Showing papers by "University of Utah published in 2008"
TL;DR: A hydraulically based theory considering carbon balance and insect resistance that allowed development and examination of hypotheses regarding survival and mortality was developed, and incorporating this hydraulic framework may be effective for modeling plant survival andortality under future climate conditions.
Abstract: Summary Severe droughts have been associated with regional-scale forest mortality worldwide. Climate change is expected to exacerbate regional mortality events; however, pre- diction remains difficult because the physiological mechanisms underlying drought survival and mortality are poorly understood. We developed a hydraulically based theory considering carbon balance and insect resistance that allowed development and examination of hypotheses regarding survival and mortality. Multiple mechanisms may cause mortality during drought. A common mechanism for plants with isohydric
3,302 citations
TL;DR: These efforts to build better models of the monovalent ions within the pairwise Coulombic and 6-12 Lennard-Jones framework are described, where the models are tuned to balance crystal and solution properties in Ewald simulations with specific choices of well-known water models.
Abstract: Alkali (Li+, Na+, K+, Rb+, and Cs+) and halide (F−, Cl−, Br−, and I−) ions play an important role in many biological phenomena, roles that range from stabilization of biomolecular structure, to influence on biomolecular dynamics, to key physiological influence on homeostasis and signaling. To properly model ionic interaction and stability in atomistic simulations of biomolecular structure, dynamics, folding, catalysis, and function, an accurate model or representation of the monovalent ions is critically necessary. A good model needs to simultaneously reproduce many properties of ions, including their structure, dynamics, solvation, and moreover both the interactions of these ions with each other in the crystal and in solution and the interactions of ions with other molecules. At present, the best force fields for biomolecules employ a simple additive, nonpolarizable, and pairwise potential for atomic interaction. In this work, we describe our efforts to build better models of the monovalent ions within t...
2,550 citations
TL;DR: An introduction to crowdsourcing is provided, both its theoretical grounding and exemplar cases, taking care to distinguish crowdsourcing from open source production.
Abstract: Crowdsourcing is an online, distributed problem-solving and production model that has emerged in recent years. Notable examples of the model include Threadless, iStockphoto, InnoCentive, the Goldcorp Challenge, and user-generated advertising contests. This article provides an introduction to crowdsourcing, both its theoretical grounding and exemplar cases, taking care to distinguish crowdsourcing from open source production. This article also explores the possibilities for the model, its potential to exploit a crowd of innovators, and its potential for use beyond forprofit sectors. Finally, this article proposes an agenda for research into crowdsourcing.
2,019 citations
TL;DR: The present review summarizes the data that appeared in the literature following publication of previous reviews in 1996 and 2002 and is organized according to the classes of organic polyvalent iodine compounds with emphasis on their synthetic application.
Abstract: Starting from the early 1990’s, the chemistry of polyvalent iodine organic compounds has experienced an explosive development. This surging interest in iodine compounds is mainly due to the very useful oxidizing properties of polyvalent organic iodine reagents, combined with their benign environmental character and commercial availability. Iodine(III) and iodine(V) derivatives are now routinely used in organic synthesis as reagents for various selective oxidative transformations of complex organic molecules. Several areas of hypervalent organoiodine chemistry have recently attracted especially active interest and research activity. These areas, in particular, include the synthetic applications of 2-iodoxybenzoic acid (IBX) and similar oxidizing reagents based on the iodine(V) derivatives, the development and synthetic use of polymer-supported and recyclable polyvalent iodine reagents, the catalytic applications of organoiodine compounds, and structural studies of complexes and supramolecular assemblies of polyvalent iodine compounds.
