Showing papers by "Yale University published in 2009"
TL;DR: The RNA-Seq approach to transcriptome profiling that uses deep-sequencing technologies provides a far more precise measurement of levels of transcripts and their isoforms than other methods.
Abstract: RNA-Seq is a recently developed approach to transcriptome profiling that uses deep-sequencing technologies. Studies using this method have already altered our view of the extent and complexity of eukaryotic transcriptomes. RNA-Seq also provides a far more precise measurement of levels of transcripts and their isoforms than other methods. This article describes the RNA-Seq approach, the challenges associated with its application, and the advances made so far in characterizing several eukaryote transcriptomes.
11,528 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
TL;DR: This revision of the consensus algorithm for the medical management of type 2 diabetes focuses on the new classes of medications that now have more clinical data and experience and addresses safety issues surrounding the thiazolidinediones.
Abstract: The consensus algorithm for the medical management of type 2 diabetes was published in August 2006 with the expectation that it would be updated, based on the availability of new interventions and new evidence to establish their clinical role. The authors continue to endorse the principles used to develop the algorithm and its major features. We are sensitive to the risks of changing the algorithm cavalierly or too frequently, without compelling new information. An update to the consensus algorithm published in January 2008 specifically addressed safety issues surrounding the thiazolidinediones. In this revision, we focus on the new classes of medications that now have more clinical data and experience.
3,807 citations
TL;DR: This review expands upon previous findings of weight bias in major domains of living, documents new areas where weight bias has been studied, and highlights ongoing research questions that need to be addressed to advance this field of study.
Abstract: Obese individuals are highly stigmatized and face multiple forms of prejudice and discrimination because of their weight (1,2). The prevalence of weight discrimination in the United States has increased by 66% over the past decade (3), and is comparable to rates of racial discrimination, especially among women (4). Weight bias translates into inequities in employment settings, health-care facilities, and educational institutions, often due to widespread negative stereotypes that overweight and obese persons are lazy, unmotivated, lacking in selfdiscipline, less competent, noncompliant, and sloppy (2,5–7). These stereotypes are prevalent and are rarely challenged in Western society, leaving overweight and obese persons vulnerable to social injustice, unfair treatment, and impaired quality of life as a result of substantial disadvantages and stigma. In 2001, Puhl and Brownell published the first comprehensive review of several decades of research documenting bias and stigma toward overweight and obese persons (2). This review summarized weight stigma in domains of employment, health care, and education, demonstrating the vulnerability of obese persons to many forms of unfair treatment. Despite evidence of weight bias in important areas of living, the authors noted many gaps in research regarding the nature and extent of weight stigma in various settings, the lack of science on emotional and physical health consequences of weight bias, and the paucity of interventions to reduce negative stigma. In recent years, attention to weight bias has increased, with a growing recognition of the pervasiveness of weight bias and stigma, and its potential harmful consequences for obese persons. The aim of this article is to provide an update of scientific evidence on weight bias toward overweight and obese adults through a systematic review of published literature since the 2001 article by Puhl and Brownell. This review expands upon previous findings of weight bias in major domains of living, documents new areas where weight bias has been studied, and highlights ongoing research questions that need to be addressed to advance this field of study. A systematic literature search of studies published between January 2000 and May 2008 was undertaken on computerized psychological, medical, social science, sport, and education databases including PsycINFO, PubMed, SCOPUS, ERIC, and SPORTDiscus. The following keyword combinations were used: weight, obese, obesity, overweight, BMI, fat, fatness, size, heavy, large, appearance, big, heavyweight, bias, biased, discrimination, discriminatory, discriminate, stigma, stigmatized, stigmatization, prejudice, prejudicial, stereotype(s), stereotypical, stereotyping, victimization, victimize(d), blame(d), blaming, shame(d), shaming, teasing, tease(d), unfair, bully, bullying, harassment, assumptions, attributions, education, health, health care, sales, employment, wages, promotion, adoption, jury, customer service, housing, media, television. Reference lists of retrieved articles and books were also reviewed, and manual searches were conducted in the databases and journals for authors who had published in this field. Most studies retrieved for this review were published in the United States. Any articles published internationally are noted with their country of origin. Research on weight stigma in adolescents and children was excluded from this review, as this literature was recently reviewed elsewhere (8). Unpublished manuscripts and dissertations were also excluded. In addition, issues pertaining to measurement of weight stigmatization, and demographic variables affecting vulnerability to weight bias such as gender, age, race, and body weight are not addressed in this review. This article instead primarily reviews the evidence of specific areas where weight bias occurs toward adults and its consequences for those affected. This article is organized similarly to the first review published by Puhl and Brownell (2), with sections on weight bias in settings of employment, health care, and education. New sections have been added including weight bias in interpersonal relationships and the media, as well as psychological and physical health consequences of weight bias, and the status of stigma-reduction research. As with the 2001 article, this review also provides an update on legal initiatives to combat weight discrimination, and outlines specific questions for future research.
