A5033467844- Diabetes and associated disorders
- Pancreatic function and diabetes
- Diet, Metabolism, and Disease
- Peptidase Inhibition and Analysis
- Ubiquitin and proteasome pathways
- RNA Research and Splicing
- Amino Acid Enzymes and Metabolism
- Alzheimer's disease research and treatments
- Biotin and Related Studies
- DNA and Nucleic Acid Chemistry
- Systemic Sclerosis and Related Diseases
- Cellular Mechanics and Interactions
- Nuclear Structure and Function
- Metabolomics and Mass Spectrometry Studies
- Cardiomyopathy and Myosin Studies
- Bioinformatics and Genomic Networks
- Signaling Pathways in Disease
- Genomics and Chromatin Dynamics
- Advanced Proteomics Techniques and Applications
- Drug Transport and Resistance Mechanisms
- Extracellular vesicles in disease
- Glycosylation and Glycoproteins Research
- Advanced biosensing and bioanalysis techniques
- Mitochondrial Function and Pathology
- Biochemical and Molecular Research
W. M. Keck Foundation
2015-2025
Yale University
2014-2024
University of South Carolina Upstate
2024
Max Planck Institute of Biochemistry
2022
University of Pennsylvania
1996-1997
University of Waterloo
1996
Drexel University
1996
This study identifies an unusual sulfur-based chemical as a novel and specific inhibitor of the tyrosine phosphatase STEP shows that it can improve cognitive function mouse model Alzheimer's disease.
Fibrocytes are collagen-producing leukocytes that accumulate in patients with systemic sclerosis (SSc; scleroderma)-related interstitial lung disease (ILD) via unknown mechanisms have been associated altered expression of neuroimmune proteins. The extracellular matrix (ECM) influences cellular phenotypes. However, a relationship between the ECM and fibrocytes SSc has not explored. aim this study was to use novel translational platform based on decellularized human lungs determine whether...
Inflammation, including reactive oxygen species and inflammatory cytokines in tissues amplify various post-translational modifications of self-proteins. A number have been identified as autoimmune biomarkers the initiation progression Type 1 diabetes. Here we show citrullination pancreatic glucokinase a result inflammation, triggering autoimmunity affecting biological functions. Glucokinase is expressed hepatocytes to regulate glycogen synthesis, beta cells glucose sensor initiate glycolysis...
Dystrophic neurites (also termed axonal spheroids) are found around amyloid deposits in Alzheimer's disease (AD), where they impair electrical conduction, disrupt neural circuits and correlate with AD severity. Despite their importance, the mechanisms underlying spheroid formation remain incompletely understood. To address this, we developed a proximity labeling approach to uncover proteome of spheroids human postmortem mouse brains. Additionally, established induced pluripotent stem cell...
Objective Systemic sclerosis–associated interstitial lung disease (SSc‐ILD) is characterized by variable clinical outcomes, activation of innate immune pattern‐recognition receptors (PRRs), and accumulation α‐smooth muscle actin (α‐SMA)–expressing myofibroblasts. The aim this study was to identify an association between these entities mitochondrial DNA (mtDNA), endogenous ligand for the intracellular DNA–sensing PRRs Toll‐like receptor 9 (TLR‐9) cyclic GMP‐AMP synthase/stimulator interferon...
The arrangement and stacking of noncovalently contiguous double-helical sections are increasingly invoked in single-stranded DNA RNA tertiary structure. These structures nucleic acids defined by their double stranded regions, orientation the molecular frame constitutes an important component acid A direct view these can be obtained fluorescence polarization anisotropy bound ethidium bromide (EB). dye yields helix. complete function for EB intercalated genome-derived duplexes was derived...
ARPP-16, ARPP-19, and ENSA are inhibitors of protein phosphatase PP2A. ARPP-19 phosphorylated by Greatwall kinase inhibit PP2A during mitosis. ARPP-16 is expressed in striatal neurons where basal phosphorylation MAST3 inhibits regulates key components signaling. The ARPP-16/19 proteins were discovered as substrates for PKA, but the function PKA unknown. We find that or mutually suppresses ability other to act on ARPP-16. Phosphorylation also acts prevent inhibition MAST3. Moreover,...
Inflammation and oxidative stress in pancreatic islets amplify the appearance of various posttranslational modifications to self-proteins. In this study, we identified a select group carbonylated islet proteins arising before onset hyperglycemia NOD mice. Of interest, carbonyl modification prolyl-4-hydroxylase β subunit (P4Hb) that is responsible for proinsulin folding trafficking as an autoantigen both human murine type 1 diabetes. We found P4Hb amplified stressed coincident with decreased...
Argonaute 2 (AGO2) is a ubiquitously expressed protein critical for regulation of mRNA translation and vital to animal development. AGO2 found in both cytoplasmic nuclear compartments, although its role well studied, the biological relevance unclear. Here, we address this problem vivo using spermatogenic cells as model. We find that transiently binds chromatin nucleus-specific transcripts hundreds genes required sperm production during male meiosis mice, germline conditional knockout (cKO)
Abstract Photosystem II (PSII) is a multi‐subunit protein‐pigment complex with diverse redox‐active cofactors, which enabled the biological availability of O 2 on Earth. The substrate specificity and underlying redox chemistry Mn 4 CaO 5 catalytic center are investigated using alternate substrates such as small molecules (ammonia methanol) halides (Cl ‐ , Br I ) instead natural water. Changes in kinetic profiles steady‐state evolution dichlorophenolindophenol (DCIP) photochemical reduction...