The chemistry of polyvalent iodine has previously been covered in four books1–4 and several comprehensive review papers.5–17 Numerous reviews on specific classes of polyvalent iodine compounds and their synthetic applications have recently been published.18–61 Most notable are the specialized reviews on [hydroxy(tosyloxy)iodo]benzene,41 the chemistry and synthetic applications of iodonium salts,29,36,38,42,43,46,47,54,55 the chemistry of iodonium ylides,56–58 the chemistry of iminoiodanes,28 hypervalent iodine fluorides,27 electrophilic perfluoroalkylations,44 perfluoroorgano hypervalent iodine compounds,61 the chemistry of benziodoxoles,24,45 polymer-supported hypervalent iodine reagents,30 hypervalent iodine-mediated ring contraction reactions,21 application of hypervalent iodine in the synthesis of heterocycles,25,40 application of hypervalent iodine in the oxidation of phenolic compounds,32,34,50–53,60 oxidation of carbonyl compounds with organohypervalent iodine reagents,37 application of hypervalent iodine in (hetero)biaryl coupling reactions,31 phosphorolytic reactivity of o-iodosylcarboxylates,33 coordination of hypervalent iodine,19 transition metal catalyzed reactions of hypervalent iodine compounds,18 radical reactions of hypervalent iodine,35,39 stereoselective reactions of hypervalent iodine electrophiles,48 catalytic applications of organoiodine compounds,20,49 and synthetic applications of pentavalent iodine reagents.22,23,26,59
The main purpose of the present review is to summarize the data that appeared in the literature following publication of our previous reviews in 1996 and 2002. In addition, a brief introductory discussion of the most important earlier works is provided in each section. The review is organized according to the classes of organic polyvalent iodine compounds with emphasis on their synthetic application. Literature coverage is through July 2008.
1,518 citations
TL;DR: The results demonstrate that MAKER provides a simple and effective means to convert a genome sequence into a community-accessible genome database, and should prove especially useful for emerging model organism genome projects for which extensive bioinformatics resources may not be readily available.
Abstract: We have developed a portable and easily configurable genome annotation pipeline called MAKER. Its purpose is to allow investigators to independently annotate eukaryotic genomes and create genome databases. MAKER identifies repeats, aligns ESTs and proteins to a genome, produces ab initio gene predictions, and automatically synthesizes these data into gene annotations having evidence-based quality indices. MAKER is also easily trainable: Outputs of preliminary runs are used to automatically retrain its gene-prediction algorithm, producing higher-quality gene-models on subsequent runs. MAKER’s inputs are minimal, and its outputs can be used to create a GMOD database. Its outputs can also be viewed in the Apollo Genome browser; this feature of MAKER provides an easy means to annotate, view, and edit individual contigs and BACs without the overhead of a database. As proof of principle, we have used MAKER to annotate the genome of the planarian Schmidtea mediterranea and to create a new genome database, SmedGD. We have also compared MAKER’s performance to other published annotation pipelines. Our results demonstrate that MAKER provides a simple and effective means to convert a genome sequence into a community-accessible genome database. MAKER should prove especially useful for emerging model organism genome projects for which extensive bioinformatics resources may not be readily available.
1,503 citations
University of Utah1, Cleveland Clinic2, University of Alabama at Birmingham3, United States Department of Veterans Affairs4, Loyola University Chicago5, National Institutes of Health6, University of Texas Southwestern Medical Center7, University of Michigan8, University of North Carolina at Chapel Hill9, Duke University10, Centers for Disease Control and Prevention11
TL;DR: A cross-sectional analysis of 1961 nonpregnant women who participated in the 2005-2006 National Health and Nutrition Examination Survey, a nationally representative survey of the US noninstitutionalized population, found no differences in prevalence by racial/ethnic group.
Abstract: Results The weighted prevalence of at least 1 pelvic floor disorder was 23.7% (95% confidence interval [CI], 21.2%-26.2%), with 15.7% of women (95% CI, 13.2%18.2%) experiencing urinary incontinence, 9.0% of women (95% CI, 7.3%-10.7%) experiencing fecal incontinence, and 2.9% of women (95% CI, 2.1%-3.7%) experiencing pelvic organ prolapse. The proportion of women reporting at least 1 disorder increased incrementally with age, ranging from 9.7% (95% CI, 7.8%-11.7%) in women between ages 20 and 39 years to 49.7% (95% CI, 40.3%-59.1%) in those aged 80 years or older (P.001), and parity (12.8% [95% CI, 9.0%-16.6%], 18.4% [95% CI, 12.9%-23.9%], 24.6% [95% CI, 19.5%-29.8%], and 32.4% [95% CI, 27.8%37.1%] for 0, 1, 2, and 3 or more deliveries, respectively; P.001). Overweight and obese women were more likely to report at least 1 pelvic floor disorder than normal weight women (26.3% [95% CI, 21.7%-30.9%], 30.4% [95% CI, 25.8%-35.0%], and 15.1% [95% CI, 11.6%-18.7%], respectively; P.001). We detected no differences in prevalence by racial/ethnic group.
1,466 citations
TL;DR: Analysis provides evidence that plant miRNA–guided silencing has a widespread translational inhibitory component that is genetically separable from endonucleolytic cleavage, and shows that the same is true of silencing mediated by small interfering RNA (siRNA) populations.
