Showing papers by "University of California, San Francisco published in 1997"
TL;DR: The cloned capsaicin receptor is also activated by increases in temperature in the noxious range, suggesting that it functions as a transducer of painful thermal stimuli in vivo.
Abstract: Capsaicin, the main pungent ingredient in 'hot' chilli peppers, elicits a sensation of burning pain by selectively activating sensory neurons that convey information about noxious stimuli to the central nervous system We have used an expression cloning strategy based on calcium influx to isolate a functional cDNA encoding a capsaicin receptor from sensory neurons This receptor is a non-selective cation channel that is structurally related to members of the TRP family of ion channels The cloned capsaicin receptor is also activated by increases in temperature in the noxious range, suggesting that it functions as a transducer of painful thermal stimuli in vivo
8,186 citations
TL;DR: This review describes progress toward understanding the mechanism of dynamic instability of pure tubulin and discusses the function and regulation of microtubule dynamic instability in living cells.
Abstract: The polymerization dynamics of microtubules are central to their biological functions. Polymerization dynamics allow microtubules to adopt spatial arrangements that can change rapidly in response to cellular needs and, in some cases, to perform mechanical work. Microtubules utilize the energy of GTP hydrolysis to fuel a unique polymerization mechanism termed dynamic instability. In this review, we first describe progress toward understanding the mechanism of dynamic instability of pure tubulin and then discuss the function and regulation of microtubule dynamic instability in living cells.
2,484 citations
TL;DR: The general energy landscape picture provides a conceptual framework for understanding both two-state and multi-state folding kinetics and hopes to learn much more about the real shapes of protein folding landscapes.
Abstract: A new view of protein folding kinetics replaces the idea of ‘folding pathways’ with the broader notions of energy landscapes and folding funnels. New experiments are needed to explore them.
2,320 citations
TL;DR: This work has shown that Cdk activity is governed by a complex network of regulatory subunits and phosphorylation events whose precise effects on Cdk conformation have been revealed by recent crystallographic studies.
Abstract: Cyclin-dependent kinases (Cdks) play a well-established role in the regulation of the eukaryotic cell division cycle and have also been implicated in the control of gene transcription and other processes. Cdk activity is governed by a complex network of regulatory subunits and phosphorylation events whose precise effects on Cdk conformation have been revealed by recent crystallographic studies. In the cell, these regulatory mechanisms generate an interlinked series of Cdk oscillators that trigger the events of cell division.
2,193 citations
TL;DR: Observations indicate that prolonged seizure discharges stimulate dentate granule cell neurogenesis, and that hippocampal network plasticity associated with epileptogenesis may arise from aberrant connections formed by newly born dentategranule cells.
Abstract: The dentate granule cell layer of the rodent hippocampal formation has the distinctive property of ongoing neurogenesis that continues throughout adult life. In both human temporal lobe epilepsy and rodent models of limbic epilepsy, this same neuronal population undergoes extensive remodeling, including reorganization of mossy fibers, dispersion of the granule cell layer, and the appearance of granule cells in ectopic locations within the dentate gyrus. The mechanistic basis of these abnormalities, as well as their potential relationship to dentate granule cell neurogenesis, is unknown. We used a systemic chemoconvulsant model of temporal lobe epilepsy and bromodeoxyuridine (BrdU) labeling to investigate the effects of prolonged seizures on dentate granule cell neurogenesis in adult rats, and to examine the contribution of newly differentiated dentate granule cells to the network changes seen in this model. Pilocarpine-induced status epilepticus caused a dramatic and prolonged increase in cell proliferation in the dentate subgranular proliferative zone (SGZ), an area known to contain neuronal precursor cells. Colocalization of BrdU-immunolabeled cells with the neuron-specific markers turned on after division, 64 kDa, class III β-tubulin, or microtubule-associated protein-2 showed that the vast majority of these mitotically active cells differentiated into neurons in the granule cell layer. Newly generated dentate granule cells also appeared in ectopic locations in the hilus and inner molecular layer of the dentate gyrus. Furthermore, developing granule cells projected axons aberrantly to both the CA3 pyramidal cell region and the dentate inner molecular layer. Induction of hippocampal seizure activity by perforant path stimulation resulted in an increase in SGZ mitotic activity similar to that seen with pilocarpine administration. These observations indicate that prolonged seizure discharges stimulate dentate granule cell neurogenesis, and that hippocampal network plasticity associated with epileptogenesis may arise from aberrant connections formed by newly born dentate granule cells.
