A5045264502- Protein Kinase Regulation and GTPase Signaling
- Electrocatalysts for Energy Conversion
- Melanoma and MAPK Pathways
- Prostate Cancer Treatment and Research
- Plant-based Medicinal Research
- Bacillus and Francisella bacterial research
- Virus-based gene therapy research
- Estrogen and related hormone effects
- Copper-based nanomaterials and applications
- Sports injuries and prevention
- Viral Infections and Immunology Research
- Chinese history and philosophy
- Cancer Mechanisms and Therapy
- Computational Drug Discovery Methods
- Viral Infectious Diseases and Gene Expression in Insects
- Yersinia bacterium, plague, ectoparasites research
- Blood Coagulation and Thrombosis Mechanisms
- PI3K/AKT/mTOR signaling in cancer
- Chemical Synthesis and Analysis
- Mosquito-borne diseases and control
- Lipid Membrane Structure and Behavior
- Hormonal and reproductive studies
- Bacteriophages and microbial interactions
- Angiogenesis and VEGF in Cancer
- Viral gastroenteritis research and epidemiology
Harvard University
2021-2025
Spaulding Rehabilitation Hospital
2021-2025
CRUK Lung Cancer Centre of Excellence
2024
Cancer Institute (WIA)
2024
AstraZeneca (United Kingdom)
2012-2022
Mayo Clinic in Arizona
2022
Colgate University
2000-2022
Brigham and Women's Hospital
2021
European Synchrotron Radiation Facility
2018
Royal Botanic Garden Sydney
2015
Herein we describe the molecular Co(4)O(4) cubane complex Co(4)O(4)(OAc)(4)(py)(4) (1), which catalyzes efficient water oxidizing activity when powered by a standard photochemical oxidation source or electrochemical oxidation. The pH dependence of catalysis, turnover frequency, and in situ monitoring catalytic species have revealed intrinsic capabilities this core type. 1 analogous Mn(4)O(4) complexes is attributed to cubical topology, that nature's catalyst, CaMn(4)O(5) cluster.
Markovian models of protein evolution that relax the assumption independent change among codons are considered. With this comparatively realistic framework, an evolutionary rate at a site can depend both on state and states surrounding sites. By allowing relatively general dependence structure sites, reflect attributes tertiary structure. To quantify impact evolution, we analyze protein-coding DNA sequence pairs with model incorporates effects solvent accessibility pairwise interactions...
Who can split water? Two polymorphs of nanocrystalline cubic spinel and rhombohedral layered lithium cobalt oxides have been prepared their application in the photocatalytic oxidation water examined. The main factor that determines catalytic activity different phases is presence a Co4O4 core, which present form catalyst, but not structure (see scheme). development catalysts (WOCs) to replace costly noble metals commercial electrolyzers solar fuel cells an unmet need preventing global...
KRAS is an archetypal high-value intractable oncology drug target. The glycine to cysteine mutation at codon 12 represents Achilles heel that has now rendered this important GTPase druggable. Herein, we report our structure-based design approach led the identification of 21, AZD4625, a clinical development candidate for treatment KRASG12C positive tumors. Highlights include quinazoline tethering strategy lock out bio-relevant binding conformation and optimization focused on reduction...
The metal-oxo M4O4 "cubane" topology is of special significance to the field water oxidation as it represents merging bioinspired structural principles derived from natural photosynthesis with successful artificial catalysts known date. Herein, we directly compare rates oxidation/O2 evolution catalyzed by six cobalt-oxo clusters including Co4O4 cubanes, Co4O4(OAc)4(py)4 and [Co4O4(OAc)2(bpy)4](2+), using common Ru(bpy)3(2+)/S2O8(2-) photo-oxidant assay. At pH 8, first-order rate constants...
Abstract Continued androgen receptor (AR) expression and signaling is a key driver in castration-resistant prostate cancer (CRPC) after classical ablation therapies have failed, therefore remains target for the treatment of progressive disease. Here, we describe biological characterization AZD3514, an orally bioavailable drug that inhibits androgen-dependent -independent AR signaling. AZD3514 modulates through two distinct mechanisms, inhibition ligand-driven nuclear translocation...
Attempts to directly drug the important oncogene KRAS have met with limited success despite numerous efforts across industry and academia. The KRASG12C mutant represents an "Achilles heel" has recently yielded covalent targeting small molecules that bind cysteine create allosteric pocket on GDP-bound RAS, locking it in inactive state. A weak inhibitor at this site was optimized through conformational of a piperazine-quinazoline motif linker modification. Subsequent introduction key methyl...