Abstract: High complementarity between plant microRNAs (miRNAs) and their messenger RNA targets is thought to cause silencing, prevalently by endonucleolytic cleavage. We have isolated Arabidopsis mutants defective in miRNA action. Their analysis provides evidence that plant miRNA-guided silencing has a widespread translational inhibitory component that is genetically separable from endonucleolytic cleavage. We further show that the same is true of silencing mediated by small interfering RNA (siRNA) populations. Translational repression is effected in part by the ARGONAUTE proteins AGO1 and AGO10. It also requires the activity of the microtubule-severing enzyme katanin, implicating cytoskeleton dynamics in miRNA action, as recently suggested from animal studies. Also as in animals, the decapping component VARICOSE (VCS)/Ge-1 is required for translational repression by miRNAs, which suggests that the underlying mechanisms in the two kingdoms are related.
1,381 citations
TL;DR: This paper found that the majority of variation in leverage ratios is driven by an unobserved time-invariant effect that generates surprisingly stable capital structures: high (low) levered firms tend to remain as such for over two decades.
Abstract: We find that the majority of variation in leverage ratios is driven by an unobserved time-invariant effect that generates surprisingly stable capital structures: High (low) levered firms tend to remain as such for over two decades. This feature of leverage is largely unexplained by previously identified determinants, is robust to firm exit, and is present prior to the IPO, suggesting that variation in capital structures is primarily determined by factors that remain stable for long periods of time. We then show that these results have important implications for empirical analysis attempting to understand capital structure heterogeneity.
1,166 citations
TL;DR: Unexpectedly, the distribution of Bmi1-expressing stem cells along the length of the small intestine suggested that mammals use more than one molecularly distinguishable adult stem cell subpopulation to maintain organ homeostasis.
Abstract: Eugenio Sangiorgi and Mario Capecchi use lineage tracing in mice to identify Bmi1 as a specific marker of a stem cell population located at the +4 position of the small intestinal crypt. Their findings address a long-standing debate in the field and support the existence of two distinct intestinal stem cell populations near the crypt base. Bmi1 plays an essential part in the self-renewal of hematopoietic and neural stem cells. To investigate its role in other adult stem cell populations, we generated a mouse expressing a tamoxifen-inducible Cre from the Bmi1 locus. We found that Bmi1 is expressed in discrete cells located near the bottom of crypts in the small intestine, predominantly four cells above the base of the crypt (+4 position). Over time, these cells proliferate, expand, self-renew and give rise to all the differentiated cell lineages of the small intestine epithelium. The induction of a stable form of β-catenin in these cells was sufficient to rapidly generate adenomas. Moreover, ablation of Bmi1+ cells using a Rosa26 conditional allele, expressing diphtheria toxin, led to crypt loss. These experiments identify Bmi1 as an intestinal stem cell marker in vivo. Unexpectedly, the distribution of Bmi1-expressing stem cells along the length of the small intestine suggested that mammals use more than one molecularly distinguishable adult stem cell subpopulation to maintain organ homeostasis.
1,051 citations
TL;DR: It is suggested that Nix-dependent loss of ΔΨm is important for targeting the mitochondria into autophagosomes for clearance during erythroid maturation, and interference with this function impairs erythyroidmaturation and results in anaemia.
Abstract: Erythroid cells undergo enucleation and the removal of organelles during terminal differentiation. Although autophagy has been suggested to mediate the elimination of organelles for erythroid maturation, the molecular mechanisms underlying this process remain undefined. Here we report a role for a Bcl-2 family member, Nix (also called Bnip3L), in the regulation of erythroid maturation through mitochondrial autophagy. Nix(-/-) mice developed anaemia with reduced mature erythrocytes and compensatory expansion of erythroid precursors. Erythrocytes in the peripheral blood of Nix(-/-) mice exhibited mitochondrial retention and reduced lifespan in vivo. Although the clearance of ribosomes proceeded normally in the absence of Nix, the entry of mitochondria into autophagosomes for clearance was defective. Deficiency in Nix inhibited the loss of mitochondrial membrane potential (DeltaPsi(m)), and treatment with uncoupling chemicals or a BH3 mimetic induced the loss of DeltaPsi(m) and restored the sequestration of mitochondria into autophagosomes in Nix(-/-) erythroid cells. These results suggest that Nix-dependent loss of DeltaPsi(m) is important for targeting the mitochondria into autophagosomes for clearance during erythroid maturation, and interference with this function impairs erythroid maturation and results in anaemia. Our study may also provide insights into molecular mechanisms underlying mitochondrial quality control involving mitochondrial autophagy.
