Showing papers by "University of Washington published in 2000"

A climbing image nudged elastic band method for finding saddle points and minimum energy paths

Abstract: A modification of the nudged elastic band method for finding minimum energy paths is presented. One of the images is made to climb up along the elastic band to converge rigorously on the highest saddle point. Also, variable spring constants are used to increase the density of images near the top of the energy barrier to get an improved estimate of the reaction coordinate near the saddle point. Applications to CH4 dissociative adsorption on Ir~111! and H2 on Si~100! using plane wave based density functional theory are presented. © 2000 American Institute of Physics. @S0021-9606~00!71246-3#

The Sloan Digital Sky Survey: Technical summary

Abstract: The Sloan Digital Sky Survey (SDSS) will provide the data to support detailed investigations of the distribution of luminous and nonluminous matter in the universe: a photometrically and astrometrically calibrated digital imaging survey of π sr above about Galactic latitude 30° in five broad optical bands to a depth of g' ~ 23 mag, and a spectroscopic survey of the approximately 106 brightest galaxies and 105 brightest quasars found in the photometric object catalog produced by the imaging survey. This paper summarizes the observational parameters and data products of the SDSS and serves as an introduction to extensive technical on-line documentation.

Improved tangent estimate in the nudged elastic band method for finding minimum energy paths and saddle points

Abstract: An improved way of estimating the local tangent in the nudged elastic band method for finding minimum energy paths is presented. In systems where the force along the minimum energy path is large compared to the restoring force perpendicular to the path and when many images of the system are included in the elastic band, kinks can develop and prevent the band from converging to the minimum energy path. We show how the kinks arise and present an improved way of estimating the local tangent which solves the problem. The task of finding an accurate energy and configuration for the saddle point is also discussed and examples given where a complementary method, the dimer method, is used to efficiently converge to the saddle point. Both methods only require the first derivative of the energy and can, therefore, easily be applied in plane wave based density-functional theory calculations. Examples are given from studies of the exchange diffusion mechanism in a Si crystal, Al addimer formation on the Al(100) surfa...

Central nervous system control of food intake

Abstract: New information regarding neuronal circuits that control food intake and their hormonal regulation has extended our understanding of energy homeostasis, the process whereby energy intake is matched to energy expenditure over time. The profound obesity that results in rodents (and in the rare human case as well) from mutation of key signalling molecules involved in this regulatory system highlights its importance to human health. Although each new signalling pathway discovered in the hypothalamus is a potential target for drug development in the treatment of obesity, the growing number of such signalling molecules indicates that food intake is controlled by a highly complex process. To better understand how energy homeostasis can be achieved, we describe a model that delineates the roles of individual hormonal and neuropeptide signalling pathways in the control of food intake and the means by which obesity can arise from inherited or acquired defects in their function.

The Female Sexual Function Index (FSFI): A Multidimensional Self-Report Instrument for the Assessment of Female Sexual Function

Abstract: This article presents the development of a brief, self-report measure of female sexual function. Initial face validity testing of questionnaire items, identified by an expert panel, was followed by a study aimed at further refining the questionnaire. It was administered to 131 normal controls and 128 age-matched subjects with female sexual arousal disorder (FSAD) at five research centers. Based on clinical interpretations of a principal components analysis, a 6- domain structure was identified, which included desire, subjective arousal, lubrication, orgasm, satisfaction, and pain. Overall test-retest reliability coefficients were high for each of the individual domains (r=0.79 to 0.86) and a high degree of internal consistency was observed (Cronbach’s alpha values of 0.82 and higher) Good construct validity was demonstrated by highly significant mean difference scores between the FSAD and control groups for each of the domains (p<0.001). Additionally, divergent validity with a scale of marital satisfactio...

