Showing papers by "University of Lausanne published in 2009"
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.
3,016 citations
TL;DR: Although resting state functional connectivity is variable and is frequently present between regions without direct structural linkage, its strength, persistence, and spatial statistics are nevertheless constrained by the large-scale anatomical structure of the human cerebral cortex.
Abstract: In the cerebral cortex, the activity levels of neuronal populations are continuously fluctuating. When neuronal activity, as measured using functional MRI (fMRI), is temporally coherent across 2 populations, those populations are said to be functionally connected. Functional connectivity has previously been shown to correlate with structural (anatomical) connectivity patterns at an aggregate level. In the present study we investigate, with the aid of computational modeling, whether systems-level properties of functional networks—including their spatial statistics and their persistence across time—can be accounted for by properties of the underlying anatomical network. We measured resting state functional connectivity (using fMRI) and structural connectivity (using diffusion spectrum imaging tractography) in the same individuals at high resolution. Structural connectivity then provided the couplings for a model of macroscopic cortical dynamics. In both model and data, we observed (i) that strong functional connections commonly exist between regions with no direct structural connection, rendering the inference of structural connectivity from functional connectivity impractical; (ii) that indirect connections and interregional distance accounted for some of the variance in functional connectivity that was unexplained by direct structural connectivity; and (iii) that resting-state functional connectivity exhibits variability within and across both scanning sessions and model runs. These empirical and modeling results demonstrate that although resting state functional connectivity is variable and is frequently present between regions without direct structural linkage, its strength, persistence, and spatial statistics are nevertheless constrained by the large-scale anatomical structure of the human cerebral cortex.
2,771 citations
TL;DR: The most important new developments in STRING 8 over previous releases include a URL-based programming interface, improved interaction prediction via genomic neighborhood in prokaryotes, and the inclusion of protein structures.
Abstract: Functional partnerships between proteins are at the core of complex cellular phenotypes, and the networks formed by interacting proteins provide researchers with crucial scaffolds for modeling, data reduction and annotation. STRING is a database and web resource dedicated to protein–protein interactions, including both physical and functional interactions. It weights and integrates information from numerous sources, including experimental repositories, computational prediction methods and public text collections, thus acting as a metadatabase that maps all interaction evidence onto a common set of genomes and proteins. The most important new developments in STRING 8 over previous releases include a URL-based programming interface, which can be used to query STRING from other resources, improved interaction prediction via genomic neighborhood in prokaryotes, and the inclusion of protein structures. Version 8.0 of STRING covers about 2.5 million proteins from 630 organisms, providing the most comprehensive view on protein–protein interactions currently available. STRING can be reached at http://string-db.org/.
2,394 citations
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, 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 role of NLRs, and in particular the inflammasomes, in the recognition of microbial and danger components and the role they play in health and disease are discussed.
Abstract: The innate immune system relies on its capacity to rapidly detect invading pathogenic microbes as foreign and to eliminate them. The discovery of Toll-like receptors (TLRs) provided a class of membrane receptors that sense extracellular microbes and trigger antipathogen signaling cascades. More recently, intracellular microbial sensors have been identified, including NOD-like receptors (NLRs). Some of the NLRs also sense nonmicrobial danger signals and form large cytoplasmic complexes called inflammasomes that link the sensing of microbial products and metabolic stress to the proteolytic activation of the proinflammatory cytokines IL-1β and IL-18. The NALP3 inflammasome has been associated with several autoinflammatory conditions including gout. Likewise, the NALP3 inflammasome is a crucial element in the adjuvant effect of aluminum and can direct a humoral adaptive immune response. In this review, we discuss the role of NLRs, and in particular the inflammasomes, in the recognition of microbial and danger components and the role they play in health and disease.
2,217 citations
TL;DR: It is shown that bona fide undifferentiated monocytes reside in the spleen and outnumber their equivalents in circulation and identifies splenic monocytes as a resource that the body exploits to regulate inflammation.
Abstract: A current paradigm states that monocytes circulate freely and patrol blood vessels but differentiate irreversibly into dendritic cells (DCs) or macrophages upon tissue entry. Here we show that bona fide undifferentiated monocytes reside in the spleen and outnumber their equivalents in circulation. The reservoir monocytes assemble in clusters in the cords of the subcapsular red pulp and are distinct from macrophages and DCs. In response to ischemic myocardial injury, splenic monocytes increase their motility, exit the spleen en masse, accumulate in injured tissue, and participate in wound healing. These observations uncover a role for the spleen as a site for storage and rapid deployment of monocytes and identify splenic monocytes as a resource that the body exploits to regulate inflammation.
