Showing papers by "Saint Louis University published in 2012"
TL;DR: The Human Microbiome Project Consortium reported the first results of their analysis of microbial communities from distinct, clinically relevant body habitats in a human cohort; the insights into the microbial communities of a healthy population lay foundations for future exploration of the epidemiology, ecology and translational applications of the human microbiome as discussed by the authors.
Abstract: The Human Microbiome Project Consortium reports the first results of their analysis of microbial communities from distinct, clinically relevant body habitats in a human cohort; the insights into the microbial communities of a healthy population lay foundations for future exploration of the epidemiology, ecology and translational applications of the human microbiome.
8,410 citations
TL;DR: The Human Microbiome Project (HMP) Consortium has established a population-scale framework which catalyzed significant development of metagenomic protocols resulting in a broad range of quality-controlled resources and data including standardized methods for creating, processing and interpreting distinct types of high-throughput metagenomics data available to the scientific community as mentioned in this paper.
Abstract: A variety of microbial communities and their genes (microbiome) exist throughout the human body, playing fundamental roles in human health and disease. The NIH funded Human Microbiome Project (HMP) Consortium has established a population-scale framework which catalyzed significant development of metagenomic protocols resulting in a broad range of quality-controlled resources and data including standardized methods for creating, processing and interpreting distinct types of high-throughput metagenomic data available to the scientific community. Here we present resources from a population of 242 healthy adults sampled at 15 to 18 body sites up to three times, which to date, have generated 5,177 microbial taxonomic profiles from 16S rRNA genes and over 3.5 Tb of metagenomic sequence. In parallel, approximately 800 human-associated reference genomes have been sequenced. Collectively, these data represent the largest resource to date describing the abundance and variety of the human microbiome, while providing a platform for current and future studies.
2,172 citations
TL;DR: The Human Connectome Project (HCP) as discussed by the authors is a 5-year effort to characterize brain connectivity and function and their variability in healthy adults using diffusion imaging (dMRI), resting-state fMRI, task-evoked fMRI (T-fMRI), T1-and T2-weighted MRI for structural and myelin mapping, plus combined magnetoencephalography (MEG/EEG).
1,975 citations
University of Colorado Denver1, Linköping University2, Hoffmann-La Roche3, Houston Methodist Hospital4, The Heart Research Institute5, Saint Louis University6, University of Oslo7, University of Glasgow8, University of Adelaide9, Cedars-Sinai Medical Center10, Montreal Heart Institute11, Mayo Clinic12
TL;DR: In patients who had had a recent acute coronary syndrome, dalcetrapib increased HDL cholesterol levels but did not reduce the risk of recurrent cardiovascular events.
Abstract: Background In observational analyses, higher levels of high-density lipoprotein (HDL) cholesterol have been associated with a lower risk of coronary heart disease events. However, whether raising HDL cholesterol levels therapeutically reduces cardiovascular risk remains uncertain. Inhibition of cholesteryl ester transfer protein (CETP) raises HDL cholesterol levels and might therefore improve cardiovascular outcomes. Methods We randomly assigned 15,871 patients who had had a recent acute coronary syndrome to receive the CETP inhibitor dalcetrapib, at a dose of 600 mg daily, or placebo, in addition to the best available evidence-based care. The primary efficacy end point was a composite of death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, unstable angina, or cardiac arrest with resuscitation. Results At the time of randomization, the mean HDL cholesterol level was 42 mg per deciliter (1.1 mmol per liter), and the mean low-density lipoprotein (LDL) cholesterol level was 76 ...
1,773 citations
TL;DR: Use of a humanized anti-interleukin-17 monoclonal antibody, ixekizumab, improved the clinical symptoms of psoriasis and further studies are needed to establish its long-term safety and efficacy in patients with Psoriasis.