1,883 citations
TL;DR: Coping processes that are associated with positive psychologicalStates in the context of intense distress are described and the theoretical implications of positive psychological states in the coping process are discussed.
1,652 citations
TL;DR: Treatment with losartan was associated with an unexpected lower mortality than that found with captopril in older heart-failure patients and there was no difference in renal dysfunction.
1,634 citations
TL;DR: Although theoretical and empirical work on topics related to meaning and meaning making proliferate, careful evaluation and integration of this area have not been carried out as discussed by the authors, which is a serious issue.
Abstract: Although theoretical and empirical work on topics related to meaning and meaning making proliferate, careful evaluation and integration of this area have not been carried out. Toward this end, this...
1,594 citations
TL;DR: The test characteristics of a two-question case-fidning instrument that asks about depressed mood and anhedonia were compared with six common case-finding instruments, using the Quick Diagnostic Interview Schedule as a criterion standard for the diagnosis of major depression.
Abstract: Objective
To determine the validity of a two-question case-finding instrument for depression as compared with six previously validated instruments.
1,555 citations
TL;DR: The wild-type Caenorhabditis elegans nematode ages rapidly, undergoing development, senescence, and death in less than 3 weeks, while mutants with reduced activity of the gene daf-2, a homolog of the insulin and insulin-like growth factor receptors, age more slowly than normal and live more than twice as long.
Abstract: The wild-type Caenorhabditis elegans nematode ages rapidly, undergoing development, senescence, and death in less than 3 weeks. In contrast, mutants with reduced activity of the gene daf-2, a homolog of the insulin and insulin-like growth factor receptors, age more slowly than normal and live more than twice as long. These mutants are active and fully fertile and have normal metabolic rates. The life-span extension caused by daf-2 mutations requires the activity of the gene daf-16. daf-16 appears to play a unique role in life-span regulation and encodes a member of the hepatocyte nuclear factor 3 (HNF-3)/forkhead family of transcriptional regulators. In humans, insulin down-regulates the expression of certain genes by antagonizing the activity of HNF-3, raising the possibility that aspects of this regulatory system have been conserved.
1,477 citations
TL;DR: In this paper, the number of GABA-expressing cells in neocortical slices is reduced by separating the neocortex from the subcortical telencephalon, and mice lacking the homeodomain proteins DLX-1/DLX-2 show no detectable cell migration from the cell to the brain.
Abstract: Although previous analyses indicate that neocortical neurons originate from the cortical proliferative zone, evidence suggests that a subpopulation of neocortical interneurons originates within the subcortical telencephalon. For example, gamma-aminobutyric acid (GABA)-expressing cells migrate in vitro from the subcortical telencephalon into the neocortex. The number of GABA-expressing cells in neocortical slices is reduced by separating the neocortex from the subcortical telencephalon. Finally, mice lacking the homeodomain proteins DLX-1 and DLX-2 show no detectable cell migration from the subcortical telencephalon to the neocortex and also have few GABA-expressing cells in the neocortex.
TL;DR: A gene encoding a trabecular meshwork protein (TIGR) mapped to the narrowest disease interval by STS content and radiation hybrid mapping and will aid in early diagnosis of glaucoma.
Abstract: Glaucoma is a major cause of blindness and is characterized by progressive degeneration of the optic nerve and is usually associated with elevated intraocular pressure. Analyses of sequence tagged site (STS) content and haplotype sharing between families affected with chromosome 1q-linked open angle glaucoma (GLC1A) were used to prioritize candidate genes for mutation screening. A gene encoding a trabecular meshwork protein (TIGR) mapped to the narrowest disease interval by STS content and radiation hybrid mapping. Thirteen glaucoma patients were found to have one of three mutations in this gene (3.9 percent of the population studied). One of these mutations was also found in a control individual (0.2 percent). Identification of these mutations will aid in early diagnosis, which is essential for optimal application of existing therapies.
TL;DR: In this paper, the α6/β4 heterodimer was found to play a significant role in directing polarity and tissue structure of mammary epithelial cells, suggesting the existence of intimate interactions between different integrin pathways as well as adherens junctions.