1,946 citations
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.
1,710 citations
TL;DR: It is shown that dying tumor cells release ATP, which then acts on P2X7 purinergic receptors from DCs and triggers the NOD-like receptor family, pyrin domain containing-3 protein (NLRP3)-dependent caspase-1 activation complex ('inflammasome'), allowing for the secretion of interleukin-1 β (IL-1β).
Abstract: The therapeutic efficacy of anticancer chemotherapies may depend on dendritic cells (DCs), which present antigens from dying cancer cells to prime tumor-specific interferon-gamma (IFN-gamma)-producing T lymphocytes. Here we show that dying tumor cells release ATP, which then acts on P2X(7) purinergic receptors from DCs and triggers the NOD-like receptor family, pyrin domain containing-3 protein (NLRP3)-dependent caspase-1 activation complex ('inflammasome'), allowing for the secretion of interleukin-1beta (IL-1beta). The priming of IFN-gamma-producing CD8+ T cells by dying tumor cells fails in the absence of a functional IL-1 receptor 1 and in Nlpr3-deficient (Nlrp3(-/-)) or caspase-1-deficient (Casp-1(-/-)) mice unless exogenous IL-1beta is provided. Accordingly, anticancer chemotherapy turned out to be inefficient against tumors established in purinergic receptor P2rx7(-/-) or Nlrp3(-/-) or Casp1(-/-) hosts. Anthracycline-treated individuals with breast cancer carrying a loss-of-function allele of P2RX7 developed metastatic disease more rapidly than individuals bearing the normal allele. These results indicate that the NLRP3 inflammasome links the innate and adaptive immune responses against dying tumor cells.
1,628 citations
TL;DR: In this article, a life-designing model for career intervention endorses five presuppositions about people and their work lives: contextual possibilities, dynamic processes, non-linear progression, multiple perspectives, and personal patterns.
1,428 citations
Christopher Newton-Cheh1, Christopher Newton-Cheh2, Toby Johnson3, Toby Johnson4 +359 more•Institutions (64)
TL;DR: In this paper, the association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 × 10(-24)), CYP1A2(P = 1 × 10-23), FGF5 (P=1 × 10 -21), SH2B3(P= 3 × 10−18), MTHFR(MTHFR), c10orf107(P), ZNF652(ZNF652), PLCD3 (P,P = 5 × 10 −9),
Abstract: Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N ≤ 71,225 European ancestry, N ≤ 12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N = 29,136). We identified association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 × 10(-24)), CYP1A2 (P = 1 × 10(-23)), FGF5 (P = 1 × 10(-21)), SH2B3 (P = 3 × 10(-18)), MTHFR (P = 2 × 10(-13)), c10orf107 (P = 1 × 10(-9)), ZNF652 (P = 5 × 10(-9)) and PLCD3 (P = 1 × 10(-8)) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease.
1,205 citations
TL;DR: It is shown that in response to treatment of mice with interferon-α (IFNα), HSCs efficiently exit G0 and enter an active cell cycle, raising the possibility for new applications of type I interferons to target cancer stem cells.
Abstract: Maintenance of the blood system is dependent on dormant haematopoietic stem cells (HSCs) with long-term self-renewal capacity. After injury these cells are induced to proliferate to quickly re-establish homeostasis. The signalling molecules promoting the exit of HSCs out of the dormant stage remain largely unknown. Here we show that in response to treatment of mice with interferon-alpha (IFNalpha), HSCs efficiently exit G(0) and enter an active cell cycle. HSCs respond to IFNalpha treatment by the increased phosphorylation of STAT1 and PKB/Akt (also known as AKT1), the expression of IFNalpha target genes, and the upregulation of stem cell antigen-1 (Sca-1, also known as LY6A). HSCs lacking the IFNalpha/beta receptor (IFNAR), STAT1 (ref. 3) or Sca-1 (ref. 4) are insensitive to IFNalpha stimulation, demonstrating that STAT1 and Sca-1 mediate IFNalpha-induced HSC proliferation. Although dormant HSCs are resistant to the anti-proliferative chemotherapeutic agent 5-fluoro-uracil, HSCs pre-treated (primed) with IFNalpha and thus induced to proliferate are efficiently eliminated by 5-fluoro-uracil exposure in vivo. Conversely, HSCs chronically activated by IFNalpha are functionally compromised and are rapidly out-competed by non-activatable Ifnar(-/-) cells in competitive repopulation assays. Whereas chronic activation of the IFNalpha pathway in HSCs impairs their function, acute IFNalpha treatment promotes the proliferation of dormant HSCs in vivo. These data may help to clarify the so far unexplained clinical effects of IFNalpha on leukaemic cells, and raise the possibility for new applications of type I interferons to target cancer stem cells.