Abstract: At 12 weeks, the percentage of patients with a reduction in the PASI score by at least 75% was significantly greater with ixekizumab (except with the lowest, 10-mg dose) ― 150 mg (82.1%), 75 mg (82.8%), and 25 mg (76.7%) ― than with placebo (7.7%, P<0.001 for each comparison), as was the percentage of patients with a reduction in the PASI score by at least 90%: 150 mg (71.4%), 75 mg (58.6%), and 25 mg (50.0%) versus placebo (0%, P<0.001 for each comparison). Similarly, a 100% reduction in the PASI score was achieved in significantly more patients in the 150-mg group (39.3%) and the 75-mg group (37.9%) than in the placebo group (0%) (P<0.001 for both comparisons). Significant differences occurred at as early as 1 week and were sustained through 20 weeks. Adverse events occurred in 63% of patients in both the combined ixekizumab groups and in the placebo group. No serious adverse events or major car diovascular events were observed. Conclusions Use of a humanized anti–interleukin-17 monoclonal antibody, ixekizumab, improved the clinical symptoms of psoriasis. Further studies are needed to establish its long-term safety and efficacy in patients with psoriasis. (Funded by Eli Lilly; ClinicalTrials.gov number, NCT01107457.)
939 citations
German Cancer Research Center1, University of Toronto2, Harvard University3, Broad Institute4, University of British Columbia5, Heidelberg University6, Memorial Sloan Kettering Cancer Center7, Vanderbilt University8, Sanford-Burnham Institute for Medical Research9, Medical University of Vienna10, Curie Institute11, University of Lausanne12, Seoul National University13, Johns Hopkins University14, University of Lyon15, University of Pittsburgh16, University of Michigan17, University of Alabama at Birmingham18, Catholic University of the Sacred Heart19, Erasmus University Rotterdam20, Boston Children's Hospital21, University of Washington22, Masaryk University23, McMaster University24, Hamilton Health Sciences25, Duke University26, McGill University27, McGill University Health Centre28, Newcastle University29, University of California, San Francisco30, University of Debrecen31, Tohoku University32, Saint Louis University33, Washington University in St. Louis34, University of California, Los Angeles35, Emory University36, University of Cincinnati37, Kumamoto University38, Semmelweis University39, University of Arkansas for Medical Sciences40, University of Naples Federico II41, Chonnam National University42, University of São Paulo43, University of Colorado Denver44, University of Ulsan45, University of Calgary46, Stanford University47
TL;DR: Somatic copy number aberrations (SCNAs) in 1,087 unique medulloblastomas are reported, including recurrent events targeting TGF-β signalling in Group 3, and NF-κB signalling in Groups 4, which suggest future avenues for rational, targeted therapy.
Abstract: Medulloblastoma, the most common malignant paediatric brain tumour, is currently treated with nonspecific cytotoxic therapies including surgery, whole-brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, previous attempts to identify targets for therapy have been underpowered because of small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1,087 unique medulloblastomas. SCNAs are common in medulloblastoma, and are predominantly subgroup-enriched. The most common region of focal copy number gain is a tandem duplication of SNCAIP, a gene associated with Parkinson's disease, which is exquisitely restricted to Group 4α. Recurrent translocations of PVT1, including PVT1-MYC and PVT1-NDRG1, that arise through chromothripsis are restricted to Group 3. Numerous targetable SCNAs, including recurrent events targeting TGF-β signalling in Group 3, and NF-κB signalling in Group 4, suggest future avenues for rational, targeted therapy.
749 citations
TL;DR: Monotherapy with metformin was associated with durable glycemic control in approximately half of children and adolescents with recent-onset type 2 diabetes and the addition of rosiglitazone, but not an intensive lifestyle intervention, was superior to meetformin alone.
