A5013703328- Alzheimer's disease research and treatments
- Computational Drug Discovery Methods
- Cholinesterase and Neurodegenerative Diseases
- Antibiotic Resistance in Bacteria
- Bacterial biofilms and quorum sensing
- Drug Transport and Resistance Mechanisms
- Parkinson's Disease Mechanisms and Treatments
- Wound Healing and Treatments
- Protein Structure and Dynamics
- Supramolecular Self-Assembly in Materials
- Glycosylation and Glycoproteins Research
- Carbohydrate Chemistry and Synthesis
- Chemical Synthesis and Analysis
- Retinoids in leukemia and cellular processes
- Neurological diseases and metabolism
- Antimicrobial Peptides and Activities
- Molecular spectroscopy and chirality
- Bacteriophages and microbial interactions
- Click Chemistry and Applications
- Toxin Mechanisms and Immunotoxins
- Cancer, Hypoxia, and Metabolism
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Vibrio bacteria research studies
- Monoclonal and Polyclonal Antibodies Research
- Diabetic Foot Ulcer Assessment and Management
Rush University Medical Center
2011-2023
Boston College
2018-2022
Amgen (United States)
2011-2020
Rush University
2016
Brigham Young University
2012
Argonne National Laboratory
2008-2011
Southmead Hospital
1997-2006
Leeds Dental Hospital
2002-2006
Bristol Royal Infirmary
1992-2003
University of Bristol
1998-2003
Parkinson's disease (PD) is a neurodegenerative disorder that pathologically characterized by the presence of intracytoplasmic Lewy bodies, major component which are filaments consisting α-synuclein. Two recently identified point mutations in α-synuclein only known genetic causes PD, but their pathogenic mechanism not understood. Here we show both wild type and mutant form insoluble fibrillar aggregates with antiparallel β-sheet structure upon incubation at physiological temperature <i>in...
Parkinson's disease (PD) is a neurodegenerative disorder that pathologically characterized by the presence of intracytoplasmic Lewy bodies, major components which are filaments consisting α-synuclein. Two recently identified point mutations in α-synuclein only known genetic causes PD. α-Synuclein fibrils similar to body can be formedin vitro, and we have shown both PD-linked accelerate their formation. This study addresses mechanism aggregation: show (i) it nucleation-dependent process...
Prior studies suggest that the impaired healing seen in diabetic wounds derives from a state of persistent hyper-inflammation characterized by harmful increases inflammatory leukocytes including macrophages. However, such have focused on at later time points (day 10 or older), and very little attention has been given to dynamics macrophage responses early after injury. Given importance macrophages for process healing, we studied response during late phases wounds. Here, report injury, wound...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTProlines and Aamyloidogenicity in Fragments of the Alzheimer's Peptide .beta./A4Stephen J. Wood, Ronald Wetzel, John D. Martin, Mark R. HurleCite this: Biochemistry 1995, 34, 3, 724–730Publication Date (Print):January 1, 1995Publication History Published online1 May 2002Published inissue 1 January 1995https://pubs.acs.org/doi/10.1021/bi00003a003https://doi.org/10.1021/bi00003a003research-articleACS PublicationsRequest reuse permissionsArticle...
Peptide deformylase (PDF) is an essential bacterial metalloenzyme which deformylates the N-formylmethionine of newly synthesized polypeptides and as such represents a novel target for antibacterial chemotherapy. To identify PDF inhibitors, we screened inhibitor library identified N-formyl-hydroxylamine derivative, BB-3497, related natural hydroxamic acid antibiotic, actinonin, potent selective inhibitors PDF. elucidate interactions that contribute to binding affinity these determined crystal...
Intraneuronal deposition of α-synuclein as fibrils and oxidative stress are both implicated in the pathogenesis Parkinson's disease. We found that critical rate-limiting step nucleation under physiological conditions is formation accumulation a dimeric, dityrosine cross-linked prenucleus. Dimer accelerated for pathogenic A30P A53T mutant α-synucleins, because their greater propensity to self-interact, which reflected smaller values osmotic second virial coefficient compared wild-type...
