Showing papers by "University of Bern published in 2009"
University of Ottawa1, Mario Negri Institute for Pharmacological Research2, University of Modena and Reggio Emilia3, Ottawa Hospital Research Institute4, University of Oxford5, University of Freiburg6, Veterans Health Administration7, Johnson & Johnson8, Johnson & Johnson Pharmaceutical Research and Development9, University of Birmingham10, McMaster University11, Johns Hopkins University12, University of Bern13, University of Copenhagen14, Medical Research Council15, GlaxoSmithKline16, University of California, San Francisco17, FHI 36018, Cochrane Collaboration19
TL;DR: Provide a structured summary including, as applicable, background, objectives, data sources, study eligibility criteria, participants, interventions, study appraisal and synthesis methods, results, limitations, conclusions and implications of key findings, systematic review registration number 2.
Abstract: Provide a structured summary including, as applicable, background, objectives, data sources, study eligibility criteria, participants, interventions, study appraisal and synthesis methods, results, limitations, conclusions and implications of key findings, systematic review registration number 2 Structured summary
3,655 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, 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 diagnostic performance of sensitive cardiac troponin assays is excellent, and these assays can substantially improve the early diagnosis of acute myocardial infarction, particularly in patients with a recent onset of chest pain.
Abstract: cantly higher with the four sensitive cardiac troponin assays than with the standard assay (AUC for Abbott–Architect Troponin I, 0.96; 95% confidence interval [CI], 0.94 to 0.98; for Roche High-Sensitive Troponin T, 0.96; 95% CI, 0.94 to 0.98; for Roche Troponin I, 0.95; 95% CI, 0.92 to 0.97; and for Siemens Troponin I Ultra, 0.96; 95% CI, 0.94 to 0.98; vs. AUC for the standard assay, 0.90; 95% CI, 0.86 to 0.94). Among patients who presented within 3 hours after the onset of chest pain, the AUCs were 0.93 (95% CI, 0.88 to 0.99), 0.92 (95% CI, 0.87 to 0.97), 0.92 (95% CI, 0.86 to 0.99), and 0.94 (95% CI, 0.90 to 0.98) for the sensitive assays, respectively, and 0.76 (95% CI, 0.64 to 0.88) for the standard assay. We did not assess the effect of the sensitive troponin assays on clinical management. Conclusions The diagnostic performance of sensitive cardiac troponin assays is excellent, and these assays can substantially improve the early diagnosis of acute myocardial infarction, particularly in patients with a recent onset of chest pain. (ClinicalTrials. gov number, NCT00470587.)
1,612 citations
TL;DR: Supplemental vitamin D in a dose of 700-1000 IU a day reduced the risk of falling among older individuals by 19% and to a similar degree as active forms of vitamin D.
Abstract: Objective To test the efficacy of supplemental vitamin D and active forms of vitamin D with or without calcium in preventing falls among older individuals. Data sources We searched Medline, the Cochrane central register of controlled trials, BIOSIS, and Embase up to August 2008 for relevant articles. Further studies were identified by consulting clinical experts, bibliographies, and abstracts. We contacted authors for additional data when necessary. Review methods Only double blind randomised controlled trials of older individuals (mean age 65 years or older) receiving a defined oral dose of supplemental vitamin D (vitamin D 3 (cholecalciferol) or vitamin D 2 (ergocalciferol)) or an active form of vitamin D (1α-hydroxyvitamin D 3 (1α-hydroxycalciferol) or 1,25-dihydroxyvitamin D 3 (1,25-dihydroxycholecalciferol)) and with sufficiently specified fall assessment were considered for inclusion. Results Eight randomised controlled trials (n=2426) of supplemental vitamin D met our inclusion criteria. Heterogeneity among trials was observed for dose of vitamin D (700-1000 IU/day v 200-600 IU/day; P=0.02) and achieved 25-hydroxyvitamin D 3 concentration (25(OH)D concentration: v ≥60 nmol/l; P=0.005). High dose supplemental vitamin D reduced fall risk by 19% (pooled relative risk (RR) 0.81, 95% CI 0.71 to 0.92; n=1921 from seven trials), whereas achieved serum 25(OH)D concentrations of 60 nmol/l or more resulted in a 23% fall reduction (pooled RR 0.77, 95% CI 0.65 to 0.90). Falls were not notably reduced by low dose supplemental vitamin D (pooled RR 1.10, 95% CI 0.89 to 1.35; n=505 from two trials) or by achieved serum 25-hydroxyvitamin D concentrations of less than 60 nmol/l (pooled RR 1.35, 95% CI 0.98 to 1.84). Two randomised controlled trials (n=624) of active forms of vitamin D met our inclusion criteria. Active forms of vitamin D reduced fall risk by 22% (pooled RR 0.78, 95% CI 0.64 to 0.94). Conclusions Supplemental vitamin D in a dose of 700-1000 IU a day reduced the risk of falling among older individuals by 19% and to a similar degree as active forms of vitamin D. Doses of supplemental vitamin D of less than 700 IU or serum 25-hydroxyvitamin D concentrations of less than 60 nmol/l may not reduce the risk of falling among older individuals.