Abstract: Background Despite the increasing prevalence of type 2 diabetes in youth, there are few data to guide treatment. We compared the efficacy of three treatment regimens to achieve durable glycemic control in children and adolescents with recent-onset type 2 diabetes. Methods Eligible patients 10 to 17 years of age were treated with metformin (at a dose of 1000 mg twice daily) to attain a glycated hemoglobin level of less than 8% and were randomly assigned to continued treatment with metformin alone or to metformin combined with rosiglitazone (4 mg twice a day) or a lifestyle-intervention program focusing on weight loss through eating and activity behaviors. The primary outcome was loss of glycemic control, defined as a glycated hemoglobin level of at least 8% for 6 months or sustained metabolic decompensation requiring insulin. Results Of the 699 randomly assigned participants (mean duration of diagnosed type 2 diabetes, 7.8 months), 319 (45.6%) reached the primary outcome over an average follow-up of 3.86 years. Rates of failure were 51.7% (120 of 232 participants), 38.6% (90 of 233), and 46.6% (109 of 234) for metformin alone, metformin plus rosiglitazone, and metformin plus lifestyle intervention, respectively. Metformin plus rosiglitazone was superior to metformin alone (P=0.006); metformin plus lifestyle intervention was intermediate but not significantly different from metformin alone or metformin plus rosiglitazone. Prespecified analyses according to sex and race or ethnic group showed differences in sustained effectiveness, with metformin alone least effective in non-Hispanic black participants and metformin plus rosiglitazone most effective in girls. Serious adverse events were reported in 19.2% of participants. Conclusions Monotherapy with metformin was associated with durable glycemic control in approximately half of children and adolescents with type 2 diabetes. The addition of rosiglitazone, but not an intensive lifestyle intervention, was superior to metformin alone. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; TODAY ClinicalTrials.gov number, NCT00081328.).
731 citations
TL;DR: In this article, a model involving three distinct elements of alertness, namely scanning and search, association and connection, and evaluation and judgment, is proposed to recognize and develop new opportunities at the heart of entrepreneurship.
666 citations
TL;DR: Neuropilin-1 is identified as a surface marker to distinguish different Foxp3+ T reg cell subsets under homeostatic conditions.
Abstract: Foxp3+ CD4+ T helper cells called regulatory T (T reg) cells play a key role in controlling reactivity to self-antigens and onset of autoimmunity. T reg cells either arise in thymus and are called natural T reg (nT reg) cells or are generated in the periphery through induction of Foxp3 and are called inducible T reg (iT reg) cells. The relative contributions of iT reg cells and nT reg cells in peripheral tolerance remain unclear as a result of an inability to separate these two subsets of T reg cells. Using a combination of novel TCR transgenic mice with a defined self-antigen specificity and conventional mouse models, we demonstrate that a cell surface molecule, neuropilin-1 (Nrp-1), is expressed at high levels on nT reg cells and can be used to separate nT reg versus iT reg cells in certain physiological settings. In addition, iT reg cells generated through antigen delivery or converted under homeostatic conditions lack Nrp-1 expression. Nrp-1lo iT reg cells show similar suppressive activity to nT reg cells in controlling ongoing autoimmune responses under homeostatic conditions. In contrast, their activity might be compromised in certain lymphopenic settings. Collectively, our data show that Nrp-1 provides an excellent marker to distinguish distinct T reg subsets and will be useful in studying the role of nT reg versus iT reg cells in different disease settings.
599 citations
Yale University1, Harvard University2, Laval University3, University of Queensland4, University of Helsinki5, American University of Beirut6, Rutgers University7, University of Cambridge8, Roger Williams Medical Center9, Alfred Hospital10, University of Iowa11, Medical College of Wisconsin12, University of California, Los Angeles13, NHS Greater Glasgow and Clyde14, Baxter International15, University of Pittsburgh16, Johns Hopkins University17, Saint Louis University18, Vanderbilt University19, University of Utah20, University of Alberta21, University College London22, University of Manchester23, Children's National Medical Center24, Duke University25, University of Texas Health Science Center at San Antonio26, Columbia University27, Yeshiva University28
TL;DR: The utility of exome sequencing in disease gene identification despite the combined complexities of locus heterogeneity, mixed models of transmission and frequent de novo mutation is demonstrated, and a fundamental role for KLHL3 and CUL3 in blood pressure, K+ and pH homeostasis is established.