A comprehensive analysis of protein–protein interactions in Saccharomyces cerevisiae

Abstract: Two large-scale yeast two-hybrid screens were undertaken to identify protein-protein interactions between full-length open reading frames predicted from the Saccharomyces cerevisiae genome sequence. In one approach, we constructed a protein array of about 6,000 yeast transformants, with each transformant expressing one of the open reading frames as a fusion to an activation domain. This array was screened by a simple and automated procedure for 192 yeast proteins, with positive responses identified by their positions in the array. In a second approach, we pooled cells expressing one of about 6,000 activation domain fusions to generate a library. We used a high-throughput screening procedure to screen nearly all of the 6,000 predicted yeast proteins, expressed as Gal4 DNA-binding domain fusion proteins, against the library, and characterized positives by sequence analysis. These approaches resulted in the detection of 957 putative interactions involving 1,004 S. cerevisiae proteins. These data reveal interactions that place functionally unclassified proteins in a biological context, interactions between proteins involved in the same biological function, and interactions that link biological functions together into larger cellular processes. The results of these screens are shown here.

Complete genome sequence of Pseudomonas aeruginosa PAO1, an opportunistic pathogen.

Abstract: Pseudomonas aeruginosa is a ubiquitous environmental bacterium that is one of the top three causes of opportunistic human infections. A major factor in its prominence as a pathogen is its intrinsic resistance to antibiotics and disinfectants. Here we report the complete sequence of P. aeruginosa strain PAO1. At 6.3 million base pairs, this is the largest bacterial genome sequenced, and the sequence provides insights into the basis of the versatility and intrinsic drug resistance of P. aeruginosa. Consistent with its larger genome size and environmental adaptability, P. aeruginosa contains the highest proportion of regulatory genes observed for a bacterial genome and a large number of genes involved in the catabolism, transport and efflux of organic compounds as well as four potential chemotaxis systems. We propose that the size and complexity of the P. aeruginosa genome reflect an evolutionary adaptation permitting it to thrive in diverse environments and resist the effects of a variety of antimicrobial substances.

Annular Modes in the Extratropical Circulation. Part I: Month-to-Month Variability*

Abstract: The leading modes of variability of the extratropical circulation in both hemispheres are characterized by deep, zonally symmetric or ‘‘annular’’ structures, with geopotential height perturbations of opposing signs in the polar cap region and in the surrounding zonal ring centered near 458 latitude. The structure and dynamics of the Southern Hemisphere (SH) annular mode have been extensively documented, whereas the existence of a Northern Hemisphere (NH) mode, herein referred to as the Arctic Oscillation (AO), has only recently been recognized. Like the SH mode, the AO can be defined as the leading empirical orthogonal function of the sea level pressure field or of the zonally symmetric geopotential height or zonal wind fields. In this paper the structure and seasonality of the NH and SH modes are compared based on data from the National Centers for Environmental Prediction‐National Center for Atmospheric Research reanalysis and supplementary datasets. The structures of the NH and SH annular modes are shown to be remarkably similar, not only in the zonally averaged geopotential height and zonal wind fields, but in the mean meridional circulations as well. Both exist year-round in the troposphere, but they amplify with height upward into the stratosphere during those seasons in which the strength of the zonal flow is conducive to strong planetary wave‐mean flow interaction: midwinter in the NH and late spring in the SH. During these ‘‘active seasons,’’ the annular modes modulate the strength of the Lagrangian mean circulation in the lower stratosphere, total column ozone and tropopause height over mid- and high latitudes, and the strength of the trade winds of their respective hemispheres. The NH mode also contains an embedded planetary wave signature with expressions in surface air temperature, precipitation, total column ozone, and tropopause height. It is argued that the horizontal temperature advection by the perturbed zonal-mean zonal wind field in the lower troposphere is instrumental in forcing this pattern. A companion paper documents the striking resemblance between the structure of the annular modes and observed climate trends over the past few decades.