1,005 citations
TL;DR: In this paper, the authors identify the key tensions underlying much of the identity literature; we foreground identity matters as encountered by individuals, understood as social; durability of identity; identity in its various conceptualizations offers creative ways to understand a range of organizational settings and phenomena while bridging the levels from micro to macro.
Abstract: Key tensions underlying much of the identity literature; we foreground identity matters as encountered by individuals, understood as social; durability of identity; identity in its various conceptualizations offers creative ways to understand a range of organizational settings and phenomena while bridging the levels from micro to macro.
TL;DR: There was robust growth of the human brain in the first two years of life, driven mainly by gray matter growth, in contrast, white matter growth was much slower.
Abstract: Brain development in the first 2 years after birth is extremely dynamic and likely plays an important role in neurodevelopmental disorders, including autism and schizophrenia Knowledge regarding this period is currently quite limited We studied structural brain development in healthy subjects from birth to 2 Ninety-eight children received structural MRI scans on a Siemens head-only 3T scanner with magnetization prepared rapid gradient echo T1-weighted, and turbo spin echo, dual-echo (proton density and T2 weighted) sequences: 84 children at 2–4 weeks, 35 at 1 year and 26 at 2 years of age Tissue segmentation was accomplished using a novel automated approach Lateral ventricle, caudate, and hippocampal volumes were also determined Total brain volume increased 101% in the first year, with a 15% increase in the second The majority of hemispheric growth was accounted for by gray matter, which increased 149% in the first year; hemispheric white matter volume increased by only 11% Cerebellum volume increased 240% in the first year Lateral ventricle volume increased 280% in the first year, with a small decrease in the second The caudate increased 19% and the hippocampus 13% from age 1 to age 2 There was robust growth of the human brain in the first two years of life, driven mainly by gray matter growth In contrast, white matter growth was much slower Cerebellum volume also increased substantially in the first year of life These results suggest the structural underpinnings of cognitive and motor development in early childhood, as well as the potential pathogenesis of neurodevelopmental disorders
TL;DR: It is shown that generic siRNAs might treat angiogenic disorders that affect 8% of the world’s population, and that si RNAs might induce unanticipated vascular or immune effects.
Abstract: Clinical trials of small interfering RNA (siRNA) targeting vascular endothelial growth factor-A (VEGFA) or its receptor VEGFR1 (also called FLT1), in patients with blinding choroidal neovascularization (CNV) from age-related macular degeneration, are premised on gene silencing by means of intracellular RNA interference (RNAi). We show instead that CNV inhibition is a siRNA-class effect: 21-nucleotide or longer siRNAs targeting non-mammalian genes, non-expressed genes, non-genomic sequences, pro- and anti-angiogenic genes, and RNAi-incompetent siRNAs all suppressed CNV in mice comparably to siRNAs targeting Vegfa or Vegfr1 without off-target RNAi or interferon-α/β activation. Non-targeted (against non-mammalian genes) and targeted (against Vegfa or Vegfr1) siRNA suppressed CNV via cell-surface toll-like receptor 3 (TLR3), its adaptor TRIF, and induction of interferon-γ and interleukin-12. Non-targeted siRNA suppressed dermal neovascularization in mice as effectively as Vegfa siRNA. siRNA-induced inhibition of neovascularization required a minimum length of 21 nucleotides, a bridging necessity in a modelled 2:1 TLR3–RNA complex. Choroidal endothelial cells from people expressing the TLR3 coding variant 412FF were refractory to extracellular siRNA-induced cytotoxicity, facilitating individualized pharmacogenetic therapy. Multiple human endothelial cell types expressed surface TLR3, indicating that generic siRNAs might treat angiogenic disorders that affect 8% of the world’s population, and that siRNAs might induce unanticipated vascular or immune effects.
TL;DR: CloudSat data has been used for cloud profiling radar (CPR) as discussed by the authors, which has been operating since 2 June 2006 and has proven to be remarkably stable since turn-on.
