Showing papers by "Emory University published in 2010"
TL;DR: Galaxy Pages are interactive, web-based documents that provide users with a medium to communicate a complete computational analysis and provide support for capturing the context and intent of computational methods.
Abstract: Increased reliance on computational approaches in the life sciences has revealed grave concerns about how accessible and reproducible computation-reliant results truly are. Galaxy http://usegalaxy.org, an open web-based platform for genomic research, addresses these problems. Galaxy automatically tracks and manages data provenance and provides support for capturing the context and intent of computational methods. Galaxy Pages are interactive, web-based documents that provide users with a medium to communicate a complete computational analysis.
3,576 citations
Max Planck Society1, Broad Institute2, University of California, Berkeley3, European Bioinformatics Institute4, National Institutes of Health5, University of Massachusetts Medical School6, Spanish National Research Council7, University of Washington8, University of Montana9, Croatian Academy of Sciences and Arts10, University of Oviedo11, University of Bonn12, Emory University13, University College Cork14, Harvard University15
TL;DR: The genomic data suggest that Neandertals mixed with modern human ancestors some 120,000 years ago, leaving traces of Ne andertal DNA in contemporary humans, suggesting that gene flow from Neand Bertals into the ancestors of non-Africans occurred before the divergence of Eurasian groups from each other.
Abstract: Neandertals, the closest evolutionary relatives of present-day humans, lived in large parts of Europe and western Asia before disappearing 30,000 years ago. We present a draft sequence of the Neandertal genome composed of more than 4 billion nucleotides from three individuals. Comparisons of the Neandertal genome to the genomes of five present-day humans from different parts of the world identify a number of genomic regions that may have been affected by positive selection in ancestral modern humans, including genes involved in metabolism and in cognitive and skeletal development. We show that Neandertals shared more genetic variants with present-day humans in Eurasia than with present-day humans in sub-Saharan Africa, suggesting that gene flow from Neandertals into the ancestors of non-Africans occurred before the divergence of Eurasian groups from each other.
3,575 citations
TL;DR: This review discusses International Union of Basic and Clinical Pharmacology glutamate receptor nomenclature, structure, assembly, accessory subunits, interacting proteins, gene expression and translation, post-translational modifications, agonist and antagonist pharmacology, allosteric modulation, mechanisms of gating and permeation, roles in normal physiological function, as well as the potential therapeutic use of pharmacological agents acting at glutamate receptors.
Abstract: The mammalian ionotropic glutamate receptor family encodes 18 gene products that coassemble to form ligand-gated ion channels containing an agonist recognition site, a transmembrane ion permeation pathway, and gating elements that couple agonist-induced conformational changes to the opening or closing of the permeation pore. Glutamate receptors mediate fast excitatory synaptic transmission in the central nervous system and are localized on neuronal and non-neuronal cells. These receptors regulate a broad spectrum of processes in the brain, spinal cord, retina, and peripheral nervous system. Glutamate receptors are postulated to play important roles in numerous neurological diseases and have attracted intense scrutiny. The description of glutamate receptor structure, including its transmembrane elements, reveals a complex assembly of multiple semiautonomous extracellular domains linked to a pore-forming element with striking resemblance to an inverted potassium channel. In this review we discuss International Union of Basic and Clinical Pharmacology glutamate receptor nomenclature, structure, assembly, accessory subunits, interacting proteins, gene expression and translation, post-translational modifications, agonist and antagonist pharmacology, allosteric modulation, mechanisms of gating and permeation, roles in normal physiological function, as well as the potential therapeutic use of pharmacological agents acting at glutamate receptors.
3,044 citations
Rutgers University1, New York University2, University of Oxford3, Harvard University4, Bangor University5, University of Copenhagen6, National Institutes of Health7, Oregon Health & Science University8, Yale University9, Nathan Kline Institute for Psychiatric Research10, Medical College of Wisconsin11, University of Oulu12, Radboud University Nijmegen13, National Yang-Ming University14, Cleveland Clinic15, Duke University16, Max Planck Society17, Emory University18, University of Queensland19, University of Michigan20, Kennedy Krieger Institute21, Washington University in St. Louis22, Technische Universität München23, Leiden University24, University of Texas at Dallas25, Charité26, University of Pittsburgh27, Southeast University28, Otto-von-Guericke University Magdeburg29, Massachusetts Institute of Technology30, University of Western Ontario31, Medical University of Vienna32, Beijing Normal University33
TL;DR: The 1000 Functional Connectomes Project (Fcon_1000) as discussed by the authors is a large-scale collection of functional connectome data from 1,414 volunteers collected independently at 35 international centers.
Abstract: Although it is being successfully implemented for exploration of the genome, discovery science has eluded the functional neuroimaging community. The core challenge remains the development of common paradigms for interrogating the myriad functional systems in the brain without the constraints of a priori hypotheses. Resting-state functional MRI (R-fMRI) constitutes a candidate approach capable of addressing this challenge. Imaging the brain during rest reveals large-amplitude spontaneous low-frequency (<0.1 Hz) fluctuations in the fMRI signal that are temporally correlated across functionally related areas. Referred to as functional connectivity, these correlations yield detailed maps of complex neural systems, collectively constituting an individual's "functional connectome." Reproducibility across datasets and individuals suggests the functional connectome has a common architecture, yet each individual's functional connectome exhibits unique features, with stable, meaningful interindividual differences in connectivity patterns and strengths. Comprehensive mapping of the functional connectome, and its subsequent exploitation to discern genetic influences and brain-behavior relationships, will require multicenter collaborative datasets. Here we initiate this endeavor by gathering R-fMRI data from 1,414 volunteers collected independently at 35 international centers. We demonstrate a universal architecture of positive and negative functional connections, as well as consistent loci of inter-individual variability. Age and sex emerged as significant determinants. These results demonstrate that independent R-fMRI datasets can be aggregated and shared. High-throughput R-fMRI can provide quantitative phenotypes for molecular genetic studies and biomarkers of developmental and pathological processes in the brain. To initiate discovery science of brain function, the 1000 Functional Connectomes Project dataset is freely accessible at www.nitrc.org/projects/fcon_1000/.