Abstract: In a recently developed human breast cancer model, treatment of tumor cells in a 3-dimensional culture with inhibitory β1-integrin antibody or its Fab fragments led to a striking morphological and functional reversion to a normal phenotype. A stimulatory β1-integrin antibody proved to be ineffective. The newly formed reverted acini re-assembled a basement membrane and re-established E-cadherin–catenin complexes, and re-organized their cytoskeletons. At the same time they downregulated cyclin D1, upregulated p21cip,waf-1, and stopped growing. Tumor cells treated with the same antibody and injected into nude mice had significantly reduced number and size of tumors in nude mice. The tissue distribution of other integrins was also normalized, suggesting the existence of intimate interactions between the different integrin pathways as well as adherens junctions. On the other hand, nonmalignant cells when treated with either α6 or β4 function altering antibodies continued to grow, and had disorganized colony morphologies resembling the untreated tumor colonies. This shows a significant role of the α6/β4 heterodimer in directing polarity and tissue structure. The observed phenotypes were reversible when the cells were disassociated and the antibodies removed. Our results illustrate that the extracellular matrix and its receptors dictate the phenotype of mammary epithelial cells, and thus in this model system the tissue phenotype is dominant over the cellular genotype.
TL;DR: Understanding the mechanisms by which pericellular proteinases are regulated and activated, the nature of their molecular targets, and how adhesion and proteolysis are integrated will provide exciting avenues for investigation over the next few years.
Brown University1, Harvard University2, International AIDS Society3, Stanford University4, University of British Columbia5, University of California, San Diego6, University of Alabama at Birmingham7, University of Colorado Denver8, Istituto Superiore di Sanità9, University of Paris10, University of California, San Francisco11
TL;DR: Accumulating data from clinical and pathogenesis studies continue to support early institution of potent antiretroviral therapy in patients with HIV infection, and increased complexity in HIV management requires ongoing monitoring of new data for optimal treatment of HIV infection.
Abstract: Objective. —To provide current recommendations for antiretroviral therapy for human immunodeficiency virus (HIV) disease. Participants. —The original International AIDS Society—USA 13-member panel representing international expertise in antiretroviral research and care of patients with HIV infection. Evidence. —The following were considered: Newly available clinical and basic science study results, including phase 3 controlled trials; clinical, virological, and immunologic end-point data; interim analyses of studies presented at national and international research conferences; studies of HIV pathophysiology; and expert opinions of panel members. Recommendations were limited to the drugs available in mid 1997. Process. —The full panel met on a regular basis (July 1996, September 1996, November 1996, January 1997, and April 1997) since the publication of its initial recommendations in mid 1996 to review new research reports and interim results. The panel discussed whether and how new information changed its initial recommendations. The recommendations contained herein were determined by group consensus. Conclusions. —New data have provided a stronger rationale for earlier initiation of more aggressive therapy than previously recommended and reinforce the importance of careful selection of initial drug regimen for each patient for optimal long-term clinical benefit and adherence. The plasma viral load is a crucial element of clinical management for assessing prognosis and the effectiveness of therapy, and such testing must be done properly. Treatment failure is most readily indicated by a rising plasma HIV RNA level and should be confirmed prior to a change of treatment. Therapeutic approaches must be updated as new data, particularly on the long-term clinical effect of aggressive antiretroviral treatment, continue to emerge.
TL;DR: Douglas Hanahan describes what is known about the process of vascular morphogenesis and maintenance and how this new factor fits into this complex regulatory system.
Abstract: [ Douglas Hanahan ][1] Blood vessels are formed and maintained by a family of soluble factors that interact with tyrosine kinase receptors on the endothelial cell surface. A new angiogenesis factor (Ang2) is reported in an article by [ Maisonpierre et al .][2] in this week's issue. Hanahan describes what is known about the process of vascular morphogenesis and maintenance and how this new factor fits into this complex regulatory system.
[][3]
[1]: http://www.sciencemag.org#affiliation
[2]: http://www.sciencemag.org/cgi/content/short/277/5322/55
[3]: http://
TL;DR: Four distinct coding mutations in JAG1 are demonstrated, providing evidence that it is the causal gene for Alagille syndrome, and supporting the hypothesis that haploinsufficiency for this gene is one of the mechanisms causing the Alagile syndrome phenotype.