1,213 citations
TL;DR: Interestingly, most of these patterns had been previously attributed to distinct selective processes, showing that taking into account the dynamic nature of a species range can lead to a paradigm shift in the authors' perception of evolutionary processes.
Abstract: Although range expansions have occurred recurrently in the history of most species, their genetic consequences have been little investigated. Theoretical studies show that range expansions are quite different from pure demographic expansions and that the extent of recent gene flow conditions expected patterns of molecular diversity within and between populations. Spatially explicit simulation studies have led to unexpected and fascinating results about genetic patterns emerging after a range expansion. For instance, spatial expansions can generate allele frequency gradients, promote the surfing of rare variants into newly occupied territories, induce the structuring of newly colonized areas into distinct sectors of low genetic diversity, or lead to massive introgression of local genes into the genome of an invading species. Interestingly, most of these patterns had been previously attributed to distinct selective processes, showing that taking into account the dynamic nature of a species range can lead to a paradigm shift in our perception of evolutionary processes.
1,154 citations
University of Bayreuth1, Institut national de la recherche agronomique2, Canterbury of New Zealand3, Lund University4, Charles University in Prague5, Academy of Sciences of the Czech Republic6, Helmholtz Centre for Environmental Research - UFZ7, University of Tartu8, University of Fribourg9, Hungarian Academy of Sciences10, ETH Zurich11, University of Leeds12, CABI13, University of Bern14, Saint Petersburg State University15, National Academy of Sciences of Belarus16, Polish Academy of Sciences17, Joseph Fourier University18, Spanish National Research Council19, Potsdam Institute for Climate Impact Research20
TL;DR: It is emphasised that global warming has enabled alien species to expand into regions in which they previously could not survive and reproduce and management practices regarding the occurrence of 'new' species could range from complete eradication to tolerance.
Abstract: Climate change and biological invasions are key processes affecting global biodiversity, yet their effects have usually been considered separately. Here, we emphasise that global warming has enabled alien species to expand into regions in which they previously could not survive and reproduce. Based on a review of climate-mediated biological invasions of plants, invertebrates, fishes and birds, we discuss the ways in which climate change influences biological invasions. We emphasise the role of alien species in a more dynamic context of shifting species' ranges and changing communities. Under these circumstances, management practices regarding the occurrence of 'new' species could range from complete eradication to tolerance and even consideration of the 'new' species as an enrichment of local biodiversity and key elements to maintain ecosystem services.
1,138 citations
TL;DR: The cross-talk between apoptosis and autophagy is a key factor in the outcome of death-related pathologies such as cancer, its development and treatment, and the molecular regulators of both pathways are inter-connected.
