A5051742482- HIV Research and Treatment
- SARS-CoV-2 and COVID-19 Research
- Renin-Angiotensin System Studies
- Immune Cell Function and Interaction
- Protein Kinase Regulation and GTPase Signaling
- Cytokine Signaling Pathways and Interactions
- Immunotherapy and Immune Responses
- HIV/AIDS Research and Interventions
- HIV/AIDS drug development and treatment
- Receptor Mechanisms and Signaling
- COVID-19 Clinical Research Studies
- Animal Virus Infections Studies
- Hormonal Regulation and Hypertension
- Cancer, Stress, Anesthesia, and Immune Response
- Cancer Mechanisms and Therapy
- Neuroscience and Neuropharmacology Research
- Apelin-related biomedical research
- Pancreatic function and diabetes
- Nuclear Receptors and Signaling
- Cytomegalovirus and herpesvirus research
- Blood groups and transfusion
- Protein Tyrosine Phosphatases
- T-cell and B-cell Immunology
- Cell death mechanisms and regulation
- Phosphodiesterase function and regulation
National Institute of Allergy and Infectious Diseases
2022-2025
National Institutes of Health
2022-2025
Nuffield Health
2023
University of Oxford
2021-2023
Medawar Building for Pathogen Research
2021-2023
Emory University
1997-2021
Weizmann Institute of Science
2013-2015
University of Alabama at Birmingham
1999
Germinal center (GC) B cells undergo proliferation at very high rates in a hypoxic microenvironment but the cellular processes driving this are incompletely understood. Here we show that mitochondria of GC highly dynamic, with significantly upregulated transcription and translation associated activity factor A, mitochondrial (TFAM). TFAM, while also necessary for normal cell development, is required entry activated precursor into germinal reaction; deletion Tfam impairs formation, function...
Angiotensin II is the effector molecule of renin-angiotensin system. Virtually all its biochemical actions are mediated through a single class cell-surface receptors called AT1. These contain structural features seven-transmembrane, G-protein-coupled receptor superfamily. II, acting AT1 receptor, also stimulates Jak/STAT pathway by inducing ligand-dependent Jak2 tyrosine phosphorylation and activation. Here, we show that glutathione S-transferase fusion protein containing carboxyl-terminal...
Abstract Pronounced immune escape by the SARS-CoV-2 Omicron variant has resulted in many individuals possessing hybrid immunity, generated through a combination of vaccination and infection. Concerns have been raised that omicron breakthrough infections triple-vaccinated result poor induction omicron-specific prior infection is associated with dampening. Taking broad comprehensive approach, we characterize mucosal blood immunity to spike non-spike antigens following BA.1/BA.2 triple...
The involvement of ceramide in death receptor-mediated apoptosis has been widely examined with most studies focusing on the role generated from sphingomyelin hydrolysis. We now analyze effect acyl chain length by studying tumor necrosis factor α receptor-1 (TNFR1)-mediated a synthase 2 (CerS2) null mouse, which cannot synthesize very-long ceramides. CerS2 mice were resistant to lipopolysaccharide/galactosamine-mediated fulminant hepatic failure even though TNFα secretion macrophages was...
Antibody secreting cells (ASCs) circulate after vaccination and infection migrate to the BM where a subset known as long-lived plasma (LLPCs) persists secrete antibodies for lifetime. The mechanisms by which circulating ASCs become LLPCs are not well elucidated. Here, we show that human blood have distinct morphology, transcriptomes, epigenetics compared with LLPCs. Compared ASCs, decreased nucleus/cytoplasm ratio but increased endoplasmic reticulum numbers of mitochondria. up-regulate...
Angiotensin II (Ang II) and insulin-like growth factor I (IGF I) stimulate intracellular signaling events through binding to their respective G-protein-coupled receptors. In rat aortic vascular smooth muscle cells, IGF (20 ng/ml) induced a sustained (>30 min) increase in the tyrosine phosphorylation of both Src-homology 2 domain-docking insulin receptor substrate 1 (IRS-1) 2-binding phosphatase 1D (PTP-1D). addition, stimulated PTP-1D activity. Ang (10−7m) also increased IRS-1 (4-fold),...