Abstract: [1] This paper reports on the early mission performance of the radar and other major aspects of the CloudSat mission. The Cloudsat cloud profiling radar (CPR) has been operating since 2 June 2006 and has proven to be remarkably stable since turn-on. A number of products have been developed using these space-borne radar data as principal inputs. Combined with other A-Train sensor data, these new observations offer unique, global views of the vertical structure of clouds and precipitation jointly. Approximately 11% of clouds detected over the global oceans produce precipitation that, in all likelihood, reaches the surface. Warm precipitating clouds are both wetter and composed of larger particles than nonprecipitating clouds. The frequency of precipitation increases significantly with increasing cloud depth, and the increased depth and water path of precipitating clouds leads to increased optical depths and substantially more sunlight reflected from precipitating clouds compared to than nonprecipitating warm clouds. The CloudSat observations also provide an authoritative estimate of global ice water paths. The observed ice water paths are larger than those predicted from most climate models. CloudSat observations also indicate that clouds radiatively heat the global mean atmospheric column (relative to clear skies) by about 10 Wm−2. Although this heating appears to be contributed almost equally by solar and infrared absorption, the latter contribution is shown to vary significantly with latitude being influenced by the predominant cloud structures of the different region in questions.
TL;DR: In this paper, the authors argue that certain simplifying assumptions are unavoidable when building these models, which introduces biases into their simulations, which sometimes are surprisingly difficult to correct and can lead to model-based projections of climate.
Abstract: Coupled climate models are sophisticated tools designed to simulate the Earth climate system and the complex interactions between its components. Currently, more than a dozen centers around the world develop climate models to enhance our understanding of climate and climate change and to support the activities of the Intergovernmental Panel on Climate Change (IPCC). However, climate models are not perfect. Our theoretical understanding of climate is still incomplete, and certain simplifying assumptions are unavoidable when building these models. This introduces biases into their simulations, which sometimes are surprisingly difficult to correct. Model imperfections have attracted criticism, with some arguing that model-based projections of climate
TL;DR: Performance of information extraction systems with clinical text has improved since the last systematic review in 1995, but they are still rarely applied outside of the laboratory they have been developed in.
Abstract: Objectives: We examine recent published research on the extraction of information from textual documents in the Electronic Health Record (EHR). Methods: Literature review of the research published after 1995, based on PubMed, conference proceedings, and the ACM Digital Library, as well as on relevant publications referenced in papers already included. Results: 174 publications were selected and are discussed in this review in terms of methods used, pre-processing of textual documents, contextual features detection and analysis, extraction of information in general, extraction of codes and of information for decision-support and enrichment of the EHR, information extraction for surveillance, research, automated terminology management, and data mining, and de-identification of clinical text. Conclusions: Performance of information extraction systems with clinical text has improved since the last systematic review in 1995, but they are still rarely applied outside of the laboratory they have been developed in. Competitive challenges for information extraction from clinical text, along with the availability of annotated clinical text corpora, and further improvements in system performance are important factors to stimulate advances in this field and to increase the acceptance and usage of these systems in concrete clinical and biomedical research contexts. Cli
TL;DR: The tropical belt has been widening over past decades, shifting the dry subtropical climate zones polewards around the world as discussed by the authors, and the observed recent rate of expansion is greater than climate model projections of expansion over the twenty-first century, suggesting that there is still much to be learned about this aspect of global climate change.