2,696 citations
TL;DR: It is demonstrated that, like their electronic counterparts, electromagnetic CESs can travel in only one direction and are very robust against scattering from disorder; it is found that even large metallic scatterers placed in the path of the propagating edge modes do not induce reflections.
Abstract: One of the most striking phenomena in condensed-matter physics is the quantum Hall effect, which arises in two-dimensional electron systems subject to a large magnetic field applied perpendicular to the plane in which the electrons reside. In such circumstances, current is carried by electrons along the edges of the system, in so-called chiral edge states (CESs). These are states that, as a consequence of nontrivial topological properties of the bulk electronic band structure, have a unique directionality and are robust against scattering from disorder. Recently, it was theoretically predicted that electromagnetic analogues of such electronic edge states could be observed in photonic crystals, which are materials having refractive-index variations with a periodicity comparable to the wavelength of the light passing through them. Here we report the experimental realization and observation of such electromagnetic CESs in a magneto-optical photonic crystal fabricated in the microwave regime. We demonstrate that, like their electronic counterparts, electromagnetic CESs can travel in only one direction and are very robust against scattering from disorder; we find that even large metallic scatterers placed in the path of the propagating edge modes do not induce reflections. These modes may enable the production of new classes of electromagnetic device and experiments that would be impossible using conventional reciprocal photonic states alone. Furthermore, our experimental demonstration and study of photonic CESs provides strong support for the generalization and application of topological band theories to classical and bosonic systems, and may lead to the realization and observation of topological phenomena in a generally much more controlled and customizable fashion than is typically possible with electronic systems.
2,383 citations
University of Tasmania1, University of California, Santa Barbara2, Woods Hole Oceanographic Institution3, Yale University4, University of São Paulo5, University of Cape Town6, South Dakota State University7, Columbia University8, California Institute of Technology9, University of Bristol10, United States Geological Survey11, University of California, Los Angeles12, University of California, Berkeley13, Monash University14, Brown University15, Ohio State University16, Royal Holloway, University of London17, University of Arizona18, VU University Amsterdam19, Arizona State University20
TL;DR: What is known and what is needed to develop a holistic understanding of the role of fire in the Earth system are reviewed, particularly in view of the pervasive impact of fires and the likelihood that they will become increasingly difficult to control as climate changes.
Abstract: Fire is a worldwide phenomenon that appears in the geological record soon after the appearance of terrestrial plants. Fire influences global ecosystem patterns and processes, including vegetation distribution and structure, the carbon cycle, and climate. Although humans and fire have always coexisted, our capacity to manage fire remains imperfect and may become more difficult in the future as climate change alters fire regimes. This risk is difficult to assess, however, because fires are still poorly represented in global models. Here, we discuss some of the most important issues involved in developing a better understanding of the role of fire in the Earth system.
2,365 citations
TL;DR: Recent research has provided clues as to why genetic or environmental insults that disinhibit stress signalling pathways can lead to symptoms of profound prefrontal cortical dysfunction in mental illness.
Abstract: Stress affects cognition and increases noradrenaline and dopamine levels in the prefrontal cortex (PFC). Amy Arnsten discusses the intracellular signalling pathways that mediate the effects of these catecholamines on PFC function during acute and chronic stress, focusing on working memory. An interview with Amy Arnsten for Neuropod is available for
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. The prefrontal cortex (PFC) — the most evolved brain region — subserves our highest-order cognitive abilities. However, it is also the brain region that is most sensitive to the detrimental effects of stress exposure. Even quite mild acute uncontrollable stress can cause a rapid and dramatic loss of prefrontal cognitive abilities, and more prolonged stress exposure causes architectural changes in prefrontal dendrites. Recent research has begun to reveal the intracellular signalling pathways that mediate the effects of stress on the PFC. This research has provided clues as to why genetic or environmental insults that disinhibit stress signalling pathways can lead to symptoms of profound prefrontal cortical dysfunction in mental illness.