Abstract: Alagille syndrome is an autosomal dominant disorder characterized by abnormal development of liver, heart, skeleton, eye, face and, less frequently, kidney Analyses of many patients with cytogenetic deletions or rearrangements have mapped the gene to chromosome 20p12, although deletions are found in a relatively small proportion of patients (< 7%) We have mapped the human Jagged1 gene (JAG1), encoding a ligand for the developmentally important Notch transmembrane receptor, to the Alagille syndrome critical region within 20p12 The Notch intercellular signalling pathway has been shown to mediate cell fate decisions during development in invertebrates and vertebrates We demonstrate four distinct coding mutations in JAG1 from four Alagille syndrome families, providing evidence that it is the causal gene for Alagille syndrome All four mutations lie within conserved regions of the gene and cause translational frameshifts, resulting in gross alterations of the protein product Patients with cytogenetically detectable deletions including JAG1 have Alagille syndrome, supporting the hypothesis that haploinsufficiency for this gene is one of the mechanisms causing the Alagille syndrome phenotype
TL;DR: Evidence is provided that neuropilin is a receptor or a component of a receptor complex that mediates the effects of Sema III on these axons, and that antibodies to neuro pilin block the ability ofSema III to repel sensory axons and to induce collapse of their growth cones.
TL;DR: The presented data are consistent with the conclusion that Crm1p is a carrier for the NES-mediated protein export pathway, and it is proposed that CRM1 be renamed exportin 1 (XPO1).
TL;DR: It is concluded that CCR2-/- mice have significant defects in both delayed-type hypersensitivity responses and production of Th1-type cytokines, suggesting an important and unexpected role for C CR2 activation in modulating the immune response, as well as in recruiting monocytes/macrophages to sites of inflammation.
Abstract: Monocyte chemoattractant protein-1 (MCP-1) is a potent agonist for mononuclear leukocytes and has been implicated in the pathogenesis of atherosclerosis and granulomatous lung disease. To determine the role of MCP-1 and related family members in vivo, we used homologous recombination in embryonic stem cells to generate mice with a targeted disruption of C-C chemokine receptor 2 (CCR2), the receptor for MCP-1. CCR2-/- mice were born at the expected Mendelian ratios and developed normally. In response to thioglycollate, the recruitment of peritoneal macrophages decreased selectively. In in vitro chemotaxis assays, CCR2-/- leukocytes failed to migrate in response to MCP-1. Granulomatous lung disease was induced in presensitized mice by embolization with beads coupled to purified protein derivative (PPD) of Mycobacterium bovis. As compared with wild-type littermates, CCR2-/- mice had a decrease in granuloma size accompanied by a dramatic decrease in the level of interferon gamma in the draining lymph nodes. Production of interferon gamma was also decreased in PPD-sensitized splenocytes from CCR2-/- mice and in naive splenocytes activated by concanavalin A. We conclude that CCR2-/- mice have significant defects in both delayed-type hypersensitivity responses and production of Th1-type cytokines. These data suggest an important and unexpected role for CCR2 activation in modulating the immune response, as well as in recruiting monocytes/macrophages to sites of inflammation.
TL;DR: It is shown here that differentiating cytotrophoblasts transform their adhesion receptor phenotype so as to resemble the endothelial cells they replace, suggesting that this adhesion phenotype switch is required for successful endovascular invasion and normal placentation.
Abstract: Establishment of the human placenta requires that fetal cytotrophoblast stem cells in anchoring chorionic villi become invasive. These cytotrophoblasts aggregate into cell columns and invade both the uterine interstitium and vasculature, anchoring the fetus to the mother and establishing blood flow to the placenta. Cytotrophoblasts colonizing spiral arterioles replace maternal endothelium as far as the first third of the myometrium. We show here that differentiating cytotrophoblasts transform their adhesion receptor phenotype so as to resemble the endothelial cells they replace. Cytotrophoblasts in cell columns show reduced E-cadherin staining and express VE-(endothelial) cadherin, platelet-endothelial adhesion molecule-1, vascular endothelial adhesion molecule-1, and alpha-4-integrins. Cytotrophoblasts in the uterine interstitium and maternal vasculature continue to express these receptors, and, like endothelial cells during angiogenesis, also stain for alphaVbeta3. In functional studies, alphaVbeta3 and VE-cadherin enhance, while E-cadherin restrains, cytotrophoblast invasiveness. Cytotrophoblasts expressing alpha4 integrins bound immobilized VCAM-1 in vitro, suggesting that this receptor-pair could mediate cytotrophoblast-endothelium or cytotrophoblast-cytotrophoblast interactions in vivo, during endovascular invasion. In the pregnancy disorder preeclampsia, in which endovascular invasion remains superficial, cytotrophoblasts fail to express most of these endothelial markers (Zhou et al., 1997. J. Clin. Invest. 99:2152-2164.), suggesting that this adhesion phenotype switch is required for successful endovascular invasion and normal placentation.
