Showing papers by "University of Michigan published in 2009"
University of Michigan1, University of Massachusetts Amherst2, University of New Mexico3, University of British Columbia4, Texas A&M University5, University of Minnesota6, University of Warwick7, Dalhousie University8, Colorado School of Mines9, University of Ljubljana10, Graz University of Technology11, Louisiana State University12
TL;DR: M mothur is used as a case study to trim, screen, and align sequences; calculate distances; assign sequences to operational taxonomic units; and describe the α and β diversity of eight marine samples previously characterized by pyrosequencing of 16S rRNA gene fragments.
Abstract: mothur aims to be a comprehensive software package that allows users to use a single piece of software to analyze community sequence data. It builds upon previous tools to provide a flexible and powerful software package for analyzing sequencing data. As a case study, we used mothur to trim, screen, and align sequences; calculate distances; assign sequences to operational taxonomic units; and describe the alpha and beta diversity of eight marine samples previously characterized by pyrosequencing of 16S rRNA gene fragments. This analysis of more than 222,000 sequences was completed in less than 2 h with a laptop computer.
17,350 citations
TL;DR: The CFIR provides a pragmatic structure for approaching complex, interacting, multi-level, and transient states of constructs in the real world by embracing, consolidating, and unifying key constructs from published implementation theories.
Abstract: Many interventions found to be effective in health services research studies fail to translate into meaningful patient care outcomes across multiple contexts. Health services researchers recognize the need to evaluate not only summative outcomes but also formative outcomes to assess the extent to which implementation is effective in a specific setting, prolongs sustainability, and promotes dissemination into other settings. Many implementation theories have been published to help promote effective implementation. However, they overlap considerably in the constructs included in individual theories, and a comparison of theories reveals that each is missing important constructs included in other theories. In addition, terminology and definitions are not consistent across theories. We describe the Consolidated Framework For Implementation Research (CFIR) that offers an overarching typology to promote implementation theory development and verification about what works where and why across multiple contexts. We used a snowball sampling approach to identify published theories that were evaluated to identify constructs based on strength of conceptual or empirical support for influence on implementation, consistency in definitions, alignment with our own findings, and potential for measurement. We combined constructs across published theories that had different labels but were redundant or overlapping in definition, and we parsed apart constructs that conflated underlying concepts. The CFIR is composed of five major domains: intervention characteristics, outer setting, inner setting, characteristics of the individuals involved, and the process of implementation. Eight constructs were identified related to the intervention (e.g., evidence strength and quality), four constructs were identified related to outer setting (e.g., patient needs and resources), 12 constructs were identified related to inner setting (e.g., culture, leadership engagement), five constructs were identified related to individual characteristics, and eight constructs were identified related to process (e.g., plan, evaluate, and reflect). We present explicit definitions for each construct. The CFIR provides a pragmatic structure for approaching complex, interacting, multi-level, and transient states of constructs in the real world by embracing, consolidating, and unifying key constructs from published implementation theories. It can be used to guide formative evaluations and build the implementation knowledge base across multiple studies and settings.
8,080 citations
National Institutes of Health1, University of Chicago2, Duke University3, Harvard University4, University of Oxford5, GlaxoSmithKline6, Johns Hopkins University7, Yale University8, deCODE genetics9, Princeton University10, Howard Hughes Medical Institute11, Washington University in St. Louis12, University of California, Berkeley13, Stanford University14, University of Michigan15, Cornell University16, University of Washington17, University of Queensland18, Vanderbilt University19, North Carolina State University20, QIMR Berghofer Medical Research Institute21
TL;DR: This paper examined potential sources of missing heritability and proposed research strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment.
Abstract: Genome-wide association studies have identified hundreds of genetic variants associated with complex human diseases and traits, and have provided valuable insights into their genetic architecture. Most variants identified so far confer relatively small increments in risk, and explain only a small proportion of familial clustering, leading many to question how the remaining, 'missing' heritability can be explained. Here we examine potential sources of missing heritability and propose research strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment.
