Showing papers by "University of Utah published in 2011"
TL;DR: In the early 1960s, the discovery of crown ethers and spherands by Pedersen, Lehn, and Cram3 led to the realization that small, complementary molecules can be made to recognize each other through non-covalent interactions such as hydrogen-bonding, charge-charge, donor-acceptor, π-π, van der Waals, hydrophilic and hydrophobic interactions to achieve these highly complex and often symmetrical architectures as mentioned in this paper.
Abstract: Fascination with supramolecular chemistry over the last few decades has led to the synthesis of an ever-increasing number of elegant and intricate functional structures with sizes that approach nanoscopic dimensions Today, it has grown into a mature field of modern science whose interfaces with many disciplines have provided invaluable opportunities for crossing boundaries both inside and between the fields of chemistry, physics, and biology This chemistry is of continuing interest for synthetic chemists; partly because of the fascinating physical and chemical properties and the complex and varied aesthetically pleasing structures that supramolecules possess For scientists seeking to design novel molecular materials exhibiting unusual sensing, magnetic, optical, and catalytic properties, and for researchers investigating the structure and function of biomolecules, supramolecular chemistry provides limitless possibilities Thus, it transcends the traditional divisional boundaries of science and represents a highly interdisciplinary field
In the early 1960s, the discovery of ‘crown ethers’, ‘cryptands’ and ‘spherands’ by Pedersen,1 Lehn,2 and Cram3 respectively, led to the realization that small, complementary molecules can be made to recognize each other through non-covalent interactions such as hydrogen-bonding, charge-charge, donor-acceptor, π-π, van der Waals, etc Such ‘programmed’ molecules can thus be self-assembled by utilizing these interactions in a definite algorithm to form large supramolecules that have different physicochemical properties than those of the precursor building blocks Typical systems are designed such that the self-assembly process is kinetically reversible; the individual building blocks gradually funnel towards an ensemble that represents the thermodynamic minimum of the system via numerous association and dissociation steps By tuning various reaction parameters, the reaction equilibrium can be shifted towards the desired product As such, self-assembly has a distinct advantage over traditional, stepwise synthetic approaches when accessing large molecules
It is well known that nature has the ability to assemble relatively simple molecular precursors into extremely complex biomolecules, which are vital for life processes Nature’s building blocks possess specific functionalities in configurations that allow them to interact with one another in a deliberate manner Protein folding, nucleic acid assembly and tertiary structure, phospholipid membranes, ribosomes, microtubules, etc are but a selective, representative example of self-assembly in nature that is of critical importance for living organisms Nature makes use of a variety of weak, non-covalent interactions such as hydrogen–bonding, charge–charge, donor–acceptor, π-π, van der Waals, hydrophilic and hydrophobic, etc interactions to achieve these highly complex and often symmetrical architectures In fact, the existence of life is heavily dependent on these phenomena The aforementioned structures provide inspiration for chemists seeking to exploit the ‘weak interactions’ described above to make scaffolds rivaling the complexity of natural systems
The breadth of supramolecular chemistry has progressively increased with the synthesis of numerous unique supramolecules each year Based on the interactions used in the assembly process, supramolecular chemistry can be broadly classified in to three main branches: i) those that utilize H-bonding motifs in the supramolecular architectures, ii) processes that primarily use other non-covalent interactions such as ion-ion, ion-dipole, π–π stacking, cation-π, van der Waals and hydrophobic interactions, and iii) those that employ strong and directional metal-ligand bonds for the assembly process However, as the scale and degree of complexity of desired molecules increases, the assembly of small molecular units into large, discrete supramolecules becomes an increasingly daunting task This has been due in large part to the inability to completely control the directionality of the weak forces employed in the first two classifications above Coordination-driven self-assembly, which defines the third approach, affords a greater control over the rational design of 2D and 3D architectures by capitalizing on the predictable nature of the metal-ligand coordination sphere and ligand lability to encode directionality Thus, this third strategy represents an alternative route to better execute the “bottom-up” synthetic strategy for designing molecules of desired dimensions, ranging from a few cubic angstroms to over a cubic nanometer For instance, a wide array of 2D systems: rhomboids, squares, rectangles, triangles, etc, and 3D systems: trigonal pyramids, trigonal prisms, cubes, cuboctahedra, double squares, adamantanoids, dodecahedra and a variety of other cages have been reported As in nature, inherent preferences for particular geometries and binding motifs are ‘encoded’ in certain molecules depending on the metals and functional groups present; these moieties help to control the way in which the building blocks assemble into well-defined, discrete supramolecules4
Since the early pioneering work by Lehn5 and Sauvage6 on the feasibility and usefulness of coordination-driven self-assembly in the formation of infinite helicates, grids, ladders, racks, knots, rings, catenanes, rotaxanes and related species,7 several groups - Stang,8 Raymond,9 Fujita,10 Mirkin,11 Cotton12 and others13,14 have independently developed and exploited novel coordination-based paradigms for the self-assembly of discrete metallacycles and metallacages with well-defined shapes and sizes In the last decade, the concepts and perspectives of coordination-driven self-assembly have been delineated and summarized in several insightful reviews covering various aspects of coordinationdriven self-assembly15 In the last decade, the use of this synthetic strategy has led to metallacages dubbed as “molecular flasks” by Fujita,16 and Raymond and Bergman,17 which due to their ability to encapsulate guest molecules, allowed for the observation of unique chemical phenomena and unusual reactions which cannot be achieved in the conventional gas, liquid or solid phases Furthermore, these assemblies found applications in supramolecular catalysis18,19 and as nanomaterials as developed by Hupp20 and others21,22
This review focuses on the journey of early coordination-driven self-assembly paradigms to more complex and discrete 2D and 3D supramolecular ensembles over the last decade We begin with a discussion of various approaches that have been developed by different groups to assemble finite supramolecular architectures The subsequent sections contain detailed discussions on the synthesis of discrete 2D and 3D systems, their functionalizations and applications
2,388 citations
Daniel J. Eisenstein1, Daniel J. Eisenstein2, David H. Weinberg3, Eric Agol4 +260 more•Institutions (62)
TL;DR: SDSS-III as mentioned in this paper is a program of four spectroscopic surveys on three scientific themes: dark energy and cosmological parameters, the history and structure of the Milky Way, and the population of giant planets around other stars.