2,320 citations
Institut Gustave Roussy1, University of Paris-Sud2, French Institute of Health and Medical Research3, 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, Boston Children's Hospital11, University of Gothenburg12, 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, Howard Hughes Medical Institute25, Yale University26, 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, University of Göttingen45, Stony Brook University46, 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
2,218 citations
TL;DR: The NF-kappaB pathway is a paradigm for understanding general principles of signal transduction and gene regulation as well as other pathway-specific mediators, and the transcription factors are themselves extensively modified.
Abstract: Nuclear factor-κB (NF-κB) consists of a family of transcription factors that play critical roles in inflammation, immunity, cell proliferation, differentiation, and survival. Inducible NF-κB activation depends on phosphorylation-induced proteosomal degradation of the inhibitor of NF-κB proteins (IκBs), which retain inactive NF-κB dimers in the cytosol in unstimulated cells. The majority of the diverse signaling pathways that lead to NF-κB activation converge on the IκB kinase (IKK) complex, which is responsible for IκB phosphorylation and is essential for signal transduction to NF-κB. Additional regulation of NF-κB activity is achieved through various post-translational modifications of the core components of the NF-κB signaling pathways. In addition to cytosolic modifications of IKK and IκB proteins, as well as other pathway-specific mediators, the transcription factors are themselves extensively modified. Tremendous progress has been made over the last two decades in unraveling the elaborate regulatory networks that control the NF-κB response. This has made the NF-κB pathway a paradigm for understanding general principles of signal transduction and gene regulation.
2,093 citations
TL;DR: It is shown that the C/C genotype strongly enhances resolution of HCV infection among individuals of both European and African ancestry, the strongest and most significant genetic effect associated with natural clearance ofHCV.
Abstract: Hepatitis C virus (HCV) infection is the most common blood-borne infection in the United States, with estimates of 4 million HCV-infected individuals in the United States and 170 million worldwide. Most (70-80%) HCV infections persist and about 30% of individuals with persistent infection develop chronic liver disease, including cirrhosis and hepatocellular carcinoma. Epidemiological, viral and host factors have been associated with the differences in HCV clearance or persistence, and studies have demonstrated that a strong host immune response against HCV favours viral clearance. Thus, variation in genes involved in the immune response may contribute to the ability to clear the virus. In a recent genome-wide association study, a single nucleotide polymorphism (rs12979860) 3 kilobases upstream of the IL28B gene, which encodes the type III interferon IFN-3, was shown to associate strongly with more than a twofold difference in response to HCV drug treatment. To determine the potential effect of rs12979860 variation on outcome to HCV infection in a natural history setting, we genotyped this variant in HCV cohorts comprised of individuals who spontaneously cleared the virus (n = 388) or had persistent infection (n = 620). We show that the C/C genotype strongly enhances resolution of HCV infection among individuals of both European and African ancestry. To our knowledge, this is the strongest and most significant genetic effect associated with natural clearance of HCV, and these results implicate a primary role for IL28B in resolution of HCV infection.
2,079 citations
Oregon Health & Science University1, Dartmouth College2, University of Utah3, Harvard University4, Seattle Cancer Care Alliance5, Kaiser Permanente6, University of Miami7, Memorial Sloan Kettering Cancer Center8, Albany College of Pharmacy and Health Sciences9, University of Wisconsin-Madison10, California Health and Human Services Agency11, Yale University12, Yeshiva University13, University of California, Davis14, University of California, San Francisco15
TL;DR: Safe and effective chronic opioid therapy for chronic noncancer pain requires clinical skills and knowledge in both the principles of opioid prescribing and on the assessment and management of risks associated with opioid abuse, addiction, and diversion.
TL;DR: The two universally required components of the intracellular membrane fusion machinery, SNARE and SM (Sec1/Munc18-like) proteins, play complementary roles in fusion and are spectacularly apparent in the exquisite speed and precision of synaptic exocytosis.