Abstract: Hypertension affects one billion people and is a principal reversible risk factor for cardiovascular disease. Pseudohypoaldosteronism type II (PHAII), a rare Mendelian syndrome featuring hypertension, hyperkalaemia and metabolic acidosis, has revealed previously unrecognized physiology orchestrating the balance between renal salt reabsorption and K(+) and H(+) excretion. Here we used exome sequencing to identify mutations in kelch-like 3 (KLHL3) or cullin 3 (CUL3) in PHAII patients from 41 unrelated families. KLHL3 mutations are either recessive or dominant, whereas CUL3 mutations are dominant and predominantly de novo. CUL3 and BTB-domain-containing kelch proteins such as KLHL3 are components of cullin-RING E3 ligase complexes that ubiquitinate substrates bound to kelch propeller domains. Dominant KLHL3 mutations are clustered in short segments within the kelch propeller and BTB domains implicated in substrate and cullin binding, respectively. Diverse CUL3 mutations all result in skipping of exon 9, producing an in-frame deletion. Because dominant KLHL3 and CUL3 mutations both phenocopy recessive loss-of-function KLHL3 mutations, they may abrogate ubiquitination of KLHL3 substrates. Disease features are reversed by thiazide diuretics, which inhibit the Na-Cl cotransporter in the distal nephron of the kidney; KLHL3 and CUL3 are expressed in this location, suggesting a mechanistic link between KLHL3 and CUL3 mutations, increased Na-Cl reabsorption, and disease pathogenesis. These findings demonstrate the utility of exome sequencing in disease gene identification despite the combined complexities of locus heterogeneity, mixed models of transmission and frequent de novo mutation, and establish a fundamental role for KLHL3 and CUL3 in blood pressure, K(+) and pH homeostasis.
556 citations
02 Jul 2012
TL;DR: Deliberative systems as mentioned in this paper is an approach to ensure that a division of deliberative labour in a system nonetheless meets both deliberative and democratic norms, and examine the problems of implementation in a real world of competing norms, competing institutions and competing powerful interests.
Abstract: 'Deliberative democracy' is often dismissed as a set of small-scale, academic experiments. This volume seeks to demonstrate how the deliberative ideal can work as a theory of democracy on a larger scale. It provides a new way of thinking about democratic engagement across the spectrum of political action, from towns and villages to nation states, and from local networks to transnational, even global systems. Written by a team of the world's leading deliberative theorists, Deliberative Systems explains the principles of this new approach, which seeks ways of ensuring that a division of deliberative labour in a system nonetheless meets both deliberative and democratic norms. Rather than simply elaborating the theory, the contributors examine the problems of implementation in a real world of competing norms, competing institutions and competing powerful interests. This pioneering book will inspire an exciting new phase of deliberative research, both theoretical and empirical.
TL;DR: How the body absorbs, uses, and loses iron is reviewed and both common and unusual causes of iron overload and treatment of the resulting disorders are explored.
Abstract: Iron is both essential and toxic. The authors review how the body absorbs, uses, and loses iron and explore both common and unusual causes of iron overload and treatment of the resulting disorders.
TL;DR: In a study population that was representative of the general population of HSV-1- and HSv-2-seronegative women, the investigational vaccine was effective in preventing HSV -1 genital disease and infection but not in preventingHSV-2 disease or infection.
Abstract: The HSV vaccine was associated with an increased risk of local reactions as compared with the control vaccine, and it elicited ELISA and neutralizing antibodies to HSV-2. Overall, the vaccine was not efficacious; vaccine efficacy was 20% (95% confidence interval [CI], −29 to 50) against genital herpes disease. However, efficacy against HSV-1 genital disease was 58% (95% CI, 12 to 80). Vaccine efficacy against HSV-1 infection (with or without disease) was 35% (95% CI, 13 to 52), but efficacy against HSV-2 infection was not observed (−8%; 95% CI, −59 to 26). Conclusions In a study population that was representative of the general population of HSV-1– and HSV-2–seronegative women, the investigational vaccine was effective in pre venting HSV-1 genital disease and infection but not in preventing HSV-2 disease or infection. (Funded by the National Institute of Allergy and Infectious Diseases and GlaxoSmithKline; ClinicalTrials.gov number, NCT00057330.)
TL;DR: Resistance to insulin action within the CNS is associated with peripheral insulin resistance, but it is possible that variable hormonal resistance syndromes exist so that resistance at one tissue bed may be independent of that at others.