Gastrointestinal Toxicity With Celecoxib vs Nonsteroidal Anti-inflammatory Drugs for Osteoarthritis and Rheumatoid Arthritis: The CLASS Study: A Randomized Controlled Trial

Abstract: ContextConventional nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with a spectrum of toxic effects, notably gastrointestinal (GI) effects, because of inhibition of cyclooxygenase (COX)-1. Whether COX-2–specific inhibitors are associated with fewer clinical GI toxic effects is unknown.ObjectiveTo determine whether celecoxib, a COX-2–specific inhibitor, is associated with a lower incidence of significant upper GI toxic effects and other adverse effects compared with conventional NSAIDs.DesignThe Celecoxib Long-term Arthritis Safety Study (CLASS), a double-blind, randomized controlled trial conducted from September 1998 to March 2000.SettingThree hundred eighty-six clinical sites in the United States and Canada.ParticipantsA total of 8059 patients (≥18 years old) with osteoarthritis (OA) or rheumatoid arthritis (RA) were enrolled in the study, and 7968 received at least 1 dose of study drug. A total of 4573 patients (57%) received treatment for 6 months.InterventionsPatients were randomly assigned to receive celecoxib, 400 mg twice per day (2 and 4 times the maximum RA and OA dosages, respectively; n = 3987); ibuprofen, 800 mg 3 times per day (n = 1985); or diclofenac, 75 mg twice per day (n = 1996). Aspirin use for cardiovascular prophylaxis (≤325 mg/d) was permitted.Main Outcome MeasuresIncidence of prospectively defined symptomatic upper GI ulcers and ulcer complications (bleeding, perforation, and obstruction) and other adverse effects during the 6-month treatment period.ResultsFor all patients, the annualized incidence rates of upper GI ulcer complications alone and combined with symptomatic ulcers for celecoxib vs NSAIDs were 0.76% vs 1.45% (P = .09) and 2.08% vs 3.54% (P = .02), respectively. For patients not taking aspirin, the annualized incidence rates of upper GI ulcer complications alone and combined with symptomatic ulcers for celecoxib vs NSAIDs were 0.44% vs 1.27% (P = .04) and 1.40% vs 2.91% (P = .02). For patients taking aspirin, the annualized incidence rates of upper GI ulcer complications alone and combined with symptomatic ulcers for celecoxib vs NSAIDs were 2.01% vs 2.12% (P = .92) and 4.70% vs 6.00% (P = .49). Fewer celecoxib-treated patients than NSAID-treated patients experienced chronic GI blood loss, GI intolerance, hepatotoxicity, or renal toxicity. No difference was noted in the incidence of cardiovascular events between celecoxib and NSAIDs, irrespective of aspirin use.ConclusionsIn this study, celecoxib, at dosages greater than those indicated clinically, was associated with a lower incidence of symptomatic ulcers and ulcer complications combined, as well as other clinically important toxic effects, compared with NSAIDs at standard dosages. The decrease in upper GI toxicity was strongest among patients not taking aspirin concomitantly.

Toll-like receptors in the induction of the innate immune response

Abstract: The innate immune response is the first line of defence against infectious disease. The principal challenge for the host is to detect the pathogen and mount a rapid defensive response. A group of proteins that comprise the Toll or Toll-like family of receptors perform this role in vertebrate and invertebrate organisms. This reflects a remarkable conservation of function and it is therefore not surprising that studies of the mechanism by which they act has revealed new and important insights into host defence.

Predicting the probability for falls in community-dwelling older adults using the Timed Up & Go Test.