Abstract: Building on the legacy of the Sloan Digital Sky Survey (SDSS-I and II), SDSS-III is a program of four spectroscopic surveys on three scientific themes: dark energy and cosmological parameters, the history and structure of the Milky Way, and the population of giant planets around other stars. In keeping with SDSS tradition, SDSS-III will provide regular public releases of all its data, beginning with SDSS DR8 (which occurred in Jan 2011). This paper presents an overview of the four SDSS-III surveys. BOSS will measure redshifts of 1.5 million massive galaxies and Lya forest spectra of 150,000 quasars, using the BAO feature of large scale structure to obtain percent-level determinations of the distance scale and Hubble expansion rate at z 100 per resolution element), H-band (1.51-1.70 micron) spectra of 10^5 evolved, late-type stars, measuring separate abundances for ~15 elements per star and creating the first high-precision spectroscopic survey of all Galactic stellar populations (bulge, bar, disks, halo) with a uniform set of stellar tracers and spectral diagnostics. MARVELS will monitor radial velocities of more than 8000 FGK stars with the sensitivity and cadence (10-40 m/s, ~24 visits per star) needed to detect giant planets with periods up to two years, providing an unprecedented data set for understanding the formation and dynamical evolution of giant planet systems. (Abridged)
2,265 citations
TL;DR: A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function, and these findings suggest potential novel therapeutic pathways for cardiovascular disease prevention.
Abstract: Blood pressure is a heritable trait(1) influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (>= 140 mm Hg systolic blood pressure or >= 90 mm Hg diastolic blood pressure)(2). Even small increments in blood pressure are associated with an increased risk of cardiovascular events(3). This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.
1,829 citations
Heribert Schunkert1, Inke R. König1, Sekar Kathiresan2, Muredach P. Reilly3 +163 more•Institutions (59)
TL;DR: This paper performed a meta-analysis of 14 genome-wide association studies of coronary artery disease (CAD) comprising 22,233 individuals with CAD (cases) and 64,762 controls of European descent followed by genotyping of top association signals in 56,682 additional individuals.
Abstract: We performed a meta-analysis of 14 genome-wide association studies of coronary artery disease (CAD) comprising 22,233 individuals with CAD (cases) and 64,762 controls of European descent followed by genotyping of top association signals in 56,682 additional individuals. This analysis identified 13 loci newly associated with CAD at P < 5 - 10'8 and confirmed the association of 10 of 12 previously reported CAD loci. The 13 new loci showed risk allele frequencies ranging from 0.13 to 0.91 and were associated with a 6% to 17% increase in the risk of CAD per allele. Notably, only three of the new loci showed significant association with traditional CAD risk factors and the majority lie in gene regions not previously implicated in the pathogenesis of CAD. Finally, five of the new CAD risk loci appear to have pleiotropic effects, showing strong association with various other human diseases or traits.
1,705 citations
1,637 citations
TL;DR: It would be profitable to address a variety of issues and factors that could affect the development of improved targeted drug delivery systems, including nanocarrier, nanovehicle, nanosystem, nanostructure, and other terms used in the literature.
1,603 citations
Hiroaki Aihara1, Carlos Allende Prieto2, Carlos Allende Prieto3, Deokkeun An4 +191 more•Institutions (58)
TL;DR: The first data release of SDSS-III is described in this article, which includes five-band imaging of roughly 5200 deg2 in the southern Galactic cap, bringing the total footprint of the Sloan Digital Sky Survey imaging to 14,555 deg2, or over a third of the Celestial Sphere.