Abstract: The two universally required components of the intracellular membrane fusion machinery, SNARE and SM (Sec1/Munc18-like) proteins, play complementary roles in fusion. Vesicular and target membrane-localized SNARE proteins zipper up into an alpha-helical bundle that pulls the two membranes tightly together to exert the force required for fusion. SM proteins, shaped like clasps, bind to trans-SNARE complexes to direct their fusogenic action. Individual fusion reactions are executed by distinct combinations of SNARE and SM proteins to ensure specificity, and are controlled by regulators that embed the SM-SNARE fusion machinery into a physiological context. This regulation is spectacularly apparent in the exquisite speed and precision of synaptic exocytosis, where synaptotagmin (the calcium-ion sensor for fusion) cooperates with complexin (the clamp activator) to control the precisely timed release of neurotransmitters that initiates synaptic transmission and underlies brain function.
TL;DR: It is argued that this framework can, theoretically, illuminate how stigma adversely affects mental health and, practically, inform clinical interventions.
Abstract: Sexual minorities are at increased risk for multiple mental health burdens compared with heterosexuals. The field has identified 2 distinct determinants of this risk, including group-specific minority stressors and general psychological processes that are common across sexual orientations. The goal of the present article is to develop a theoretical framework that integrates the important insights from these literatures. The framework postulates that (a) sexual minorities confront increased stress exposure resulting from stigma; (b) this stigma-related stress creates elevations in general emotion dysregulation, social/interpersonal problems, and cognitive processes conferring risk for psychopathology; and (c) these processes in turn mediate the relationship between stigma-related stress and psychopathology. It is argued that this framework can, theoretically, illuminate how stigma adversely affects mental health and, practically, inform clinical interventions. Evidence for the predictive validity of this framework is reviewed, with particular attention paid to illustrative examples from research on depression, anxiety, and alcohol-use disorders.
TL;DR: Comparisons of quantitative measurements of reactions in live cells with computer simulations of mathematical models will help generate meaningful insights and present a summary of the key questions in the field.
Abstract: The protein actin forms filaments that provide cells with mechanical support and driving forces for movement. Actin contributes to biological processes such as sensing environmental forces, internalizing membrane vesicles, moving over surfaces, and dividing the cell in two. These cellular activities are complex; they depend on interactions of actin monomers and filaments with numerous other proteins. Here, we present a summary of the key questions in the field and suggest how those questions might be answered. Understanding actin-based biological phenomena will depend on identifying the participating molecules and defining their molecular mechanisms. Comparisons of quantitative measurements of reactions in live cells with computer simulations of mathematical models will also help generate meaningful insights.
B. I. Abelev1, Madan M. Aggarwal2, Zubayer Ahammed3, A. V. Alakhverdyants4 +345 more•Institutions (49)
TL;DR: The cellular prion protein (PrPC) is identified as an amyloid-β-oligomer receptor by expression cloning, and PrPC-specific pharmaceuticals may have therapeutic potential for Alzheimer’s disease.
Abstract: A pathological hallmark of Alzheimer's disease is an accumulation of insoluble plaque containing the amyloid-beta peptide of 40-42 amino acid residues. Prefibrillar, soluble oligomers of amyloid-beta have been recognized to be early and key intermediates in Alzheimer's-disease-related synaptic dysfunction. At nanomolar concentrations, soluble amyloid-beta oligomers block hippocampal long-term potentiation, cause dendritic spine retraction from pyramidal cells and impair rodent spatial memory. Soluble amyloid-beta oligomers have been prepared from chemical syntheses, transfected cell culture supernatants, transgenic mouse brain and human Alzheimer's disease brain. Together, these data imply a high-affinity cell-surface receptor for soluble amyloid-beta oligomers on neurons-one that is central to the pathophysiological process in Alzheimer's disease. Here we identify the cellular prion protein (PrP(C)) as an amyloid-beta-oligomer receptor by expression cloning. Amyloid-beta oligomers bind with nanomolar affinity to PrP(C), but the interaction does not require the infectious PrP(Sc) conformation. Synaptic responsiveness in hippocampal slices from young adult PrP null mice is normal, but the amyloid-beta oligomer blockade of long-term potentiation is absent. Anti-PrP antibodies prevent amyloid-beta-oligomer binding to PrP(C) and rescue synaptic plasticity in hippocampal slices from oligomeric amyloid-beta. Thus, PrP(C) is a mediator of amyloid-beta-oligomer-induced synaptic dysfunction, and PrP(C)-specific pharmaceuticals may have therapeutic potential for Alzheimer's disease.