With a resurgence in interest covalent drugs, there is need to identify new moieties capable of cysteine bond formation that are differentiated from commonly employed systems such as acrylamide. Herein, we report on the discovery alkynyl benzoxazine and dihydroquinazoline reaction with cysteine. Their utility alternative electrophilic warheads for chemical biological probes drug molecules demonstrated through site-selective protein modification incorporation into kinase scaffolds. A potent...
Background: Previous research has reported higher rates of both injury and illness among Paralympic athletes compared with Olympic during the Winter Games, but no studies have directly incidence between competing in a Summer Games. Purpose: To compare Team USA Tokyo 2020 Study Design: Descriptive epidemiology study. Methods: All injuries illnesses that occurred or Games were documented. A total 701 (53.6% female) competed across 34 different sports. For 245 (51.6% 20 Incidence (IRs) per 1000...
ABSTRACT A 3-dose (0, 1, and 6 months) intramuscular (3-IM) priming series of a human dose (HuAVA) dilutions up to 1:10 anthrax vaccine adsorbed (AVA) provided statistically significant levels protection (60 100%) against inhalation for 4 years in rhesus macaques. Serum anti-protective antigen (anti-PA) IgG lethal toxin neutralization activity (TNA) were detectable following single injection HuAVA or 1:5 AVA two injections diluted (1:10, 1:20, 1:40 AVA). Anti-PA TNA highly correlated...
To investigate the evolutionary impact of protein structure, experimentally determined tertiary structure and protein-coding DNA sequence were collected for each 1,195 genes. These genes studied via a model change that explicitly incorporates effects on rates due to structure. In model, these act solvent accessibility environments pairwise amino acid interactions are induced by compare hypotheses does not have strong influence evolution, Bayes factors estimated sequences. Most strongly...
Metabolic plasticity is an emerging hallmark of cancer, and increased glycolysis often observed in transformed cells. Small molecule inhibitors that target driver oncogenes can potentially inhibit the glycolytic pathway. Osimertinib (AZD9291) a novel EGFR tyrosine kinase inhibitor (TKI) potent selective for sensitising (EGFRm) T790M resistance mutations. Clinical studies have shown osimertinib to be efficacious patients with EGFRm/ advanced NSCLC who progressed after EGFR-TKI treatment....
Was spaltet Wasser? Zwei Lithiumcobaltoxid-Polymorphe – ein nanokristalliner kubischer Spinell und eine rhomboedrische Schichtstruktur wurden erzeugt in der photokatalytischen Wasseroxidation getestet (siehe Schema). Als entscheidend für die Aktivität unterschiedlichen Phasen erwies sich das Vorliegen eines würfelförmigen Co4O4-Motivs, kubischen Form des Katalysators vorhanden war, hingegen fehlte. Detailed facts of importance to specialist readers are published as "Supporting Information"....
The RAS-regulated RAF-MEK1/2-ERK1/2 (RAS/MAPK) signaling pathway is a major driver in oncogenesis and frequently dysregulated human cancers, primarily by mutations BRAF or RAS genes. clinical benefit of inhibitors this as single agents has only been realized BRAF-mutant melanoma, with limited effect single-agent KRAS-mutant tumors. Combined inhibition multiple nodes within pathway, such MEK1/2 ERK1/2, may be necessary to effectively suppress tumors achieve meaningful benefit. Here, we report...
Rapid protamine reversal of heparin anticoagulation in awake sheep caused, after 1 min, a approximately 15-fold increase arterial plasma thromboxane B2 (TxB2) levels, 4-fold rise pulmonary vascular resistance (PVR), 2-fold pressure, and 3 ovine complement C3a levels (P less than 0.05). Infusion nafamstat mesilate (FUT-175), protease pathway inhibitor, before reduced these increases by 60–90% FUT-175 did not modify + protamine-induced leukopenia, suggesting that incompletely blocked C5a...
Formalin-inactivated Venezuelan equine encephalomyelitis vaccine was prepared from virus grown in rolling-bottle cultures of chicken embryo cells. Trinidad strain propagated these with a maintenance medium consisting serum-free 199 containing 0.25% human serum albumin (USP) and antibiotics. Manipulation multiplicity inoculum (0.06 to 0.00006) volume (100 300 ml) resulted high-titered yields only moderate cell destruction when fluids infected were harvested at 18 24 hr. The inactivated 37 C...
The NASA/American Cancer Society (ACS) flow cytometer can simultaneously analyze the electronic nuclear volume (ENV) and DNA content of cells. This study describes schematics, resolution, reproducibility, sensitivity biological standards analyzed on this unit.Calibrated beads (lymphocytes, trout erythrocytes [TRBC], calf thymocytes, tumor cells) were for ENV versus content. Parallel data (forward scatter DNA) from a conventional obtained.ENV linearity studies yielded an R value 0.999. TRBC...