Abstract: It is not surprising that the demise of a cell is a complex well-controlled process. Apoptosis, the first genetically programmed death process identified, has been extensively studied and its contribution to the pathogenesis of disease well documented. Yet, apoptosis does not function alone to determine a cell's fate. More recently, autophagy, a process in which de novo-formed membrane-enclosed vesicles engulf and consume cellular components, has been shown to engage in a complex interplay with apoptosis. In some cellular settings, it can serve as a cell survival pathway, suppressing apoptosis, and in others, it can lead to death itself, either in collaboration with apoptosis or as a back-up mechanism when the former is defective. The molecular regulators of both pathways are inter-connected; numerous death stimuli are capable of activating either pathway, and both pathways share several genes that are critical for their respective execution. The cross-talk between apoptosis and autophagy is therefore quite complex, and sometimes contradictory, but surely critical to the overall fate of the cell. Furthermore, the cross-talk is a key factor in the outcome of death-related pathologies such as cancer, its development and treatment.
1,120 citations
TL;DR: These results identify distinct molecular requirements and ports of lymphocyte entry into uninflamed versus inflamed CNS and suggest that the CCR6-CCL20 axis in the choroid plexus controls immune surveillance of the CNS.
Abstract: Interleukin 17-producing T helper cells (T(H)-17 cells) are important in experimental autoimmune encephalomyelitis, but their route of entry into the central nervous system (CNS) and their contribution relative to that of other effector T cells remain to be determined. Here we found that mice lacking CCR6, a chemokine receptor characteristic of T(H)-17 cells, developed T(H)-17 responses but were highly resistant to the induction of experimental autoimmune encephalomyelitis. Disease susceptibility was reconstituted by transfer of wild-type T cells that entered into the CNS before disease onset and triggered massive CCR6-independent recruitment of effector T cells across activated parenchymal vessels. The CCR6 ligand CCL20 was constitutively expressed in epithelial cells of choroid plexus in mice and humans. Our results identify distinct molecular requirements and ports of lymphocyte entry into uninflamed versus inflamed CNS and suggest that the CCR6-CCL20 axis in the choroid plexus controls immune surveillance of the CNS.
1,081 citations
TL;DR: Studies of heterosexual discordant couples observed no transmission in patients treated with ART and with viral load below 400 copies/ml, but data were compatible with one transmission per 79 person-years, which is needed to better define the risk of HIV transmission from patients on ART.
Abstract: OBJECTIVES: To synthesize the evidence on the risk of HIV transmission through unprotected sexual intercourse according to viral load and treatment with combination antiretroviral therapy (ART). DESIGN: Systematic review and meta-analysis. METHODS: We searched Medline, Embase and conference abstracts from 1996-2009. We included longitudinal studies of serodiscordant couples reporting on HIV transmission according to plasma viral load or use of ART and used random-effects Poisson regression models to obtain summary transmission rates [with 95% confidence intervals, (CI)]. If there were no transmission events we estimated an upper 97.5% confidence limit. RESULTS: We identified 11 cohorts reporting on 5021 heterosexual couples and 461 HIV-transmission events. The rate of transmission overall from ART-treated patients was 0.46 (95% CI 0.19-1.09) per 100 person-years, based on five events. The transmission rate from a seropositive partner with viral load below 400 copies/ml on ART, based on two studies, was zero with an upper 97.5% confidence limit of 1.27 per 100 person-years, and 0.16 (95% CI 0.02-1.13) per 100 person-years if not on ART, based on five studies and one event. There were insufficient data to calculate rates according to the presence or absence of sexually transmitted infections, condom use, or vaginal or anal intercourse. CONCLUSION: Studies of heterosexual discordant couples observed no transmission in patients treated with ART and with viral load below 400 copies/ml, but data were compatible with one transmission per 79 person-years. Further studies are needed to better define the risk of HIV transmission from patients on ART.
991 citations
TL;DR: Gene therapy, combined with reduced-intensity conditioning, is a safe and effective treatment for SCID in patients with ADA deficiency and effective protection against infections and improvement in physical development made a normal lifestyle possible.