Abstract: Some of the earliest unequivocal signs of climate change have been the warming of the air and ocean, thawing of land and melting of ice in the Arctic But recent studies are showing that the tropics are also changing Several lines of evidence show that over the past few decades the tropical belt has expanded This expansion has potentially important implications for subtropical societies and may lead to profound changes in the global climate system Most importantly, poleward movement of large-scale atmospheric circulation systems, such as jet streams and storm tracks, could result in shifts in precipitation patterns affecting natural ecosystems, agriculture, and water resources The implications of the expansion for stratospheric circulation and the distribution of ozone in the atmosphere are as yet poorly understood The observed recent rate of expansion is greater than climate model projections of expansion over the twenty-first century, which suggests that there is still much to be learned about this aspect of global climate change The tropical belt has been widening over past decades — as estimated from a number of independent lines of evidence — shifting the dry subtropical climate zones polewards around the world
TL;DR: It is shown that lipopolysaccharide from Gram-negative bacteria activates interleukin-5 (IL-5)- or interferon-γ–primed eosinophils to release mitochondrial DNA in a reactive oxygen species–dependent manner, but independent of eosInophil death, suggesting a previously undescribed mechanism of eOSinophil-mediated innate immune responses that might be crucial for maintaining the intestinal barrier function after inflammation-associated epithelial cell damage
Abstract: Although eosinophils are considered useful in defense mechanisms against parasites, their exact function in innate immunity remains unclear. The aim of this study is to better understand the role of eosinophils within the gastrointestinal immune system. We show here that lipopolysaccharide from Gram-negative bacteria activates interleukin-5 (IL-5)- or interferon-gamma-primed eosinophils to release mitochondrial DNA in a reactive oxygen species-dependent manner, but independent of eosinophil death. Notably, the process of DNA release occurs rapidly in a catapult-like manner--in less than one second. In the extracellular space, the mitochondrial DNA and the granule proteins form extracellular structures able to bind and kill bacteria both in vitro and under inflammatory conditions in vivo. Moreover, after cecal ligation and puncture, Il5-transgenic but not wild-type mice show intestinal eosinophil infiltration and extracellular DNA deposition in association with protection against microbial sepsis. These data suggest a previously undescribed mechanism of eosinophil-mediated innate immune responses that might be crucial for maintaining the intestinal barrier function after inflammation-associated epithelial cell damage, preventing the host from uncontrolled invasion of bacteria.
TL;DR: This review focuses on recent development of the preparation and application for drug delivery of the block copolymer hydrogels that respond to temperature, pH or both stimuli, including poly(N-substituted acrylamide)-based blockcopolymers, poloxamers and their derivatives, poly(ethylene glycol)-polyester block copolemers, polyelectrolyte-based blockCopolymers and the polyelectrodynamic-modified thermo-sensitive block
TL;DR: This review highlights recent progress of the pH-sensitive nanotechnology developed in Bae research group to overcome multidrug resistance of various tumors.
TL;DR: High Resolution Fly's Eye's measurement of the flux of ultrahigh energy cosmic rays shows a sharp suppression at an energy of 6 x 10(19) eV, consistent with the expected cutoff energy.
Abstract: The High Resolution Fly's Eye (HiRes) experiment has observed the Greisen-Zatsepin-Kuzmin suppression (called the GZK cutoff) with a statistical significance of five standard deviations. HiRes' measurement of the flux of ultrahigh energy cosmic rays shows a sharp suppression at an energy of $6\ifmmode\times\else\texttimes\fi{}{10}^{19}\text{ }\text{ }\mathrm{eV}$, consistent with the expected cutoff energy. We observe the ankle of the cosmic-ray energy spectrum as well, at an energy of $4\ifmmode\times\else\texttimes\fi{}{10}^{18}\text{ }\text{ }\mathrm{eV}$. We describe the experiment, data collection, and analysis and estimate the systematic uncertainties. The results are presented and the calculation of the statistical significance of our observation is described.
01 Jul 2008
TL;DR: A wireless wearable system that was developed to provide quantitative gait analysis outside the confines of the traditional motion laboratory, the GaitShoe proved highly capable of detecting heel-strike and toe-off, as well as estimating foot orientation and position, inter alia.
Abstract: We describe a wireless wearable system that was developed to provide quantitative gait analysis outside the confines of the traditional motion laboratory. The sensor suite includes three orthogonal accelerometers, three orthogonal gyroscopes, four force sensors, two bidirectional bend sensors, two dynamic pressure sensors, as well as electric field height sensors. The "GaitShoe" was built to be worn in any shoe, without interfering with gait and was designed to collect data unobtrusively, in any environment, and over long periods. The calibrated sensor outputs were analyzed and validated with results obtained simultaneously from the Massachusetts General Hospital, Biomotion Laboratory. The GaitShoe proved highly capable of detecting heel-strike and toe-off, as well as estimating foot orientation and position, inter alia.
TL;DR: The ACMG strongly recommends that the clinical and technical validation of sequence variation detection be performed in a CLIA-approved laboratory and interpreted by a board-certified clinical molecular geneticist or equivalent.
TL;DR: Current genetic evidence implies dispersal from a single Siberian population toward the Bering Land Bridge no earlier than about 30,000 years ago, then migration from Beringia to the Americas sometime after 16,500 years ago.