Abstract: The Sloan Digital Sky Survey (SDSS) started a new phase in 2008 August, with new instrumentation and new surveys focused on Galactic structure and chemical evolution, measurements of the baryon oscillation feature in the clustering of galaxies and the quasar Lyα forest, and a radial velocity search for planets around ~8000 stars. This paper describes the first data release of SDSS-III (and the eighth counting from the beginning of the SDSS). The release includes five-band imaging of roughly 5200 deg2 in the southern Galactic cap, bringing the total footprint of the SDSS imaging to 14,555 deg2, or over a third of the Celestial Sphere. All the imaging data have been reprocessed with an improved sky-subtraction algorithm and a final, self-consistent photometric recalibration and flat-field determination. This release also includes all data from the second phase of the Sloan Extension for Galactic Understanding and Exploration (SEGUE-2), consisting of spectroscopy of approximately 118,000 stars at both high and low Galactic latitudes. All the more than half a million stellar spectra obtained with the SDSS spectrograph have been reprocessed through an improved stellar parameter pipeline, which has better determination of metallicity for high-metallicity stars.
1,578 citations
TL;DR: This progress report covers both basic concepts and recent advances in the development of HA‐based hydrogels for biomedical applications.
Abstract: Hyaluronic acid (HA), an immunoneutral polysaccharide that is ubiquitous in the human body, is crucial for many cellular and tissue functions and has been in clinical use for over thirty years. When chemically modified, HA can be transformed into many physical forms-viscoelastic solutions, soft or stiff hydrogels, electrospun fibers, non-woven meshes, macroporous and fibrillar sponges, flexible sheets, and nanoparticulate fluids-for use in a range of preclinical and clinical settings. Many of these forms are derived from the chemical crosslinking of pendant reactive groups by addition/condensation chemistry or by radical polymerization. Clinical products for cell therapy and regenerative medicine require crosslinking chemistry that is compatible with the encapsulation of cells and injection into tissues. Moreover, an injectable clinical biomaterial must meet marketing, regulatory, and financial constraints to provide affordable products that can be approved, deployed to the clinic, and used by physicians. Many HA-derived hydrogels meet these criteria, and can deliver cells and therapeutic agents for tissue repair and regeneration. This progress report covers both basic concepts and recent advances in the development of HA-based hydrogels for biomedical applications.
1,575 citations
TL;DR: MAKER2 is the first annotation engine specifically designed for second-generation genome projects, which scales to datasets of any size, requires little in the way of training data, and can use mRNA-seq data to improve annotation quality.
Abstract: Second-generation sequencing technologies are precipitating major shifts with regards to what kinds of genomes are being sequenced and how they are annotated. While the first generation of genome projects focused on well-studied model organisms, many of today's projects involve exotic organisms whose genomes are largely terra incognita. This complicates their annotation, because unlike first-generation projects, there are no pre-existing 'gold-standard' gene-models with which to train gene-finders. Improvements in genome assembly and the wide availability of mRNA-seq data are also creating opportunities to update and re-annotate previously published genome annotations. Today's genome projects are thus in need of new genome annotation tools that can meet the challenges and opportunities presented by second-generation sequencing technologies. We present MAKER2, a genome annotation and data management tool designed for second-generation genome projects. MAKER2 is a multi-threaded, parallelized application that can process second-generation datasets of virtually any size. We show that MAKER2 can produce accurate annotations for novel genomes where training-data are limited, of low quality or even non-existent. MAKER2 also provides an easy means to use mRNA-seq data to improve annotation quality; and it can use these data to update legacy annotations, significantly improving their quality. We also show that MAKER2 can evaluate the quality of genome annotations, and identify and prioritize problematic annotations for manual review. MAKER2 is the first annotation engine specifically designed for second-generation genome projects. MAKER2 scales to datasets of any size, requires little in the way of training data, and can use mRNA-seq data to improve annotation quality. It can also update and manage legacy genome annotation datasets.
1,504 citations
University of California, San Diego1, University of Utah2, University of Pennsylvania3, Rhode Island Hospital4, Boston Children's Hospital5, Children's Mercy Hospital6, Baylor College of Medicine7, Cleveland Clinic8, University of Texas Southwestern Medical Center9, Centers for Disease Control and Prevention10, University of Missouri–Kansas City11, Emory University12
TL;DR: Eidenced-based guidelines for management of infants and children with community-acquired pneumonia (CAP) were prepared by an expert panel comprising clinicians and investigators representing community pediatrics, public health, and the pediatric specialties of critical care, emergency medicine, hospital medicine, infectious diseases, pulmonology, and surgery.
Abstract: Evidenced-based guidelines for management of infants and children with community-acquired pneumonia (CAP) were prepared by an expert panel comprising clinicians and investigators representing community pediatrics, public health, and the pediatric specialties of critical care, emergency medicine, hospital medicine, infectious diseases, pulmonology, and surgery. These guidelines are intended for use by primary care and subspecialty providers responsible for the management of otherwise healthy infants and children with CAP in both outpatient and inpatient settings. Site-of-care management, diagnosis, antimicrobial and adjunctive surgical therapy, and prevention are discussed. Areas that warrant future investigations are also highlighted.
