A5084640106- HIV/AIDS drug development and treatment
- Poxvirus research and outbreaks
- HIV Research and Treatment
- Click Chemistry and Applications
- Immunotherapy and Immune Responses
- Glycosylation and Glycoproteins Research
- Respiratory viral infections research
- Biochemical and Molecular Research
- Bacillus and Francisella bacterial research
- Cholinesterase and Neurodegenerative Diseases
- Malaria Research and Control
- Ferrocene Chemistry and Applications
- Cell death mechanisms and regulation
- vaccines and immunoinformatics approaches
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Synthesis and Biological Evaluation
- RNA and protein synthesis mechanisms
- PI3K/AKT/mTOR signaling in cancer
- Protein Tyrosine Phosphatases
- 14-3-3 protein interactions
- Trypanosoma species research and implications
- Protein Kinase Regulation and GTPase Signaling
- Cytokine Signaling Pathways and Interactions
- Viral gastroenteritis research and epidemiology
- Phosphodiesterase function and regulation
United States Military Academy
2008-2025
University of California, San Francisco
2015-2025
Merck & Co., Inc., Rahway, NJ, USA (United States)
2011-2019
National Institute of Allergy and Infectious Diseases
1993-2016
National Institutes of Health
2005-2016
Shandong University
2009-2010
University of Virginia
2000-2002
Carter Center
2000
Signaling through the programmed death 1 (PD-1) inhibitory receptor upon binding its ligand, PD-L1, suppresses immune responses against autoantigens and tumors plays an important role in maintenance of peripheral tolerance. Release from PD-1 signaling revives "exhausted" virus-specific T cells chronic viral infections. Here we present crystal structure murine complex with human PD-L1. PD-L1 interact conserved front side their Ig variable (IgV) domains, as do IgV domains antibodies cell...
The prompt clearance of cells undergoing apoptosis is critical during embryonic development, normal tissue turnover, as well inflammation and autoimmunity. molecular details the engulfment apoptotic are not fully understood. ced-6 its human homologue gulp, encode an adapter protein, whose function in highly evolutionarily conserved; however, upstream downstream components CED-6 mediated signaling known. Recently, ced-1 has been shown to a transmembrane protein on phagocytic cells, with two...
Abstract Respiratory syncytial virus (RSV) infection is the leading cause of hospitalization and infant mortality under six months age worldwide; therefore, prevention RSV in all infants represents a significant unmet medical need. Here we report isolation potent broadly neutralizing monoclonal antibody derived from human memory B-cell. This antibody, RB1, equipotent on A B subtypes, potently neutralizes diverse panel clinical isolates vitro demonstrates vivo protection. It binds to highly...
The smallpox vaccine is widely considered the gold standard for human vaccines, yet key antibody targets in humans remain unclear. We endeavored to identify a stereotypic, dominant, mature virion (MV) neutralizing target which could be used as diagnostic serological marker of protective humoral immunity induced by (vaccinia virus [VACV]). have instead found that diversity defining characteristic response vaccine. show H3 most immunodominant VACV target, determined correlation analysis...
ABSTRACT HIV/AIDS continues to be a menace public health. Several drugs currently on the market have successfully improved ability manage viral burden in infected patients. However, new are needed combat rapid emergence of mutated forms virus that resistant existing therapies. Currently, approved target three four major enzyme activities encoded by critical HIV life cycle. Although number inhibitors RNase H activity been reported, few inhibit directly engaging active site. Here, we describe...
The JAK-STAT pathway mediates signaling by cytokines, which control survival, proliferation, and differentiation of a variety cells. In recent years, single point mutation (V617F) in the tyrosine kinase JAK2 was found to be present with high incidence myeloproliferative disorders (MPDs). This led hyperactivation JAK2, cytokine-independent signaling, subsequent activation downstream networks. genetic, biological, physiological evidence suggests that inhibitors could effective treating MPDs....
We have identified several series of small molecule inhibitors TrkA with unique binding modes. The starting leads were chosen to maximize the structural and mode diversity derived from a high throughput screen our internal compound collection. These optimized for potency selectivity employing structure based drug design approach adhering principles ligand efficiency affinity without overly relying on lipophilic interactions. This endeavor resulted in identification pan-Trk inhibitor that...
The highly conserved H3 poxvirus protein is a major target of the human antibody response against poxviruses and likely key contributor to protection infection. Here, we present crystal structure from vaccinia virus at 1.9-Å resolution. looks like glycosyltransferase, family enzymes that transfer carbohydrate molecules variety acceptor substrates. Like glycosyltransferases, binds UDP-glucose, as shown by saturation difference (STD) nuclear magnetic resonance (NMR) spectroscopy, this binding...