Abstract: Background and Purpose. This study examined the sensitivity and specificity of the Timed Up & Go Test (TUG) under single-task versus dual-task conditions for identifying elderly individuals who are prone to falling. Subjects. Fifteen older adults with no history of falls (mean age578 years, SD56, range565‐ 85) and 15 older adults with a history of 2 or more falls in the previous 6 months (mean age586.2 years, SD56, range576 ‐95) participated. Methods. Time taken to complete the TUG under 3 conditions (TUG, TUG with a subtraction task [TUG cognitive], and TUG while carrying a full cup of water [TUG manual]) was measured. A multivariate analysis of variance and discriminant function and logistic regression analyses were performed. Results. The TUG was found to be a sensitive (sensitivity587%) and specific (specificity587%) measure for identifying elderly individuals who are prone to falls. For both groups of older adults, simultaneous performance of an additional task increased the time taken to complete the TUG, with the greatest effect in the older adults with a history of falls. The TUG scores with or without an additional task (cognitive or manual) were equivalent with respect to identifying fallers and nonfallers. Conclusions and Discussion. The results suggest that the TUG is a sensitive and specific measure for identifying communitydwelling adults who are at risk for falls. The ability to predict falls is not enhanced by adding a secondary task when performing the TUG. [Shumway-Cook A, Brauer S, Woollacott M. Predicting the probability for falls in community-dwelling older adults using the Timed Up & Go Test. Phys Ther. 2000;80:896 ‐903.]

Theoretical approaches to x-ray absorption fine structure

Abstract: Dramatic advances in the understanding of x-ray absorption fine structure (XAFS) have been made over the past few decades, which have led ultimately to a highly quantitative theory. This review covers these developments from a unified multiple-scattering viewpoint. The authors focus on extended x-ray absorption fine structure (EXAFS) well above an x-ray edge, and, to a lesser extent, on x-ray absorption near-edge structure (XANES) closer to an edge. The discussion includes both formal considerations, derived from a many-electron formulation, and practical computational methods based on independent-electron models, with many-body effects lumped into various inelastic losses and energy shifts. The main conceptual issues in XAFS theory are identified and their relative importance is assessed; these include the convergence of the multiple-scattering expansion, curved-wave effects, the scattering potential, inelastic losses, self-energy shifts, and vibrations and structural disorder. The advantages and limitations of current computational approaches are addressed, with particular regard to quantitative experimental comparisons.

Support vector machine classification and validation of cancer tissue samples using microarray expression data

Abstract: Motivation: DNA microarray experiments generating thousands of gene expression measurements, are being used to gather information from tissue and cell samples regarding gene expression differences that will be useful in diagnosing disease. We have developed a new method to analyse this kind of data using support vector machines (SVMs). This analysis consists of both classification of the tissue samples, and an exploration of the data for mis-labeled or questionable tissue results. Results: We demonstrate the method in detail on samples consisting of ovarian cancer tissues, normal ovarian tissues, and other normal tissues. The dataset consists of expression experiment results for 97 802 cDNAs for each tissue. As a result of computational analysis, a tissue sample is discovered and confirmed to be wrongly labeled. Upon correction of this mistake and the removal of an outlier, perfect classification of tissues is achieved, but not with high confidence. We identify and analyse a subset of genes from the ovarian dataset whose expression is highly differentiated between the types of tissues. To show robustness of the SVM method, two previously published datasets from other types of tissues or cells are analysed. The results are comparable to those previously obtained. We show that other machine learning methods also perform comparably to the SVM on many of those datasets. Availability: The SVM software is available at http:// www. cs.columbia.edu/ ∼bgrundy/ svm.

Structure and regulation of voltage-gated Ca2+ channels.

Abstract: Voltage-gated Ca(2+) channels mediate Ca(2+) entry into cells in response to membrane depolarization. Electrophysiological studies reveal different Ca(2+) currents designated L-, N-, P-, Q-, R-, and T-type. The high-voltage-activated Ca(2+) channels that have been characterized biochemically are complexes of a pore-forming alpha1 subunit of approximately 190-250 kDa; a transmembrane, disulfide-linked complex of alpha2 and delta subunits; an intracellular beta subunit; and in some cases a transmembrane gamma subunit. Ten alpha1 subunits, four alpha2delta complexes, four beta subunits, and two gamma subunits are known. The Cav1 family of alpha1 subunits conduct L-type Ca(2+) currents, which initiate muscle contraction, endocrine secretion, and gene transcription, and are regulated primarily by second messenger-activated protein phosphorylation pathways. The Cav2 family of alpha1 subunits conduct N-type, P/Q-type, and R-type Ca(2+) currents, which initiate rapid synaptic transmission and are regulated primarily by direct interaction with G proteins and SNARE proteins and secondarily by protein phosphorylation. The Cav3 family of alpha1 subunits conduct T-type Ca(2+) currents, which are activated and inactivated more rapidly and at more negative membrane potentials than other Ca(2+) current types. The distinct structures and patterns of regulation of these three families of Ca(2+) channels provide a flexible array of Ca(2+) entry pathways in response to changes in membrane potential and a range of possibilities for regulation of Ca(2+) entry by second messenger pathways and interacting proteins.