7,797 citations
Johns Hopkins University1, University of Michigan2, University of Colorado Denver3, Ohio State University4, Boston University5, University of Pennsylvania6, University of Florida7, Mayo Clinic8, University of Siena9, Institut Gustave Roussy10, University of Cincinnati11, Memorial Sloan Kettering Cancer Center12
TL;DR: Evidence-based recommendations in response to the appointment as an independent task force by the American Thyroid Association to assist in the clinical management of patients with thyroid nodules and differentiated thyroid cancer represent, in the authors' opinion, contemporary optimal care for patients with these disorders.
Abstract: Background: Thyroid nodules are a common clinical problem, and differentiated thyroid cancer is becoming increasingly prevalent. Since the publication of the American Thyroid Association's guidelines for the management of these disorders was published in 2006, a large amount of new information has become available, prompting a revision of the guidelines. Methods: Relevant articles through December 2008 were reviewed by the task force and categorized by topic and level of evidence according to a modified schema used by the United States Preventative Services Task Force. Results: The revised guidelines for the management of thyroid nodules include recommendations regarding initial evaluation, clinical and ultrasound criteria for fine-needle aspiration biopsy, interpretation of fine-needle aspiration biopsy results, and management of benign thyroid nodules. Recommendations regarding the initial management of thyroid cancer include those relating to optimal surgical management, radioiodine remnant ablation, a...
7,525 citations
TL;DR: An overview of the CHARMM program as it exists today is provided with an emphasis on developments since the publication of the original CHARMM article in 1983.
Abstract: CHARMM (Chemistry at HARvard Molecular Mechanics) is a highly versatile and widely used molecu- lar simulation program. It has been developed over the last three decades with a primary focus on molecules of bio- logical interest, including proteins, peptides, lipids, nucleic acids, carbohydrates, and small molecule ligands, as they occur in solution, crystals, and membrane environments. For the study of such systems, the program provides a large suite of computational tools that include numerous conformational and path sampling methods, free energy estima- tors, molecular minimization, dynamics, and analysis techniques, and model-building capabilities. The CHARMM program is applicable to problems involving a much broader class of many-particle systems. Calculations with CHARMM can be performed using a number of different energy functions and models, from mixed quantum mechanical-molecular mechanical force fields, to all-atom classical potential energy functions with explicit solvent and various boundary conditions, to implicit solvent and membrane models. The program has been ported to numer- ous platforms in both serial and parallel architectures. This article provides an overview of the program as it exists today with an emphasis on developments since the publication of the original CHARMM article in 1983.
7,035 citations
Kevork N. Abazajian1, Jennifer K. Adelman-McCarthy2, Marcel A. Agüeros3, S. Allam2 +220 more•Institutions (77)
TL;DR: A series of improvements to the spectroscopic reductions are described, including better flat fielding and improved wavelength calibration at the blue end, better processing of objects with extremely strong narrow emission lines, and an improved determination of stellar metallicities.
Abstract: This paper describes the Seventh Data Release of the Sloan Digital Sky Survey (SDSS), marking the completion of the original goals of the SDSS and the end of the phase known as SDSS-II. It includes 11,663 deg^2 of imaging data, with most of the ~2000 deg^2 increment over the previous data release lying in regions of low Galactic latitude. The catalog contains five-band photometry for 357 million distinct objects. The survey also includes repeat photometry on a 120° long, 2°.5 wide stripe along the celestial equator in the Southern Galactic Cap, with some regions covered by as many as 90 individual imaging runs. We include a co-addition of the best of these data, going roughly 2 mag fainter than the main survey over 250 deg^2. The survey has completed spectroscopy over 9380 deg^2; the spectroscopy is now complete over a large contiguous area of the Northern Galactic Cap, closing the gap that was present in previous data releases. There are over 1.6 million spectra in total, including 930,000 galaxies, 120,000 quasars, and 460,000 stars. The data release includes improved stellar photometry at low Galactic latitude. The astrometry has all been recalibrated with the second version of the USNO CCD Astrograph Catalog, reducing the rms statistical errors at the bright end to 45 milliarcseconds per coordinate. We further quantify a systematic error in bright galaxy photometry due to poor sky determination; this problem is less severe than previously reported for the majority of galaxies. Finally, we describe a series of improvements to the spectroscopic reductions, including better flat fielding and improved wavelength calibration at the blue end, better processing of objects with extremely strong narrow emission lines, and an improved determination of stellar metallicities.