A novel, highly diastereoselective, and metal-free synthesis of multisubstituted piperidines via an SN1 approach is reported in this study. The method allows for the preparation functionalized compounds with exceptional diastereomeric selectivities consistently reproducible yields. These are significant interest due to their remarkable biological activities toward influenza endonuclease.
Background: Endovascular thrombectomy (EVT) has improved both short-term and long-term outcomes for acute ischemic stroke (AIS) patients caused by large vessel occlusion (LVO). However, the relationships between blood pressure (BP) after EVT had not been determined. As BP is dynamically changes, present study investigated effects of trajectories on in AIS with LVO using Group-Based Trajectory Modeling (GBTM). Methods: This was a retrospective, single-center observational study. The anterior...
Current therapies for chronic pain can have insufficient efficacy and lead to side effects, necessitating research of novel targets against pain. Although originally identified as an oncogene, Tropomyosin-related kinase A (TrkA) is linked elevated levels NGF (the ligand TrkA) are associated with Antibodies that block TrkA interaction its ligand, NGF, in clinical trials relief. Here, we describe the identification TrkA-specific inhibitors structural basis their selectivity over other Trk...
Using the HIV-1 protease binding mode of MK-8718 and PL-100 as inspiration, a novel aspartate bicyclic piperazine sulfonamide core was designed synthesized. The resulting inhibitor containing this showed an 60-fold increase in enzyme affinity 10-fold antiviral activity relative to MK-8718.
Although eradicated from nature more than two decades ago, the threat of smallpox has reemerged because concerns over its use as a biological weapon. We present structure poxvirus L1 protein, molecule that is conserved throughout family and nearly identical in vaccinia virus variola virus, which causes smallpox. myristoylated envelope protein potent target for neutralizing antibodies an important component current experimental vaccines. The reveals hydrophobic cavity located adjacent to N...
Plasmodium falciparum malaria parasites, living in red blood cells, express proteins of the erythrocyte membrane protein-1 (PfEMP1) family on cell surface. The binding PfEMP1 molecules to human surface receptors mediates adherence infected cells tissues. sequences 60 genes each parasite genome vary greatly from parasite, yet variant maintain receptor binding. Almost all parasites isolated directly patients bind CD36 receptor. Of several kinds highly polymorphic cysteine-rich interdomain...
The inositol phosphatase SHIP binds to the FcγRIIB1 receptor and plays a critical role in FcγRIIB1-mediated inhibition of B-cell proliferation immunoglobulin synthesis. molecular details function are not fully understood. While point mutations signature motifs domain abolish SHIP's ability inhibit calcium flux B cells, little is known about evolutionarily conserved, putative noncatalytic regions vivo. In this study, through systematic mutagenesis approach, we identified between amino acids...
ABSTRACT The current vaccine against smallpox is an infectious form of vaccinia virus that has significant side effects. Alternative approaches using recombinant viral proteins are being developed. A target subunit strategies the poxvirus protein A33, a conserved in Chordopoxvirinae subfamily Poxviridae expressed on outer envelope. Here we have determined structure A33 ectodomain virus. revealed C-type lectin-like domains (CTLDs) occur as dimers crystals with five different crystal lattices....
Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infection in young children and older adults. Currently, no licensed vaccine available, therapeutic options are limited. The primary target neutralizing antibodies to RSV the surface fusion (F) glycoprotein. Understanding recognition with high neutralization potencies F antigen will provide critical insights developing efficacious vaccines. In this study, we isolated characterized panel monoclonal (mAbs) binding...
Phagocytosis of apoptotic cells is a key step in the completion programmed cell death that occurs throughout life multicellular organisms. The molecular events involved clearance are just beginning to be elucidated. Recently, CED-6, an adapter protein engulfment has been cloned in<i>Caenorhabditis elegans</i> and humans. CED-6 composed phosphotyrosine-binding (PTB) domain proline-rich C-terminal with no apparent catalytic domain. Since PTB domains, originally identified Shc, mediate...
Prostasin (also called channel activating protease-1 (CAP1)) is an extracellular serine protease implicated in the modulation of fluid and electrolyte regulation via proteolysis epithelial sodium channel. Several disease states, particularly hypertension, can be affected by activity. Thus, understanding biochemical function prostasin developing specific agents to inhibit its activity could have a significant impact on widespread disease. We report expression proenzyme Escherichia coli as...