2,787 citations
University of Kiel1, Cedars-Sinai Medical Center2, Wellcome Trust Sanger Institute3, University of Pennsylvania4, QIMR Berghofer Medical Research Institute5, Peninsula College of Medicine and Dentistry6, University of Edinburgh7, University of Cambridge8, University of Otago9, University of Washington10, University of Groningen11, University of Liège12, Harvard University13, Casa Sollievo della Sofferenza14, King's College London15, University of Chicago16, Yale University17, Johns Hopkins University18, Ludwig Maximilian University of Munich19, Charité20, McGill University21, Lille University of Science and Technology22, Cincinnati Children's Hospital Medical Center23, Ghent University24, Torbay Hospital25, Mater Health Services26, Université libre de Bruxelles27, RWTH Aachen University28, University of Utah29, Örebro University30, Leiden University31, University of Paris32, Technion – Israel Institute of Technology33, University of Western Australia34, Tel Aviv University35, University of Dundee36, University of Manchester37, University of Pittsburgh38, Royal Hospital for Sick Children39, Katholieke Universiteit Leuven40, Guy's and St Thomas' NHS Foundation Trust41, University of Bern42, University of Toronto43, University of Amsterdam44, Karolinska Institutet45, University of Zurich46, Université de Montréal47, Emory University48, Newcastle University49
TL;DR: A meta-analysis of six Crohn's disease genome-wide association studies and a series of in silico analyses highlighted particular genes within these loci implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP.
Abstract: We undertook a meta-analysis of six Crohn's disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association signals in 15,694 cases, 14,026 controls and 414 parent-offspring trios. We identified 30 new susceptibility loci meeting genome-wide significance (P < 5 × 10⁻⁸). A series of in silico analyses highlighted particular genes within these loci and, together with manual curation, implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP. Combined with previously confirmed loci, these results identify 71 distinct loci with genome-wide significant evidence for association with Crohn's disease.
2,482 citations
Boston Children's Hospital1, Emory University2, University of Washington3, GeneDx4, National Institutes of Health5, University of Utah6, Wellcome Trust Sanger Institute7, Salisbury University8, University of California, San Francisco9, Uppsala University10, University of British Columbia11, Johns Hopkins University School of Medicine12, Drexel University13, University of Groningen14, University of Pennsylvania15, University of California, Santa Cruz16, Brigham and Women's Hospital17, The Centre for Applied Genomics18, Research Triangle Park19, Mayo Clinic20, Katholieke Universiteit Leuven21, University of Chicago22, American College of Medical Genetics23
TL;DR: Chromosomal microarray (CMA) is increasingly utilized for genetic testing of individuals with unexplained developmental delay/intellectual disability (DD/ID), autism spectrum disorders (ASD), or multiple congenital anomalies (MCA).
Abstract: Chromosomal microarray (CMA) is increasingly utilized for genetic testing of individuals with unexplained developmental delay/intellectual disability (DD/ID), autism spectrum disorders (ASD), or multiple congenital anomalies (MCA). Performing CMA and G-banded karyotyping on every patient substantially increases the total cost of genetic testing. The International Standard Cytogenomic Array (ISCA) Consortium held two international workshops and conducted a literature review of 33 studies, including 21,698 patients tested by CMA. We provide an evidence-based summary of clinical cytogenetic testing comparing CMA to G-banded karyotyping with respect to technical advantages and limitations, diagnostic yield for various types of chromosomal aberrations, and issues that affect test interpretation. CMA offers a much higher diagnostic yield (15%–20%) for genetic testing of individuals with unexplained DD/ID, ASD, or MCA than a G-banded karyotype (~3%, excluding Down syndrome and other recognizable chromosomal syndromes), primarily because of its higher sensitivity for submicroscopic deletions and duplications. Truly balanced rearrangements and low-level mosaicism are generally not detectable by arrays, but these are relatively infrequent causes of abnormal phenotypes in this population (<1%). Available evidence strongly supports the use of CMA in place of G-banded karyotyping as the first-tier cytogenetic diagnostic test for patients with DD/ID, ASD, or MCA. G-banded karyotype analysis should be reserved for patients with obvious chromosomal syndromes (e.g., Down syndrome), a family history of chromosomal rearrangement, or a history of multiple miscarriages.
2,294 citations
Emory University1, University of Iowa2, Wayne State University3, Brown University4, Case Western Reserve University5, University of Cincinnati6, University of Alabama at Birmingham7, University of Texas Health Science Center at Houston8, Indiana University9, University of California, San Diego10, Yale University11, University of Miami12, University of Texas Southwestern Medical Center13, Wake Forest University14, Duke University15, Stanford University16, University of Utah17, University of Rochester18, Tufts University19, University of New Mexico20, National Institutes of Health21
TL;DR: Although the majority of infants with GAs of ≥24 weeks survive, high rates of morbidity among survivors continue to be observed.