Christine G. Elsik1, Christine G. Elsik2, Christine G. Elsik3, Ross L. Tellam3 +325 more•Institutions (65)
TL;DR: To understand the biology and evolution of ruminants, the cattle genome was sequenced to about sevenfold coverage and provides a resource for understanding mammalian evolution and accelerating livestock genetic improvement for milk and meat production.
Abstract: To understand the biology and evolution of ruminants, the cattle genome was sequenced to about sevenfold coverage. The cattle genome contains a minimum of 22,000 genes, with a core set of 14,345 orthologs shared among seven mammalian species of which 1217 are absent or undetected in noneutherian (marsupial or monotreme) genomes. Cattle-specific evolutionary breakpoint regions in chromosomes have a higher density of segmental duplications, enrichment of repetitive elements, and species-specific variations in genes associated with lactation and immune responsiveness. Genes involved in metabolism are generally highly conserved, although five metabolic genes are deleted or extensively diverged from their human orthologs. The cattle genome sequence thus provides a resource for understanding mammalian evolution and accelerating livestock genetic improvement for milk and meat production.
University of Milano-Bicocca1, University of Paris2, University of Brescia3, University of Bologna4, University of Lausanne5, Queen Mary University of London6, Ghent University7, University of Barcelona8, University of Glasgow9, Istanbul University10, Katholieke Universiteit Leuven11, Hannover Medical School12, University of Manchester13, University of Oslo14, Joseph Fourier University15, Gdańsk Medical University16, University of Copenhagen17, University of Münster18, University of Valencia19, Complutense University of Madrid20, University of Erlangen-Nuremberg21, Maastricht University22, University of Amsterdam23, University of Milan24
TL;DR: The objective of this study was to establish a baseline for the design of a systematic literature review of this type of treatment for high blood pressure using a simple, straightforward, and scalable procedure.
Abstract: Abbreviations ACE: angiotensin-converting enzyme; BP: blood pressure; DBP: diastolic blood pressure; eGFR: estimated glomerular filtration rate; ESC: European Society of Cardiology; ESH: European Society of Hypertension; ET: endothelin; IMT: carotid intima-media thickness; JNC: Joint National Commit
University of Geneva1, Howard Hughes Medical Institute2, Max Planck Society3, University of California, Los Angeles4, University of Lausanne5, Imperial College London6, University College London7, École Polytechnique Fédérale de Lausanne8, Picower Institute for Learning and Memory9, Janelia Farm Research Campus10, University of California, San Francisco11
TL;DR: A chronic cranial window is described to obtain optical access to the mouse cerebral cortex for long-term imaging and the entire dendritic and axonal arbor of individual neurons can be reconstructed.
Abstract: To understand the cellular and circuit mechanisms of experience-dependent plasticity, neurons and their synapses need to be studied in the intact brain over extended periods of time. Two-photon excitation laser scanning microscopy (2PLSM), together with expression of fluorescent proteins, enables high-resolution imaging of neuronal structure in vivo. In this protocol we describe a chronic cranial window to obtain optical access to the mouse cerebral cortex for long-term imaging. A small bone flap is replaced with a coverglass, which is permanently sealed in place with dental acrylic, providing a clear imaging window with a large field of view (approximately 0.8-12 mm(2)). The surgical procedure can be completed within approximately 1 h. The preparation allows imaging over time periods of months with arbitrary imaging intervals. The large size of the imaging window facilitates imaging of ongoing structural plasticity of small neuronal structures in mice, with low densities of labeled neurons. The entire dendritic and axonal arbor of individual neurons can be reconstructed.