1,333 citations
Wellcome Trust Sanger Institute1, Université de Montréal2, University of Edinburgh3, University of Kiel4, Karolinska Institutet5, Cedars-Sinai Medical Center6, University of Cambridge7, University of Pennsylvania8, Casa Sollievo della Sofferenza9, University of Pittsburgh10, Université libre de Bruxelles11, University of Otago12, Johns Hopkins University13, Ludwig Maximilian University of Munich14, Charité15, Lille University of Science and Technology16, Cincinnati Children's Hospital Medical Center17, Ghent University18, Torbay Hospital19, University of Groningen20, Mater Health Services21, University of Liège22, University of Washington23, University of Utah24, QIMR Berghofer Medical Research Institute25, University of Paris26, University of Western Australia27, Tel Aviv University28, University of Dundee29, Harvard University30, University of Manchester31, Utrecht University32, University of Florence33, King's College London34, Yale University35, Royal Hospital for Sick Children36, Katholieke Universiteit Leuven37, Guy's and St Thomas' NHS Foundation Trust38, University of Barcelona39, University of Chicago40, University of Bern41, Agency for Science, Technology and Research42, University of California, San Francisco43, University of Toronto44, University of Oslo45, Leiden University46, University of Amsterdam47, Aarhus University48, National and Kapodistrian University of Athens49, Lithuanian University of Health Sciences50, Newcastle University51, Emory University52, Örebro University53, French Institute of Health and Medical Research54, Center for Applied Genomics55
TL;DR: A meta-analysis of six ulcerative colitis genome-wide association study datasets found many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1.
Abstract: Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 × 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis.
TL;DR: Among patients with acute decompensated heart failure, there were no significant differences in patients' global assessment of symptoms or in the change in renal function when diuretic therapy was administered by bolus as compared with continuous infusion or at a high dose asCompared with a low dose.
Abstract: Among patients with acute decompensated heart failure, there were no significant differences in patients’ global assessment of symptoms or in the change in renal function when diuretic therapy was administered by bolus as compared with continuous infusion or at a high dose as compared with a low dose. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT00577135.)
TL;DR: The 2010 i2b2/VA Workshop on Natural Language Processing Challenges for Clinical Records presented three tasks, which showed that machine learning approaches could be augmented with rule-based systems to determine concepts, assertions, and relations.
University of Utah1, University of Alabama2, National Institutes of Health3, Henry Ford Health System4, Georgetown University5, Marshfield Clinic6, University of Colorado Denver7, University of Minnesota8, Washington University in St. Louis9, University of Pittsburgh10, University of California, Los Angeles11, Westat12, University of Toronto13
TL;DR: Among women in the general US population, simultaneous screening with CA-125 and transvaginal ultrasound compared with usual care did not reduce ovarian cancer mortality.
Abstract: Context Screening for ovarian cancer with cancer antigen 125 (CA-125) and transvaginal ultrasound has an unknown effect on mortality. Objective To evaluate the effect of screening for ovarian cancer on mortality in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Design, Setting, and Participants Randomized controlled trial of 78 216 women aged 55 to 74 years assigned to undergo either annual screening (n = 39 105) or usual care (n = 39 111) at 10 screening centers across the United States between November 1993 and July 2001. Intervention The intervention group was offered annual screening with CA-125 for 6 years and transvaginal ultrasound for 4 years. Participants and their health care practitioners received the screening test results and managed evaluation of abnormal results. The usual care group was not offered annual screening with CA-125 for 6 years or transvaginal ultrasound but received their usual medical care. Participants were followed up for a maximum of 13 years (median [range], 12.4 years [10.9-13.0 years]) for cancer diagnoses and death until February 28, 2010. Main Outcome Measures Mortality from ovarian cancer, including primary peritoneal and fallopian tube cancers. Secondary outcomes included ovarian cancer incidence and complications associated with screening examinations and diagnostic procedures. Results Ovarian cancer was diagnosed in 212 women (5.7 per 10 000 person-years) in the intervention group and 176 (4.7 per 10 000 person-years) in the usual care group (rate ratio [RR], 1.21; 95% confidence interval [CI], 0.99-1.48). There were 118 deaths caused by ovarian cancer (3.1 per 10 000 person-years) in the intervention group and 100 deaths (2.6 per 10 000 person-years) in the usual care group (mortality RR, 1.18; 95% CI, 0.82-1.71). Of 3285 women with false-positive results, 1080 underwent surgical follow-up; of whom, 163 women experienced at least 1 serious complication (15%). There were 2924 deaths due to other causes (excluding ovarian, colorectal, and lung cancer) (76.6 per 10 000 person-years) in the intervention group and 2914 deaths (76.2 per 10 000 person-years) in the usual care group (RR, 1.01; 95% CI, 0.96-1.06). Conclusions Among women in the general US population, simultaneous screening with CA-125 and transvaginal ultrasound compared with usual care did not reduce ovarian cancer mortality. Diagnostic evaluation following a false-positive screening test result was associated with complications. Trial Registration clinicaltrials.gov Identifier: NCT00002540
Constantine A. Gatsonis1, Denise R. Aberle2, Christine D. Berg, William C. Black3 +1333 more•Institutions (31)
TL;DR: The National Lung Screening Trial (NLST) is a randomized multicenter study comparing low-dose helical computed tomography with chest radiography in the screening of older current and former heavy smokers for early detection of lung cancer.