Abstract: OBJECTIVE: This report presents data from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network on care of and morbidity and mortality rates for very low birth weight infants, according to gestational age (GA). METHODS: Perinatal/neonatal data were collected for 9575 infants of extremely low GA (22–28 weeks) and very low birth weight (401–1500 g) who were born at network centers between January 1, 2003, and December 31, 2007. RESULTS: Rates of survival to discharge increased with increasing GA (6% at 22 weeks and 92% at 28 weeks); 1060 infants died at ≤12 hours, with most early deaths occurring at 22 and 23 weeks (85% and 43%, respectively). Rates of prenatal steroid use (13% and 53%, respectively), cesarean section (7% and 24%, respectively), and delivery room intubation (19% and 68%, respectively) increased markedly between 22 and 23 weeks. Infants at the lowest GAs were at greatest risk for morbidities. Overall, 93% had respiratory distress syndrome, 46% patent ductus arteriosus, 16% severe intraventricular hemorrhage, 11% necrotizing enterocolitis, and 36% late-onset sepsis. The new severity-based definition of bronchopulmonary dysplasia classified more infants as having bronchopulmonary dysplasia than did the traditional definition of supplemental oxygen use at 36 weeks (68%, compared with 42%). More than one-half of infants with extremely low GAs had undetermined retinopathy status at the time of discharge. Center differences in management and outcomes were identified. CONCLUSION: Although the majority of infants with GAs of ≥24 weeks survive, high rates of morbidity among survivors continue to be observed.
2,277 citations
TL;DR: In this paper, the authors address the strengths and weaknesses of the main available measures of political regime and extend the dichotomous regime classification first introduced in Alvarez et al. (Stud. Comp. Int. Dev. 31(2):3-36, 1996).
Abstract: We address the strengths and weaknesses of the main available measures of political regime and extend the dichotomous regime classification first introduced in Alvarez et al. (Stud. Comp. Int. Dev. 31(2):3–36, 1996). This extension focuses on how incumbents are removed from office. We argue that differences across regime measures must be taken seriously and that they should be evaluated in terms of whether they (1) serve to address important research questions, (2) can be interpreted meaningfully, and (3) are reproducible. We argue that existing measures of democracy are not interchangeable and that the choice of measure should be guided by its theoretical and empirical underpinnings. We show that the choice of regime measure matters by replicating studies published in leading journals.
1,922 citations
TL;DR: Results support the emerging view that the gut microbiota contributes to metabolic disease and suggest that malfunction of the innate immune system may promote the development of metabolic syndrome.
Abstract: Metabolic syndrome is a group of obesity-related metabolic abnormalities that increase an individual's risk of developing type 2 diabetes and cardiovascular disease. Here, we show that mice genetically deficient in Toll-like receptor 5 (TLR5), a component of the innate immune system that is expressed in the gut mucosa and that helps defend against infection, exhibit hyperphagia and develop hallmark features of metabolic syndrome, including hyperlipidemia, hypertension, insulin resistance, and increased adiposity. These metabolic changes correlated with changes in the composition of the gut microbiota, and transfer of the gut microbiota from TLR5-deficient mice to wild-type germ-free mice conferred many features of metabolic syndrome to the recipients. Food restriction prevented obesity, but not insulin resistance, in the TLR5-deficient mice. These results support the emerging view that the gut microbiota contributes to metabolic disease and suggest that malfunction of the innate immune system may promote the development of metabolic syndrome.
1,804 citations
TL;DR: In this paper, the authors evaluated the strength of associations between out-of-hospital cardiac arrest and key factors (event witnessed by a bystander or emergency medical services [EMS], provision of bystander cardiopulmonary resuscitation [CPR], initial cardiac rhythm, or the return of spontaneous circulation) and examined trends in OHCA survival over time.
Abstract: Background— Prior studies have identified key predictors of out-of-hospital cardiac arrest (OHCA), but differences exist in the magnitude of these findings In this meta-analysis, we evaluated the strength of associations between OHCA and key factors (event witnessed by a bystander or emergency medical services [EMS], provision of bystander cardiopulmonary resuscitation [CPR], initial cardiac rhythm, or the return of spontaneous circulation) We also examined trends in OHCA survival over time Methods and Results— An electronic search of PubMed, EMBASE, Web of Science, CINAHL, Cochrane DSR, DARE, ACP Journal Club, and CCTR was conducted (January 1, 1950 to August 21, 2008) for studies reporting OHCA of presumed cardiac etiology in adults Data were extracted from 79 studies involving 142 740 patients The pooled survival rate to hospital admission was 238% (95% CI, 211 to 266) and to hospital discharge was 76% (95% CI, 67 to 84) Stratified by baseline rates, survival to hospital discharge was more
1,584 citations
TL;DR: A tooth found in Denisova Cave carries a mitochondrial genome highly similar to that of the finger bone, further indicating that Denisovans have an evolutionary history distinct from Neanderthals and modern humans.
Abstract: Using DNA extracted from a finger bone found in Denisova Cave in southern Siberia, we have sequenced the genome of an archaic hominin to about 1.9-fold coverage. This individual is from a group that shares a common origin with Neanderthals. This population was not involved in the putative gene flow from Neanderthals into Eurasians; however, the data suggest that it contributed 4–6% of its genetic material to the genomes of present-day Melanesians. We designate this hominin population ‘Denisovans’ and suggest that it may have been widespread in Asia during the Late Pleistocene epoch. A tooth found in Denisova Cave carries a mitochondrial genome highly similar to that of the finger bone. This tooth shares no derived morphological features with Neanderthals or modern humans, further indicating that Denisovans have an evolutionary history distinct from Neanderthals and modern humans.
TL;DR: Galaxy is a software system that provides informatics support through a framework that gives experimentalists simple interfaces to powerful tools, while automatically managing the computational details.
Abstract: High-throughput data production has revolutionized molecular biology. However, massive increases in data generation capacity require analysis approaches that are more sophisticated, and often very computationally intensive. Thus, making sense of high-throughput data requires informatics support. Galaxy (http://galaxyproject.org) is a software system that provides this support through a framework that gives experimentalists simple interfaces to powerful tools, while automatically managing the computational details. Galaxy is distributed both as a publicly available Web service, which provides tools for the analysis of genomic, comparative genomic, and functional genomic data, or a downloadable package that can be deployed in individual laboratories. Either way, it allows experimentalists without informatics or programming expertise to perform complex large-scale analysis with just a Web browser.