Time-Dependent ROC Curves for Censored Survival Data and a Diagnostic Marker

Abstract: ROC curves are a popular method for displaying sensitivity and specificity of a continuous diagnostic marker, X, for a binary disease variable, D. However, many disease outcomes are time dependent, D(t), and ROC curves that vary as a function of time may be more appropriate. A common example of a time-dependent variable is vital status, where D(t) = 1 if a patient has died prior to time t and zero otherwise. We propose summarizing the discrimination potential of a marker X, measured at baseline (t = 0), by calculating ROC curves for cumulative disease or death incidence by time t, which we denote as ROC(t). A typical complexity with survival data is that observations may be censored. Two ROC curve estimators are proposed that can accommodate censored data. A simple estimator is based on using the Kaplan-Meier estimator for each possible subset X > c. However, this estimator does not guarantee the necessary condition that sensitivity and specificity are monotone in X. An alternative estimator that does guarantee monotonicity is based on a nearest neighbor estimator for the bivariate distribution function of (X, T), where T represents survival time (Akritas, M. J., 1994, Annals of Statistics 22, 1299-1327). We present an example where ROC(t) is used to compare a standard and a modified flow cytometry measurement for predicting survival after detection of breast cancer and an example where the ROC(t) curve displays the impact of modifying eligibility criteria for sample size and power in HIV prevention trials.

Mining high-speed data streams

Abstract: Many organizations today have more than very large databases; they have databases that grow without limit at a rate of several million records per day. Mining these continuous data streams brings unique opportunities, but also new challenges. This paper describes and evaluates VFDT, an anytime system that builds decision trees using constant memory and constant time per example. VFDT can incorporate tens of thousands of examples per second using off-the-shelf hardware. It uses Hoeffding bounds to guarantee that its output is asymptotically nearly identical to that of a conventional learner. We study VFDT's properties and demonstrate its utility through an extensive set of experiments on synthetic data. We apply VFDT to mining the continuous stream of Web access data from the whole University of Washington main campus.

The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between Toll-like receptors

Abstract: Toll-like receptors (TLRs) have been shown to participate in the recognition of pathogens by the innate immune system, but it is not clear how a restricted family of receptors has the capacity to recognize the wide spectrum of TLR stimuli known to exist. We report here that two members of the TLR family, TLR2 and TLR6, together coordinate macrophage activation by Gram-positive bacteria and the yeast cell-wall particle, zymosan. TLR6 and TLR2 both are recruited to the macrophage phagosome, where they recognize peptidoglycan, a Gram-positive pathogen component. By contrast, TLR2 recognizes another component, bacterial lipopeptide, without TLR6. The requirement for TLR cooperation is supported by the finding that TLR2 needs a partner to activate tumor necrosis factor-α production in macrophages. Dimerization of the cytoplasmic domain of TLR2 does not induce tumor necrosis factor-α production in macrophages, whereas similar dimerization of the TLR4 cytoplasmic domain does. We show that the cytoplasmic domain of TLR2 can form functional pairs with TLR6 or TLR1, and this interaction leads to cytokine induction. Thus, the cytoplasmic tails of TLRs are not functionally equivalent, with certain TLRs requiring assembly into heteromeric complexes, whereas others are active as homomeric complexes. Finally, we show that TLR6, TLR2, and TLR1 are recruited to macrophage phagosomes that contain IgG-coated erythrocytes that do not display microbial components. The data suggest that TLRs sample the contents of the phagosome independent of the nature of the contents, and can establish a combinatorial repertoire to discriminate among the large number of pathogen-associated molecular patterns found in nature.

