University of California, San Francisco

About: University of California, San Francisco is a education organization based out in San Francisco, California, United States. It is known for research contribution in the topics: Population & Health care. The organization has 83381 authors who have published 186236 publications receiving 12068420 citations. The organization is also known as: UCSF & UC San Francisco.

DOCK 4.0: Search strategies for automated molecular docking of flexible molecule databases

Abstract: In this paper we describe the search strategies developed for docking flexible molecules to macomolecular sites that are incorporated into the widely distributed DOCK software, version 40 The search strategies include incremental construction and random conformation search and utilize the existing Coulombic and Lennard-Jones grid-based scoring function The incremental construction strategy is tested with a panel of 15 crystallographic testcases, created from 12 unique complexes whose ligands vary in size and flexibility For all testcases, at least one docked position is generated within 2 A of the crystallographic position For 7 of 15 testcases, the top scoring position is also within 2 A of the crystallographic position The algorithm is fast enough to successfully dock a few testcases within seconds and most within 100 s The incremental construction and the random search strategy are evaluated as database docking techniques with a database of 51 molecules docked to two of the crystallographic testcases Incremental construction outperforms random search and is fast enough to reliably rank the database of compounds within 15 s per molecule on an SGI R10000 cpu

Common variants on chromosome 6p22.1 are associated with schizophrenia

Abstract: Schizophrenia, a devastating psychiatric disorder, has a prevalence of 0.5-1%, with high heritability (80-85%) and complex transmission. Recent studies implicate rare, large, high-penetrance copy number variants in some cases, but the genes or biological mechanisms that underlie susceptibility are not known. Here we show that schizophrenia is significantly associated with single nucleotide polymorphisms (SNPs) in the extended major histocompatibility complex region on chromosome 6. We carried out a genome-wide association study of common SNPs in the Molecular Genetics of Schizophrenia (MGS) case-control sample, and then a meta-analysis of data from the MGS, International Schizophrenia Consortium and SGENE data sets. No MGS finding achieved genome-wide statistical significance. In the meta-analysis of European-ancestry subjects (8,008 cases, 19,077 controls), significant association with schizophrenia was observed in a region of linkage disequilibrium on chromosome 6p22.1 (P = 9.54 x 10(-9)). This region includes a histone gene cluster and several immunity-related genes--possibly implicating aetiological mechanisms involving chromatin modification, transcriptional regulation, autoimmunity and/or infection. These results demonstrate that common schizophrenia susceptibility alleles can be detected. The characterization of these signals will suggest important directions for research on susceptibility mechanisms.

Shaping the nuclear action of NF-κB

Abstract: The NF-κB/REL family of transcription factors pivotally control the inflammatory and immune responses, as well as other genetic programmes that are central to cell growth and survival. The cytoplasmic regulation of NF-κB is well characterized and, recently, significant progress has been made in understanding how its nuclear action is regulated. Post-translational modification of the NF-κB subunits as well as histones surrounding the NF-κB target genes has a key role in this regulation. Here, we review the important advances that constitute this new and exciting chapter in NF-κB biology.

Leptin regulation of bone resorption by the sympathetic nervous system and CART

Abstract: Bone remodelling, the mechanism by which vertebrates regulate bone mass, comprises two phases, namely resorption by osteoclasts and formation by osteoblasts; osteoblasts are multifunctional cells also controlling osteoclast differentiation. Sympathetic signalling via beta2-adrenergic receptors (Adrb2) present on osteoblasts controls bone formation downstream of leptin. Here we show, by analysing Adrb2-deficient mice, that the sympathetic nervous system favours bone resorption by increasing expression in osteoblast progenitor cells of the osteoclast differentiation factor Rankl. This sympathetic function requires phosphorylation (by protein kinase A) of ATF4, a cell-specific CREB-related transcription factor essential for osteoblast differentiation and function. That bone resorption cannot increase in gonadectomized Adrb2-deficient mice highlights the biological importance of this regulation, but also contrasts sharply with the increase in bone resorption characterizing another hypogonadic mouse with low sympathetic tone, the ob/ob mouse. This discrepancy is explained, in part, by the fact that CART ('cocaine amphetamine regulated transcript'), a neuropeptide whose expression is controlled by leptin and nearly abolished in ob/ob mice, inhibits bone resorption by modulating Rankl expression. Our study establishes that leptin-regulated neural pathways control both aspects of bone remodelling, and demonstrates that integrity of sympathetic signalling is necessary for the increase in bone resorption caused by gonadal failure.