5,665 citations
TL;DR: A new method is proposed which attempts to keep the sensitivity benefits of cluster-based thresholding (and indeed the general concept of "clusters" of signal), while avoiding (or at least minimising) these problems, and is referred to as "threshold-free cluster enhancement" (TFCE).
4,466 citations
TL;DR: The statistical update brings together the most up-to-date statistics on heart disease, stroke, other vascular diseases, and their risk factors and presents them in its Heart Disease and Stroke Statistical Update.
Abstract: We thank Drs Sean Coady, Eric L. Ding, Brian Eigel, Gregg C. Fonarow, Linda Geiss, Cherie James, Michael Mussolino, and Michael Wolz for their valuable comments and contributions. We acknowledge Tim Anderson and Tom Schneider for their editorial contributions, and Karen Modesitt for her administrative assistance.
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# Summary {#article-title-2}
Each year, the American Heart Association, in conjunction with the Centers for Disease Control and Prevention, the National Institutes of Health, and other government agencies, brings together the most up-to-date statistics on heart disease, stroke, other vascular diseases, and their risk factors and presents them in its Heart Disease and Stroke Statistical Update. The Statistical Update is a valuable resource for researchers, clinicians, healthcare policy makers, media professionals, the lay …
4,003 citations
TL;DR: The current knowledge on the key genes composing the autophagy machinery in eukaryotes from yeast to mammalian cells and the signaling pathways that sense the status of different types of stress and induce autophagic for cell survival and homeostasis are presented.
Abstract: Autophagy is a process of self-degradation of cellular components in which double-membrane autophagosomes sequester organelles or portions of cytosol and fuse with lysosomes or vacuoles for breakdown by resident hydrolases. Autophagy is upregulated in response to extra- or intracellular stress and signals such as starvation, growth factor deprivation, ER stress, and pathogen infection. Defective autophagy plays a significant role in human pathologies, including cancer, neurodegeneration, and infectious diseases. We present our current knowledge on the key genes composing the autophagy machinery in eukaryotes from yeast to mammalian cells and the signaling pathways that sense the status of different types of stress and induce autophagy for cell survival and homeostasis. We also review the recent advances on the molecular mechanisms that regulate the autophagy machinery at various levels, from transcriptional activation to post-translational protein modification.
3,249 citations
TL;DR: It is reported that rapamycin, an inhibitor of the mTOR pathway, extends median and maximal lifespan of both male and female mice when fed beginning at 600 days of age.
Abstract: Inhibition of the TOR signalling pathway by genetic or pharmacological intervention extends lifespan in invertebrates, including yeast, nematodes and fruitflies; however, whether inhibition of mTOR signalling can extend lifespan in a mammalian species was unknown. Here we report that rapamycin, an inhibitor of the mTOR pathway, extends median and maximal lifespan of both male and female mice when fed beginning at 600 days of age. On the basis of age at 90% mortality, rapamycin led to an increase of 14% for females and 9% for males. The effect was seen at three independent test sites in genetically heterogeneous mice, chosen to avoid genotype-specific effects on disease susceptibility. Disease patterns of rapamycin-treated mice did not differ from those of control mice. In a separate study, rapamycin fed to mice beginning at 270 days of age also increased survival in both males and females, based on an interim analysis conducted near the median survival point. Rapamycin may extend lifespan by postponing death from cancer, by retarding mechanisms of ageing, or both. To our knowledge, these are the first results to demonstrate a role for mTOR signalling in the regulation of mammalian lifespan, as well as pharmacological extension of lifespan in both genders. These findings have implications for further development of interventions targeting mTOR for the treatment and prevention of age-related diseases.
3,216 citations
University of Alabama at Birmingham1, University of Michigan2, University of Wisconsin-Madison3, Duke University4, University of Lausanne5, University of California, Los Angeles6, Georgia Regents University7, Radboud University Nijmegen8, University of Texas at Austin9, Rowan University10, AstraZeneca11, National Institutes of Health12, Wayne State University13
TL;DR: These updated guidelines replace the previous guidelines published in the 15 January 2004 issue of Clinical Infectious Diseases and are intended for use by health care providers who care for patients who either have or are at risk of these infections.