Stanford University1, Indiana University – Purdue University Indianapolis2, Emory University3, University of Oklahoma4, University of Kansas5, Cornell University6, Thomas Jefferson University7, Marshfield Clinic8, Veterans Health Administration9, University of California, Los Angeles10, St. Joseph's Hospital and Medical Center11, Rush University Medical Center12, University of Pennsylvania13, University of California, San Francisco14, University of Virginia15, Columbia University16, Harvard University17, Medtronic plc18
TL;DR: A multicenter, double‐blind, randomized trial of bilateral stimulation of the anterior nuclei of the thalamus for localization‐related epilepsy is reported.
Abstract: Summary
Purpose: We report a multicenter, double-blind, randomized trial of bilateral stimulation of the anterior nuclei of the thalamus for localization-related epilepsy
Methods: Participants were adults with medically refractory partial seizures, including secondarily generalized seizures Half received stimulation and half no stimulation during a 3-month blinded phase; then all received unblinded stimulation
Results: One hundred ten participants were randomized Baseline monthly median seizure frequency was 195 In the last month of the blinded phase the stimulated group had a 29% greater reduction in seizures compared with the control group, as estimated by a generalized estimating equations (GEE) model (p = 0002) Unadjusted median declines at the end of the blinded phase were 145% in the control group and 404% in the stimulated group Complex partial and “most severe” seizures were significantly reduced by stimulation By 2 years, there was a 56% median percent reduction in seizure frequency; 54% of patients had a seizure reduction of at least 50%, and 14 patients were seizure-free for at least 6 months Five deaths occurred and none were from implantation or stimulation No participant had symptomatic hemorrhage or brain infection Two participants had acute, transient stimulation-associated seizures Cognition and mood showed no group differences, but participants in the stimulated group were more likely to report depression or memory problems as adverse events
Discussion: Bilateral stimulation of the anterior nuclei of the thalamus reduces seizures Benefit persisted for 2 years of study Complication rates were modest Deep brain stimulation of the anterior thalamus is useful for some people with medically refractory partial and secondarily generalized seizures
National Heart Foundation of Australia1, University of Toronto2, Cleveland Clinic3, University of Chicago4, University of Alberta5, Inova Fairfax Hospital6, Ochsner Health System7, University of Alabama at Birmingham8, Newcastle upon Tyne Hospitals NHS Foundation Trust9, Ludwig Maximilian University of Munich10, Saint Barnabas Medical Center11, Duke University12, Primary Children's Hospital13, University of Pittsburgh14, University of Utah15, University of Maryland, Baltimore16, University of Vienna17, Stanford University18, University College London19, Washington University in St. Louis20, Loma Linda University21, University of A Coruña22, The Texas Heart Institute23, Katholieke Universiteit Leuven24, Northwestern University25, University of Wisconsin-Madison26, Yeshiva University27, Cincinnati Children's Hospital Medical Center28, University of Colorado Denver29, Drexel University30, University of Pennsylvania31, Mayo Clinic32, St Vincent Hospital33, Papworth Hospital34, Emory University35, Johns Hopkins University36
TL;DR: Institutional Affiliations Chair Costanzo MR: Midwest Heart Foundation, Lombard Illinois, USA Task Force 1 Dipchand A: Hospital for Sick Children, Toronto Ontario, Canada; Starling R: Cleveland Clinic Foundation, Cleveland, Ohio, USA; Starlings R: University of Chicago, Chicago, Illinois,USA; Chan M: university of Alberta, Edmonton, Alberta, Canada ; Desai S: Inova Fairfax Hospital, Fairfax, Virginia, USA.
Abstract: Institutional Affiliations Chair Costanzo MR: Midwest Heart Foundation, Lombard Illinois, USA Task Force 1 Dipchand A: Hospital for Sick Children, Toronto Ontario, Canada; Starling R: Cleveland Clinic Foundation, Cleveland, Ohio, USA; Anderson A: University of Chicago, Chicago, Illinois, USA; Chan M: University of Alberta, Edmonton, Alberta, Canada; Desai S: Inova Fairfax Hospital, Fairfax, Virginia, USA; Fedson S: University of Chicago, Chicago, Illinois, USA; Fisher P: Ochsner Clinic, New Orleans, Louisiana, USA; Gonzales-Stawinski G: Cleveland Clinic Foundation, Cleveland, Ohio, USA; Martinelli L: Ospedale Niguarda, Milano, Italy; McGiffin D: University of Alabama, Birmingham, Alabama, USA; Parisi F: Ospedale Pediatrico Bambino Gesu, Rome, Italy; Smith J: Freeman Hospital, Newcastle upon Tyne, UK Task Force 2 Taylor D: Cleveland Clinic Foundation, Cleveland, Ohio, USA; Meiser B: University of Munich/Grosshaden, Munich, Germany; Baran D: Newark Beth Israel Medical Center, Newark, New Jersey, USA; Carboni M: Duke University Medical Center, Durham, North Carolina, USA; Dengler T: University of Hidelberg, Heidelberg, Germany; Feldman D: Minneapolis Heart Institute, Minneapolis, Minnesota, USA; Frigerio M: Ospedale Niguarda, Milano, Italy; Kfoury A: Intermountain Medical Center, Murray, Utah, USA; Kim D: University of Alberta, Edmonton, Alberta, Canada; Kobashigawa J: Cedar-Sinai Heart Institute, Los Angeles, California, USA; Shullo M: University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Stehlik J: University of Utah, Salt Lake City, Utah, USA; Teuteberg J: University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Uber P: University of Maryland, Baltimore, Maryland, USA; Zuckermann A: University of Vienna, Vienna, Austria. Task Force 3 Hunt S: Stanford University, Palo Alto, California, USA; Burch M: Great Ormond Street Hospital, London, UK; Bhat G: Advocate Christ Medical Center, Oak Lawn, Illinois, USA; Canter C: St. Louis Children Hospital, St. Louis, Missouri, USA; Chinnock R: Loma Linda University Children's Hospital, Loma Linda, California, USA; Crespo-Leiro M: Hospital Universitario A Coruna, La Coruna, Spain; Delgado R: Texas Heart Institute, Houston, Texas, USA; Dobbels F: Katholieke Universiteit Leuven, Leuven, Belgium; Grady K: Northwestern University, Chicago, Illlinois, USA; Kao W: University of Wisconsin, Madison Wisconsin, USA; Lamour J: Montefiore Medical Center, New York, New York, USA; Parry G: Freeman Hospital, Newcastle upon Tyne, UK; Patel J: Cedar-Sinai Heart Institute, Los Angeles, California, USA; Pini