Carbon to volume relationships for dinoflagellates, diatoms, and other protist plankton

Abstract: Cellular carbon and nitrogen content and cell volume of nutritionally and morphologically diverse dinoflagellate species were measured to determine carbon to volume (C : vol) and nitrogen to volume (N : vol) relationships. Cellular C and N content ranged from 48 to 3.0 3 10 4 pgC cell 21 21 5

Observational evidence of recent change in the northern high-latitude environment

Abstract: Studies from a variety of disciplines documentrecentchange in the northern high-latitude environment.Prompted by predictions of an amplified response oftheArctic to enhanced greenhouse forcing, we present asynthesis of these observations. Pronounced winter andspring warming over northern continents since about 1970ispartly compensated by cooling over the northern NorthAtlantic. Warming is also evident over the centralArcticOcean. There is a downward tendency in sea ice extent,attended by warming and increased areal extent of theArctic Ocean's Atlantic layer. Negative snow coveranomalies have dominated over both continents sincethelate 1980s and terrestrial precipitation has increasedsince 1900. Small Arctic glaciers have exhibitedgenerally negative mass balances. While permafrost haswarmed in Alaska and Russia, it has cooled in easternCanada. There is evidence of increased plant growth,attended by greater shrub abundance and northwardmigration of the tree line. Evidence also suggeststhatthe tundra has changed from a net sink to a net sourceofatmospheric carbon dioxide.Taken together, these results paint a reasonablycoherent picture of change, but their interpretationassignals of enhanced greenhouse warming is open todebate.Many of the environmental records are either short,areof uncertain quality, or provide limited spatialcoverage. The recent high-latitude warming is also nolarger than the interdecadal temperature range duringthis century. Nevertheless, the general patterns ofchange broadly agree with model predictions. Roughlyhalfof the pronounced recent rise in Northern Hemispherewinter temperatures reflects shifts in atmosphericcirculation. However, such changes are notinconsistentwith anthropogenic forcing and include generallypositive phases of the North Atlantic and ArcticOscillations and extratropical responses to theEl-NinoSouthern Oscillation. An anthropogenic effect is alsosuggested from interpretation of the paleoclimaterecord,which indicates that the 20th century Arctic is thewarmest of the past 400 years.

Molecular classification of cutaneous malignant melanoma by gene expression profiling

Abstract: The most common human cancers are malignant neoplasms of the skin. Incidence of cutaneous melanoma is rising especially steeply, with minimal progress in non-surgical treatment of advanced disease. Despite significant effort to identify independent predictors of melanoma outcome, no accepted histopathological, molecular or immunohistochemical marker defines subsets of this neoplasm. Accordingly, though melanoma is thought to present with different 'taxonomic' forms, these are considered part of a continuous spectrum rather than discrete entities. Here we report the discovery of a subset of melanomas identified by mathematical analysis of gene expression in a series of samples. Remarkably, many genes underlying the classification of this subset are differentially regulated in invasive melanomas that form primitive tubular networks in vitro, a feature of some highly aggressive metastatic melanomas. Global transcript analysis can identify unrecognized subtypes of cutaneous melanoma and predict experimentally verifiable phenotypic characteristics that may be of importance to disease progression.

Monodispersed Colloidal Spheres: Old Materials with New Applications

Abstract: This article presents an overview of current research activities that center on monodispersed colloidal spheres whose diameter falls anywhere in the range of 10 nm to 1 μm. It is organized into three parts: The first part briefly discusses several useful methods that have been developed for producing monodispersed colloidal spheres with tightly controlled sizes and well-defined properties (both surface and bulk). The second part surveys some techniques that have been demonstrated for organizing these colloidal spheres into two- and three-dimensionally ordered lattices. The third part highlights a number of unique applications of these crystalline assemblies, such as their uses as photonic bandgap (PBG) crystals; as removable templates to fabricate macroporous materials with highly ordered and three-dimensionally interconnected porous structures; as physical masks in lithographic patterning; and as diffractive elements to fabricate new types of optical sensors. Finally, we conclude with some personal perspectives on the directions towards which future research in this area might be directed.