Abstract: The National Lung Screening Trial (NLST) is a randomized multicenter study comparing low-dose helical computed tomography (CT) with chest radiography in the screening of older current and former heavy smokers for early detection of lung cancer, which is the leading cause of cancer-related death in the United States Five-year survival rates approach 70% with surgical resection of stage IA disease; however, more than 75% of individuals have incurable locally advanced or metastatic disease, the latter having a 5-year survival of less than 5% It is plausible that treatment should be more effective and the likelihood of death decreased if asymptomatic lung cancer is detected through screening early enough in its preclinical phase For these reasons, there is intense interest and intuitive appeal in lung cancer screening with low-dose CT The use of survival as the determinant of screening effectiveness is, however, confounded by the well-described biases of lead time, length, and overdiagnosis Despite previous attempts, no test has been shown to reduce lung cancer mortality, an endpoint that circumvents screening biases and provides a definitive measure of benefit when assessed in a randomized controlled trial that enables comparison of mortality rates between screened individuals and a control group that does not undergo the screening intervention of interest The NLST is such a trial The rationale for and design of the NLST are presented
Marcos Daniel Actis1, G. Agnetta2, Felix Aharonian3, A. G. Akhperjanian +682 more•Institutions (109)
TL;DR: The ground-based gamma-ray astronomy has had a major breakthrough with the impressive results obtained using systems of imaging atmospheric Cherenkov telescopes as mentioned in this paper, which is an international initiative to build the next generation instrument, with a factor of 5-10 improvement in sensitivity in the 100 GeV-10 TeV range and the extension to energies well below 100GeV and above 100 TeV.
Abstract: Ground-based gamma-ray astronomy has had a major breakthrough with the impressive results obtained using systems of imaging atmospheric Cherenkov telescopes. Ground-based gamma-ray astronomy has a huge potential in astrophysics, particle physics and cosmology. CTA is an international initiative to build the next generation instrument, with a factor of 5-10 improvement in sensitivity in the 100 GeV-10 TeV range and the extension to energies well below 100 GeV and above 100 TeV. CTA will consist of two arrays (one in the north, one in the south) for full sky coverage and will be operated as open observatory. The design of CTA is based on currently available technology. This document reports on the status and presents the major design concepts of CTA.
TL;DR: Direct, genetic evidence is provided that satellite cells are required for muscle regeneration and resident fibroblasts are identified as a novel and vital component of the niche regulating satellite cell expansion during regeneration, and it is demonstrated that reciprocal interactions between fibroblast and satellite cells contribute significantly to efficient, effective muscle regeneration.
Abstract: Muscle regeneration requires the coordinated interaction of multiple cell types. Satellite cells have been implicated as the primary stem cell responsible for regenerating muscle, yet the necessity of these cells for regeneration has not been tested. Connective tissue fibroblasts also are likely to play a role in regeneration, as connective tissue fibrosis is a hallmark of regenerating muscle. However, the lack of molecular markers for these fibroblasts has precluded an investigation of their role. Using Tcf4, a newly identified fibroblast marker, and Pax7, a satellite cell marker, we found that after injury satellite cells and fibroblasts rapidly proliferate in close proximity to one another. To test the role of satellite cells and fibroblasts in muscle regeneration in vivo, we created Pax7CreERT2 and Tcf4CreERT2 mice and crossed these to R26RDTA mice to genetically ablate satellite cells and fibroblasts. Ablation of satellite cells resulted in a complete loss of regenerated muscle, as well as misregulation of fibroblasts and a dramatic increase in connective tissue. Ablation of fibroblasts altered the dynamics of satellite cells, leading to premature satellite cell differentiation, depletion of the early pool of satellite cells, and smaller regenerated myofibers. Thus, we provide direct, genetic evidence that satellite cells are required for muscle regeneration and also identify resident fibroblasts as a novel and vital component of the niche regulating satellite cell expansion during regeneration. Furthermore, we demonstrate that reciprocal interactions between fibroblasts and satellite cells contribute significantly to efficient, effective muscle regeneration.
Proceedings Article•
12 Dec 2011TL;DR: A spectral clustering framework is proposed that achieves this goal by co-regularizing the clustering hypotheses, and two co- regularization schemes are proposed to accomplish this.
Abstract: In many clustering problems, we have access to multiple views of the data each of which could be individually used for clustering. Exploiting information from multiple views, one can hope to find a clustering that is more accurate than the ones obtained using the individual views. Often these different views admit same underlying clustering of the data, so we can approach this problem by looking for clusterings that are consistent across the views, i.e., corresponding data points in each view should have same cluster membership. We propose a spectral clustering framework that achieves this goal by co-regularizing the clustering hypotheses, and propose two co-regularization schemes to accomplish this. Experimental comparisons with a number of baselines on two synthetic and three real-world datasets establish the efficacy of our proposed approaches.