Abstract: When did humans colonize the Americas? From where did they come and what routes did they take? These questions have gripped scientists for decades, but until recently answers have proven difficult to find. Current genetic evidence implies dispersal from a single Siberian population toward the Bering Land Bridge no earlier than about 30,000 years ago (and possibly after 22,000 years ago), then migration from Beringia to the Americas sometime after 16,500 years ago. The archaeological records of Siberia and Beringia generally support these findings, as do archaeological sites in North and South America dating to as early as 15,000 years ago. If this is the time of colonization, geological data from western Canada suggest that humans dispersed along the recently deglaciated Pacific coastline.
TL;DR: The present work develops a formal statistical mechanical framework for the MS-CG method and demonstrates that the variational principle underlying the method may, in principle, be employed to determine the many-body potential of mean force (PMF) that governs the equilibrium distribution of positions of the CG sites for theMS-CG models.
Abstract: Coarse-grained (CG) models provide a computationally efficient method for rapidly investigating the long time- and length-scale processes that play a critical role in many important biological and soft matter processes Recently, Izvekov and Voth introduced a new multiscale coarse-graining (MS-CG) method [J Phys Chem B 109, 2469 (2005); J Chem Phys 123, 134105 (2005)] for determining the effective interactions between CG sites using information from simulations of atomically detailed models The present work develops a formal statistical mechanical framework for the MS-CG method and demonstrates that the variational principle underlying the method may, in principle, be employed to determine the many-body potential of mean force (PMF) that governs the equilibrium distribution of positions of the CG sites for the MS-CG models A CG model that employs such a PMF as a “potential energy function” will generate an equilibrium probability distribution of CG sites that is consistent with the atomically detailed model from which the PMF is derived Consequently, the MS-CG method provides a formal multiscale bridge rigorously connecting the equilibrium ensembles generated with atomistic and CG models The variational principle also suggests a class of practical algorithms for calculating approximations to this many-body PMF that are optimal These algorithms use computer simulation data from the atomically detailed model Finally, important generalizations of the MS-CG method are introduced for treating systems with rigid intramolecular constraints and for developing CG models whose equilibrium momentum distribution is consistent with that of an atomically detailed model
TL;DR: The use of complete-genome sequencing in the characterization of spontaneously arising mutations in the yeast Saccharomyces cerevisiae yields numerous unexpected findings, in particular a very high rate of point mutation and skewed distribution of base-substitution types in the mitochondrion and segmental duplication and deletion in the nuclear genome.
Abstract: The mutation process ultimately defines the genetic features of all populations and, hence, has a bearing on a wide range of issues involving evolutionary genetics, inheritance, and genetic disorders, including the predisposition to cancer. Nevertheless, formidable technical barriers have constrained our understanding of the rate at which mutations arise and the molecular spectrum of their effects. Here, we report on the use of complete-genome sequencing in the characterization of spontaneously arising mutations in the yeast Saccharomyces cerevisiae. Our results confirm some findings previously obtained by indirect methods but also yield numerous unexpected findings, in particular a very high rate of point mutation and skewed distribution of base-substitution types in the mitochondrion, a very high rate of segmental duplication and deletion in the nuclear genome, and substantial deviations in the mutational profile among various model organisms.
TL;DR: Current findings often show a robust relationship in which social and emotional support from others can be protective for health, however, the next generation of studies must explain why this relationship exists and the specificity of such links.
Abstract: During the last 30 years, researchers have shown greatinterestinthephenomenonofsocialsupport,particularlyin the context of health. Prior work has found that thosewith high quantity or quality of social networks have adecreased risk of mortality in comparison with thosewho have low quantity or quality of social relationships,even after statistically controlling for baseline healthstatus [1]. In fact, social isolation itself was identifiedasanindependentmajorriskfactorforall-causemortality[2]. Current research has focused on expanding severalareas of knowledge in this field. These include social-support influences on morbidity, mortality, and qualityof life in chronic disease populations, understandingthe mechanisms responsible for such associations, andhow we might apply such findings to design relevantinterventions.It is important to note that social support in these studiesisoperationalizedinseveraldifferentways.Mostbroadly,support can be conceptualized in terms of the structuralcomponents(e.g.socialintegration:being apartofdiffer-ent networks and participating socially [3 ]) and thefunctional components (e.g. different types of trans-actions between individuals, such as emotional supportor favors [4 ]). How the functional components aremeasured often varies between studies; transactionsmay be summarized by actual support received (oftenascertained by asking the support providers [5 ]),perceived support received or available [6 ], or thediscrepancy between perceived support and receivedsupport [7 ]. Support is often further broken down intodifferent types—for instance, instrumental support andemotional support—as people often have preferences fordifferent types of aid depending on the circumstances.This diversity of ways in which support is defined isimportant and can provide greater specificity (context) toresearch findings.
