A5010535788- Parasitic Infections and Diagnostics
- Bacterial Genetics and Biotechnology
- Biochemical and Molecular Research
- Escherichia coli research studies
- RNA and protein synthesis mechanisms
- Bacteriophages and microbial interactions
- Carbohydrate Chemistry and Synthesis
- Sleep and Wakefulness Research
- Pancreatic function and diabetes
- Antibiotic Resistance in Bacteria
- Protein Tyrosine Phosphatases
- Orthopedic Infections and Treatments
- Pneumocystis jirovecii pneumonia detection and treatment
- Colorectal Cancer Treatments and Studies
- Regulation of Appetite and Obesity
- PI3K/AKT/mTOR signaling in cancer
- Lipid metabolism and biosynthesis
- Protein Structure and Dynamics
- Cancer-related Molecular Pathways
- Legume Nitrogen Fixing Symbiosis
- Veterinary medicine and infectious diseases
- HIV/AIDS drug development and treatment
- Neuroscience and Neuropharmacology Research
- Diet, Metabolism, and Disease
- Enzyme Structure and Function
Frederick National Laboratory for Cancer Research
2024-2025
Yale University
2008-2024
Wesleyan University
2011-2018
We have previously demonstrated that modulation of gamma-aminobutyric acid (GABA) inhibitory tone in the ventromedial hypothalamus (VMH), an important glucose-sensing region brain, modulates magnitude glucagon and sympathoadrenal responses to hypoglycemia. In current study, we examined whether increased VMH GABAergic may contribute suppression counterregulatory after recurrent hypoglycemia.To test this hypothesis, quantified expression GABA synthetic enzyme, glutamic decarboxylase (GAD),...
Mutations in RAS and PI3Kα are major drivers of human cancer. Their interaction plays a crucial role activating amplifying the PI3K-AKT-mTOR pathway. Disrupting RAS-PI3Kα enhances survival lung skin cancer models reduces tumor growth angiogenesis, although structural details this remain unclear. Here, we present structures KRAS, RRAS2, MRAS bound to catalytic subunit (p110α) PI3Kα, elucidating interfaces local conformational changes upon complex formation. Structural mutational analyses...
Local delivery of glucose into a critical glucose-sensing region within the brain, ventromedial hypothalamus (VMH), can suppress counterregulatory responses to systemic hypoglycemia. Here, we investigated whether this suppression was accomplished through changes in GABA output VMH. Sprague-Dawley rats had catheters and guide cannulas implanted. Eight ten days later, microdialysis-microinjection probes were inserted VMH, they dialyzed with varying concentrations from 0 100 mM. Two groups...
OBJECTIVE Impaired glucose counterregulation during hypoglycemia is well documented in patients with type 1 diabetes; however, the molecular mechanisms underlying this defect remain uncertain. We reported that inhibitory neurotransmitter γ-aminobutyric acid (GABA), a crucial glucose-sensing region within brain, ventromedial hypothalamus (VMH), plays an important role modulating magnitude of glucagon and epinephrine responses to investigated whether VMH GABAergic tone altered diabetes...
Abstract PI3Kα is the most mutated kinase and second oncogene in human cancer. Activation of PI3Ka can be achieved by receptor tyrosine kinases such as insulin insulin-like growth factor 1 and/or directly interacting with RAS family members. Previous elegant preclinical studies have established that RAS-driven activation important tumor cells but may not involved cell types controlling glucose metabolism. Alpelisib, a small molecule inhibitor activity PI3Ka, has been approved for treatment...
Heptosyltransferase I (HepI) is responsible for the transfer of l-glycero-d-manno-heptose to a 3-deoxy-α-d-oct-2-ulopyranosonic acid (Kdo) growing core region lipopolysaccharide (LPS). The catalytic efficiency HepI with fully deacylated analogue Escherichia coli LipidA 12-fold greater than acylated substrate, kcat/Km 2.7 × 106 M–1 s–1, compared value 2.2 105 s–1 Kdo2-LipidA substrate. Not only this first demonstration that an LPS biosynthetic enzyme catalytically enhanced by absence lipids,...
Heptosyltransferase I (HepI) catalyzes the addition of l-glycero-β-d-manno-heptose to Kdo2-Lipid A, as part biosynthesis core region lipopolysaccharide (LPS). Gram-negative bacteria with gene knockouts HepI have reduced virulence and enhanced susceptibility hydrophobic antibiotics, making design inhibitors interest. Because protein dynamics are partially rate-limiting, disruption might provide a new strategy for inhibiting HepI. Discerning global mechanism is anticipated aid development LPS...
Heptosyltransferase I (HepI), the enzyme responsible for transfer of l-glycero-d-manno-heptose to a 3-deoxy-α-d-manno-oct-2-ulopyranosonic acid (Kdo) growing core region lipopolysaccharide, is member GT-B structural class enzymes. Crystal structures have revealed open and closed conformations apo ligand-bound enzymes, implying that large-scale protein conformational dynamics play role in their reaction mechanism. Here we report transient kinetic analysis changes HepI reported by intrinsic...
Thymidylate synthase (TS), found in all organisms, is an essential enzyme responsible for the de novo synthesis of deoxythymidine monophosphate. The TS active sites protozoal parasite Cryptosporidium hominis and human are relatively conserved. Evaluation antifolate compound 1 its R-enantiomer 2 against both enzymes reveals divergent inhibitor selectivity stereospecificity. To establish how C. (ChTS hTS) selectively discriminate 2, respectively, we determined crystal structures ChTS complexed...
Enteric-coated oral nanotherapy shows in vivo anticryptosporidial efficacy.
HepI (heptosyltransferase I from E. coli) catalyzes the addition of heptose ADP-β-L-glycero-D-manno-heptose (ADPH) onto Kdo 2-Lipid A, a crucial step in formation lipopolysaccharides (LPS) Gram-negative bacteria. LPS is major cell surface component that maintains structural integrity bacterial outer membrane, contributes to biofilms, and provides protection extracellular hazards. Disruption has been shown result truncated LPS, resulting bacteria display increased susceptibility hydrophobic...