TL;DR: Disparities in suicidality and depression may be influenced by negative experiences including discrimination and victimization and Clinicians should assess sexual orientation, analyze psychosocial histories to identify associated risk factors, and promote prevention and intervention opportunities for SMY and their families.
Emory University1, University of Texas Southwestern Medical Center2, University of Utah3, Indiana University4, Stanford University5, Yale University6, Duke University7, Tufts University8, Wayne State University9, University of Texas Health Science Center at Houston10, University of Alabama at Birmingham11, University of New Mexico12, University of Iowa13, Case Western Reserve University14, University of Cincinnati15, Brown University16, Centers for Disease Control and Prevention17, National Institutes of Health18
TL;DR: In the era of intrapartum chemoprophylaxis to reduce GBS, rates of EO infection have declined but reflect a continued burden of disease, suggesting that Escherichia coli is an important EO pathogen.
Abstract: BACKGROUND: Guidelines for prevention of group B streptococcal (GBS) infection have successfully reduced early onset (EO) GBS disease. Study results suggest that Escherichia coli is an important EO pathogen. OBJECTIVE: To determine EO infection rates, pathogens, morbidity, and mortality in a national network of neonatal centers. METHODS: Infants with EO infection were identified by prospective surveillance at Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Network centers. Infection was defined by positive culture results for blood and cerebrospinal fluid obtained from infants aged ≤72 hours plus treatment with antibiotic therapy for ≥5 days. Mother and infant characteristics, treatments, and outcomes were studied. Numbers of cases and total live births (LBs) were used to calculate incidence. RESULTS: Among 396 586 LBs (2006–2009), 389 infants developed EO infection (0.98 cases per 1000 LBs). Infection rates increased with decreasing birth weight. GBS (43%, 0.41 per 1000 LBs) and E coli (29%, 0.28 per 1000 LBs) were most frequently isolated. Most infants with GBS were term (73%); 81% with E coli were preterm. Mothers of 67% of infected term and 58% of infected preterm infants were screened for GBS, and results were positive for 25% of those mothers. Only 76% of mothers with GBS colonization received intrapartum chemoprophylaxis. Although 77% of infected infants required intensive care, 20% of term infants were treated in the normal newborn nursery. Sixteen percent of infected infants died, most commonly with E coli infection (33%). CONCLUSION: In the era of intrapartum chemoprophylaxis to reduce GBS, rates of EO infection have declined but reflect a continued burden of disease. GBS remains the most frequent pathogen in term infants, and E coli the most significant pathogen in preterm infants. Missed opportunities for GBS prevention continue. Prevention of E coli sepsis, especially among preterm infants, remains a challenge.
TL;DR: It is found that the adverse event detection methods commonly used to track patient safety in the United States today-voluntary reporting and the Agency for Healthcare Research and Quality's Patient Safety Indicators-fared very poorly compared to other methods and missed 90 percent of the adverse events.
Abstract: Identification and measurement of adverse medical events is central to patient safety, forming a foundation for accountability, prioritizing problems to work on, generating ideas for safer care, and testing which interventions work. We compared three methods to detect adverse events in hospitalized patients, using the same patient sample set from three leading hospitals. We found that the adverse event detection methods commonly used to track patient safety in the United States today—voluntary reporting and the Agency for Healthcare Research and Quality's Patient Safety Indicators—fared very poorly compared to other methods and missed 90 percent of the adverse events. The Institute for Healthcare Improvement's Global Trigger Tool found at least ten times more confirmed, serious events than these other methods. Overall, adverse events occurred in one-third of hospital admissions. Reliance on voluntary reporting and the Patient Safety Indicators could produce misleading conclusions about the current safety of care in the US health care system and misdirect efforts to improve patient safety.
University of Western Ontario1, Spanish National Research Council2, Ghent University3, University of Utah4, SupAgro5, Instituto Gulbenkian de Ciência6, University of Lisbon7, University of Arizona8, Johns Hopkins University School of Medicine9, University of Bordeaux10, Valparaiso University11, Autonomous University of Madrid12, Georgia Institute of Technology13, University of Texas at Arlington14, Centre national de la recherche scientifique15, Graduate University for Advanced Studies16, Katholieke Universiteit Leuven17, Max Planck Society18, University of Guelph19, Boyce Thompson Institute for Plant Research20, Agriculture and Agri-Food Canada21, Joint Genome Institute22, University of Nice Sophia Antipolis23
TL;DR: The Tetranychus urticae genome is the smallest known arthropod genome as discussed by the authors, which represents the first complete chelicerate genome for a pest and has been annotated with genes associated with feeding on different hosts.