D: Istituto Clinico Humanitas, Rozzano, Italy; Pinney S: Mount Sinai Medical Center, New York, New York, USA; Towbin J: Cincinnati Children's Hospital, Cincinnati, Ohio, USA; Wolfel G: University of Colorado, Denver, Colorado, USA Independent Reviewers Delgado D: University of Toronto, Toronto, Ontario, Canada; Eisen H: Drexler University College of Medicine, Philadelphia, Pennsylvania, USA; Goldberg L: University of Pennsylvania, Philadelphia, Pennsylvania, USA; Hosenpud J: Mayo Clinic, Jacksonville, Florida, USA; Johnson M: University of Wisconsin, Madison, Wisconsin, USA; Keogh A: St Vincent Hospital, Sidney, New South Wales, Australia; Lewis C: Papworth Hospital Cambridge, UK; O'Connell J: St. Joseph Hospital, Atlanta, Georgia, USA; Rogers J: Duke University Medical Center, Durham, North Carolina, USA; Ross H: University of Toronto, Toronto, Ontario, Canada; Russell S: Johns Hopkins Hospital, Baltimore, Maryland, USA; Vanhaecke J: University Hospital Gasthuisberg, Leuven, Belgium.
TL;DR: Extensive spectroscopic, electrochemical, and inhibition studies firmly indicate that [Co4(H2O)2(PW9O34)2]10– is stable under catalytic turnover conditions: Neither hydrated cobalt ions nor cobalt hydroxide/oxide particles form in situ.
Abstract: Traditional homogeneous water oxidation catalysts are plagued by instability under the reaction conditions. We report that the complex [Co4(H2O)2(PW9O34)2]10-, comprising a Co4O4 core stabilized by oxidatively resistant polytungstate ligands, is a hydrolytically and oxidatively stable homogeneous water oxidation catalyst that self-assembles in water from salts of earth-abundant elements (Co, W, and P). With [Ru(bpy)3]3+ (bpy is 2,2'-bipyridine) as the oxidant, we observe catalytic turnover frequencies for O2 production > or = 5 s(-1) at pH = 8. The rate's pH sensitivity reflects the pH dependence of the four-electron O2-H2O couple. Extensive spectroscopic, electrochemical, and inhibition studies firmly indicate that [Co4(H2O)2(PW9O34)2]10- is stable under catalytic turnover conditions: Neither hydrated cobalt ions nor cobalt hydroxide/oxide particles form in situ.
Stephen Richards1, Richard A. Gibbs1, Nicole M. Gerardo2, Nancy A. Moran3 +220 more•Institutions (58)
TL;DR: The genome of the pea aphid shows remarkable levels of gene duplication and equally remarkable gene absences that shed light on aspects of aphid biology, most especially its symbiosis with Buchnera.
Abstract: Aphids are important agricultural pests and also biological models for studies of insect-plant interactions, symbiosis, virus vectoring, and the developmental causes of extreme phenotypic plasticity. Here we present the 464 Mb draft genome assembly of the pea aphid Acyrthosiphon pisum. This first published whole genome sequence of a basal hemimetabolous insect provides an outgroup to the multiple published genomes of holometabolous insects. Pea aphids are host-plant specialists, they can reproduce both sexually and asexually, and they have coevolved with an obligate bacterial symbiont. Here we highlight findings from whole genome analysis that may be related to these unusual biological features. These findings include discovery of extensive gene duplication in more than 2000 gene families as well as loss of evolutionarily conserved genes. Gene family expansions relative to other published genomes include genes involved in chromatin modification, miRNA synthesis, and sugar transport. Gene losses include genes central to the IMD immune pathway, selenoprotein utilization, purine salvage, and the entire urea cycle. The pea aphid genome reveals that only a limited number of genes have been acquired from bacteria; thus the reduced gene count of Buchnera does not reflect gene transfer to the host genome. The inventory of metabolic genes in the pea aphid genome suggests that there is extensive metabolite exchange between the aphid and Buchnera, including sharing of amino acid biosynthesis between the aphid and Buchnera. The pea aphid genome provides a foundation for post-genomic studies of fundamental biological questions and applied agricultural problems.
TL;DR: There is definite hope that by 2020, new cocktails of drugs will be available to target the key molecular pathways involved in gliomas and reduce their mortality and morbidity, a positive development for patients, their families, and medical professionals alike.
Abstract: Malignant gliomas are the most common and deadly brain tumors. Nevertheless, survival for patients with glioblastoma, the most aggressive glioma, although individually variable, has improved from an average of 10 months to 14 months after diagnosis in the last 5 years due to improvements in the standard of care. Radiotherapy has been of key importance to the treatment of these lesions for decades, and the ability to focus the beam and tailor it to the irregular contours of brain tumors and minimize the dose to nearby critical structures with intensitymodulated or image-guided techniques has improved greatly. Temozolomide, an alkylating agent with simple oral administration and a favorable toxicity profile, is used in conjunction with and after radiotherapy. Newer surgical techniques, such as fluorescence-guided resection and neuroendoscopic approaches, have become important in the management of malignant gliomas. Furthermore, new discoveries are being made in basic and translational research, which are likely to improve this situation further in the next 10 years. These include agents that block 1 or more of the disordered tumor proliferation signaling pathways, and that overcome resistance to already existing treatments. Targeted therapies such as antiangiogenic therapy with antivascular endothelial growth factor antibodies (bevacizumab) are finding their way into clinical practice. Large-scale research efforts are ongoing to provide a comprehensive understanding of all the genetic alterations and gene expression changes underlying glioma formation. These have already refined the classification of glioblastoma into 4 distinct molecular entities that may lead to different treatment regimens. The role of cancer stem-like cells is another area of active investigation. There is definite hope that by 2020, new cocktails of drugs will be available to target the key molecular pathways involved in gliomas and reduce their mortality and morbidity, a positive development for patients, their families, and medical professionals alike. CA Cancer J Clin 2010;60:166-193. © 2010 American Cancer Society, Inc.