TL;DR: This meta-analysis yielded no evidence that the serotonin transporter genotype alone or in interaction with stressful life events is associated with an elevated risk of depression in men alone, women alone, or in both sexes combined.
Abstract: Context Substantial resources are being devoted to identify candidate genes for complex mental and behavioral disorders through inclusion of environmental exposures following the report of an interaction between the serotonin transporter linked polymorphic region (5-HTTLPR) and stressful life events on an increased risk of major depression. Objective To conduct a meta-analysis of the interaction between the serotonin transporter gene and stressful life events on depression using both published data and individual-level original data. Data Sources Search of PubMed, EMBASE, and PsycINFO databases through March 2009 yielded 26 studies of which 14 met criteria for the meta-analysis. Study Selection Criteria for studies for the meta-analyses included published data on the association between 5-HTTLPR genotype (SS, SL, or LL), number of stressful life events (0, 1, 2, ≥3) or equivalent, and a categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or the International Statistical Classification of Diseases, 10th Revision (ICD-10) or use of a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies published prior to 2008 that met inclusion criteria. Of the 14 studies included in the meta-analysis, 10 were also included in a second sex-specific meta-analysis of original individual-level data. Data Extraction Logistic regression was used to estimate the effects of the number of short alleles at 5-HTTLPR, the number of stressful life events, and their interaction on depression. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated separately for each study and then weighted averages of the individual estimates were obtained using random-effects meta-analysis. Both sex-combined and sex-specific meta-analyses were conducted. Of a total of 14 250 participants, 1769 were classified as having depression; 12 481 as not having depression. Results In the meta-analysis of published data, the number of stressful life events was significantly associated with depression (OR, 1.41; 95% CI,1.25-1.57). No association was found between 5-HTTLPR genotype and depression in any of the individual studies nor in the weighted average (OR, 1.05; 95% CI, 0.98-1.13) and no interaction effect between genotype and stressful life events on depression was observed (OR, 1.01; 95% CI, 0.94-1.10). Comparable results were found in the sex-specific meta-analysis of individual-level data. Conclusion This meta-analysis yielded no evidence that the serotonin transporter genotype alone or in interaction with stressful life events is associated with an elevated risk of depression in men alone, women alone, or in both sexes combined.
TL;DR: Recommendations from the ACE and the ADA generally endorsed tight glycemic control in critical care units and for patients in general medical and surgical units, where RCT evidence regarding treatment targets was lacking, glycemic goals similar to those advised for outpatients were advocated.
Abstract: People with diabetes are more likely to be hospitalized and to have longer durations of hospital stay than those without diabetes. A recent survey estimated that 22% of all hospital inpatient days were incurred by people with diabetes and that hospital inpatient care accounted for half of the 174 billion USD total U.S. medical expenditures for this disease (1). These findings are due, in part, to the continued expansion of the worldwide epidemic of type 2 diabetes. In the U.S. alone, there are ∼1.6 million new cases of diabetes each year, with an over all prevalence of 23.6 million people (7.8% of the population, with one-fourth of the cases remaining undiagnosed). An additional 57 million American adults are at high risk for type 2 diabetes (2). Although the costs of illness-related stress hyperglycemia are not known, they are likely to be considerable in light of the poor prognosis of such patients (3–6).
There is substantial observational evidence linking hyperglycemia in hospitalized patients (with or without diabetes) to poor outcomes. Cohort studies as well as a few early randomized controlled trials (RCTs) have suggested that intensive treatment of hyperglycemia improved hospital outcomes (5–8). In 2004, this evidence led the American College of Endocrinology (ACE) and the American Association of Clinical Endocrinologists (AACE), in collaboration with the American Diabetes Association (ADA) and other medical organizations, to develop recommendations for treatment of inpatient hyperglycemia (9). In 2005, the ADA added recommendations for treatment of hyperglycemia in the hospitalto itsannual Standards of Medical Care (10). Recommendations from the ACE and the ADA generally endorsed tight glycemic control in critical care units. For patients in general medical and surgical units, where RCT evidence regarding treatment targets was lacking, glycemic goals similar to those advised for outpatients were advocated (9, …
Brigham and Women's Hospital1, Harvard University2, University of California, San Francisco3, Yale University4, St Christopher's Hospice5, Cedars-Sinai Medical Center6, University of California, Los Angeles7, University of Western Sydney8, University of Missouri–St. Louis9, Stony Brook University10, University of Memphis11, Columbia University12, Memorial Sloan Kettering Cancer Center13, Utrecht University14, University of Zurich15, Boston University16, Veterans Health Administration17
TL;DR: The psychometric validity of criteria for prolonged grief disorder (PGD) is tested to enhance the detection and care of bereaved individuals at heightened risk of persistent distress and dysfunction.