01 Jun 2008
TL;DR: This work believes that in comparison with an electrically-connected many-core alternative that uses the same on-stack interconnect power, Corona can provide 2 to 6 times more performance on many memory intensive workloads, while simultaneously reducing power.
Abstract: We expect that many-core microprocessors will push performance per chip from the 10 gigaflop to the 10 teraflop range in the coming decade. To support this increased performance, memory and inter-core bandwidths will also have to scale by orders of magnitude. Pin limitations, the energy cost of electrical signaling, and the non-scalability of chip-length global wires are significant bandwidth impediments. Recent developments in silicon nanophotonic technology have the potential to meet these off- and on-stack bandwidth requirements at acceptable power levels. Corona is a 3D many-core architecture that uses nanophotonic communication for both inter-core communication and off-stack communication to memory or I/O devices. Its peak floating-point performance is 10 teraflops. Dense wavelength division multiplexed optically connected memory modules provide 10 terabyte per second memory bandwidth. A photonic crossbar fully interconnects its 256 low-power multithreaded cores at 20 terabyte per second bandwidth. We have simulated a 1024 thread Corona system running synthetic benchmarks and scaled versions of the SPLASH-2 benchmark suite. We believe that in comparison with an electrically-connected many-core alternative that uses the same on-stack interconnect power, Corona can provide 2 to 6 times more performance on many memory intensive workloads, while simultaneously reducing power.
TL;DR: Using zebrafish embryos, evidence is provided for a coupled mechanism of 5-meC demethylation, whereby AID deaminates 5- meC, followed by thymine base excision by Mbd4, promoted by Gadd45.
Boston University1, Cleveland Clinic2, University of Alabama3, Washington University in St. Louis4, University of Iowa5, Duke University6, Maine Medical Center7, University of Texas Southwestern Medical Center8, University of Utah9, Tufts University10, Vanderbilt University11, Wake Forest University12, Veterans Health Administration13, National Institutes of Health14, University of Pennsylvania15
TL;DR: Clopidogrel reduces the frequency of early thrombosis of new arteriovenous fistulas but does not increase the proportion of fistulas that become suitable for dialysis.
Abstract: Context The arteriovenous fistula is the preferred type of vascular access for hemodialysis because of lower thrombosis and infection rates and lower health care expenditures compared with synthetic grafts or central venous catheters. Early failure of fistulas due to thrombosis or inadequate maturation is a barrier to increasing the prevalence of fistulas among patients treated with hemodialysis. Small, inconclusive trials have suggested that antiplatelet agents may reduce thrombosis of new fistulas. Objective To determine whether clopidogrel reduces early failure of hemodialysis fistulas. Design, Setting, and Participants Randomized, double-blind, placebo-controlled trial conducted at 9 US centers composed of academic and community nephrology practices in 2003-2007. Eight hundred seventy-seven participants with end-stage renal disease or advanced chronic kidney disease were followed up until 150 to 180 days after fistula creation or 30 days after initiation of dialysis, whichever occurred later. Intervention Participants were randomly assigned to receive clopidogrel (300-mg loading dose followed by daily dose of 75 mg; n = 441) or placebo (n = 436) for 6 weeks starting within 1 day after fistula creation. Main Outcome Measures The primary outcome was fistula thrombosis, determined by physical examination at 6 weeks. The secondary outcome was failure of the fistula to become suitable for dialysis. Suitability was defined as use of the fistula at a dialysis machine blood pump rate of 300 mL/min or more during 8 of 12 dialysis sessions. Results Enrollment was stopped after 877 participants were randomized based on a stopping rule for intervention efficacy. Fistula thrombosis occurred in 53 (12.2%) participants assigned to clopidogrel compared with 84 (19.5%) participants assigned to placebo (relative risk, 0.63; 95% confidence interval, 0.46-0.97; P = .018). Failure to attain suitability for dialysis did not differ between the clopidogrel and placebo groups (61.8% vs 59.5%, respectively; relative risk, 1.05; 95% confidence interval, 0.94-1.17; P = .40). Conclusion Clopidogrel reduces the frequency of early thrombosis of new arteriovenous fistulas but does not increase the proportion of fistulas that become suitable for dialysis. Trial Registration clinicaltrials.gov Identifier: NCT00067119