TL;DR: This analysis suggests that widespread implementation of reasonably effective preventive interventions focused on high-risk subgroups of the population can considerably reduce, but not eliminate, future increases in diabetes prevalence.
Abstract: People with diabetes can suffer from diverse complications that seriously erode quality of life. Diabetes, costing the United States more than $174 billion per year in 2007, is expected to take an increasingly large financial toll in subsequent years. Accurate projections of diabetes burden are essential to policymakers planning for future health care needs and costs. Using data on prediabetes and diabetes prevalence in the United States, forecasted incidence, and current US Census projections of mortality and migration, the authors constructed a series of dynamic models employing systems of difference equations to project the future burden of diabetes among US adults. A three-state model partitions the US population into no diabetes, undiagnosed diabetes, and diagnosed diabetes. A four-state model divides the state of "no diabetes" into high-risk (prediabetes) and low-risk (normal glucose) states. A five-state model incorporates an intervention designed to prevent or delay diabetes in adults at high risk. The authors project that annual diagnosed diabetes incidence (new cases) will increase from about 8 cases per 1,000 in 2008 to about 15 in 2050. Assuming low incidence and relatively high diabetes mortality, total diabetes prevalence (diagnosed and undiagnosed cases) is projected to increase from 14% in 2010 to 21% of the US adult population by 2050. However, if recent increases in diabetes incidence continue and diabetes mortality is relatively low, prevalence will increase to 33% by 2050. A middle-ground scenario projects a prevalence of 25% to 28% by 2050. Intervention can reduce, but not eliminate, increases in diabetes prevalence. These projected increases are largely attributable to the aging of the US population, increasing numbers of members of higher-risk minority groups in the population, and people with diabetes living longer. Effective strategies will need to be undertaken to moderate the impact of these factors on national diabetes burden. Our analysis suggests that widespread implementation of reasonably effective preventive interventions focused on high-risk subgroups of the population can considerably reduce, but not eliminate, future increases in diabetes prevalence.
TL;DR: Data will be reviewed using the acoustic startle reflex in rats and humans based on attempts to operationally define fear vs anxiety, finding that symptoms of clinical anxiety are better detected in sustained rather than phasic fear paradigms.
TL;DR: Dramatic reductions in IPD after PCV7 introduction in the United States remain evident 7 years later, and IPD rates caused by serotype 19A and other non-PCV7 types have increased but remain low relative to decreases in PCV 7-type IPD.
Abstract: Background. Changes in invasive pneumococcal disease (IPD) incidence were evaluated after 7 years of 7-valent pneumococcal conjugate vaccine (PCV7) use in US children. Methods. Laboratory-confirmed IPD cases were identified during 1998-2007 by 8 active population-based surveillance sites. We compared overall, age group-specific, syndrome-specific, and serotype group-specific IPD incidence in 2007 with that in 1998-1999 (before PCV7) and assessed potential serotype coverage of new conjugate vaccine formulations. Results. Overall and PCV7-type IPD incidence declined by 45% (from 24.4 to 13.5 cases per 100,000 population) and 94% (from 15.5 to 1.0 cases per 100,000 population), respectively (P<.01 for all age groups). The incidence of IPD caused by serotype 19A and other non-PCV7 types increased from 0.8 to 2.7 cases per 100,000 population and from 6.1 to 7.9 cases per 100,000 population, respectively (P<.01 for all age groups). The rates of meningitis and invasive pneumonia caused by non-PCV7 types increased for all age groups (P<.05), whereas the rates of primary bacteremia caused by these serotypes did not change. In 2006-2007, PCV7 types caused 2% of IPD cases, and the 6 additional serotypes included in an investigational 13-valent conjugate vaccine caused 63% of IPD cases among children <5 years-old. Conclusions. Dramatic reductions in IPD after PCV7 introduction in the United States remain evident 7 years later. IPD rates caused by serotype 19A and other non-PCV7 types have increased but remain low relative to decreases in PCV7-type IPD.
TL;DR: Criteria for considering or establishing a diagnosis of TBI is discussed, with a particular focus on how a diagnosis can be made when patients present late after injury and how mild TBI may be differentiated from non-TBI causes with similar symptoms.
TL;DR: A framework for understanding platform-based ecosystems is presented and five broad research questions are discussed that present significant research opportunities for contributing homegrown theory about their evolutionary dynamics.
Abstract: The emergence of software-based platforms is shifting competition toward platform-centric ecosystems, although this phenomenon has not received much attention in information systems research. Our premise is that the coevolution of the design, governance, and environmental dynamics of such ecosystems influences how they evolve. We present a framework for understanding platform-based ecosystems and discuss five broad research questions that present significant research opportunities for contributing homegrown theory about their evolutionary dynamics to the information systems discipline and distinctive information technology-artifact-centric contributions to the strategy, economics, and software engineering reference disciplines.
TL;DR: Relationship power inequity and intimate partner violence increase risk of incident HIV infection in young South African women and policy, interventions, and programmes for HIV prevention must address both of these risk factors and allocate appropriate resources.
