, and G protein-coupled receptor class C group 5 member D but strategies to identify additional targets are needed. We have utilized two large datasets of genomic data and integrated them with existing databases to identify expressed cell surface targets in myeloma patients. Importantly, we also identify targets specific to genomic defined subgroups of patients including primary translocations and high-risk subgroups. Examples of subgroup targets include ROBO3 in t(4;14), CD109 in t(14;16), CD20 in t(11;14), GPRC5D in 1q+, and ADAM28 in biallelic TP53 samples. Expression was validated by flow cytometry and CRISPR-Cas9 knock out models. Sub-clonal differences in expression were noted, as was alternative splicing of existing immunotherapy targets such as FCRL5. These results highlight the use of genomic stratification to identify novel therapeutic targets. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=157 HEIGHT=200 SRC="FIGDIR/small/635544v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@6965e6org.highwire.dtl.DTLVardef@1a0e567org.highwire.dtl.DTLVardef@34fc30org.highwire.dtl.DTLVardef@98c3d4_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2024

Factors that influence the caste ratio in a bacterial division of labour

Colonies of the bacteria Streptomyces coelicolor divide labour between cells that specialize on growth and sporulation and cells that specialize on antibiotic production. This division of labour arises due to costly chromosome deletions in the antibiotic overproducers. However, little is known about when and where these mutations occur or whether their frequency - which we liken to the caste ratio in social insects - is phenotypically plastic. To elucidate changes in the proportions of specialized cells (measured as the mutation frequency), we sampled S. coelicolor colonies grown under different conditions. Temporally, mutation frequency increased linearly with colony age and size. Spatially, mutations accumulated disproportionately in the colony center, despite greater growth and sporulation at the periphery. Exposing colonies to sub-inhibitory concentrations of some antibiotics, a competitive cue in Streptomyces, increased mutation frequencies. Finally, direct competition with other Streptomyces that naturally produce antibiotics increased mutation frequencies, while also increasing spore production. Our findings provide insights into the intrinsic and environmental factors driving division of labor in Streptomyces colonies by showing that mutation frequencies are dynamic and responsive to the competitive environment. These results show that chromosome deletions are phenotypically plastic and suggest that Streptomyces can flexibly adjust their caste ratio.

evolutionary biology↗

bioRxiv2021

Pathogenic bacteria grown in iron and zinc milieu exhibit magnetotaxis

The growing number of multiple drug resistant (MDR) bacteria and the dwindling pipeline of new antibiotics are driving us towards a post-antibiotic era in which even common infections would become difficult to treat. To address this, an antibiotic-free strategy that can combat multiple bacteria is recommended. Most of the proposed approaches nevertheless have several limitations, including bacterial targeting. To overcome such limitations, the proposed strategy employs the bacterial machinery to self-destruct. Herein, the biosynthesis of magnetic nanoparticle (MNP) is reported for the first time in multiple pathogenic bacteria, including MDR bacteria. The intracellular MNPs composed of superparamagnetic zinc ferrites were formed in presence of iron and zinc precursors. Exposure of the treated bacteria/biofilms to an alternating magnetic field (AMF) exhibited hyperthermia (5-6{degrees}C) and a dramatic decrease in bacterial viability, suggesting the MNPs therapeutic potential. Likewise, the bacteria existing in vivo biosynthesize the MNPs by mining these elements from the host. To determine its therapeutic efficacy, the infected tissues were exposed directly to AMF. A 3-4 log reduction in bacterial burden, as compared to antibiotics treatment, confirmed the significance of using naturally existing MNPs to combat bacterial infections. The proposed broad-spectrum approach can therefore aid in overcoming the challenges facing anti-bacterial therapies.

microbiology↗

bioRxiv2019

Latent Toxoplasma gondii infection increases soluble mutant huntingtin and promotes neurodegeneration in the YAC128 mouse model of Huntington's disease

Toxoplasma gondii causes a prevalent neuroinvasive protozoal pathogen that in immune competent individuals results in latent infection characterized by intra-cellular parasite cysts in brain. Despite life-long infection, the role of latent toxoplasmosis on chronic neurodegenerative processes is poorly understood. Huntingtons disease (HD) is a progressive neurodegenerative disorder caused by a dominant CAG repeat expansion in the huntingtin gene (HTT) that results in the expression and accumulation of mutant huntingtin protein (mHTT). The mutant HD gene is fully penetrant. However, there is significant variability in disease progression that is in part explained by as yet unidentified environmental factors. The kynurenine pathway of tryptophan metabolism (KP) is an inflammatory pathway and its activation is implicated in HD pathogenesis. KP upregulation also occurs in response to infection with Toxoplasma gondii suggesting that the latent infection may promote HD. We discovered that mice on the FVB/NJ background develop latent toxoplasmosis following infection with the ME49 strain of T. gondii. This finding enabled us to address the hypothesis that latent toxoplasmosis potentiates disease in the YAC128 mouse model of HD, as these mice are maintained on the FVB/NJ background. Wild-type and HD mice were infected at 2-months of age. During the 10-month follow-up, infection had adverse effects on mice of both genotypes. However, YAC128 HD mice demonstrated specific vulnerability to latent toxoplasmosis, as demonstrated by the presence of increased striatal degeneration, high levels of the blood neurodegeneration marker neurofilament light protein, and elevated brain soluble mHTT. Our studies have uncovered a novel HD-infection interaction in mice that provides insights into the large variability of the human HD phenotype.

neuroscience↗