Abstract: Background: Bereavement is a universal experience, and its association with excess morbidity and mortality is well established. Nevertheless, grief becomes a serious health concern for a relative few. For such individuals, intense grief persists, is distressing and disabling, and may meet criteria as a distinct mental disorder. At present, grief is not recognized as a mental disorder in the DSM-IV or ICD-10. The goal of this study was to determine the psychometric validity of criteria for prolonged grief disorder (PGD) to enhance the detection and potential treatment of bereaved individuals at heightened risk of persistent distress and dysfunction. Methods and Findings: A total of 291 bereaved respondents were interviewed three times, grouped as 0–6, 6–12, and 12– 24 mo post-loss. Item response theory (IRT) analyses derived the most informative, unbiased PGD symptoms. Combinatoric analyses identified the most sensitive and specific PGD algorithm that was then tested to evaluate its psychometric validity. Criteria require reactions to a significant loss that involve the experience of yearning (e.g., physical or emotional suffering as a result of the desired, but unfulfilled, reunion with the deceased) and at least five of the following nine symptoms experienced at least daily or to a disabling degree: feeling emotionally numb, stunned, or that life is meaningless; experiencing mistrust; bitterness over the loss; difficulty accepting the loss; identity confusion; avoidance of the reality of the loss; or difficulty moving on with life. Symptoms must be present at sufficiently high levels at least six mo from the death and be associated with functional impairment. Conclusions: The criteria set for PGD appear able to identify bereaved persons at heightened risk for enduring distress and dysfunction. The results support the psychometric validity of the criteria for PGD that we propose for inclusion in DSM-V and ICD-11. Please see later in the article for the Editors’ Summary.
TL;DR: It is found that expression of the transcription factor Bcl6 in CD4+ T cells is both necessary and sufficient for in vivo TFH differentiation and T cell help to B cells in mice, and that Bcl 6 and Blimp-1 play central but opposing roles inTFH differentiation.
Abstract: Effective B cell–mediated immunity and antibody responses often require help from CD4+ T cells. It is thought that a distinct CD4+ effector T cell subset, called T follicular helper cells (TFH), provides this help; however, the molecular requirements for TFH differentiation are unknown. We found that expression of the transcription factor Bcl6 in CD4+ T cells is both necessary and sufficient for in vivo TFH differentiation and T cell help to B cells in mice. In contrast, the transcription factor Blimp-1, an antagonist of Bcl6, inhibits TFH differentiation and help, thereby preventing B cell germinal center and antibody responses. These findings demonstrate that TFH cells are required for proper B cell responses in vivo and that Bcl6 and Blimp-1 play central but opposing roles in TFH differentiation.
TL;DR: Supporting evidence is provided that the residual breast tumor cell populations surviving after conventional treatment may be enriched for subpopulations of cells with both tumor-initiating and mesenchymal features.
Abstract: Some breast cancers have been shown to contain a small fraction of cells characterized by CD44+/CD24−/low cell-surface antigen profile that have high tumor-initiating potential. In addition, breast cancer cells propagated in vitro as mammospheres (MSs) have also been shown to be enriched for cells capable of self-renewal. In this study, we have defined a gene expression signature common to both CD44+/CD24−/low and MS-forming cells. To examine its clinical significance, we determined whether tumor cells surviving after conventional treatments were enriched for cells bearing this CD44+/CD24−/low-MS signature. The CD44+/CD24−/low-MS signature was found mainly in human breast tumors of the recently identified “claudin-low” molecular subtype, which is characterized by expression of many epithelial-mesenchymal-transition (EMT)-associated genes. Both CD44+/CD24−/low-MS and claudin-low signatures were more pronounced in tumor tissue remaining after either endocrine therapy (letrozole) or chemotherapy (docetaxel), consistent with the selective survival of tumor-initiating cells posttreatment. We confirmed an increased expression of mesenchymal markers, including vimentin (VIM) in cytokeratin-positive epithelial cells metalloproteinase 2 (MMP2), in two separate sets of postletrozole vs. pretreatment specimens. Taken together, these data provide supporting evidence that the residual breast tumor cell populations surviving after conventional treatment may be enriched for subpopulations of cells with both tumor-initiating and mesenchymal features. Targeting proteins involved in EMT may provide a therapeutic strategy for eliminating surviving cells to prevent recurrence and improve long-term survival in breast cancer patients.