Abstract: Guidelines for the management of patients with invasive candidiasis and mucosal candidiasis were prepared by an Expert Panel of the Infectious Diseases Society of America. These updated guidelines replace the previous guidelines published in the 15 January 2004 issue of Clinical Infectious Diseases and are intended for use by health care providers who care for patients who either have or are at risk of these infections. Since 2004, several new antifungal agents have become available, and several new studies have been published relating to the treatment of candidemia, other forms of invasive candidiasis, and mucosal disease, including oropharyngeal and esophageal candidiasis. There are also recent prospective data on the prevention of invasive candidiasis in high-risk neonates and adults and on the empiric treatment of suspected invasive candidiasis in adults. This new information is incorporated into this revised document.
TL;DR: The 2009 update of the American Association for the Study of Liver Diseases (AASLD) Practice Guidelines for Management of Chronic Hepatitis B is now posted online at www.aasld.org, and the recommendation for first-line oral antiviral medications has been changed to tenofovir or entecavir, and adefovir has been moved to second-line Oral antiviral medication.
TL;DR: In this article, a field is emerging that leverages the capacity to collect and analyze data at a scale that may reveal patterns of individual and group behaviors at a large scale, such as behavior patterns.
Abstract: A field is emerging that leverages the capacity to collect and analyze data at a scale that may reveal patterns of individual and group behaviors.
University of Paris-Sud1, French Institute of Health and Medical Research2, Institut Gustave Roussy3, Icahn School of Medicine at Mount Sinai4, University of Texas Southwestern Medical Center5, Thomas Jefferson University6, McMaster University7, University of Massachusetts Medical School8, LSU Health Sciences Center New Orleans9, Roswell Park Cancer Institute10, University of Gothenburg11, Boston Children's Hospital12, University of Freiburg13, University of California, San Francisco14, Buck Institute for Research on Aging15, Centre national de la recherche scientifique16, National Institutes of Health17, Technion – Israel Institute of Technology18, University of Leicester19, University of Chieti-Pescara20, Istituto Superiore di Sanità21, University of North Carolina at Chapel Hill22, New York University23, University of Pennsylvania24, Yale University25, Howard Hughes Medical Institute26, University of Ulm27, University of Burgundy28, Aix-Marseille University29, Pasteur Institute30, University of Strasbourg31, Johns Hopkins University32, University of Zurich33, University of Tokyo34, Weizmann Institute of Science35, University of Michigan36, University College London37, Duke University38, University of Graz39, Ghent University40, Trinity College, Dublin41, University of Amsterdam42, University of Lyon43, University of Rome Tor Vergata44, Stony Brook University45, University of Göttingen46, Kyoto University47, Merck & Co.48, Austrian Academy of Sciences49, National University of Singapore50, University of Chicago51, Royal College of Surgeons in Ireland52, La Trobe University53, University of Buenos Aires54, University of Padua55, University of Lisbon56, University of Cambridge57, University of Würzburg58, University of Geneva59, University of Bern60, Rockefeller University61, University of Lausanne62, Osaka University63, University of California, San Diego64, University of Glasgow65, Harvard University66, Karolinska Institutet67
TL;DR: A nonexhaustive comparison of methods to detect cell death with apoptotic or nonapoptotic morphologies, their advantages and pitfalls is provided and the importance of performing multiple, methodologically unrelated assays to quantify dying and dead cells is emphasized.