International Agency for Research on Cancer1, Catholic University of the Sacred Heart2, Fred Hutchinson Cancer Research Center3, Universidade Federal do Rio Grande do Sul4, University of São Paulo5, National Institutes of Health6, Harvard University7, Brown University8, Oswaldo Cruz Foundation9, University of Milan10, Pennsylvania State University11, University of Lausanne12, University of Buenos Aires13, Universidade Federal de Pelotas14, Boston University15, University of North Carolina at Chapel Hill16, University of Iowa17, University of Texas MD Anderson Cancer Center18, Nofer Institute of Occupational Medicine19, Russian Academy20, Medical University of Warsaw21, University of California, Los Angeles22
TL;DR: It is confirmed that the joint effect between tobacco and alcohol use is greater than multiplicative on head and neck cancer risk, however, a substantial proportion of head and head cancers cannot be attributed to tobacco or alcohol use, particularly for oral cavity cancer and for head andneck cancer among women and among young-onset cases.
Abstract: Background: The magnitude of risk conferred by the interaction between tobacco and alcohol use on the risk of head and neck cancers is not clear because studies have used various methods to quantify the excess head and neck cancer burden. Methods: We analyzed individual-level pooled data from 17 European and American case-control studies (11,221 cases and 16,168 controls) participating in the International Head and Neck Cancer Epidemiology consortium. We estimated the multiplicative interaction parameter ( ψ ) and population attributable risks (PAR). Results: A greater than multiplicative joint effect between ever tobacco and alcohol use was observed for head and neck cancer risk ( ψ = 2.15; 95% confidence interval, 1.53-3.04). The PAR for tobacco or alcohol was 72% (95% confidence interval, 61-79%) for head and neck cancer, of which 4% was due to alcohol alone, 33% was due to tobacco alone, and 35% was due to tobacco and alcohol combined. The total PAR differed by subsite (64% for oral cavity cancer, 72% for pharyngeal cancer, 89% for laryngeal cancer), by sex (74% for men, 57% for women), by age (33% for cases 60 years), and by region (84% in Europe, 51% in North America, 83% in Latin America). Conclusions: Our results confirm that the joint effect between tobacco and alcohol use is greater than multiplicative on head and neck cancer risk. However, a substantial proportion of head and neck cancers cannot be attributed to tobacco or alcohol use, particularly for oral cavity cancer and for head and neck cancer among women and among young-onset cases. (Cancer Epidemiol Biomarkers Prev 2009;18(2):541–50)
TL;DR: The results demonstrate the molecular basis for IL-1β production after fungal infection and identify a crucial function for the Nlrp3 inflammasome in mammalian host defence in vivo.
Abstract: Immunocompromised individuals are at high risk from fungal infection, yet the molecular mechanisms that govern host defence against fungi are not well understood. Gross et al. now show that Candida albicans infection in mice activates the NALP3 inflammasome via a mechanism involving Sky-induced production of reactive oxygen induced by the tyrosine kinase Syk.
TL;DR: A higher prevalence of frailty in southern countries is consistent with previous findings of a north-south gradient for other health indicators in SHARE, and the data suggest that socioeconomic factors like education contribute to these differences in frailty and prefrailty.
Abstract: MOST industrialized countries will need to adapt their health care systems to meet the challenges arising from population aging. This will require meaningful estimates of population health from epidemiological surveys. Functional impairments in the oldest age group have been discussed with regard to current and projected long-term care needs; however, this limits the view of the future needs of aging populations. In Europe, the large cohort of post–World War II baby boomers will reach retirement age over the next two decades. And although preventing an unfavorable evolution toward loss of autonomy in this generation is a public health priority, little is known regarding the proportion at risk for functional decline in middle age and beyond. Health indicators based on selected chronic conditions or unhealthy behaviors are difficult to interpret because multiple combinations of degenerative diseases result in considerable heterogeneity in the risk for functional loss and health care needs.
Thus, the geriatric concept of frailty (1–3) is of particular interest because frailty is likely to be a precursor of disability (4–6) and may be reversible in its early stages (7). The prevalence of frailty might summarize health and the needs for prevention in middle-aged and older populations (8,9). A major impediment to measuring frailty in population-based surveys is the lack of an operational definition. However, Fried and colleagues (4,10) identified a frailty phenotype that was predictive of adverse outcomes such as falls and fractures (11,12), mobility and functional declines (4,5,12), hospitalizations (4), nursing home admissions (5), and death (4–6,11–13). The prevalence of this phenotype has mainly been estimated for Northern America and scant data are available for Europe (14,15). The population of European countries could experience different levels of frailty due to cultural, regional, or political distinctions.