TL;DR: It is concluded that SF is useful to identify NAFLD patients at risk for NASH and advanced fibrosis and is an independent predictor of advanced hepatic fibrosis among patients withNAFLD.
TL;DR: The term severe asthma associated with fungal sensitization (SAFS) has been coined to illustrate the high rate of fungal sensitivity in patients with persistent severe asthma and improvement with antifungal treatment.
Abstract: Asthma is a common disorder that in 2009 afflicted 8.2% of adults and children, 24.6 million persons, in the United States. In patients with moderate and severe persistent asthma, there is significantly increased morbidity, use of health care support, and health care costs. Epidemiologic studies in the United States and Europe have associated mold sensitivity, particularly to Alternaria alternata and Cladosporium herbarum, with the development, persistence, and severity of asthma. In addition, sensitivity to Aspergillus fumigatus has been associated with severe persistent asthma in adults. Allergic bronchopulmonary aspergillosis (ABPA) is caused by A fumigatus and is characterized by exacerbations of asthma, recurrent transient chest radiographic infiltrates, coughing up thick mucus plugs, peripheral and pulmonary eosinophilia, and increased total serum IgE and fungus-specific IgE levels, especially during exacerbation. The airways appear to be chronically or intermittently colonized by A fumigatus in patients with ABPA. ABPA is the most common form of allergic bronchopulmonary mycosis (ABPM); other fungi, including Candida, Penicillium, and Curvularia species, are implicated. The characteristics of ABPM include severe asthma, eosinophilia, markedly increased total IgE and specific IgE levels, bronchiectasis, and mold colonization of the airways. The term severe asthma associated with fungal sensitization (SAFS) has been coined to illustrate the high rate of fungal sensitivity in patients with persistent severe asthma and improvement with antifungal treatment. The immunopathology of ABPA, ABPM, and SAFS is incompletely understood. Genetic risks identified in patients with ABPA include HLA association and certain T(H)2-prominent and cystic fibrosis variants, but these have not been studied in patients with ABPM and SAFS. Oral corticosteroid and antifungal therapies appear to be partially successful in patients with ABPA. However, the role of antifungal and immunomodulating therapies in patients with ABPA, ABPM, and SAFS requires additional larger studies.
TL;DR: This survey provides important insights into behavior and attitudes among current and former statin users and the results suggest that more effective dialogue between healthcare providers and patients may increase persistence of statin use, particularly when the patient has concerns about side effects and drug costs.
University of Bedfordshire1, Saint Louis University2, University of Naples Federico II3, Cardiff University4, Bethesda Hospital5, Geneva College6, The Chinese University of Hong Kong7, University of Adelaide8, Deakin University9, University of British Columbia10, Sheba Medical Center11, University of Vienna12, Stanford University13
TL;DR: A collaborative Expert Group of the IAGG and EDWPOP and an International Task Force have explored the key issues that affect diabetes in older people using a robust method comprising a Delphi process and an evidence-based review of the literature.
TL;DR: This review discusses how alterations in the amount, assembly, organization, or chemical properties of the elastic fibers affect arterial stiffness and blood pressure and Therapies that have a direct effect on arterIAL stiffness through alterations to the elastic fiber in the wall may be an effective treatment for essential hypertension.
Abstract: Large artery stiffness, as measured by pulse wave velocity, is correlated with high blood pressure and may be a causative factor in essential hypertension. The extracellular matrix components, specifically the mix of elastin and collagen in the vessel wall, determine the passive mechanical properties of the large arteries. Elastin is organized into elastic fibers in the wall during arterial development in a complex process that requires spatial and temporal coordination of numerous proteins. The elastic fibers last the lifetime of the organism but are subject to proteolytic degradation and chemical alterations that change their mechanical properties. This review discusses how alterations in the amount, assembly, organization, or chemical properties of the elastic fibers affect arterial stiffness and blood pressure. Strategies for encouraging or reversing alterations to the elastic fibers are addressed. Methods for determining the efficacy of these strategies, by measuring elastin amounts and arterial stiffness, are summarized. Therapies that have a direct effect on arterial stiffness through alterations to the elastic fibers in the wall may be an effective treatment for essential hypertension.