Abstract: Cell death is essential for a plethora of physiological processes, and its deregulation characterizes numerous human diseases Thus, the in-depth investigation of cell death and its mechanisms constitutes a formidable challenge for fundamental and applied biomedical research, and has tremendous implications for the development of novel therapeutic strategies It is, therefore, of utmost importance to standardize the experimental procedures that identify dying and dead cells in cell cultures and/or in tissues, from model organisms and/or humans, in healthy and/or pathological scenarios Thus far, dozens of methods have been proposed to quantify cell death-related parameters However, no guidelines exist regarding their use and interpretation, and nobody has thoroughly annotated the experimental settings for which each of these techniques is most appropriate Here, we provide a nonexhaustive comparison of methods to detect cell death with apoptotic or nonapoptotic morphologies, their advantages and pitfalls These guidelines are intended for investigators who study cell death, as well as for reviewers who need to constructively critique scientific reports that deal with cellular demise Given the difficulties in determining the exact number of cells that have passed the point-of-no-return of the signaling cascades leading to cell death, we emphasize the importance of performing multiple, methodologically unrelated assays to quantify dying and dead cells
TL;DR: In this paper, the authors discuss the role of the chairperson of FAHA and the chair's role in the FAHA Board of Trustee selection process and propose a new chairperson for FAHA.
TL;DR: The scaffolding theory of aging and cognition (STAC) is proposed, suggesting that pervasive increased frontal activation with age is a marker of an adaptive brain that engages in compensatory scaffolding in response to the challenges posed by declining neural structures and function.
Abstract: There are declines with age in speed of processing, working memory, inhibitory function, and long-term memory, as well as decreases in brain structure size and white matter integrity. In the face of these decreases, functional imaging studies have demonstrated, somewhat surprisingly, reliable increases in prefrontal activation. To account for these joint phenomena, we propose the scaffolding theory of aging and cognition (STAC). STAC provides an integrative view of the aging mind, suggesting that pervasive increased frontal activation with age is a marker of an adaptive brain that engages in compensatory scaffolding in response to the challenges posed by declining neural structures and function. Scaffolding is a normal process present across the lifespan that involves use and development of complementary, alternative neural circuits to achieve a particular cognitive goal. Scaffolding is protective of cognitive function in the aging brain, and available evidence suggests that the ability to use this mechanism is strengthened by cognitive engagement, exercise, and low levels of default network engagement.
TL;DR: The understanding of the risk factors and causes of GHVD, the cellular and cytokine networks implicated in its pathophysiology, and current strategies to prevent and treat the disease are reviewed.
TL;DR: The author presents 3 questions for psychologists to ask: Who is included within this category?
Abstract: Feminist and critical race theories offer the concept of intersectionality to describe analytic approaches that simultaneously consider the meaning and consequences of multiple categories of identity, difference, and disadvantage. To understand how these categories depend on one another for meaning and are jointly associated with outcomes, reconceptualization of the meaning and significance of the categories is necessary. To accomplish this, the author presents 3 questions for psychologists to ask: Who is included within this category? What role does inequality play? Where are there similarities? The 1st question involves attending to diversity within social categories. The 2nd conceptualizes social categories as connoting hierarchies of privilege and power that structure social and material life. The 3rd looks for commonalities across categories commonly viewed as deeply different. The author concludes with a discussion of the implications and value of these 3 questions for each stage of the research process.
TL;DR: Sarcosine, an N-methyl derivative of the amino acid glycine, was identified as a differential metabolite that was highly increased during prostate cancer progression to metastasis and can be detected non-invasively in urine.
Abstract: Multiple, complex molecular events characterize cancer development and progression. Deciphering the molecular networks that distinguish organ-confined disease from metastatic disease may lead to the identification of critical biomarkers for cancer invasion and disease aggressiveness. Although gene and protein expression have been extensively profiled in human tumours, little is known about the global metabolomic alterations that characterize neoplastic progression. Using a combination of high-throughput liquid-and-gas-chromatography-based mass spectrometry, we profiled more than 1,126 metabolites across 262 clinical samples related to prostate cancer (42 tissues and 110 each of urine and plasma). These unbiased metabolomic profiles were able to distinguish benign prostate, clinically localized prostate cancer and metastatic disease. Sarcosine, an N-methyl derivative of the amino acid glycine, was identified as a differential metabolite that was highly increased during prostate cancer progression to metastasis and can be detected non-invasively in urine. Sarcosine levels were also increased in invasive prostate cancer cell lines relative to benign prostate epithelial cells. Knockdown of glycine-N-methyl transferase, the enzyme that generates sarcosine from glycine, attenuated prostate cancer invasion. Addition of exogenous sarcosine or knockdown of the enzyme that leads to sarcosine degradation, sarcosine dehydrogenase, induced an invasive phenotype in benign prostate epithelial cells. Androgen receptor and the ERG gene fusion product coordinately regulate components of the sarcosine pathway. Here, by profiling the metabolomic alterations of prostate cancer progression, we reveal sarcosine as a potentially important metabolic intermediary of cancer cell invasion and aggressivity.