University of Modena and Reggio Emilia1, Emory University2, University of Pennsylvania3, National Institutes of Health4, University College London5, Johns Hopkins University6, The Catholic University of America7, University of Turin8, Seconda Università degli Studi di Napoli9, University of Siena10, University of Palermo11, University of Cagliari12, Georgetown University13
TL;DR: Exome sequencing data broaden the phenotype of IBMPFD to include motor neuron degeneration, suggest that VCP mutations may account for ∼1%-2% of familial ALS, and provide evidence directly implicating defects in the ubiquitination/protein degradation pathway in motor neurons degeneration.
TL;DR: Advancing the field will require establishing relevant translational animal models that produce vulnerable plaques at risk for rupture and further testing of these modalities in large prospective clinical trials, including optical coherence tomography, high-resolution MRI, molecular biomarkers, and other techniques.
Abstract: Today's concept of vulnerable plaque has evolved primarily from the early pioneering work uncovering the pivotal role of plaque rupture and coronary thrombosis as the major cause of acute myocardial infarction and sudden cardiac death. Since the first historical description of plaque rupture in 1844, several key studies by leading researchers and clinicians have lead to the current accepted views on lesion instability. Important to the complex paradigm of plaque destabilization and thrombosis are many discoveries beginning with the earliest descriptions of advanced plaques, reminiscent of abscesses encapsulated by fibrous tissue capable of rupture. It was not until the late 1980s that studies of remodeling provided keen insight into the growth of advanced plaques, beyond the simple accumulation of lipid. The emphasis in the next decade, however, was on a focused shift toward the mechanisms of lesion vulnerability based on the contribution of tissue proteolysis by matrix metalloproteinases as an essential factor responsible for thinning and rupture of the fibrous cap. In an attempt to unify the understanding of what constitutes a vulnerable plaque, morphological studies, mostly from autopsy, suggest the importance of necrotic core size, inflammation, and fibrous cap thickness. Definitive proof of the vulnerable plaque, however, remains elusive because animal or human data supporting a cause-and-effect relationship are lacking. Although emerging imagining technologies involving optical coherence tomography, high-resolution MRI, molecular biomarkers, and other techniques have far surpassed the limits of the early days of angiography, advancing the field will require establishing relevant translational animal models that produce vulnerable plaques at risk for rupture and further testing of these modalities in large prospective clinical trials.
Washington University in St. Louis1, Emory University2, Thomas Jefferson University3, Medical University of Vienna4, Vita-Salute San Raffaele University5, University of Texas Health Science Center at Houston6, Universidade Federal de Ciências da Saúde de Porto Alegre7, Mayo Clinic8, GlaxoSmithKline9
TL;DR: Over the course of the 4-year study period, dutasteride reduced the risk of incident prostate cancer detected on biopsy and improved the outcomes related to benign prostatic hyperplasia.
Abstract: Background We conducted a study to determine whether dutasteride reduces the risk of incident prostate cancer, as detected on biopsy, among men who are at increased risk for the disease. Methods In this 4-year, multicenter, randomized, double-blind, placebo-controlled, parallelgroup study, we compared dutasteride, at a dose of 0.5 mg daily, with placebo. Men were eligible for inclusion in the study if they were 50 to 75 years of age, had a prostate-specific antigen (PSA) level of 2.5 to 10.0 ng per milliliter, and had had one negative prostate biopsy (6 to 12 cores) within 6 months before enrollment. Subjects underwent a 10-core transrectal ultrasound-guided biopsy at 2 and 4 years. Results Among 6729 men who underwent a biopsy or prostate surgery, cancer was detected in 659 of the 3305 men in the dutasteride group, as compared with 858 of the 3424 men in the placebo group, representing a relative risk reduction with dutasteride of 22.8% (95% confidence interval, 15.2 to 29.8) over the 4-year study period (P<0.001). Overall, in years 1 through 4, among the 6706 men who underwent a needle biopsy, there were 220 tumors with a Gleason score of 7 to 10 among 3299 men in the dutasteride group and 233 among 3407 men in the placebo group (P = 0.81). During years 3 and 4, there were 12 tumors with a Gleason score of 8 to 10 in the dutasteride group, as compared with only 1 in the placebo group (P = 0.003). Dutasteride therapy, as compared with placebo, resulted in a reduction in the rate of acute urinary retention (1.6% vs. 6.7%, a 77.3% relative reduction). The incidence of adverse events was similar to that in studies of dutasteride therapy for benign prostatic hyperplasia, except that in our study, as compared with previous studies, the relative incidence of the composite category of cardiac failure was higher in the dutasteride group than in the placebo group (0.7% [30 men] vs. 0.4% [16 men], P = 0.03). Conclusions Over the course of the 4-year study period, dutasteride reduced the risk of incident prostate cancer detected on biopsy and improved the outcomes related to benign prostatic hyperplasia. (ClinicalTrials.gov number, NCT00056407.)
University of California, San Diego1, University of Alabama at Birmingham2, Case Western Reserve University3, Brown University4, University of Utah5, University of Cincinnati6, Tufts University7, Emory University8, University of Texas Southwestern Medical Center9, University of Texas Health Science Center at Houston10, University of Rochester11, Indiana University12, Duke University13, Stanford University14, University of Miami15, Wayne State University16, Wake Forest University17, University of Iowa18, Yale University19, University of New Mexico20, National Institutes of Health21
TL;DR: The results of this study support consideration of CPAP as an alternative to intubation and surfactant in preterm infants.
