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Papers by Sanjay Bhattarai

Journal of the American Chemical Society

Herein, we describe the synthesis and structure-activity relationships of dehydroaltenusin deriva... more Herein, we describe the synthesis and structure-activity relationships of dehydroaltenusin derivatives as inhibitors of a mammalian DNA polymerase a. We have newly synthesized nine dehydroaltenusin derivatives modified at the side chains or benzoquinone moiety. We also achieved the first synthesis of desmethylaltenusin and desmethyldehydroaltenusin, metabolites of Alternaria sp. or Talaromyces flavus, respectively. Among all synthesized derivatives, demethoxydehydroaltenusin was the most selective inhibitor of DNA polymerase a. The o-hydroxy-p-benzoquinone (2-hydroxycyclohexa-2,5-dienone) moiety is essential for the inhibition of DNA polymerases. Substitution at the 5-position of dehydroaltenusin is important for the inhibitory potency. Because dehydroaltenusin is conjugated with N-acetylcysteine methyl ester at the o-hydroxy-p-benzoquinone moiety, one or more cysteine residues of DNA polymerase a may act as a target for this compound.

Alzheimer's & Dementia, 2022

Machine Learning and Systems Biology in Genomics and Health, 2022

Journal of Veterinary Behavior, 2022

Bulletin of the American Physical Society, 2020

Research and Exploration in Laboratory, 2003

With the development of laboratory, the needs for advanced software increase rapidly. How to impo... more With the development of laboratory, the needs for advanced software increase rapidly. How to import and manage software becomes more and more important. The characteristics of software, the problems during the process of software import and management and the related experience were presented in the paper.

A series of analogs based on a prototype aryl aminothiazole γ-secretase modulator (GSM) were synt... more A series of analogs based on a prototype aryl aminothiazole γ-secretase modulator (GSM) were synthesized and tested for their effects on the profile of 37-to-42-residue amyloid β-peptides (Aβ), generated through processive proteolysis of precursor protein substrate by γ-secretase. Certain substitutions on the terminal aryl D ring resulted in an altered profile of Aβ production compared to that seen with the parent molecule. Small structural changes led to concentration-dependent increases in Aβ37 and Aβ38 production without parallel decreases in their precursors Aβ40 and Aβ42, respectively. The new compounds therefore apparently also stimulate carboxypeptidase trimming of Aβ peptides ≥43 residues, providing novel chemical tools for mechanistic studies of processive proteolysis by γ-secretase.Graphical Abstract

Journal of Neurology, 2020

The article Patient perspectives on the therapeutic profile of botulinum neurotoxin type A in cer... more The article Patient perspectives on the therapeutic profile of botulinum neurotoxin type A in cervical dystonia, written by Cynthia Comella, Joaquim J. Ferreira, Emilie Pain, Marion Azoulai and Savary Om, was originally published electronically on the publisher’s internet portal on 16 September 2020 without open access. With the author(s)’ decision to opt for Open Choice the copyright of the article changed on 25 September 2020 to © The Authors 2020 and this article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made

ABSTRACTThe transmembrane domain (TMD) of the amyloid precursor protein of Alzheimer’s disease is... more ABSTRACTThe transmembrane domain (TMD) of the amyloid precursor protein of Alzheimer’s disease is processively cut by γ-secretase through endoproteolysis and tricarboxypeptidase “trimming”. We recently developed a prototype substrate TMD mimetic for structural analysis—composed of a helical peptide inhibitor linked to a transition-state analog—that simultaneously engages a substrate exosite and the active site and is pre-organized to trap the carboxypeptidase transition state. Here we developed variants of this prototype designed to allow visualization of transition states for endoproteolysis, TMD helix unwinding, and lateral gating of substrate, identifying potent inhibitors for each class. These TMD mimetics exhibited non-competitive inhibition and occupy both exosite and active site as demonstrated by inhibitor cross competition experiments and photoaffinity probe binding assays. The new probes should be important structural tools for trapping different stages of substrate recogn...