The purposes of this study were to quantify the prevalence of frailty in community-dwelling middle-aged and older Europeans participating in the Survey of Health, Aging and Retirement in Europe (SHARE) in 2004, compare this prevalence among the 10 countries included in this survey, and evaluate selected population characteristics as potential explanations for international differences observed in the 65 years and older (65+) subgroup.
TL;DR: Genomic islands play a crucial role in the evolution of a broad spectrum of bacteria as they are involved in the dissemination of variable genes, including antibiotic resistance and virulence genes leading to generation of hospital ‘superbugs’, as well as catabolic genes lead to formation of new metabolic pathways.
Abstract: Bacterial genomes evolve through mutations, rearrangements or horizontal gene transfer. Besides the core genes encoding essential metabolic functions, bacterial genomes also harbour a number of accessory genes acquired by horizontal gene transfer that might be beneficial under certain environmental conditions. The horizontal gene transfer contributes to the diversification and adaptation of microorganisms, thus having an impact on the genome plasticity. A significant part of the horizontal gene transfer is or has been facilitated by genomic islands (GEIs). GEIs are discrete DNA segments, some of which are mobile and others which are not, or are no longer mobile, which differ among closely related strains. A number of GEIs are capable of integration into the chromosome of the host, excision, and transfer to a new host by transformation, conjugation or transduction. GEIs play a crucial role in the evolution of a broad spectrum of bacteria as they are involved in the dissemination of variable genes, including antibiotic resistance and virulence genes leading to generation of hospital 'superbugs', as well as catabolic genes leading to formation of new metabolic pathways. Depending on the composition of gene modules, the same type of GEIs can promote survival of pathogenic as well as environmental bacteria.
TL;DR: The data suggest that gut homeostasis is maintained through a balance between cell damage due to the collateral effects of bacteria killing and epithelial repair by stem cell division, and this study should prove to be a useful resource for such further studies.
Wellcome Trust Centre for Human Genetics1, Medical Research Council2, Broad Institute3, Harvard University4, Wellcome Trust Sanger Institute5, King's College London6, deCODE genetics7, Boston University8, University of Michigan9, Erasmus University Rotterdam10, National Institutes of Health11, VU University Amsterdam12, University of Oulu13, Lund University14, University of Virginia15, University Hospital of Lausanne16, University of Lausanne17, University of Southern California18, Imperial College London19, Ninewells Hospital20, University of California, Los Angeles21, University of Düsseldorf22, Novartis23, Swiss Institute of Bioinformatics24, European Bioinformatics Institute25, University of Eastern Finland26, GlaxoSmithKline27, University of North Carolina at Chapel Hill28, Oulu University Hospital29, University Medical Center Groningen30, University of Helsinki31, Ludwig Maximilian University of Munich32, University of Cambridge33, VU University Medical Center34, Leiden University Medical Center35, Brigham and Women's Hospital36, Massachusetts Institute of Technology37, University of Iceland38, University of Oxford39
TL;DR: Variants in the gene encoding melatonin receptor 1B (MTNR1B) were consistently associated with fasting glucose across all ten genome-wide association scans, and previous associations of fasting glucose with variants at the G6PC2 and GCK loci are confirmed.
Abstract: To identify previously unknown genetic loci associated with fasting glucose concentrations, we examined the leading association signals in ten genome-wide association scans involving a total of 36,610 individuals of European descent. Variants in the gene encoding melatonin receptor 1B (MTNR1B) were consistently associated with fasting glucose across all ten studies. The strongest signal was observed at rs10830963, where each G allele (frequency 0.30 in HapMap CEU) was associated with an increase of 0.07 (95% CI = 0.06-0.08) mmol/l in fasting glucose levels (P = 3.2 x 10(-50)) and reduced beta-cell function as measured by homeostasis model assessment (HOMA-B, P = 1.1 x 10(-15)). The same allele was associated with an increased risk of type 2 diabetes (odds ratio = 1.09 (1.05-1.12), per G allele P = 3.3 x 10(-7)) in a meta-analysis of 13 case-control studies totaling 18,236 cases and 64,453 controls. Our analyses also confirm previous associations of fasting glucose with variants at the G6PC2 (rs560887, P = 1.1 x 10(-57)) and GCK (rs4607517, P = 1.0 x 10(-25)) loci.