TL;DR: This review describes most successful mitochondrially-targeted redox-active compounds, Mn porphyrins and MitoQ(10) in detail, and briefly addresses several other compounds that are either catalysts of O(2)(-) dismutation, or its non-catalytic scavengers, and that reportedly attenuate mitochondrial dysfunction.
TL;DR: Three simple bedside tools based on frailty phenotypes with a Frailty Index using the multiple deficit approach in the prediction of mortality and physical limitation after 4 years are compared.
Abstract: Objectives: To compare three simple bedside tools based on frailty phenotypes with a Frailty Index using the multiple deficit approach in the prediction of mortality and physical limitation after 4 years.
Design: Cohort study.
Setting: Hong Kong, China.
Pariticipants: Four thousand men and women aged 65 and older living in the community who were ambulatory enough to attend the study center.
Methods: Interviewers obtained information regarding physical, psychological, and functional health; body mass index (BMI), grip strength, blood pressure, and ankle brachial index were determined. Three clinical frailty scales based on the Fried phenotype (Cardiovascular Health Study (CHS); Fatigue, Resistance, Ambulation, Illness, and Loss (FRAIL); and Hubbard) and a frailty index (FI) were constructed from these variables, and their ability to predict incident mortality and physical function limitations was compared using receiver operating characteristic (ROC) curves.
Results: All tools predicted adverse outcomes. More participants were categorized into frail and prefrail categories using the CHS than with the other two clinical scales. For all frailty measures, with increasing levels of frailty, the sensitivity fell and the specificity increased to greater than 90%; the area under the ROC curve values were approximately 0.6.
Conclusion: Simple frailty scores are comparable with a multidimensional deficit accumulation FI in predicting mortality and physical limitations. The newer FRAIL, proposed for use in a clinical setting, is comparable with other existing short screening tools, as well as tools based on the multiple-deficits model used for research settings. Addition of a physical performance measure to screening tools may increase predictive accuracy.
TL;DR: This review will address the impact that the anatomic substrate has on the perioperative management of Tetralogy of Fallot, the most common form of cyanotic congenital heart disease.
Abstract: Tetralogy of Fallot is the most common form of cyanotic congenital heart disease. In this condition, episodic worsening of hypoxemia results from dynamic shifts in physiology, so-called "Tet spells." The relative frequency of this lesion and the risks of exacerbating "Tet spells" make anesthetic management of this patient population challenging. The conduct of palliative and reparative cardiac surgery is determined in large part by the anatomic variations within the spectrum of this disorder, most notably the severity of right ventricular outflow tract obstruction. This review will address the impact that the anatomic substrate has on the perioperative management of this interesting patient population.
David C. Whitcomb1, Jessica LaRusch1, Alyssa M. Krasinskas1, Lambertus Klei1 +198 more•Institutions (46)
TL;DR: Two associations at genome-wide significance identified and replicated at PRSS1-PRSS2 and X-linked CLDN2 are reported and could partially explain the high frequency of alcohol-related pancreatitis in men.
Abstract: Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR and SPINK1 variants were associated with pancreatitis risk. We now report two associations at genome-wide significance identified and replicated at PRSS1-PRSS2 (P < 1 × 10(-12)) and X-linked CLDN2 (P < 1 × 10(-21)) through a two-stage genome-wide study (stage 1: 676 cases and 4,507 controls; stage 2: 910 cases and 4,170 controls). The PRSS1 variant likely affects disease susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele is associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous (or hemizygous in males) CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men (male hemizygote frequency is 0.26, whereas female homozygote frequency is 0.07).
TL;DR: The authors found that overconfident managers will tend to delay loss recognition and generally use less conservative accounting, and they further found that external monitoring does not appear to mitigate this effect, which supports the findings in Schrand and Zechman [2011] that overconfidence affects financial reporting behavior.