TL;DR: A method for whole-exome sequencing coupling Roche/NimbleGen whole exome arrays to the Illumina DNA sequencing platform is reported, demonstrating the ability to capture approximately 95% of the targeted coding sequences with high sensitivity and specificity for detection of homozygous and heterozygous variants.
Abstract: Protein coding genes constitute only approximately 1% of the human genome but harbor 85% of the mutations with large effects on disease-related traits. Therefore, efficient strategies for selectively sequencing complete coding regions (i.e., “whole exome”) have the potential to contribute to the understanding of rare and common human diseases. Here we report a method for whole-exome sequencing coupling Roche/NimbleGen whole exome arrays to the Illumina DNA sequencing platform. We demonstrate the ability to capture approximately 95% of the targeted coding sequences with high sensitivity and specificity for detection of homozygous and heterozygous variants. We illustrate the utility of this approach by making an unanticipated genetic diagnosis of congenital chloride diarrhea in a patient referred with a suspected diagnosis of Bartter syndrome, a renal salt-wasting disease. The molecular diagnosis was based on the finding of a homozygous missense D652N mutation at a position in SLC26A3 (the known congenital chloride diarrhea locus) that is virtually completely conserved in orthologues and paralogues from invertebrates to humans, and clinical follow-up confirmed the diagnosis. To our knowledge, whole-exome (or genome) sequencing has not previously been used to make a genetic diagnosis. Five additional patients suspected to have Bartter syndrome but who did not have mutations in known genes for this disease had homozygous deleterious mutations in SLC26A3. These results demonstrate the clinical utility of whole-exome sequencing and have implications for disease gene discovery and clinical diagnosis.
TL;DR: Imaging procedures are an important source of exposure to ionizing radiation in the United States and can result in high cumulative effective doses of radiation, which increased with advancing age and were higher in women than in men.
Abstract: Results During the study period, 655,613 enrollees (68.8%) underwent at least one imaging procedure associated with radiation exposure. The mean (±SD) cumulative effective dose from imaging procedures was 2.4±6.0 mSv per enrollee per year; however, a wide distribution was noted, with a median effective dose of 0.1 mSv per enrollee per year (interquartile range, 0.0 to 1.7). Overall, moderate effective doses of radiation were incurred in 193.8 enrollees per 1000 per year, whereas high and very high doses were incurred in 18.6 and 1.9 enrollees per 1000 per year, respectively. In general, cumulative effective doses of radiation from imaging procedures increased with advancing age and were higher in women than in men. Computed tomographic and nuclear imaging accounted for 75.4% of the cumulative effective dose, with 81.8% of the total administered in outpatient settings. Conclusions Imaging procedures are an important source of exposure to ionizing radiation in the United States and can result in high cumulative effective doses of radiation.
TL;DR: How novelties that make us human may have been introduced during evolution are described, based on findings in the embryonic cerebral cortex in different mammalian species.
Abstract: The enlargement and species-specific elaboration of the cerebral neocortex during evolution holds the secret to the mental abilities of humans; however, the genetic origin and cellular mechanisms that generated the distinct evolutionary advancements are not well understood. This article describes how novelties that make us human may have been introduced during evolution, based on findings in the embryonic cerebral cortex in different mammalian species. The data on the differences in gene expression, new molecular pathways and novel cellular interactions that have led to these evolutionary advances may also provide insight into the pathogenesis and therapies for human-specific neuropsychiatric disorders.
TL;DR: A review of the current state of the art in the research field of cold and ultracold molecules can be found in this paper, where a discussion is based on recent experimental and theoretical work and concludes with a summary of anticipated future directions and open questions in rapidly expanding research field.