University of Texas MD Anderson Cancer Center1, Case Western Reserve University2, Cleveland Clinic3, University of Colorado Denver4, University of Texas Health Science Center at San Antonio5, National Institutes of Health6, University of California, San Diego7, University of Western Ontario8, Duke University9, Mayo Clinic10, University of Washington11, University of California, Los Angeles12, Columbia University13, University of British Columbia14, University of California, Irvine15, University of Michigan16
TL;DR: Selenium or vitamin E, alone or in combination at the doses and formulations used, did not prevent prostate cancer in this population of relatively healthy men.
Abstract: Context Secondary analyses of 2 randomized controlled trials and supportive epidemiologic and preclinical data indicated the potential of selenium and vitamin E for preventing prostate cancer. Objective To determine whether selenium, vitamin E, or both could prevent prostate cancer and other diseases with little or no toxicity in relatively healthy men. Design, Setting, and Participants A randomized, placebo-controlled trial (Selenium and Vitamin E Cancer Prevention Trial [SELECT]) of 35 533 men from 427 participating sites in the United States, Canada, and Puerto Rico randomly assigned to 4 groups (selenium, vitamin E, selenium + vitamin E, and placebo) in a double-blind fashion between August 22, 2001, and June 24, 2004. Baseline eligibility included age 50 years or older (African American men) or 55 years or older (all other men), a serum prostate-specific antigen level of 4 ng/mL or less, and a digital rectal examination not suspicious for prostate cancer. Interventions Oral selenium (200 μg/d from L-selenomethionine) and matched vitamin E placebo, vitamin E (400 IU/d of all rac-α-tocopheryl acetate) and matched selenium placebo, selenium + vitamin E, or placebo + placebo for a planned follow-up of minimum of 7 years and a maximum of 12 years. Main Outcome Measures Prostate cancer and prespecified secondary outcomes, including lung, colorectal, and overall primary cancer. Results As of October 23, 2008, median overall follow-up was 5.46 years (range, 4.17-7.33 years). Hazard ratios (99% confidence intervals [CIs]) for prostate cancer were 1.13 (99% CI, 0.95-1.35; n = 473) for vitamin E, 1.04 (99% CI, 0.87-1.24; n = 432) for selenium, and 1.05 (99% CI, 0.88-1.25; n = 437) for selenium + vitamin E vs 1.00 (n = 416) for placebo. There were no significant differences (all P>.15) in any other prespecified cancer end points. There were statistically nonsignificant increased risks of prostate cancer in the vitamin E group (P = .06) and type 2 diabetes mellitus in the selenium group (relative risk, 1.07; 99% CI, 0.94-1.22; P = .16) but not in the selenium + vitamin E group. Conclusion Selenium or vitamin E, alone or in combination at the doses and formulations used, did not prevent prostate cancer in this population of relatively healthy men. Trial Registration clinicaltrials.gov identifier: NCT00006392Published online December 9, 2008 (doi:10.1001/jama.2008.864).
TL;DR: Results indicated that OCBs are related to a number of individual-level outcomes, including managerial ratings of employee performance, reward allocation decisions, and a variety of withdrawal-related criteria, and some evidence that O CBs are causally related to these criteria is provided.
Abstract: Although one of the main reasons for the interest in organizational citizenship behaviors (OCBs) is the potential consequences of these behaviors, no study has been reported that summarizes the research regarding the relationships between OCBs and their outcomes. Therefore, the purpose of this study is to provide a meta-analytic examination of the relationships between OCBs and a variety of individual- and organizational-level outcomes. Results, based on 168 independent samples (N 51,235 individuals), indicated that OCBs are related to a number of individual-level outcomes, including managerial ratings of employee performance, reward allocation decisions, and a variety of withdrawal-related criteria (e.g., employee turnover intentions, actual turnover, and absenteeism). In addition, OCBs were found to be related (k 38; N 3,611 units) to a number of organizational-level outcomes (e.g., productivity, efficiency, reduced costs, customer satisfaction, and unit-level turnover). Of interest, somewhat stronger relationships were observed between OCBs and unit-level performance measures in longitudinal studies than in cross-sectional studies, providing some evidence that OCBs are causally related to these criteria. The implications of these findings for both researchers and practitioners are discussed.
