A5024935006- Computational Drug Discovery Methods
- Cholinesterase and Neurodegenerative Diseases
- Pesticide Exposure and Toxicity
- Endoplasmic Reticulum Stress and Disease
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Phagocytosis and Immune Regulation
- Animal testing and alternatives
- Kruppel-like factors research
- Metabolomics and Mass Spectrometry Studies
- Environmental Toxicology and Ecotoxicology
- Galectins and Cancer Biology
- Chemistry and Chemical Engineering
- Immune Cell Function and Interaction
- Protein Structure and Dynamics
- Chronic Myeloid Leukemia Treatments
- Renal Diseases and Glomerulopathies
- Hydrogen's biological and therapeutic effects
- Chemical Reaction Mechanisms
- Lipid metabolism and disorders
- Biomedical Research and Pathophysiology
- Neuroscience and Neuropharmacology Research
- Neurological diseases and metabolism
- Antimicrobial agents and applications
- Ear Surgery and Otitis Media
- Lysosomal Storage Disorders Research
Dow Chemical (United States)
2018-2024
European Centre for Ecotoxicology and Toxicology of Chemicals
2024
FMC (United States)
2020-2023
University of Michigan–Ann Arbor
2009-2021
Bipar
2004-2015
la diffusion de documents scientifiques niveau recherche, publiés ou non, émanant des établissements d'enseignement et recherche français étrangers, laboratoires publics privés.
Abstract Calreticulin is a calcium-binding chaperone that normally localized in the endoplasmic reticulum. detectable on surface of apoptotic cells under some apoptosis-inducing conditions, where it promotes phagocytosis and immunogenicity dying cells. However, precise mechanism by which calreticulin, soluble protein, localizes to outer plasma membrane unknown, as are molecular mechanisms relevant calreticulin-induced cellular phagocytosis. comprises three distinct structural domains:...
Calreticulin is a soluble calcium-binding chaperone of the endoplasmic reticulum (ER) that also detected on cell surface and in cytosol. contains single high affinity site within globular domain multiple low sites C-terminal acidic region. We show secondary structure calreticulin remarkably thermostable at given calcium concentration. Rather than corresponding to complete unfolding events, heat-induced structural transitions observed for relate tertiary changes expose hydrophobic residues...
Calreticulin is an endoplasmic reticulum chaperone with specificity for monoglucosylated glycoproteins. also inhibits precipitation of nonglycosylated proteins and thus contains generic protein-binding sites, but their location contributions to substrate folding are unknown. We show that calreticulin binds glycosylated similar affinities distinct interaction kinetics. Although both interactions involve the glycan-binding site or its vicinity, arm-like proline-rich (P-) domain contributes...
Patatin is a non-specific plant lipase and the eponymous member of broad class serine hydrolases termed patatin-like phospholipase domain containing proteins (PNPLAs). Certain PNPLA family members can be inhibited by organophosphorus (OP) compounds. Currently, no structural data are available on modes interaction between PNPLAs OP compounds or their native substrates. To this end, we present crystal structure patatin-17 (pat17) in its state as well following inhibition with methyl...
We present a mechanistic machine-learning quantitative structure-activity relationship (QSAR) model to predict mammalian acute oral toxicity. trained our using rat toxicity database compiled by the US National Toxicology Program. profiled new and published profilers identified most plausible mechanisms that drive high (LD50 ≤ 50 mg/kg; GHS categories 1 or 2). Our QSAR assigns primary compounds, followed predicting their LD50 random-forest model. These predictions were further refined based...
The MHC class I peptide loading complex (PLC) facilitates the assembly of molecules with peptides, but factors that regulate stability and dynamics are largely uncharacterized. Based on initial findings ATP, in addition to I-specific peptide, is able induce dissociation from PLC, we investigated interaction ATP chaperone calreticulin, an endoplasmic reticulum (ER) luminal, calcium-binding component PLC known bind ATP. We combined computational experimental measurements identify residues...
It is prudent to assess the chemical reactivity of compounds during early stages product development, given that formation covalent adducts between electrophilic and biological nucleophiles serves as molecular initiating event in a range adverse outcome pathways (AOPs). In vitro assays such direct peptide assay (DPRA) have been developed facile reactivity. However, these approaches still require test material laboratory resources, are less conducive rapid high-throughput screening than...
Myeloproliferative neoplasms (MPNs) are frequently driven by mutations within the C-terminal domain (C-domain) of calreticulin (CRT). CRTDel52 and CRTIns5 recurrent mutations. Oncogenic transformation requires both mutated CRT thrombopoietin receptor (Mpl), but molecular mechanism CRT-mediated constitutive activation Mpl is unknown. We show that acquired C-domain mediates binding disulfide-linked dimerization. Cysteine novel (C400A C404A) conserved N-terminal (N-domain; C163A) required to...
Astrocytes are acutely sensitive to 1,3-dinitrobenzene (1,3-DNB) while adjacent neurons relatively unaffected, consistent with other chemically-induced energy deprivation syndromes.Previous studies have investigated the role of astrocytes in protecting from hypoxia and chemical injury via adenosine release.Adenosine is considered neuroprotective, but it rapidly removed by extracellular deaminases such as deaminase (ADA).The present study tested hypothesis that ADA inhibited 1,3-DNB a...
We are developing computational approaches for mechanisms of acute toxicity. Facile chemical reactivity involves formation covalent adducts between electrophiles and nucleophiles can be molecular initiating events adverse outcome pathways. Using an open-source Konstanz Information Miner workflow, we developed a profiler to identify reactive moieties that covers five chemically facile-reactive classes: (1) Michael acceptors, (2) Schiff base formation, (3) acylation, (4) nucleophilic aromatic...
Introduction: We are using big-data mining to develop computational models that predict whether previously uncharacterized compounds will or not target important biological pathways. Mitochondria play essential life-sustaining roles, with their dysfunction linked diverse pathologies. Materials and Methods: built a mitochondrial inhibition model combines molecular scaffolding fingerprinting of large database compiled primarily from in vitro high-throughput screening (HTS) data. refined the...
Introduction: We are developing computational models for basic nervous system pathways use in toxicology, pharmacology, and medicine. γ-Amino butyric acid (GABA) is the major inhibitory neurotransmitter central system, acts through GABAA (cys-loop) or GABAB (G-protein–coupled) receptors. Materials Methods: mined publicly available data compounds reported to interact (actives) not (negative controls) with either of these receptors, used train binary random-forest machine-learning predict such...