Abstract: This paper presents a review of the current state of the art in the research field of cold and ultracold molecules. It serves as an introduction to the focus issue of New Journal of Physics on Cold and Ultracold Molecules and describes new prospects for fundamental research and technological development. Cold and ultracold molecules may revolutionize physical chemistry and few-body physics, provide techniques for probing new states of quantum matter, allow for precision measurements of both fundamental and applied interest, and enable quantum simulations of condensed-matter phenomena. Ultracold molecules offer promising applications such as new platforms for quantum computing, precise control of molecular dynamics, nanolithography and Bose-enhanced chemistry. The discussion is based on recent experimental and theoretical work and concludes with a summary of anticipated future directions and open questions in this rapidly expanding research field.
TL;DR: The results of the review suggest that anxiety, whether measured categorically or dimensionally, is indeed common in children and adolescents with autism spectrum disorders and may be a source of additional morbidity.
TL;DR: A fully biological self-assembly approach, which is implemented through a rapid prototyping bioprinting method for scaffold-free small diameter vascular reconstruction and has the ability to engineer vessels of distinct shapes and hierarchical trees that combine tubes of distinct diameters.
29 Jun 2009
TL;DR: A benchmark consisting of a collection of tasks that are run on an open source version of MR as well as on two parallel DBMSs shows a dramatic performance difference between the two paradigms.
Abstract: There is currently considerable enthusiasm around the MapReduce (MR) paradigm for large-scale data analysis [17]. Although the basic control flow of this framework has existed in parallel SQL database management systems (DBMS) for over 20 years, some have called MR a dramatically new computing model [8, 17]. In this paper, we describe and compare both paradigms. Furthermore, we evaluate both kinds of systems in terms of performance and development complexity. To this end, we define a benchmark consisting of a collection of tasks that we have run on an open source version of MR as well as on two parallel DBMSs. For each task, we measure each system's performance for various degrees of parallelism on a cluster of 100 nodes. Our results reveal some interesting trade-offs. Although the process to load data into and tune the execution of parallel DBMSs took much longer than the MR system, the observed performance of these DBMSs was strikingly better. We speculate about the causes of the dramatic performance difference and consider implementation concepts that future systems should take from both kinds of architectures.
TL;DR: In this paper, the production of mesons containing strange quarks (KS, φ) and both singly and doubly strange baryons (,, and − + +) are measured at mid-rapidity in pp collisions at √ s = 0.9 TeV with the ALICE experiment at the LHC.
TL;DR: Results from randomized controlled trials have demonstrated conclusively that the risk of microvascular complications can be reduced by intensive glycemic control in patients with type 1 and type 2 diabetes, leading the American Diabetes Association to recommend an A1C goal of <7% for most adults with diabetes.
Abstract: Diabetes is defined by its association with hyperglycemia-specific microvascular complications; however, it also imparts a two- to fourfold risk of cardiovascular disease (CVD). Although microvascular complications can lead to significant morbidity and premature mortality, by far the greatest cause of death in people with diabetes is CVD.
Results from randomized controlled trials have demonstrated conclusively that the risk of microvascular complications can be reduced by intensive glycemic control in patients with type 1 (1,2) and type 2 diabetes (3–5). In the Diabetes Control and Complications Trial (DCCT), there was an ∼60% reduction in development or progression of diabetic retinopathy, nephropathy, and neuropathy between the intensively treated group (goal A1C <6.05%, mean achieved A1C ∼7%) and the standard group (A1C ∼9%) over an average of 6.5 years. The relationship between glucose control (as reflected by the mean on-study A1C value) and risk of complications was log-linear and extended down to the normal A1C range (<6%) with no threshold noted.
In the UK Prospective Diabetes Study (UKPDS), participants newly diagnosed with type 2 diabetes were followed for 10 years, and intensive control (median A1C 7.0%) was found to reduce the overall microvascular complication rate by 25% compared with conventional treatment (median A1C 7.9%). Here, too, secondary analyses showed a continuous relationship between the risk of microvascular complications and glycemia extending into the normal range of A1C, with no glycemic threshold.
On the basis of these two large controlled trials, along with smaller studies and numerous epidemiologic reports, the consistent findings related to microvascular risk reduction with intensive glycemic control have led the American Diabetes Association (ADA) to recommend an A1C goal of <7% for most adults with diabetes (6), recognizing that more or less stringent goals may be appropriate for certain patients. Whereas many epidemiologic studies and meta-analyses …