Abstract: The spider mite Tetranychus urticae is a cosmopolitan agricultural pest with an extensive host plant range and an extreme record of pesticide resistance. Here we present the completely sequenced and annotated spider mite genome, representing the first complete chelicerate genome. At 90 megabases T. urticae has the smallest sequenced arthropod genome. Compared with other arthropods, the spider mite genome shows unique changes in the hormonal environment and organization of the Hox complex, and also reveals evolutionary innovation of silk production. We find strong signatures of polyphagy and detoxification in gene families associated with feeding on different hosts and in new gene families acquired by lateral gene transfer. Deep transcriptome analysis of mites feeding on different plants shows how this pest responds to a changing host environment. The T. urticae genome thus offers new insights into arthropod evolution and plant-herbivore interactions, and provides unique opportunities for developing novel plant protection strategies.
University of Toronto1, Yale University2, Saarland University3, University of Utah4, Oregon Health & Science University5, University of Lyon6, University of Pennsylvania7, Georgia Regents University8, National Institutes of Health9, Harvard University10, Washington University in St. Louis11, Western General Hospital12, University of Bari13, Mayo Clinic14, Johns Hopkins University15, University Health Network16
TL;DR: The goal of this international HHT guidelines process was to develop evidence-informed consensus guidelines regarding the diagnosis of HHT and the prevention of H HT-related complications and treatment of symptomatic disease.
Abstract: Background HHT is an autosomal dominant disease with an estimated prevalence of at least 1/5000 which can frequently be complicated by the presence of clinically significant arteriovenous malformations in the brain, lung, gastrointestinal tract and liver. HHT is under-diagnosed and families may be unaware of the available screening and treatment, leading to unnecessary stroke and life-threatening hemorrhage in children and adults.
Objective The goal of this international HHT guidelines process was to develop evidence-informed consensus guidelines regarding the diagnosis of HHT and the prevention of HHT-related complications and treatment of symptomatic disease.
Methods The overall guidelines process was developed using the AGREE framework, using a systematic search strategy and literature retrieval with incorporation of expert evidence in a structured consensus process where published literature was lacking. The Guidelines Working Group included experts (clinical and genetic) from eleven countries, in all aspects of HHT, guidelines methodologists, health care workers, health care administrators, HHT clinic staff, medical trainees, patient advocacy representatives and patients with HHT. The Working Group determined clinically relevant questions during the pre-conference process. The literature search was conducted using the OVID MEDLINE database, from 1966 to October 2006. The Working Group subsequently convened at the Guidelines Conference to partake in a structured consensus process using the evidence tables generated from the systematic searches.
Results The outcome of the conference was the generation of 33 recommendations for the diagnosis and management of HHT, with at least 80% agreement amongst the expert panel for 30 of the 33 recommendations.
TL;DR: This article presents a definitional framework of CMC that consists of substantial family-identified service needs, characteristic chronic and severe conditions, functional limitations, and high health care use and suggests a research agenda that uses a uniform definition.
Abstract: Children with medical complexity (CMC) have medical fragility and intensive care needs that are not easily met by existing health care models. CMC may have a congenital or acquired multisystem disease, a severe neurologic condition with marked functional impairment, and/or technology dependence for activities of daily living. Although these children are at risk of poor health and family outcomes, there are few well-characterized clinical initiatives and research efforts devoted to improving their care. In this article, we present a definitional framework of CMC that consists of substantial family-identified service needs, characteristic chronic and severe conditions, functional limitations, and high health care use. We explore the diversity of existing care models and apply the principles of the chronic care model to address the clinical needs of CMC. Finally, we suggest a research agenda that uses a uniform definition to accurately describe the population and to evaluate outcomes from the perspectives of the child, the family, and the broader health care system.
TL;DR: The history of ZFN development is reviewed, considerable progress has been made in methods for deriving zinc-finger sets for new genomic targets, but approaches to design and selection are still being perfected.
Abstract: Zinc-finger nucleases (ZFNs) are targetable DNA cleavage reagents that have been adopted as gene-targeting tools. ZFN-induced double-strand breaks are subject to cellular DNA repair processes that lead to both targeted mutagenesis and targeted gene replacement at remarkably high frequencies. This article briefly reviews the history of ZFN development and summarizes applications that have been made to genome editing in many different organisms and situations. Considerable progress has been made in methods for deriving zinc-finger sets for new genomic targets, but approaches to design and selection are still being perfected. An issue that needs more attention is the extent to which available mechanisms of double-strand break repair limit the scope and utility of ZFN-initiated events. The bright prospects for future applications of ZFNs, including human gene therapy, are discussed.
Université libre de Bruxelles1, University of Miami2, University of Alberta3, Suffolk University4, Bond University5, St. Joseph's Healthcare Hamilton6, Durham University7, Salt Lake Regional Medical Center8, University of Utah9, Oslo University Hospital10, State University of New York System11, University of California, Los Angeles12, University of Limerick13, Konyang University14, University of Nevada, Reno15, Washington State University16, University of the Pacific (United States)17
TL;DR: Myalgic encephalomyelitis: International Consensus Criteria (Review).