TL;DR: There is now considerable concern that bovine prions may have been passed to humans, resulting in a new form of CJD.
Abstract: Bovine spongiform encephalopathy (BSE) and human Creutzfeldt-Jakob disease (CJD) are among the most notable central nervous system degenerative disorders caused by prions. CJD may present as a sporadic, genetic, or infectious illness. Prions are transmissible particles that are devoid of nucleic acid and seem to be composed exclusively of a modified protein (PrP Sc ). The normal, cellular prion protein (PrP C ) is converted into PrP Sc through a posttranslational process during which it acquires a high β-sheet content. It is thought that BSE is a result of cannibalism in which faulty industrial practices produced prion-contaminated feed for cattle. There is now considerable concern that bovine prions may have been passed to humans, resulting in a new form of CJD.
TL;DR: The results suggest that preeclampsia is associated with failure of cytotrophoblasts to mimic a vascular adhesion phenotype, and the functional consequences of this abnormality are unknown, but are likely to affect negatively cytotrophicoblast endovascular invasion and uterine arteriole remodeling.
Abstract: In human pregnancy, placental cytotrophoblasts that invade the uterus downregulate the expression of adhesion receptors that are characteristic of their epithelial origin, and upregulate the expression of adhesion receptors that are expressed by vascular cells. We suggest that this transformation could be critical to endovascular invasion, the process whereby cytotrophoblasts invade the uterine spiral arterioles and line their walls (Zhou et al. J. Clin. Invest. 1997. 99: 2139-2151.). To better understand the in vivo significance of these findings, we tested the hypothesis that in preeclampsia, an important disease of pregnancy in which endovascular invasion is abrogated, cytotrophoblasts fail to adopt a vascular adhesion phenotype. In experiments described here we stained placental bed biopsy specimens from age-matched control pregnancies and from those complicated by preeclampsia with antibodies that recognize adhesion molecules that are normally modulated during this transformation. In preeclampsia, differentiating/invading cytotrophoblasts fail to express properly many of these molecules, including integrin, cadherin, and Ig superfamily members. These results suggest that preeclampsia is associated with failure of cytotrophoblasts to mimic a vascular adhesion phenotype. The functional consequences of this abnormality are unknown, but are likely to affect negatively cytotrophoblast endovascular invasion and uterine arteriole remodeling, thereby compromising blood flow to the maternal-fetal interface.
TL;DR: In this study, cytotrophoblasts cultured under hypoxic conditions (2 percent oxygen), mimicking the environment near the uterine surface before 10 weeks of gestation, continued proliferating and differentiated poorly, but when cultured in 20 percent oxygen, mimickingThe environment near uterine arterioles, the cells stopped proliferating
Abstract: Cytotrophoblasts, specialized placental cells, proliferate early in pregnancy and then differentiate into tumor-like cells that establish blood flow to the placenta by invading the uterus and its vasculature. In this study, cytotrophoblasts cultured under hypoxic conditions (2 percent oxygen), mimicking the environment near the uterine surface before 10 weeks of gestation, continued proliferating and differentiated poorly. When cultured in 20 percent oxygen, mimicking the environment near uterine arterioles, the cells stopped proliferating and differentiated normally. Thus, oxygen tension determines whether cytotrophoblasts proliferate or invade, thereby regulating placental growth and cellular architecture.
TL;DR: Cl cloning and characterization of a new human thrombin receptor, designated protease-activated receptor 3 (PAR3) is reported, which can mediate throm-bin-triggered phosphoinositide hydrolysis and is expressed in a variety of tissues, making it a candidate for the sought-after second platelet throm bin receptor.
