San Francisco, CA, United States

University of California at San Francisco
San Francisco, CA, United States

The University of California, San Francisco , is a center of health science research, patient care, and education; located in San Francisco, California, and is widely regarded as one of the world's leading universities in health science.Though one of the 10 campuses of the University of California, it is the only University of California campus dedicated solely to graduate education, and in health and biomedical science. Some of UCSF's treatment centers include kidney transplants and liver transplantation, radiology, neurosurgery, neurology, oncology, ophthalmology, gene therapy, women's health, fetal surgery, pediatrics, and internal medicine. With a work force of 22,800 people and annual economic impact of $2 billion, UCSF is San Francisco's second largest employer.Founded in 1873, the mission of UCSF is to serve as a "public university dedicated to saving lives and improving health." The UCSF Medical Center is consistently ranked among the top 10 hospitals in the United States by U.S. News & World Report, who also ranked UCSF's medical school as one of the top 10 in a number of specialties, including a specialty program in AIDS medical care ranked first in the country. Wikipedia.

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Prusiner S.B.,University of California at San Francisco
Annual Review of Genetics | Year: 2013

Prions are proteins that acquire alternative conformations that become self-propagating. Transformation of proteins into prions is generally accompanied by an increase in β-sheet structure and a propensity to aggregate into oligomers. Some prions are beneficial and perform cellular functions, whereas others cause neurodegeneration. In mammals, more than a dozen proteins that become prions have been identified, and a similar number has been found in fungi. In both mammals and fungi, variations in the prion conformation encipher the biological properties of distinct prion strains. Increasing evidence argues that prions cause many neurodegenerative diseases (NDs), including Alzheimer's, Parkinson's, Creutzfeldt-Jakob, and Lou Gehrig's diseases, as well as the tauopathies. The majority of NDs are sporadic, and 10% to 20% are inherited. The late onset of heritable NDs, like their sporadic counterparts, may reflect the stochastic nature of prion formation; the pathogenesis of such illnesses seems to require prion accumulation to exceed some critical threshold before neurological dysfunction manifests. © 2013 by Annual Reviews. All rights reserved.

The conserved transcriptional regulator heat shock factor 1 (Hsf1) is a key sensor of proteotoxic and other stress in the eukaryotic cytosol. We surveyed Hsf1 activity in a genome-wide loss-of-function library in Saccaromyces cerevisiae as well as ~78,000 double mutants and found Hsf1 activity to be modulated by highly diverse stresses. These included disruption of a ribosome-bound complex we named the Ribosome Quality Control Complex (RQC) comprising the Ltn1 E3 ubiquitin ligase, two highly conserved but poorly characterized proteins (Tae2 and Rqc1), and Cdc48 and its cofactors. Electron microscopy and biochemical analyses revealed that the RQC forms a stable complex with 60S ribosomal subunits containing stalled polypeptides and triggers their degradation. A negative feedback loop regulates the RQC, and Hsf1 senses an RQC-mediated translation-stress signal distinctly from other stresses. Our work reveals the range of stresses Hsf1 monitors and elucidates a conserved cotranslational protein quality control mechanism. Copyright © 2012 Elsevier Inc. All rights reserved.

Giudice L.C.,University of California at San Francisco
New England Journal of Medicine | Year: 2010

A healthy 25-year-old woman presents with worsening dysmenorrhea, pain of recent onset in the left lower quadrant, and dyspareunia. She has regular menstrual cycles, and her last menstrual period was 3 weeks before presentation. How should this patient be evaluated and treated? Copyright © 2010 Massachusetts Medical Society.

Brodsky F.M.,University of California at San Francisco
Annual Review of Cell and Developmental Biology | Year: 2012

Clathrin is considered the prototype vesicle coat protein whose self-assembly mediates sorting of membrane cargo and recruitment of lipid modifiers. Detailed knowledge of clathrin biochemistry, structure, and interacting proteins has accumulated since the first observation, almost 50 years ago, of its role in receptor-mediated endocytosis of yolk protein. This review summarizes that knowledge, and focuses on properties of the clathrin heavy and light chain subunits and interaction of the latter with Hip proteins, to address the diversity of clathrin function beyond conventional receptor-mediated endocytosis. The distinct functions of the two human clathrin isoforms (CHC17 and CHC22) are discussed, highlighting CHC22's specialized involvement in traffic of the GLUT4 glucose transporter and consequent role in human glucose metabolism. Analysis of clathrin light chain function and interaction with the actin-binding Hip proteins during bacterial inflection defines a novel actin-organizing function for CHC17 clathrin. By considering these diverse clathrin functions, along with intracellular sorting roles and inflluences on mitosis, further relevance of clathrin function to human health and disease is established. Copyright © 2012 by Annual Reviews. All rights reserved.