TL;DR: In this article, the authors show that real exchange rate volatility can have a significant impact on productivity growth, but the effect depends critically on a country's level of financial development, and they also offer a simple monetary growth model in which real exchange-rate uncertainty exacerbates the negative investment effects of domestic credit market constraints.
Cecilia M. Lindgren1, Iris M. Heid2, Joshua C. Randall1, Claudia Lamina3 +152 more•Institutions (36)
TL;DR: By focusing on anthropometric measures of central obesity and fat distribution, a meta-analysis of 16 genome-wide association studies informative for adult waist circumference and waist–hip ratio identified three loci implicated in the regulation of human adiposity.
Abstract: To identify genetic loci influencing central obesity and fat distribution, we performed a meta-analysis of 16 genome-wide association studies (GWAS, N = 38,580) informative for adult waist circumference (WC) and waist-hip ratio (WHR). We selected 26 SNPs for follow-up, for which the evidence of association with measures of central adiposity (WC and/or WHR) was strong and disproportionate to that for overall adiposity or height. Follow-up studies in a maximum of 70,689 individuals identified two loci strongly associated with measures of central adiposity; these map near TFAP2B (WC, P = 1.9x10(-11)) and MSRA (WC, P = 8.9x10(-9)). A third locus, near LYPLAL1, was associated with WHR in women only (P = 2.6x10(-8)). The variants near TFAP2B appear to influence central adiposity through an effect on overall obesity/fat-mass, whereas LYPLAL1 displays a strong female-only association with fat distribution. By focusing on anthropometric measures of central obesity and fat distribution, we have identified three loci implicated in the regulation of human adiposity.
Swiss Institute of Bioinformatics1, University of Lausanne2, University Hospital of Lausanne3, University of Greifswald4, Western General Hospital5, Prevention Institute6, King's College London7, University of Cambridge8, Wellcome Trust Centre for Human Genetics9, University of Oxford10, Uppsala University11, QIMR Berghofer Medical Research Institute12, Erasmus University Rotterdam13, University of Edinburgh14, University of Glasgow15, Innsbruck Medical University16, National Institute for Health Research17, GlaxoSmithKline18, Queen Mary University of London19, University of Leicester20, National Institutes of Health21, Ludwig Maximilian University of Munich22, Wellcome Trust Sanger Institute23
TL;DR: In this article, a meta-analysis of genome-wide association scans from 14 studies with 28,141 participants of European descent was conducted, resulting in identification of 954 SNPs distributed across nine loci that exceeded the threshold of genomewide significance, five of which are novel.
Abstract: Elevated serum uric acid levels cause gout and are a risk factor for cardiovascular disease and diabetes. To investigate the polygenetic basis of serum uric acid levels, we conducted a meta-analysis of genome-wide association scans from 14 studies totalling 28,141 participants of European descent, resulting in identification of 954 SNPs distributed across nine loci that exceeded the threshold of genome-wide significance, five of which are novel. Overall, the common variants associated with serum uric acid levels fall in the following nine regions: SLC2A9 (p = 5.2x10(-201)), ABCG2 (p = 3.1x10(-26)), SLC17A1 (p = 3.0x10(-14)), SLC22A11 (p = 6.7x10(-14)), SLC22A12 (p = 2.0x10(-9)), SLC16A9 (p = 1.1x10(-8)), GCKR (p = 1.4x10(-9)), LRRC16A (p = 8.5x10(-9)), and near PDZK1 (p = 2.7x10(-9)). Identified variants were analyzed for gender differences. We found that the minor allele for rs734553 in SLC2A9 has greater influence in lowering uric acid levels in women and the minor allele of rs2231142 in ABCG2 elevates uric acid levels more strongly in men compared to women. To further characterize the identified variants, we analyzed their association with a panel of metabolites. rs12356193 within SLC16A9 was associated with DL-carnitine (p = 4.0x10(-26)) and propionyl-L-carnitine (p = 5.0x10(-8)) concentrations, which in turn were associated with serum UA levels (p = 1.4x10(-57) and p = 8.1x10(-54), respectively), forming a triangle between SNP, metabolites, and UA levels. Taken together, these associations highlight additional pathways that are important in the regulation of serum uric acid levels and point toward novel potential targets for pharmacological intervention to prevent or treat hyperuricemia. In addition, these findings strongly support the hypothesis that transport proteins are key in regulating serum uric acid levels.