Abstract —p130 Cas is a signaling molecule that was initially found to be tyrosine-phosphorylated in v-Crk and v-Src transformed cells. We characterized the regulation of p130 tyrosine phosphorylation vascular smooth muscle cells by angiotensin II (Ang II). This ligand induced transient increase phosphorylation, which sensitive actin polymerization inhibitor cytochalasin D intracellular Ca 2+ chelator BAPTA-AM but not channel blocker verapamil. The Ang II–induced also dependent on an active...
HIV-1 uses a number of means to manipulate the immune system, avoid recognition and highjack signaling pathways. infected cells show limited Toll-Like Receptor (TLR) responsiveness via as yet unknown mechanisms. Using biochemical biophysical approaches, we demonstrate that trans-membrane domain (TMD) envelope (ENV) directly interacts with TLR2 TMD within membrane milieu. This interaction attenuates TNFα, IL-6 MCP-1 secretion in macrophages, induced by natural ligands both vitro vivo models....
Tumor necrosis factor α (TNFα) is an inflammatory cytokine that plays intimate role in septic shock. Injection of high levels lipopolysaccharide induces shock and death mice within 30 h, whereas ceramide synthase 2 (CerS2) null mice, defective the synthesis very-long acyl chain ceramides, die ∼10 h. The augmented rate CerS2 due to elevated TNFα secretion as a result enhanced activity TNFα-converting enzyme (TACE). We discuss relationship between sphingolipid length TACE relevance this data
Angiotensin II activates the Jak-STAT pathway via AT(1) receptor. We studied two mutant receptors, termed M5 and M6, that contain Y to F substitutions for tyrosine residues naturally found in third intracellular loop carboxyl terminus. After binding ligand, both M6 receptors trigger STAT1 phosphorylation equivalent observed with wild type receptor, indicating angiotensin II-mediated of is independent these receptor residues. In response II, Jak2 autophosphorylates on tyrosine, physically...
Abstract Proteasome inhibitors have achieved clinical success because they trigger intrinsic and extrinsic cell death to eliminate susceptible human cancers. The ubiquitin-proteasome protein degradation system regulates signaling pathways by controlling levels of components such as cellular inhibitor apoptosis (cIAP)1 cIAP2 in TNF-mediated death. Here, we sought evaluate the contribution necroptosis pattern induced specific proteasome Carfilzomib (Cf). inhibitor-sensitive multiple myeloma...
Abstract —The binding of angiotensin II (Ang II) to AT 1 is known increase the kinase activity several nonreceptor tyrosine kinases including Jak2 and c-Src. In present study, we demonstrate that treatment vascular smooth muscle cells with Ang results in a rapid transient association This dependent on catalytically active kinase, because it blocked both by pharmacological means inability inactive associate c-Src bound phosphorylated but was unable bind an equal amount unphosphorylated...
Recent work with interleukins has shown a convergence of tyrosine phosphorylation signal transduction cascades at the level Janus and Src families kinases. Here we demonstrate that activation seven-transmembrane AT<sub>1</sub> receptor by angiotensin II induces physical association between Jak2 Fyn, <i>in vivo</i>. This requires catalytic activity but not Fyn. Deletion studies indicate region binds Fyn is located amino acids 1 240. Studies SH2 SH3 domains domain plays primary role in...
In response to angiotensin II, Jak2 autophosphorylates and binds the II AT(1) receptor. By studying a variety of deletion proteins, we now show that protein motif (231)YRFRR is required for co-association this kinase with We also used full-length containing (231)FAAAA amino acid substitution. Although still autophosphorylated in it did not co-associate This uncoupling indicates AT(1)/Jak2 necessary II-induced autophosphorylation per se insufficient receptor co-association. Jak2-(231)FAAAA...
People living with HIV (PLWH) multidrug-resistant (MDR) viruses have limited therapeutic options and present challenges regarding clinical management. Recent studies shown that passive transfer of combination broadly neutralizing antibodies (bNAbs) against anti-domain 1 CD4 antibody UB-421 can sustain virologic suppression in PLWH the absence antiretroviral therapy (ART). Yet addressing potential these and/or detailed characterization immunologic parameters MDR are lacking. We examined...