Julius D.,University of California at San Francisco
Annual Review of Cell and Developmental Biology | Year: 2013

Nociception is the process whereby primary afferent nerve fibers of the somatosensory system detect noxious stimuli. Pungent irritants from pepper, mint, and mustard plants have served as powerful pharmacological tools for identifying molecules and mechanisms underlying this initial step of pain sensation. These natural products have revealed three members of the transient receptor potential (TRP) ion channel familymdashTRPV1, TRPM8, and TRPA1mdashas molecular detectors of thermal and chemical stimuli that activate sensory neurons to produce acute or persistent pain. Analysis of TRP channel function and expression has validated the existence of nociceptors as a specialized group of somatosensory neurons devoted to the detection of noxious stimuli. These studies are also providing insight into the coding logic of nociception and how specification of nociceptor subtypes underlies behavioral discrimination of noxious thermal, chemical, and mechanical stimuli. Biophysical and pharmacological characterization of these channels has provided the intellectual and technical foundation for developing new classes of analgesic drugs. © 2013 by Annual Reviews. All rights reserved.

Fang M.C.,University of California at San Francisco
Journal of the American College of Cardiology | Year: 2011

The purpose of this study was to develop a risk stratification score to predict warfarin-associated hemorrhage. Optimal decision making regarding warfarin use for atrial fibrillation requires estimation of hemorrhage risk. We followed up 9,186 patients with atrial fibrillation contributing 32,888 person-years of follow-up on warfarin, obtaining data from clinical databases and validating hemorrhage events using medical record review. We used Cox regression models to develop a hemorrhage risk stratification score, selecting candidate variables using bootstrapping approaches. The final model was internally validated by split-sample testing and compared with 6 published hemorrhage risk schemes. We observed 461 first major hemorrhages during follow-up (1.4% annually). Five independent variables were included in the final model and weighted by regression coefficients: anemia (3 points), severe renal disease (e.g., glomerular filtration rate <30 ml/min or dialysis-dependent, 3 points), age ≥75 years (2 points), prior bleeding (1 point), and hypertension (1 point). Major hemorrhage rates ranged from 0.4% (0 points) to 17.3% per year (10 points). Collapsed into a 3-category risk score, major hemorrhage rates were 0.8% for low risk (0 to 3 points), 2.6% for intermediate risk (4 points), and 5.8% for high risk (5 to 10 points). The c-index for the continuous risk score was 0.74 and 0.69 for the 3-category score, higher than in the other risk schemes. There was net reclassification improvement versus all 6 comparators (from 27% to 56%). A simple 5-variable risk score was effective in quantifying the risk of warfarin-associated hemorrhage in a large community-based cohort of patients with atrial fibrillation. Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Cheng Y.,University of California at San Francisco
Cell | Year: 2015

Until only a few years ago, single-particle electron cryo-microscopy (cryo-EM) was usually not the first choice for many structural biologists due to its limited resolution in the range of nanometer to subnanometer. Now, this method rivals X-ray crystallography in terms of resolution and can be used to determine atomic structures of macromolecules that are either refractory to crystallization or difficult to crystallize in specific functional states. In this review, I discuss the recent breakthroughs in both hardware and software that transformed cryo-microscopy, enabling understanding of complex biomolecules and their functions at atomic level. © 2015 Elsevier Inc.

Chapman H.A.,University of California at San Francisco
Annual Review of Physiology | Year: 2011

Lung epithelial cells have emerged as a frequent target of injury, a driver of normal repair, and a key element in the pathobiology of fibrotic lung diseases. An important aspect of epithelial cells is their capacity to respond to microenvironmental cues by undergoing epithelial-mesenchymal transition (EMT). EMT is not simply widespread conversion of epithelial cells to fibroblasts but a graded response whereby epithelial cells reversibly acquire mesenchymal features and enhanced capacity for mesenchymal cross-talk. Recent studies elucidate distinct integrin-sensing systems that coordinate activity of TGFβ1, a critical signaling element regulating EMT, with the presence of proinflammatory signals and cell injury. Repeated injury superimposes persistent inflammation and hypoxia onto these highly regulated repair pathways, potentially overwhelming orderly repair and creating sustained fibrogenesis. Understanding specific signaling mechanisms driving the mesenchymal response to TGFβ1 may reveal therapeutics to attenuate fibrogenesis yet preserve the important homeostatic functions of TGFβ1. © 2011 by Annual Reviews. All rights reserved.

Ortiz De Montellano P.R.,University of California at San Francisco
Chemical Reviews | Year: 2010

A study was conducted to demonstrate hydrocarbon hydroxylation by cytochrome P450 enzymes. The cytochrome P450 enzymes were defined by the presence in the proteins heme prosthetic group coordinated on the proximal side by a thiolate ion. Investigations revealed that the principles of cytochrome P450 enzymes hydrocarbon hydroxylation applied to other hydroxylation reactions, including those that occurred on carbons adjacent to nitrogen, sulfur, or oxygen. The P450 enzyme was in the ferric state and had a thiolate proximal ligand and the distal ligand was a water molecule. Reduction in the ferrous enzyme was followed by binding of molecular oxygen to give the ferrous dioxy complex. This complex was observed and characterized by P450 cam by diverse physical techniques.

Kenyon C.J.,University of California at San Francisco
Nature | Year: 2010

The nematode Caenorhabditis elegans ages and dies in a few weeks, but humans can live for 100 years or more. Assuming that the ancestor we share with nematodes aged rapidly, this means that over evolutionary time mutations have increased lifespan more than 2,000-fold. Which genes can extend lifespan? Can we augment their activities and live even longer? After centuries of wistful poetry and wild imagination, we are now getting answers, often unexpected ones, to these fundamental questions. © 2010 Macmillan Publishers Limited. All rights reserved.

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