Aromatase CYP19A1 catalyzes the synthesis of estrogens in endocrine, reproductive and central nervous systems. Higher levels 17β-estradiol (E2) are associated with malignancies diseases breast, ovary endometrium, while low E2 increase risk for osteoporosis, cardiovascular cognitive disorders. E2, transcriptional activator estrogen receptors, is also known to be involved non-genomic signaling as a neurotransmitter/neuromodulator, recent evidence rapid (RES) within synaptic terminal. Although...
Mitogen-activated protein kinase 4 (MAP4K4) regulates the MEK cascade and is implicated in cytoskeletal rearrangement migration; however, identifying MAP4K4 substrates has remained a challenge. To ascertain MAP4K4-dependent phosphorylation events, we combined phosphoproteomic studies of inhibition with vitro assessment its specificity. We identified 235 phosphosites affected by cells found that pTP pSP motifs were predominant among them. In contrast, specificity showed favors pTL motif....
Protein ubiquitylation is an important posttranslational modification affecting a wide range of cellular processes. Due to the low abundance ubiquitylated species in biological samples, considerable effort has been spent on methods purify and detect proteins. We have developed characterized novel tool for ubiquitin detection purification based OtUBD, high-affinity ubiquitin-binding domain (UBD) derived from Orientia tsutsugamushi deubiquitylase (DUB). demonstrate that OtUBD can be used both...
Tissue mechanical properties are determined mainly by the extracellular matrix (ECM) and actively maintained resident cells. Despite its broad importance to biology medicine, tissue homeostasis remains poorly understood. To explore cell-mediated control of stiffness, we developed mutations in mechanosensitive protein talin 1 alter cellular sensing ECM. Mutation a site between rod-domain helix bundles R1 R2 increased cell spreading tension exertion on compliant substrates. These promote...
Abstract It is widely believed that tissue mechanical properties, determined mainly by the extracellular matrix (ECM), are actively maintained. However, despite its broad importance to biology and medicine, homeostasis poorly understood. To explore this hypothesis, we developed mutations in mechanosensitive protein talin1 alter cellular sensing of ECM stiffness. Mutation a novel site between rod domain helix bundles 1 2 (R1 R2) shifted stiffness curves, enabling cells spread exert tension on...
Age is the most significant risk factor for Alzheimer's disease (AD), and understanding its role in specific aspects of AD pathology will be critical therapeutic development. Neurofibrillary tangles composed hyperphosphorylated tau are a quintessential hallmark AD. To study age-related changes phosphorylation, we developed simple, antibody-free approach single shot analysis phosphorylation across entire protein by liquid-chromatography tandem mass spectrometry. This methodology species...
1. Hexamethylenediisocyanate (HDI) is a widely used aliphatic diisocyanate and well-recognized cause of occupational asthma.2. “Self” molecules (peptides/proteins) in the lower airways, susceptible to chemical reactivity with HDI, have been hypothesized play role asthma pathogenesis and/or metabolism, but remain poorly characterized.3. This study employed unique approaches identify characterize “self” targets HDI airways. Anesthetized rabbits free breathed through tracheostomy tube connected...
The pathogen Mycobacterium tuberculosis (M.tb) resides in human macrophages, wherein it exploits host lipids for survival. However, little is known about the interaction between M.tb and macrophage plasmalogens, a subclass of glycerophospholipids with vinyl ether bond at sn-1 position glycerol backbone. Lysoplasmalogens, produced from plasmalogens by hydrolysis sn-2 carbon phospholipase A
The nucleocapsid (N) protein of coronavirus becomes heavily phosphorylated within its central Ser-Arg (SR) domain by host glycogen synthase kinase-3 (GSK-3) after the virus enters cell. GSK-3 is a unique Ser/Thr kinase, preferring substrates that are another kinase four residues downstream own phosphorylation site. biochemical mechanism N hyperphosphorylation, and functional significance, were not completely understood. Here we present mass spectrometry data showing GSK-3-mediated highly...
Upon entry into host cells, the nucleocapsid (N) protein of coronavirus becomes heavily phosphorylated within its central Ser-Arg domain by glycogen synthase kinase-3 (GSK-3). Most substrates for GSK-3 need to be phosphorylated, or primed, another Ser/Thr kinase four residues downstream phosphorylation site. It was widely assumed that hyperphosphorylation SARS-CoV-2s N requires independent priming at Ser-188 and Ser-206, which initiates sequential GSK-3. Here we present biochemical mass...
Polyadenylation controls mRNA biogenesis, nucleo-cytoplasmic export, translation and decay. These processes are interdependent coordinately regulated by poly(A)-binding proteins (PABPs), yet how PABPs themselves is not fully understood. Here, we report the discovery that human nuclear PABPN1 phosphorylated mitotic kinases at four specific sites during mitosis, a time when nucleoplasm cytoplasm mix. To understand functional consequences of phosphorylation, generated panel stable cell lines...