Abstract: Background We investigated the long-term outcome of gene therapy for severe combined immunodeficiency (SCID) due to the lack of adenosine deaminase (ADA), a fatal disorder of purine metabolism and immunodeficiency. Methods We infused autologous CD34+ bone marrow cells transduced with a retroviral vector containing the ADA gene into 10 children with SCID due to ADA deficiency who lacked an HLA-identical sibling donor, after nonmyeloablative conditioning with busulfan. Enzyme-replacement therapy was not given after infusion of the cells. Results All patients are alive after a median follow-up of 4.0 years (range, 1.8 to 8.0). Transduced hematopoietic stem cells have stably engrafted and differentiated into myeloid cells containing ADA (mean range at 1 year in bone marrow lineages, 3.5 to 8.9%) and lymphoid cells (mean range in peripheral blood, 52.4 to 88.0%). Eight patients do not require enzyme-replacement therapy, their blood cells continue to express ADA, and they have no signs of defective detoxificati...
936 citations
TL;DR: It is shown that tests not accounting for a hierarchical structure, when it exists, do generate a large excess of false positive loci, whereas the hierarchical island model is robust to uncertainties about the exact number of groups and demes per group in the system.
Abstract: Patterns of genetic diversity between populations are often used to detect loci under selection in genome scans. Indeed, loci involved in local adaptations should show high F(ST) values, whereas loci under balancing selection should rather show low F(ST) values. Most tests of selection based on F(ST) use a null distribution generated under a simple island model of population differentiation. Although this model has been shown to be robust, many species have a more complex genetic structure, with some populations sharing a recent ancestry or due to the presence of barriers to gene flow between different parts of a species range. In this paper, we propose the use of a hierarchical island model, in which demes exchange more migrants within groups than between groups, to generate the joint distribution of genetic diversity within and between populations. We show that tests not accounting for a hierarchical structure, when it exists, do generate a large excess of false positive loci, whereas the hierarchical island model is robust to uncertainties about the exact number of groups and demes per group in the system. Our approach also explicitly takes into account the mutational process, and does not just rely on allele frequencies, which is important for short tandem repeat (STR) data. An application to human and stickleback STR data sets reveals a much lower number of significant loci than previously obtained under a non-hierarchical model. The elimination of false positive loci from genome scans should allow us to better determine on which specific class of genes selection is operating.
TL;DR: Nonvertebral fracture prevention with vitamin D is dose dependent, and a higher dose should reduce fractures by at least 20% for individuals aged 65 years or older.
Abstract: Results: The pooled relative risk (RR) was 0.86 (95% confidence interval [CI], 0.77-0.96) for prevention of nonvertebral fractures and 0.91 (95% CI, 0.78-1.05) for the prevention of hip fractures, but with significant heterogeneity for both end points. Including all trials, antifracture efficacy increased significantly with a higher dose and higher achieved blood 25-hydroxyvitamin D levels for both end points. Consistently, pooling trials with a higher received dose of more than 400 IU/d resolved heterogeneity. For the higher dose, the pooled RR was 0.80 (95% CI, 0.72-0.89; n=33 265 subjects from 9 trials) for nonvertebral fractures and 0.82 (95% CI, 0.69-0.97; n=31 872 subjects from 5 trials) for hip fractures. The higher dose reduced nonvertebral fractures in communitydwelling individuals (�29%) and institutionalized older individuals (�15%), and its effect was independent of additional calcium supplementation. Conclusion: Nonvertebral fracture prevention with vitamin D is dose dependent, and a higher dose should reduce fractures by at least 20% for individuals aged 65 years or older.
University of Ottawa1, University of Ioannina2, University of Bern3, Centers for Disease Control and Prevention4, PLOS5, University of Bristol6, Ottawa Hospital Research Institute7, University of Texas Health Science Center at Houston8, University of Western Ontario9, Erasmus University Rotterdam10, Cancer Care Ontario11, McGill University12, Harvard University13
TL;DR: The STREGA recommendations are presented, which are aimed at improving the reporting of genetic association studies and are designed to improve the quality of studies.