TL;DR: A new vector series is designed, and a large number of stably transformed plants expressing membrane protein fusions to spectrally distinct, fluorescent tags are generated, demonstrating the power of this multicolor 'Wave' marker set for rapid, combinatorial analysis of plant cell membrane compartments, both in live-imaging and immunoelectron microscopy.
Abstract: Plant membrane compartments and trafficking pathways are highly complex, and are often distinct from those of animals and fungi. Progress has been made in defining trafficking in plants using transient expression systems. However, many processes require a precise understanding of plant membrane trafficking in a developmental context, and in diverse, specialized cell types. These include defense responses to pathogens, regulation of transporter accumulation in plant nutrition or polar auxin transport in development. In all of these cases a central role is played by the endosomal membrane system, which, however, is the most divergent and ill-defined aspect of plant cell compartmentation. We have designed a new vector series, and have generated a large number of stably transformed plants expressing membrane protein fusions to spectrally distinct, fluorescent tags. We selected lines with distinct subcellular localization patterns, and stable, non-toxic expression. We demonstrate the power of this multicolor 'Wave' marker set for rapid, combinatorial analysis of plant cell membrane compartments, both in live-imaging and immunoelectron microscopy. Among other findings, our systematic co-localization analysis revealed that a class of plant Rab1-homologs has a much more extended localization than was previously assumed, and also localizes to trans-Golgi/endosomal compartments. Constructs that can be transformed into any genetic background or species, as well as seeds from transgenic Arabidopsis plants, will be freely available, and will promote rapid progress in diverse areas of plant cell biology.
TL;DR: The model suggests that dynamic lesion effects can be predicted on the basis of specific network measures of structural brain networks and that these effects may be related to known behavioral and cognitive consequences of brain lesions.
Abstract: Lesions of anatomical brain networks result in functional disturbances of brain systems and behavior which depend sensitively, often unpredictably, on the lesion site. The availability of whole-brain maps of structural connections within the human cerebrum and our increased understanding of the physiology and large-scale dynamics of cortical networks allow us to investigate the functional consequences of focal brain lesions in a computational model. We simulate the dynamic effects of lesions placed in different regions of the cerebral cortex by recording changes in the pattern of endogenous (“resting-state”) neural activity. We find that lesions produce specific patterns of altered functional connectivity among distant regions of cortex, often affecting both cortical hemispheres. The magnitude of these dynamic effects depends on the lesion location and is partly predicted by structural network properties of the lesion site. In the model, lesions along the cortical midline and in the vicinity of the temporo-parietal junction result in large and widely distributed changes in functional connectivity, while lesions of primary sensory or motor regions remain more localized. The model suggests that dynamic lesion effects can be predicted on the basis of specific network measures of structural brain networks and that these effects may be related to known behavioral and cognitive consequences of brain lesions.
TL;DR: A design science approach is proposed to bridge practice to theory, not vice versa, theory to practice, to make novel theoretical insights and practical relevance complementary in operations management research.
Abstract: Despite ambitious efforts in various fields of research over multiple decades, the goal of making academic research relevant to the practitioner remains elusive: theoretical and academic research interests do not seem to coincide with the interests of managerial practice. This challenge is more fundamental than knowledge transfer, it is one of diverging knowledge interests and means of knowledge production. In this article, we look at this fundamental challenge through the lens of design science, which is an approach aimed primarily at discovery and problem solving as opposed to accumulation of theoretical knowledge. We explore in particular the ways in which problem-solving research and theory-oriented academic research can complement one another. In operations management (OM) research, recognizing and building on this complementarity is especially crucial, because problem-solving–oriented research produces the very artifacts (e.g., technologies) that empirical OM research subsequently evaluates in an attempt to build explanatory theory. It is indeed the practitioner—not the academic scientist—who engages in basic research in OM. This idiosyncrasy prompts the question: how can we enhance the cross-fertilization between academic research and research practice to make novel theoretical insights and practical relevance complementary? This article proposes a design science approach to bridge practice to theory rather than theory to practice.
TL;DR: It is demonstrated that uptake of microparticulate adjuvants by DCs activates the NALP3 inflammasome, and this contributes to their enhancing effects on innate and antigen-specific cellular immunity.