The digital Michelangelo project: 3D scanning of large statues

Abstract: We describe a hardware and software system for digitizing the shape and color of large fragile objects under non-laboratory conditions Our system employs laser triangulation rangefinders, laser time-of-flight rangefinders, digital still cameras, and a suite of software for acquiring, aligning, merging, and viewing scanned data As a demonstration of this system, we digitized 10 statues by Michelangelo, including the well-known figure of David, two building interiors, and all 1,163 extant fragments of the Forma Urbis Romae, a giant marble map of ancient Rome Our largest single dataset is of the David - 2 billion polygons and 7,000 color images In this paper, we discuss the challenges we faced in building this system, the solutions we employed, and the lessons we learned We focus in particular on the unusual design of our laser triangulation scanner and on the algorithms and software we developed for handling very large scanned models

Regulation of Contraction in Striated Muscle

Abstract: Ca(2+) regulation of contraction in vertebrate striated muscle is exerted primarily through effects on the thin filament, which regulate strong cross-bridge binding to actin. Structural and biochemical studies suggest that the position of tropomyosin (Tm) and troponin (Tn) on the thin filament determines the interaction of myosin with the binding sites on actin. These binding sites can be characterized as blocked (unable to bind to cross bridges), closed (able to weakly bind cross bridges), or open (able to bind cross bridges so that they subsequently isomerize to become strongly bound and release ATP hydrolysis products). Flexibility of the Tm may allow variability in actin (A) affinity for myosin along the thin filament other than through a single 7 actin:1 tropomyosin:1 troponin (A(7)TmTn) regulatory unit. Tm position on the actin filament is regulated by the occupancy of NH-terminal Ca(2+) binding sites on TnC, conformational changes resulting from Ca(2+) binding, and changes in the interactions among Tn, Tm, and actin and as well as by strong S1 binding to actin. Ca(2+) binding to TnC enhances TnC-TnI interaction, weakens TnI attachment to its binding sites on 1-2 actins of the regulatory unit, increases Tm movement over the actin surface, and exposes myosin-binding sites on actin previously blocked by Tm. Adjacent Tm are coupled in their overlap regions where Tm movement is also controlled by interactions with TnT. TnT also interacts with TnC-TnI in a Ca(2+)-dependent manner. All these interactions may vary with the different protein isoforms. The movement of Tm over the actin surface increases the "open" probability of myosin binding sites on actins so that some are in the open configuration available for myosin binding and cross-bridge isomerization to strong binding, force-producing states. In skeletal muscle, strong binding of cycling cross bridges promotes additional Tm movement. This movement effectively stabilizes Tm in the open position and allows cooperative activation of additional actins in that and possibly neighboring A(7)TmTn regulatory units. The structural and biochemical findings support the physiological observations of steady-state and transient mechanical behavior. Physiological studies suggest the following. 1) Ca(2+) binding to Tn/Tm exposes sites on actin to which myosin can bind. 2) Ca(2+) regulates the strong binding of M.ADP.P(i) to actin, which precedes the production of force (and/or shortening) and release of hydrolysis products. 3) The initial rate of force development depends mostly on the extent of Ca(2+) activation of the thin filament and myosin kinetic properties but depends little on the initial force level. 4) A small number of strongly attached cross bridges within an A(7)TmTn regulatory unit can activate the actins in one unit and perhaps those in neighboring units. This results in additional myosin binding and isomerization to strongly bound states and force production. 5) The rates of the product release steps per se (as indicated by the unloaded shortening velocity) early in shortening are largely independent of the extent of thin filament activation ([Ca(2+)]) beyond a given baseline level. However, with a greater extent of shortening, the rates depend on the activation level. 6) The cooperativity between neighboring regulatory units contributes to the activation by strong cross bridges of steady-state force but does not affect the rate of force development. 7) Strongly attached, cycling cross bridges can delay relaxation in skeletal muscle in a cooperative manner. 8) Strongly attached and cycling cross bridges can enhance Ca(2+) binding to cardiac TnC, but influence skeletal TnC to a lesser extent. 9) Different Tn subunit isoforms can modulate the cross-bridge detachment rate as shown by studies with mutant regulatory proteins in myotubes and in in vitro motility assays. (ABSTRACT TRUNCATED)