Abstract: Making sense of rapidly evolving evidence on genetic associations is crucial to making genuine advances in human genomics and the eventual integration of this information in the practice of medicine and public health. Assessment of the strengths and weaknesses of this evidence, and hence the ability to synthesize it, has been limited by inadequate reporting of results. The STrengthening the REporting of Genetic Association studies (STREGA) initiative builds on the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement and provides additions to 12 of the 22 items on the STROBE checklist. The additions concern population stratification, genotyping errors, modelling haplotype variation, Hardy-Weinberg equilibrium, replication, selection of participants, rationale for choice of genes and variants, treatment effects in studying quantitative traits, statistical methods, relatedness, reporting of descriptive and outcome data, and the volume of data issues that are important to consider in genetic association studies. The STREGA recommendations do not prescribe or dictate how a genetic association study should be designed but seek to enhance the transparency of its reporting, regardless of choices made during design, conduct, or analysis.
TL;DR: It is shown that, following priming with granulocyte/macrophage colony-stimulating factor and subsequent short-term toll-like receptor 4 or complement factor 5a receptor stimulation, viable neutrophils are able to generate NETs.
Abstract: Neutrophil extracellular traps (NETs) represent extracellular structures able to bind and kill microorganisms. It is believed that they are generated by neutrophils undergoing cell death, allowing these dying or dead cells to kill microbes. We show that, following priming with granulocyte/macrophage colony-stimulating factor (GM-CSF) and subsequent short-term toll-like receptor 4 (TLR4) or complement factor 5a (C5a) receptor stimulation, viable neutrophils are able to generate NETs. Strikingly, NETs formed by living cells contain mitochondrial, but no nuclear, DNA. Pharmacological or genetic approaches to block reactive oxygen species (ROS) production suggested that NET formation is ROS dependent. Moreover, neutrophil populations stimulated with GM-CSF and C5a showed increased survival compared with resting neutrophils, which did not generate NETs. In conclusion, mitochondrial DNA release by neutrophils and NET formation do not require neutrophil death and do also not limit the lifespan of these cells.
TL;DR: In patients with AML who are older than 60 years of age, escalation of the dose of daunorubicin to twice the conventional dose, with the entire dose administered in the first induction cycle, effects a more rapid response and a higher response rate than does the conventional doses, without additional toxic effects.
Abstract: BACKGROUND: A complete remission is essential for prolonging survival in patients with acute myeloid leukemia (AML). Daunorubicin is a cornerstone of the induction regimen, but the optimal dose is unknown. In older patients, it is usual to give daunorubicin at a dose of 45 to 50 mg per square meter of body-surface area. METHODS: Patients in whom AML or high-risk refractory anemia had been newly diagnosed and who were 60 to 83 years of age (median, 67) were randomly assigned to receive cytarabine, at a dose of 200 mg per square meter by continuous infusion for 7 days, plus daunorubicin for 3 days, either at the conventional dose of 45 mg per square meter (411 patients) or at an escalated dose of 90 mg per square meter (402 patients); this treatment was followed by a second cycle of cytarabine at a dose of 1000 mg per square meter for 6 days. The primary end point was event-free survival. RESULTS: The complete remission rates were 64% in the group that received the escalated dose of daunorubicin and 54% in the group that received the conventional dose (P=0.002); the rates of remission after the first cycle of induction treatment were 52% and 35%, respectively (P<0.001). There was no significant difference between the two groups in the incidence of hematologic toxic effects, 30-day mortality (11% and 12% in the two groups, respectively), or the incidence of moderate, severe, or life-threatening adverse events (P=0.08). Survival end points in the two groups did not differ significantly overall, but patients in the escalated-treatment group who were 60 to 65 years of age, as compared with the patients in the same age group who received the conventional dose, had higher rates of complete remission (73% vs. 51%), event-free survival (29% vs. 14%), and overall survival (38% vs. 23%). CONCLUSIONS: In patients with AML who are older than 60 years of age, escalation of the dose of daunorubicin to twice the conventional dose, with the entire dose administered in the first induction cycle, effects a more rapid response and a higher response rate than does the conventional dose, without additional toxic effects. (Current Controlled Trials number, ISRCTN77039377; and Netherlands National Trial Register number, NTR212.)