Abstract: Overconfident managers overestimate future returns from their firms’ investments. Thus, we predict that overconfident managers will tend to delay loss recognition and generally use less conservative accounting. Furthermore, we test whether external monitoring helps to mitigate this effect. Using measures of both conditional and unconditional conservatism respectively, we find robust evidence of a negative relation between CEO overconfidence and accounting conservatism. We further find that external monitoring does not appear to mitigate this effect. Our findings add to the growing literature on overconfidence and complement the findings in Schrand and Zechman [2011] that overconfidence affects financial reporting behavior.
TL;DR: It is shown that conformational selection is associated with a rich repertoire of kinetic properties, with k(obs) decreasing or increasing with [L] depending on the relative magnitude of the rate of ligand dissociation, k(off), and the rates of conformational isomerization, r.
Abstract: For almost five decades, two competing mechanisms of ligand recognition, conformational selection and induced fit, have dominated our interpretation of ligand binding in biological macromolecules. ...
TL;DR: Body-worn motion sensors detected mobility differences between MS and healthy controls when traditional timed tests could not, and may prove a useful outcome measure for early mobility changes in MS.
TL;DR: It is shown that purified polyclonal MAIT cells potently inhibit intracellular bacterial growth of Mycobacterium bovis BCG in macrophages in coculture assays, and this inhibitory activity was dependent upon MAIT cell selection by MR1, secretion of gamma interferon (IFN-γ), and an innate interleukin 12 (IL-12) signal from infected MΦ.
Abstract: Mucosa-associated invariant T (MAIT) cells are a unique population of αβ T cells in mammals that reside preferentially in mucosal tissues and express an invariant Vα paired with limited Vβ T-cell receptor (TCR) chains. Furthermore, MAIT cell development is dependent upon the expression of the evolutionarily conserved major histocompatibility complex (MHC) class Ib molecule MR1. Using in vitro assays, recent studies have shown that mouse and human MAIT cells are activated by antigen-presenting cells (APCs) infected with diverse microbes, including numerous bacterial strains and yeasts, but not viral pathogens. However, whether MAIT cells play an important, and perhaps unique, role in controlling microbial infection has remained unclear. To probe MAIT cell function, we show here that purified polyclonal MAIT cells potently inhibit intracellular bacterial growth of Mycobacterium bovis BCG in macrophages (MΦ) in coculture assays, and this inhibitory activity was dependent upon MAIT cell selection by MR1, secretion of gamma interferon (IFN-γ), and an innate interleukin 12 (IL-12) signal from infected MΦ. Surprisingly, however, the cognate recognition of MR1 by MAIT cells on the infected MΦ was found to play only a minor role in MAIT cell effector function. We also report that MAIT cell-deficient mice had higher bacterial loads at early times after infection compared to wild-type (WT) mice, demonstrating that MAIT cells play a unique role among innate lymphocytes in protective immunity against bacterial infection.
TL;DR: In this paper, the authors investigate lead-lag relationships among country stock returns and identify a leading role for the United States: lagged U.S. returns significantly predict returns in numerous non-U.S industrialized countries (after controlling for national economic variables and countries' own lagged returns).
Abstract: We investigate lead-lag relationships among country stock returns and identify a leading role for the United States: lagged U.S. returns significantly predict returns in numerous non-U.S. industrialized countries (after controlling for national economic variables and countries' own lagged returns), while lagged non-U.S. returns display little predictive ability with respect to U.S. returns. The predictive power of lagged U.S. returns is robust across a number of dimensions, including out-of-sample tests. Information frictions seem a ready explanation of the predictive power of lagged U.S. returns; indeed, structural estimation of a news-diffusion model indicates that return shocks emanating in the United States are only fully reflected in equity prices outside of the United States with a lag. Overall, our results indicate that predictive regressions for non-U.S. countries should be augmented with lagged U.S. returns to capture an important source of international return predictability.
TL;DR: In a large, well-characterized population with biopsy-proven NAFLD, modest alcohol consumption was associated with lesser degree of severity as determined by lower odds of the key features that comprise a diagnosis of steatohepatitis, as well as fibrosis.
TL;DR: In conclusion, at 3 years after transplantation, immunosuppression with belatacept resulted in similar patient survival, graft survival and acute rejection, with better renal function compared with cyclosporine.