Abstract: 12 FatigueConsultationClinic,SaltLake RegionalMedicalCenter; 13 InternalMedicine,FamilyPractice,UniversityofUtah,SaltLakeCity,UT,USA; 14 ME ⁄CFSCenter,OsloUniversity HospitalHF,Norway; 15 DepartmentofPaediatrics,StateUniversityofNewYork,Buffalo,NY,USA; 16 Independent,Pavia,Italy; 17 Harbor-UCLA MedicalCenter,UniversityofCalifornia,LosAngeles,CA; 18 EVMedResearch,Lomita,CA,USA; 19 UniversityofLimerick,Limerick,Ireland; 20 Pain Clinic,KonyangUniversityHospital,Daejeon,Korea; 21 DonvaleSpecialistMedicalCentre,Donvale,Victoria,Australia; 22 Departmentsof Anesthesiology,NeurobiologyandAnatomy,UniversityofUtah,SaltLakeCity,UT,USA; 23 DepartmentofMedicinaNuclear,ClinicaLasCondes, Santiago,Chile; 24 WhittemorePetersonInstitute,UniversityofNevada,Reno,NV,USA; 25 MiwaNaikaClinic,Toyama,Japan; 26 A.Kirchenstein InstituteofMicrobiologyandVirology,RigaStradinsUniversity,Riga,Latvia; 27 DepartmentofBiochemistryBand 28 DepartmentofSportsSciences,UniversityofthePacific,Stockton,CAUSA
04 Jun 2011
TL;DR: Csmith, a randomized test-case generation tool, is created and spent three years using it to find compiler bugs, and a collection of qualitative and quantitative results about the bugs it found are presented.
Abstract: Compilers should be correct. To improve the quality of C compilers, we created Csmith, a randomized test-case generation tool, and spent three years using it to find compiler bugs. During this period we reported more than 325 previously unknown bugs to compiler developers. Every compiler we tested was found to crash and also to silently generate wrong code when presented with valid input. In this paper we present our compiler-testing tool and the results of our bug-hunting study. Our first contribution is to advance the state of the art in compiler testing. Unlike previous tools, Csmith generates programs that cover a large subset of C while avoiding the undefined and unspecified behaviors that would destroy its ability to automatically find wrong-code bugs. Our second contribution is a collection of qualitative and quantitative results about the bugs we have found in open-source C compilers.
TL;DR: The parameters remove destabilization of the anti region found in the ff99 force field and thus prevent formation of spurious ladder-like structural distortions in RNA simulations, and improve the description of the syn region and the syn–anti balance as well as enhance MD simulations of various RNA structures.
Abstract: We report a reparameterization of the glycosidic torsion χ of the Cornell et al. AMBER force field for RNA, χOL. The parameters remove destabilization of the anti region found in the ff99 force field and thus prevent formation of spurious ladder-like structural distortions in RNA simulations. They also improve the description of the syn region and the syn–anti balance as well as enhance MD simulations of various RNA structures. Although χOL can be combined with both ff99 and ff99bsc0, we recommend the latter. We do not recommend using χOL for B-DNA because it does not improve upon ff99bsc0 for canonical structures. However, it might be useful in simulations of DNA molecules containing syn nucleotides. Our parametrization is based on high-level QM calculations and differs from conventional parametrization approaches in that it incorporates some previously neglected solvation-related effects (which appear to be essential for obtaining correct anti/high-anti balance). Our χOL force field is compared with sev...
TL;DR: The American College of Medical Genetics has developed the following professional guidelines for the interpretation and reporting of copy number variation: evaluation of constitutional copy number variants detected in the postnatal setting.
Howard Hughes Medical Institute1, Baylor College of Medicine2, Johns Hopkins University3, Johns Hopkins University School of Medicine4, Beckman Coulter5, National Institutes of Health6, University of Utah7, University of California, San Diego8, University of California, San Francisco9, University of São Paulo10, Children's Hospital of Philadelphia11, Duke University12, University of Toronto13, Harvard University14
TL;DR: Key differences between the genetic landscapes of adult and childhood cancers are demonstrated, dysregulation of developmental pathways as an important mechanism underlying MBs is highlighted, and a role for a specific type of histone methylation in human tumorigenesis is identified.
Abstract: Medulloblastoma (MB) is the most common malignant brain tumor of children To identify the genetic alterations in this tumor type, we searched for copy number alterations using high-density microarrays and sequenced all known protein-coding genes and microRNA genes using Sanger sequencing in a set of 22 MBs We found that, on average, each tumor had 11 gene alterations, fewer by a factor of 5 to 10 than in the adult solid tumors that have been sequenced to date In addition to alterations in the Hedgehog and Wnt pathways, our analysis led to the discovery of genes not previously known to be altered in MBs Most notably, inactivating mutations of the histone-lysine N-methyltransferase genes MLL2 or MLL3 were identified in 16% of MB patients These results demonstrate key differences between the genetic landscapes of adult and childhood cancers, highlight dysregulation of developmental pathways as an important mechanism underlying MBs, and identify a role for a specific type of histone methylation in human tumorigenesis