Abstract: BACKGROUND There are limited data to inform the choice between early treatment with continuous positive airway pressure (CPAP) and early surfactant treatment as the initial support for extremely-low-birth-weight infants. METHODS We performed a randomized, multicenter trial, with a 2-by-2 factorial design, involving infants who were born between 24 weeks 0 days and 27 weeks 6 days of gestation. Infants were randomly assigned to intubation and surfactant treatment (within 1 hour after birth) or to CPAP treatment initiated in the delivery room, with subsequent use of a protocol-driven limited ventilation strategy. Infants were also randomly assigned to one of two target ranges of oxygen saturation. The primary outcome was death or bronchopulmonary dysplasia as defined by the requirement for supplemental oxygen at 36 weeks (with an attempt at withdrawal of supplemental oxygen in neonates who were receiving less than 30% oxygen). RESULTS A total of 1316 infants were enrolled in the study. The rates of the primary outcome did not differ significantly between the CPAP group and the surfactant group (47.8% and 51.0%, respectively; relative risk with CPAP, 0.95; 95% confidence interval [CI], 0.85 to 1.05) after adjustment for gestational age, center, and familial clustering. The results were similar when bronchopulmonary dysplasia was defined according to the need for any supplemental oxygen at 36 weeks (rates of primary outcome, 48.7% and 54.1%, respectively; relative risk with CPAP, 0.91; 95% CI, 0.83 to 1.01). Infants who received CPAP treatment, as compared with infants who received surfactant treatment, less frequently required intubation or postnatal corticosteroids for bronchopulmonary dysplasia (P<0.001), required fewer days of mechanical ventilation (P=0.03), and were more likely to be alive and free from the need for mechanical ventilation by day 7 (P=0.01). The rates of other adverse neonatal outcomes did not differ significantly between the two groups. CONCLUSIONS The results of this study support consideration of CPAP as an alternative to intubation and surfactant in preterm infants. (ClinicalTrials.gov number, NCT00233324.)
TL;DR: In patients with Parkinson's disease the loss of dopamine is predominantly in the posterior putamen, a region of the basal ganglia associated with the control of habitual behaviour, and patients may be forced into a progressive reliance on the goal-directed mode of action control that is mediated by comparatively preserved processing in the rostromedial striatum.
Abstract: Progressive loss of the ascending dopaminergic projection in the basal ganglia is a fundamental pathological feature of Parkinson's disease. Studies in animals and humans have identified spatially segregated functional territories in the basal ganglia for the control of goal-directed and habitual actions. In patients with Parkinson's disease the loss of dopamine is predominantly in the posterior putamen, a region of the basal ganglia associated with the control of habitual behaviour. These patients may therefore be forced into a progressive reliance on the goal-directed mode of action control that is mediated by comparatively preserved processing in the rostromedial striatum. Thus, many of their behavioural difficulties may reflect a loss of normal automatic control owing to distorting output signals from habitual control circuits, which impede the expression of goal-directed action.
TL;DR: The strongest direct evidence that chronic neuroinflammation may have a more important role to play in PD versus other neurodegenerative diseases is reviewed and genetic deficiency is not the only way to reduce protective factors in the brain which may function to keep microglial responses in check or regulate the sensitivity of DA neurons are proposed.
National Institutes of Health1, Wake Forest University2, University of North Carolina at Chapel Hill3, Case Western Reserve University4, Cleveland Clinic5, Eli Lilly and Company6, University of Arkansas for Medical Sciences7, Veterans Health Administration8, University of Iowa9, Regions Hospital10, Emory University11
TL;DR: Symptomatic, severe hypoglycaemia was associated with an increased risk of death within each study arm, however, among participants who experienced at least one episode of hypglycaemia, the risk ofdeath was lower in such participants in the intensive arm than in the standard arm.
Abstract: Objective To determine whether there is a link between hypoglycaemia and mortality among participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Design Retrospective epidemiological analysis of data from the ACCORD trial. Setting Diabetes clinics, research clinics, and primary care clinics. Participants Patients were eligible for the ACCORD study if they had type 2 diabetes, a glycated haemoglobin (haemoglobin A 1C ) concentration of 7.5% or more during screening, and were aged 40-79 years with established cardiovascular disease or 55-79 years with evidence of subclinical disease or two additional cardiovascular risk factors. Intervention Intensive (haemoglobin A 1C 1C 7.0-7.9%) glucose control. Outcome measures Symptomatic, severe hypoglycaemia, manifest as either blood glucose concentration of less than 2.8 mmol/l ( Results 10 194 of the 10 251 participants enrolled in the ACCORD study who had at least one assessment for hypoglycaemia during regular follow-up for vital status were included in this analysis. Unadjusted annual mortality among patients in the intensive glucose control arm was 2.8% in those who had one or more episodes of hypoglycaemia requiring any assistance compared with 1.2% for those with no episodes (53 deaths per 1924 person years and 201 deaths per 16 315 person years, respectively; adjusted hazard ratio (HR) 1.41, 95% CI 1.03 to 1.93). A similar pattern was seen among participants in the standard glucose control arm (3.7% (21 deaths per 564 person years) v 1.0% (176 deaths per 17 297 person years); adjusted HR 2.30, 95% CI 1.46 to 3.65). On the other hand, among participants with at least one hypoglycaemic episode requiring any assistance, a non-significantly lower risk of death was seen in those in the intensive arm compared with those in the standard arm (adjusted HR 0.74, 95% 0.46 to 1.23). A significantly lower risk was observed in the intensive arm compared with the standard arm in participants who had experienced at least one hypoglycaemic episode requiring medical assistance (adjusted HR 0.55, 95% CI 0.31 to 0.99). Of the 451 deaths that occurred in ACCORD up to the time when the intensive treatment arm was closed, one death was adjudicated as definitely related to hypoglycaemia. Conclusion Symptomatic, severe hypoglycaemia was associated with an increased risk of death within each study arm. However, among participants who experienced at least one episode of hypoglycaemia, the risk of death was lower in such participants in the intensive arm than in the standard arm. Symptomatic, severe hypoglycaemia does not appear to account for the difference in mortality between the two study arms up to the time when the ACCORD intensive glycaemia arm was discontinued. Trial registration NCT00000620.