Abstract: Many currently used and candidate vaccine adjuvants are particulate in nature, but their mechanism of action is not well understood. Here, we show that particulate adjuvants, including biodegradable poly(lactide-co-glycolide) (PLG) and polystyrene microparticles, dramatically enhance secretion of interleukin-1β (IL-1β) by dendritic cells (DCs). The ability of particulates to promote IL-1β secretion and caspase 1 activation required particle uptake by DCs and NALP3. Uptake of microparticles induced lysosomal damage, whereas particle-mediated enhancement of IL-1β secretion required phagosomal acidification and the lysosomal cysteine protease cathepsin B, suggesting a role for lysosomal damage in inflammasome activation. Although the presence of a Toll-like receptor (TLR) agonist was required to induce IL-1β production in vitro, injection of the adjuvants in the absence of TLR agonists induced IL-1β production at the injection site, indicating that endogenous factors can synergize with particulates to promote inflammasome activation. The enhancement of antigen-specific antibody production by PLG microparticles was independent of NALP3. However, the ability of PLG microparticles to promote antigen-specific IL-6 production by T cells and the recruitment and activation of a population of CD11b+Gr1− cells required NALP3. Our data demonstrate that uptake of microparticulate adjuvants by DCs activates the NALP3 inflammasome, and this contributes to their enhancing effects on innate and antigen-specific cellular immunity.
TL;DR: In this article, the authors assess whether climate change-induced habitat losses predicted at the European scale (10 × 10′ grid cells) are also predicted from local-scale data and modeling (25 m × 25 m grid cells), in two regions of the Swiss Alps.
Abstract: Mountain ecosystems will likely be affected by global warming during the 21st century, with substantial biodiversity loss predicted by species distribution models (SDMs). Depending on the geographic extent, elevation range, and spatial resolution of data used in making these models, different rates of habitat loss have been predicted, with associated risk of species extinction. Few coordinated across-scale comparisons have been made using data of different resolutions and geographic extents. Here, we assess whether climate change-induced habitat losses predicted at the European scale (10 × 10′ grid cells) are also predicted from local-scale data and modeling (25 m × 25 m grid cells) in two regions of the Swiss Alps. We show that local-scale models predict persistence of suitable habitats in up to 100% of species that were predicted by a European-scale model to lose all their suitable habitats in the area. Proportion of habitat loss depends on climate change scenario and study area. We find good agreement between the mismatch in predictions between scales and the fine-grain elevation range within 10 × 10′ cells. The greatest prediction discrepancy for alpine species occurs in the area with the largest nival zone. Our results suggest elevation range as the main driver for the observed prediction discrepancies. Local-scale projections may better reflect the possibility for species to track their climatic requirement toward higher elevations.
TL;DR: In this paper, the effects of changes in the duration of paid, job-protected parental leave on mothers' higher-order fertility and post-birth labor market careers were analyzed.
Abstract: This paper analyzes the effects of changes in the duration of paid, job-protected parental leave on mothers' higher-order fertility and postbirth labor market careers. Identification is based on a major Austrian reform increasing the duration of parental leave from one year to two years for any child born on or after July 1, 1990. We find that mothers who give birth to their first child immediately after the reform have more second children than prereform mothers, and that extended parental leave significantly reduces return to work. Employment and earnings also decrease in the short run, but not in the long run. Fertility and work responses vary across the population in ways suggesting that both cash transfers and job protection are relevant. Increasing parental leave for a future child increases fertility strongly but leaves short-run postbirth careers relatively unaffected. Partially reversing the 1990 extension, a second 1996 reform improves employment and earnings while compressing the time between births.
TL;DR: Two active learning algorithms for semiautomatic definition of training samples in remote sensing image classification, based on predefined heuristics, are proposed, which reach the same level of accuracy as larger data sets.
Abstract: In this paper, we propose two active learning algorithms for semiautomatic definition of training samples in remote sensing image classification. Based on predefined heuristics, the classifier ranks the unlabeled pixels and automatically chooses those that are considered the most valuable for its improvement. Once the pixels have been selected, the analyst labels them manually and the process is iterated. Starting with a small and nonoptimal training set, the model itself builds the optimal set of samples which minimizes the classification error. We have applied the proposed algorithms to a variety of remote sensing data, including very high resolution and hyperspectral images, using support vector machines. Experimental results confirm the consistency of the methods. The required number of training samples can be reduced to 10% using the methods proposed, reaching the same level of accuracy as larger data sets. A comparison with a state-of-the-art active learning method, margin sampling, is provided, highlighting advantages of the methods proposed. The effect of spatial resolution and separability of the classes on the quality of the selection of pixels is also discussed.