Using fragment-based screening of a focused fragment library, 2-aminoquinoline 1 was identified as an initial hit for BACE1. Further SAR development supported by X-ray structures BACE1 cocrystallized with various ligands and molecular modeling studies to expedite the discovery potent compounds. These strategies enabled us integrate C-3 side chain on extending deep into P2′ binding pocket enhancing ligand's potency. We were able improve potency subnanomolar range, over 106-fold more than (900...
Abstract A unique, protective cell envelope contributes to the broad drug resistance of nosocomial pathogen Acinetobacter baumannii . Here we use transposon insertion sequencing identify A. mutants displaying altered susceptibility a panel diverse antibiotics. By examining with antibiotic profiles that parallel mutations in characterized genes, infer function multiple uncharacterized proteins, some which have roles division or elongation. Remarkably, affecting predicted wall hydrolase lead...
Parkinson's disease (PD) is a neurodegenerative disorder that pathologically characterized by the presence of intracytoplasmic Lewy bodies. Recently, two point mutations in α-synuclein were found to be associated with familial PD, but as yet no have been described homologous genes β- and γ-synuclein. α-Synuclein forms major fibrillar component bodies, these do not stain for or This result very surprising, given extent sequence conservation high similarity expression subcellular localization,...
While Tn-Seq is a powerful tool to determine genome-wide bacterial fitness in high-throughput, culturing transposon-mutant libraries pools can mask community or other complex single-cell phenotypes. Droplet (dTn-Seq) solves this problem by microfluidics facilitated encapsulation of individual transposon mutants into growth medium-in-oil droplets, thereby enabling isolated growth, free from the influence population. Here we describe and validate microfluidic chip design, production,...
Detailed knowledge on how bacteria evade antibiotics and eventually develop resistance could open avenues for novel therapeutics diagnostics. It is thereby key to a comprehensive genome-wide understanding of process antibiotic stress, modulation the involved processes affects their ability overcome said stress. Here we undertake genetic analysis human pathogen Streptococcus pneumoniae responds 20 antibiotics. We build atlas drug susceptibility determinants generated interaction network that...
Infection is a major co-morbidity that contributes to impaired healing in diabetic wounds. Although impairments neutrophils have been blamed for this co-morbidity, what causes these and whether they can be overcome, remain largely unclear. Diabetic neutrophils, isolated from individuals, exhibit chemotaxis impairment but peculiar functional has ignored because it appears contradict the clinical findings which blame excessive neutrophil influx as impediment chronic ulcers. Here, we report...
Apolipoprotein E is immunochemically localized to amyloid plaque in Alzheimer's brains, and the allelic distribution of ApoE individuals associated with a disposition toward disease. We show here that all three isotypes exhibit strong specific ability inhibit both nucleation seeding fibril formation by Aβ peptide vitro. Aβ(1−40) depleted aggregates requires long incubation times before onset formation, but addition very low levels fibrils such reactions sufficient reduce or eliminate this...
A series of benzofuran derivatives have been identified as inhibitors fibril formation in the β-amyloid peptide. The activity these compounds has assessed by a novel fibril-formation-specific immunoassay and for their effects on production biologically active product. inhibition afforded seems to be associated with binding β-amyloid, scintillation proximity assay. Binding assays NMR studies also indicate that is self-aggregation compounds. There close correlation between benzofurans ability...
A structure- and property-based drug design approach was employed to identify aminooxazoline xanthenes as potent selective human β-secretase inhibitors. These compounds exhibited good isolated enzyme, cell potency, selectivity against the structurally related aspartyl protease cathepsin D. Our efforts resulted in identification of a potent, orally bioavailable CNS penetrant compound that vivo efficacy. single oral dose 11a significant reduction Aβ40 naive rats.
A series of potent hydroxyethyl amine (HEA) derived inhibitors β-site APP cleaving enzyme (BACE1) was optimized to address suboptimal pharmacokinetics and poor CNS partitioning. This work identified a benzodioxolane analogues that possessed improved metabolic stability increased oral bioavailability. Subsequent efforts focused on improving exposure by limiting susceptibility Pgp-mediated efflux an inhibitor which demonstrated robust sustained reduction β-amyloid (Aβ) in Sprague–Dawley rats...