Broad Institute1, University of Pavia2, Uppsala University3, University of Bologna4, University of Kentucky5, University of Adelaide6, University of Tampa7, University of Veterinary Medicine Vienna8, University of Bern9, University of California, Davis10, Wellcome Trust Sanger Institute11, Cornell University12, Royal Veterinary College13, Institut national de la recherche agronomique14, Japan Racing Association15, University College Dublin16, Genetic Information Research Institute17, Swedish University of Agricultural Sciences18, University of Minnesota19, University of Bari20, Texas A&M University21, Animal Health Trust22, Massachusetts Institute of Technology23
TL;DR: The analysis reveals an evolutionarily new centromere on equine chromosome 11 that displays properties of an immature but fully functioning Centromere and is devoid of centromeric satellite sequence, suggesting thatCentromeric function may arise before satellite repeat accumulation.
Abstract: We report a high-quality draft sequence of the genome of the horse (Equus caballus). The genome is relatively repetitive but has little segmental duplication. Chromosomes appear to have undergone few historical rearrangements: 53% of equine chromosomes show conserved synteny to a single human chromosome. Equine chromosome 11 is shown to have an evolutionary new centromere devoid of centromeric satellite DNA, suggesting that centromeric function may arise before satellite repeat accumulation. Linkage disequilibrium, showing the influences of early domestication of large herds of female horses, is intermediate in length between dog and human, and there is long-range haplotype sharing among breeds.
TL;DR: A review of studies of introgression in species with sex-biased dispersal largely confirms that species delimitation should be more effective with markers experiencing high levels of gene flow, a simple but not widely appreciated prediction.
Abstract: A defining feature of species is that their constituting populations are connected by gene flow. However, interspecific gene flow (introgression) can affect species integrity. If some genome components were less prone to introgression than others, they should be particularly suitable to delimitate species. Recent simulation studies have predicted a negative correlation between intra- and interspecific gene flow, suggesting that markers associated with the most dispersing sex should better delimitate species. A review of studies of introgression in species with sex-biased dispersal largely confirms this prediction. Hence, species delimitation should be more effective with markers experiencing high levels of gene flow, a simple but not widely appreciated prediction.
TL;DR: Recent evidence is reviewed indicating that variability in the completeness of speciation can also be associated with the nature of divergent selection itself, with speciation being greatly promoted by (i) stronger selection on a given, single trait (the 'stronger selection' hypothesis) and (ii) Selection on a greater number of traits ( the 'multifarious selection' hypotheses).
Abstract: Divergent natural selection has been shown to promote speciation in many taxa. However, although divergent selection often initiates the process of speciation, it often fails to complete it. Several time-based, geographic and genetic factors have been recognized to explain this variability in how far speciation proceeds. We review here recent evidence indicating that variability in the completeness of speciation can also be associated with the nature of divergent selection itself, with speciation being greatly promoted by (i) stronger selection on a given, single trait (the 'stronger selection' hypothesis) and (ii) selection on a greater number of traits (the 'multifarious selection' hypothesis). However, evidence for each selective hypothesis is still scarce, and further work is required to determine their relative importance.
TL;DR: Evidence that the disease can be monitored and to some extent controlled with a rigorous reporting and testing system in place should be motivation to expand appropriate programs worldwide.