TL;DR: A novel mammalian autophagy factor, Atg13, is reported, which forms a stable approximately 3-MDa protein complex with ULK1 and FIP200, and suggests that mTORC1 suppressesAutophagy through direct regulation of the approximately 3,MDa ULK 1-Atg13-FIP200 complex.
Abstract: Autophagy is an intracellular degradation system, by which cytoplasmic contents are degraded in lysosomes. Autophagy is dynamically induced by nutrient depletion to provide necessary amino acids within cells, thus helping them adapt to starvation. Although it has been suggested that mTOR is a major negative regulator of autophagy, how it controls autophagy has not yet been determined. Here, we report a novel mammalian autophagy factor, Atg13, which forms a stable approximately 3-MDa protein complex with ULK1 and FIP200. Atg13 localizes on the autophagic isolation membrane and is essential for autophagosome formation. In contrast to yeast counterparts, formation of the ULK1-Atg13-FIP200 complex is not altered by nutrient conditions. Importantly, mTORC1 is incorporated into the ULK1-Atg13-FIP200 complex through ULK1 in a nutrient-dependent manner and mTOR phosphorylates ULK1 and Atg13. ULK1 is dephosphorylated by rapamycin treatment or starvation. These data suggest that mTORC1 suppresses autophagy through direct regulation of the approximately 3-MDa ULK1-Atg13-FIP200 complex.
TL;DR: A primary challenge in the development of clinical practice guidelines is keeping pace with the stream of new data on which recommendations are based as discussed by the authors, and the American College of Cardiology Foundation/American Heart Association (ACCF/AHA) is to respond promptly to new evidence.
Abstract: ### Preamble
A primary challenge in the development of clinical practice guidelines is keeping pace with the stream of new data on which recommendations are based. In an effort to respond promptly to new evidence, the American College of Cardiology Foundation/American Heart Association (ACCF/AHA)
Cristen J. Willer, Elizabeth K. Speliotes1, Elizabeth K. Speliotes2, Ruth J. F. Loos +163 more•Institutions (36)
TL;DR: Several of the likely causal genes are highly expressed or known to act in the central nervous system (CNS), emphasizing, as in rare monogenic forms of obesity, the role of the CNS in predisposition to obesity.
Abstract: Common variants at only two loci, FTO and MC4R, have been reproducibly associated with body mass index (BMI) in humans. To identify additional loci, we conducted meta-analysis of 15 genome-wide association studies for BMI (n > 32,000) and followed up top signals in 14 additional cohorts (n > 59,000). We strongly confirm FTO and MC4R and identify six additional loci (P < 5 x 10(-8)): TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2 and NEGR1 (where a 45-kb deletion polymorphism is a candidate causal variant). Several of the likely causal genes are highly expressed or known to act in the central nervous system (CNS), emphasizing, as in rare monogenic forms of obesity, the role of the CNS in predisposition to obesity.
TL;DR: The complexities of genealogical discordance are discussed and the issues that new methods for multilocus species tree inference will need to address are reviewed to account successfully for naturally occurring genomic variability in evolutionary histories.
Abstract: The field of phylogenetics is entering a new era in which trees of historical relationships between species are increasingly inferred from multilocus and genomic data. A major challenge for incorporating such large amounts of data into inference of species trees is that conflicting genealogical histories often exist in different genes throughout the genome. Recent advances in genealogical modeling suggest that resolving close species relationships is not quite as simple as applying more data to the problem. Here we discuss the complexities of genealogical discordance and review the issues that new methods for multilocus species tree inference will need to address to account successfully for naturally occurring genomic variability in evolutionary histories.