Volume 5B: Heat Transfer — General Interest; Internal Air Systems; Internal Cooling, 2021

Transpiration cooling is able to provide more uniform coolant coverage than film cooling to effec... more Transpiration cooling is able to provide more uniform coolant coverage than film cooling to effectively protect the component surface from contacting the hot gas. Due to numerous coolant ejection outlets within a small area at the target surface, the experimental thermo-fluid investigation on transpiration cooing becomes a significant challenge. Two classic methods to investigate film cooling, the steady-state foil heater method and the transient thermography technique, both fail for transpiration cooling because the foil heater would block numerous coolant outlets, and the semi-infinite solid conduction model no longer holds for porous plates. In this study, a micro-lithography method to fabricate a silver coil pattern on top of the additively manufactured polymer porous media as the surface heater was proposed. The circuit was deliberately designed to cover the solid surface in a combination of series connection and parallel connection to ensure the power in each unit cell area at...

The membrane-embedded γ-secretase complex processively cleaves within the transmembrane domain of... more The membrane-embedded γ-secretase complex processively cleaves within the transmembrane domain of amyloid precursor protein (APP) to produce 37-to-43-residue amyloid β-peptides (Aβ) of Alzheimer’s disease (AD). Despite its importance in pathogenesis, the mechanism of processive proteolysis by γ-secretase remains poorly understood. Here, mass spectrometry and western blotting were used to quantify the efficiency of the first tripeptide trimming step (Aβ49→Aβ46) of wildtype (WT) and familial AD (FAD) mutant APP substrate. In comparison to WT APP, the efficiency of this first trimming step was similar for the I45F, A42T and V46F APP FAD mutants, but substantially diminished for the I45T and T48P mutants. In parallel with biochemical experiments, all-atom simulations using a novel Peptide Gaussian accelerated molecular dynamics (Pep-GaMD) method were applied to investigate tripeptide trimming of Aβ49 by γ-secretase. The starting structure was active γ-secretase bound to Aβ49 and APP int...

Journal of Physics G: Nuclear and Particle Physics, 2020

Charge trapping degrades the energy resolution of germanium (Ge) detectors, which require to have... more Charge trapping degrades the energy resolution of germanium (Ge) detectors, which require to have increased experimental sensitivity in searching for dark matter and neutrinoless double-beta decay. We investigate the charge trapping processes utilizing nine planar detectors fabricated from USD-grown crystals with well-known net impurity levels. The charge collection efficiency as a function of charge trapping length is derived from the Shockley-Ramo theorem. Furthermore, we develop a model that correlates the energy resolution with the charge collection efficiency. This model is then applied to the experimental data. As a result, charge collection efficiency and charge trapping length are determined accordingly. Utilizing the Lax model (further developed by CDMS collaborators), the absolute impurity levels are determined for nine detectors. The knowledge of these parameters when combined with other traits such as the Fano factor serve as a reliable indicator of the intrinsic nature of charge trapping within the crystals. We demonstrate that electron trapping is more severe than hole trapping in a p-type detector and the charge collection efficiency depends on the absolute impurity level of the Ge crystal when an adequate bias voltage is applied to the detector. Negligible charge trapping is found when the absolute impurity level is less than 1.0×10 11 /cm 3 for collecting electrons and 2.0×10 11 /cm 3 for collecting holes.

Journal of Medicinal Chemistry, 2020

Biophysical Journal, 2020

Journal of the American Chemical Society, 2020

Amyloid β-peptide, the principal component of characteristic cerebral plaques of Alzheimer’s dise... more Amyloid β-peptide, the principal component of characteristic cerebral plaques of Alzheimer’s disease (AD), is produced through intramembrane proteolysis of the amyloid precursor protein (APP) by γ-secretase. Despite the importance in pathogenesis of AD, the mechanisms of intramembrane proteolysis and substrate processing by γ-secretase remain poorly understood. Here, complementary all-atom simulations using a robust Gaussian accelerated molecular dynamics (GaMD) method and biochemical experiments were combined to investigate substrate processing of wildtype and mutant APP by γ-secretase. The GaMD simulations captured spontaneous activation of γ-secretase, with hydrogen bonded catalytic aspartates and water poised for proteolysis of APP at the ε cleavage site. Furthermore, GaMD simulations revealed that familial AD mutations I45F and T48P enhanced the initial ε cleavage between residues Leu49-Val50, while M51F mutation shifted the ε cleavage site to the amide bond between Thr48-Leu49...