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rabindra.tharu.np@gmail.com
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The simplicity of protein sequence-function relationships
How complex are the rules by which a protein’s sequence determines its function? High-order epistatic interactions among residues are thought to be pervasive, suggesting an idiosyncratic and unpredictable sequence-function relationship. But many prior studies may have overestimated epistasis, because they analyzed sequence-function relationships relative to a single reference sequence-which causes measurement noise and local idiosyncrasies to snowball…
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rabindra.tharu.np@gmail.com
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Implementing reactivity in molecular dynamics simulations with harmonic force fields
The simulation of chemical reactions and mechanical properties including failure from atoms to the micrometer scale remains a longstanding challenge in chemistry and materials science. Bottlenecks include computational feasibility, reliability, and cost. We introduce a method for reactive molecular dynamics simulations using a clean replacement of non-reactive classical harmonic bond potentials with reactive, energy-conserving Morse…
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rabindra.tharu.np@gmail.com
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The evolution of heteroresistance via small colony variants in Escherichia coli following long term exposure to bacteriostatic antibiotics
Traditionally, bacteriostatic antibiotics are agents able to arrest bacterial growth. Despite being traditionally viewed as unable to kill bacterial cells, when they are used clinically the outcome of these drugs is frequently as effective as when a bactericidal drug is used. We explore the dynamics of Escherichia coli after exposure to two ribosome-targeting bacteriostatic antibiotics,…
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rabindra.tharu.np@gmail.com
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Comprehensive detection and characterization of human druggable pockets through binding site descriptors
Druggable pockets are protein regions that have the ability to bind organic small molecules, and their characterization is essential in target-based drug discovery. However, deriving pocket descriptors is challenging and existing strategies are often limited in applicability. We introduce PocketVec, an approach to generate pocket descriptors via inverse virtual screening of lead-like molecules. PocketVec performs…
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rabindra.tharu.np@gmail.com
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Prenatal environment is associated with the pace of cortical network development over the first three years of life
Environmental influences on brain structure and function during early development have been well-characterized, but whether early environments are associated with the pace of brain development is not clear. In pre-registered analyses, we use flexible non-linear models to test the theory that prenatal disadvantage is associated with differences in trajectories of intrinsic brain network development from…
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rabindra.tharu.np@gmail.com
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Targeting PRMT3 impairs methylation and oligomerization of HSP60 to boost anti-tumor immunity by activating cGAS/STING signaling
Immune checkpoint blockade (ICB) has emerged as a promising therapeutic option for hepatocellular carcinoma (HCC), but resistance to ICB occurs and patient responses vary. Here, we uncover protein arginine methyltransferase 3 (PRMT3) as a driver for immunotherapy resistance in HCC. We show that PRMT3 expression is induced by ICB-activated T cells via an interferon-gamma (IFNγ)-STAT1…
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rabindra.tharu.np@gmail.com
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LOXHD1 is indispensable for maintaining TMC1 auditory mechanosensitive channels at the site of force transmission
Hair cell bundles consist of stereocilia arranged in rows of increasing heights, connected by tip links that transmit sound-induced forces to shorter stereocilia tips. Auditory mechanotransduction channel complexes, composed of proteins TMC1/2, TMIE, CIB2, and LHFPL5, are located at the tips of shorter stereocilia. While most components can interact with the tip link in vitro,…
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rabindra.tharu.np@gmail.com
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A mouse protozoan boosts antigen-specific mucosal IgA responses in a specific lipid metabolism- and signaling-dependent manner
IgA antibodies play an important role in mucosal immunity. However, there is still no effective way to consistently boost mucosal IgA responses, and the factors influencing these responses are not fully understood. We observed that colonization with the murine intestinal symbiotic protozoan Tritrichomonas musculis (T.mu) boosted antigen-specific mucosal IgA responses in wild-type C57BL/6 mice. This…
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rabindra.tharu.np@gmail.com
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Deep intravital brain tumor imaging enabled by tailored three-photon microscopy and analysis
Intravital 2P-microscopy enables the longitudinal study of brain tumor biology in superficial mouse cortex layers. Intravital microscopy of the white matter, an important route of glioblastoma invasion and recurrence, has not been feasible, due to low signal-to-noise ratios and insufficient spatiotemporal resolution. Here, we present an intravital microscopy and artificial intelligence-based analysis workflow (Deep3P) that…
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rabindra.tharu.np@gmail.com
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Entorhinal cortex vulnerability to human APP expression promotes hyperexcitability and tau pathology
Preventative treatment for Alzheimer’s Disease (AD) is dire, yet mechanisms underlying early regional vulnerability remain unknown. In AD, one of the earliest pathophysiological correlates to cognitive decline is hyperexcitability, which is observed first in the entorhinal cortex. Why hyperexcitability preferentially emerges in specific regions in AD is unclear. Using regional, cell-type-specific proteomics and electrophysiology in…