TL;DR: Findings on three dissociable psychological components of reward: 'liking' (hedonic impact), 'wanting' (incentive salience), and learning (predictive associations and cognitions) are highlighted.
TL;DR: A new algorithm is proposed that naturally extends the original AdaBoost algorithm to the multiclass case without reducing it to multiple two-class problems and is extremely easy to implement and is highly competitive with the best currently available multi-class classification methods.
Abstract: Boosting has been a very successful technique for solving the two-class classification problem. In going from two-class to multi-class classification, most algorithms have been restricted to reducing the multi-class classification problem to multiple two-class problems. In this paper, we propose a new algorithm that naturally extends the original AdaBoost algorithm to the multiclass case without reducing it to multiple two-class problems. Similar to AdaBoost in the twoclass case, this new algorithm combines weak classifiers and only requires the performance of each weak classifier be better than random guessing (rather than 1/2). We further provide a statistical justification for the new algorithm using a novel multi-class exponential loss function and forward stage-wise additive modeling. As shown in the paper, the new algorithm is extremely easy to implement and is highly competitive with the best currently available multi-class classification methods.
TL;DR: A primary challenge in the development of clinical practice guidelines is keeping pace with the stream of new data on which recommendations are based as mentioned in this paper, and the American College of Cardiology Foundation/American Heart Association (ACCF/AHA) is to respond promptly to new evidence.
TL;DR: Members of the Nod-like receptor family, including NLRP1, NLRP3 and NLRC4, and the adaptor ASC are critical components of the inflammasome that link microbial and endogenous 'danger' signals to caspase-1 activation.
Abstract: The inflammasome is a multiprotein complex that mediates the activation of caspase-1, which promotes secretion of the proinflammatory cytokines interleukin 1beta (IL-1beta) and IL-18, as well as 'pyroptosis', a form of cell death induced by bacterial pathogens. Members of the Nod-like receptor family, including NLRP1, NLRP3 and NLRC4, and the adaptor ASC are critical components of the inflammasome that link microbial and endogenous 'danger' signals to caspase-1 activation. Several diseases are associated with dysregulated activation of caspase-1 and secretion of IL-1beta. Thus, understanding inflammasome pathways may provide insight into disease pathogenesis that might identify potential targets for therapeutic intervention.
University of Michigan1, University of Texas at Austin2, ETH Zurich3, Ludwig Maximilian University of Munich4, Carnegie Institution for Science5, University of California, Santa Cruz6, University of California, Berkeley7, University of Arizona8, Durham University9, Ohio Northern University10, Université libre de Bruxelles11
TL;DR: In this article, improved versions of the relations between supermassive black hole mass (M BH) and host-galaxy bulge velocity dispersion (σ) and luminosity (L; the M-σ and M-L relations), based on 49 M BH measurements and 19 upper limits, were derived.
Abstract: We derive improved versions of the relations between supermassive black hole mass (M BH) and host-galaxy bulge velocity dispersion (σ) and luminosity (L; the M-σ and M-L relations), based on 49 M BH measurements and 19 upper limits. Particular attention is paid to recovery of the intrinsic scatter (e0) in both relations. We find log(M BH/M) = α + βlog(σ/200 km s-1) with (α, β, e0) = (8.12 0.08, 4.24 0.41, 0.44 0.06) for all galaxies and (α, β, e0) = (8.23 0.08, 3.96 0.42, 0.31 0.06) for ellipticals. The results for ellipticals are consistent with previous studies, but the intrinsic scatter recovered for spirals is significantly larger. The scatter inferred reinforces the need for its consideration when calculating local black hole mass function based on the M-σ relation, and further implies that there may be substantial selection bias in studies of the evolution of the M-σ relation. We estimate the M-L relationship as log(M BH/M) = α + βlog(LV /1011 L V) of (α, β, e0) = (8.95 0.11, 1.11 0.18, 0.38 0.09); using only early-type galaxies. These results appear to be insensitive to a wide range of assumptions about the measurement errors and the distribution of intrinsic scatter. We show that culling the sample according to the resolution of the black hole's sphere of influence biases the relations to larger mean masses, larger slopes, and incorrect intrinsic residuals. © 2009. The American Astronomical Society.