Review of Particle Physics

Abstract: This biennial Review summarizes much of particle physics. Using data from previous editions., plus 2778 new measurements from 645 papers, we list, evaluate, and average measured properties of gauge bosons, leptons, quarks, mesons, and baryons. We also summarize searches for hypothetical particles such as Higgs bosons, heavy neutrinos, and supersymmetric particles. All the particle properties and search limits are listed in Summary Tables. We also give numerous tables, figures, formulae, and reviews of topics such as the Standard Model, particle detectors., probability, and statistics. Among the 108 reviews are many that are new or heavily revised including those on CKM quark-mixing matrix, V-ud & V-us, V-cb & V-ub, top quark, muon anomalous magnetic moment, extra dimensions, particle detectors, cosmic background radiation, dark matter, cosmological parameters, and big bang cosmology.

Depression and diabetes: impact of depressive symptoms on adherence, function, and costs.

Abstract: Background Depression is common among patients with chronic medical illness. We explored the impact of depressive symptoms in primary care patients with diabetes on diabetes self-care, adherence to medication regimens, functioning, and health care costs. Methods We administered a questionnaire to 367 patients with types 1 and 2 diabetes from 2 health maintenance organization primary care clinics to obtain data on demographics, depressive symptoms, diabetes knowledge, functioning, and diabetes self-care. On the basis of automated data, we measured medical comorbidity, health care costs, glycosylated hemoglobin (HbA 1c ) levels, and oral hypoglycemic prescription refills. Using depressive symptom severity tertiles (low, medium, or high), we performed regression analyses to determine the impact of depressive symptoms on adherence to diabetes self-care and oral hypoglycemic regimens, HbA 1c levels, functional impairment, and health care costs. Results Compared with patients in the low-severity depression symptom tertile, those in the medium- and high-severity tertiles were significantly less adherent to dietary recommendations. Patients in the high-severity tertile were significantly distinct from those in the low-severity tertile by having a higher percentage of days in nonadherence to oral hypoglycemic regimens (15% vs 7%); poorer physical and mental functioning; greater probability of having any emergency department, primary care, specialty care, medical inpatient, and mental health costs; and among users of health care within categories, higher primary (51% higher), ambulatory (75% higher), and total health care costs (86% higher). Conclusions Depressive symptom severity is associated with poorer diet and medication regimen adherence, functional impairment, and higher health care costs in primary care diabetic patients. Further studies testing the effectiveness and cost-effectiveness of enhanced models of care of diabetic patients with depression are needed.

Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus

Abstract: Type 2 or non-insulin-dependent diabetes mellitus (NIDDM) is the most common form of diabetes worldwide, affecting approximately 4% of the world's adult population. It is multifactorial in origin with both genetic and environmental factors contributing to its development. A genome-wide screen for type 2 diabetes genes carried out in Mexican Americans localized a susceptibility gene, designated NIDDM1, to chromosome 2. Here we describe the positional cloning of a gene located in the NIDDM1 region that shows association with type 2 diabetes in Mexican Americans and a Northern European population from the Botnia region of Finland. This putative diabetes-susceptibility gene encodes a ubiquitously expressed member of the calpain-like cysteine protease family, calpain-10 (CAPN10). This finding suggests a novel pathway that may contribute to the development of type 2 diabetes.