Abstract: Thrombin is a coagulation protease that activates platelets, leukocytes, endothelial and mesenchymal cells at sites of vascular injury, acting partly through an unusual proteolytically activated G-protein-coupled receptor1–3. Knockout of the gene encoding this receptor provided definitive evidence for a second thrombin receptor in mouse platelets and for tissue-specific roles for different thrombin receptors4. We now report the cloning and characterization of a new human thrombin receptor, designated protease-activated receptor 3 (PAR3). PAR3 can mediate throm-bin-triggered phosphoinositide hydrolysis and is expressed in a variety of tissues, including human bone marrow and mouse megakaryocytes, making it a candidate for the sought-after second platelet thrombin receptor. PAR3 provides a new tool for understanding thrombin signalling and a possible target for therapeutics designed selectively to block thrombotic, inflammatory and proliferative responses to thrombin.
TL;DR: It is shown that Ire1p is a bifunctional enzyme: in addition to being a kinase, it is a site-specific endoribonuclease that cleaves HAC1 mRNA specifically at both splice junctions and the addition of purified tRNA ligase completes splicing.
TL;DR: Emphasis was placed on the major structural components of the tissue, including the collagen based organic matrix and its mineral reinforcement, the distribution of these components and their microstructural organization as related to mechanical properties and response to demineralization.
TL;DR: Results suggest that leptin acts as a signal triggering puberty, thus supporting the hypothesis that fat accumulation enhances maturation of the reproductive tract.
Abstract: Numerous studies have revealed an association between nutritional status, adiposity, and reproductive maturity. The role of leptin, a hormone secreted from adipose tissue, in the onset of reproductive function was investigated. Normal prepubertal female mice injected with leptin grew at a slower rate than controls as a result of the hormone's thinning effects, but they reproduced up to 9 days earlier than controls and showed earlier maturation of the reproductive tract. These results suggest that leptin acts as a signal triggering puberty, thus supporting the hypothesis that fat accumulation enhances maturation of the reproductive tract.
TL;DR: A rat homologue of unc-47 is expressed by central GABA neurons and confers vesicular GABA transport in transfected cells with kinetics and substrate specificity similar to those previously reported for synaptic vesicles from the brain, and thus VGAT is the first of a new family of neurotransmitter transporters.
Abstract: Synaptic transmission involves the regulated exocytosis of vesicles filled with neurotransmitter. Classical transmitters are synthesized in the cytoplasm, and so must be transported into synaptic vesicles. Although the vesicular transporters for monoamines and acetylcholine have been identified, the proteins responsible for packaging the primary inhibitory and excitatory transmitters, γ-aminobutyric acid (GABA) and glutamate remain unknown1,2. Studies in the nematode Caenorhabditis elegans have implicated the gene unc-47 in the release of GABA3. Here we show that the sequence of unc-47 predicts a protein with ten transmembrane domains, that the gene is expressed by GABA neurons, and that the protein colocalizes with synaptic vesicles. Further, a rat homologue of unc-47 is expressed by central GABA neurons and confers vesicular GABA transport in transfected cells with kinetics and substrate specificity similar to those previously reported for synaptic vesicles from the brain. Comparison of this vesicular GABA transporter (VGAT) with a vesicular transporter for monoamines shows that there are differences in the bioenergetic dependence of transport, and these presumably account for the differences in structure. Thus VGAT is the first of a new family of neurotransmitter transporters.
TL;DR: Bayesian statistical analysis of the conformations of side chains in proteins from the Protein Data Bank shows a strong similarity with the experimental distributions, indicating that proteins attain their lowest energy rotamers with respect to local backbone‐side‐chain interactions.
Abstract: We present a Bayesian statistical analysis of the conformations of side chains in proteins from the Protein Data Bank. This is an extension of the backbone-dependent rotamer library, and includes rotamer populations and average chi angles for a full range of phi, psi values. The Bayesian analysis used here provides a rigorous statistical method for taking account of varying amounts of data. Bayesian statistics requires the assumption of a prior distribution for parameters over their range of possible values. This prior distribution can be derived from previous data or from pooling some of the present data. The prior distribution is combined with the data to form the posterior distribution, which is a compromise between the prior distribution and the data. For the chi 2, chi 3, and chi 4 rotamer prior distributions, we assume that the probability of each rotamer type is dependent only on the previous chi rotamer in the chain. For the backbone-dependence of the chi 1 rotamers, we derive prior distributions from the product of the phi-dependent and psi-dependent probabilities. Molecular mechanics calculations with the CHARMM22 potential show a strong similarity with the experimental distributions, indicating that proteins attain their lowest energy rotamers with respect to local backbone-side-chain interactions. The new library is suitable for use in homology modeling, protein folding simulations, and the refinement of X-ray and NMR structures.