Abstract: Summary: Throughout much of the world, Trichinella spp. are found to be the causative agents of human trichinellosis, a disease that not only is a public health hazard by affecting human patients but also represents an economic problem in porcine animal production and food safety. Due to the predominantly zoonotic importance of infection, the main efforts in many countries have focused on the control of Trichinella or the elimination of Trichinella from the food chain. The most important source of human infection worldwide is the domestic pig, but, e.g., in Europe, meats of horses and wild boars have played a significant role during outbreaks within the past 3 decades. Infection of humans occurs with the ingestion of Trichinella larvae that are encysted in muscle tissue of domestic or wild animal meat. Early clinical diagnosis of trichinellosis is rather difficult because pathognomonic signs or symptoms are lacking. Subsequent chronic forms of the disease are not easy to diagnose, irrespective of parameters including clinical findings, laboratory findings (nonspecific laboratory parameters such as eosinophilia, muscle enzymes, and serology), and epidemiological investigations. New regulations laying down rules for official controls for Trichinella in meat in order to improve food safety for consumers have recently been released in Europe. The evidence that the disease can be monitored and to some extent controlled with a rigorous reporting and testing system in place should be motivation to expand appropriate programs worldwide.
TL;DR: A novel algorithm is introduced which allows us to approximately, or suboptimally, compute edit distance in a substantially faster way and is emprically verified that the accuracy of the suboptimal distance remains sufficiently accurate for various pattern recognition applications.
TL;DR: GDB-13 enumerates small organic molecules containing up to 13 atoms of C, N, O, S, and Cl following simple chemical stability and synthetic feasibility rules.
Abstract: GDB-13 enumerates small organic molecules containing up to 13 atoms of C, N, O, S, and Cl following simple chemical stability and synthetic feasibility rules. With 977 468 314 structures, GDB-13 is the largest publicly available small organic molecule database to date.
University of East Anglia1, Australian Institute of Marine Science2, Cooperative Research Centre3, University of Copenhagen4, University of Bern5, Alfred University6, Environment Canada7, Pennsylvania State University8, Goddard Institute for Space Studies9, National Center for Atmospheric Research10, Columbia University11, Georgia Institute of Technology12, Swiss Federal Institute for Forest, Snow and Landscape Research13, Université catholique de Louvain14, Hydrologic Research Center15, University of Bergen16, Ohio State University17, University of Arizona18, University of Bremen19, University of Edinburgh20, British Antarctic Survey21
TL;DR: A review of late-Holocene palaeoclimaoclimatology represents the results from a PAGES/CLIVAR Intersection Panel meeting that took place in June 2006 as mentioned in this paper, emphasizing current issues in their use for climate reconstruction; various approaches that have been adopted to combine multiple climate proxy records to provide estimates of past annual-to-decadal timescale Northern Hemisphere surface temperatures and other climate variables, such as large-scale circulation indices; and the forcing histories used in climate model simulations of the past millennium.
Abstract: This review of late-Holocene palaeoclimatology represents the results from a PAGES/CLIVAR Intersection Panel meeting that took place in June 2006. The review is in three parts: the principal high-resolution proxy disciplines (trees, corals, ice cores and documentary evidence), emphasizing current issues in their use for climate reconstruction; the various approaches that have been adopted to combine multiple climate proxy records to provide estimates of past annual-to-decadal timescale Northern Hemisphere surface temperatures and other climate variables, such as large-scale circulation indices; and the forcing histories used in climate model simulations of the past millennium. We discuss the need to develop a framework through which current and new approaches to interpreting these proxy data may be rigorously assessed using pseudo-proxies derived from climate model runs, where the `answer' is known. The article concludes with a list of recommendations. First, more raw proxy data are required from the diverse disciplines and from more locations, as well as replication, for all proxy sources, of the basic raw measurements to improve absolute dating, and to better distinguish the proxy climate signal from noise. Second, more effort is required to improve the understanding of what individual proxies respond to, supported by more site measurements and process studies. These activities should also be mindful of the correlation structure of instrumental data, indicating which adjacent proxy records ought to be in agreement and which not. Third, large-scale climate reconstructions should be attempted using a wide variety of techniques, emphasizing those for which quantified errors can be estimated at specified timescales. Fourth, a greater use of climate model simulations is needed to guide the choice of reconstruction techniques (the pseudo-proxy concept) and possibly help determine where, given limited resources, future sampling should be concentrated.
TL;DR: By surface-assisted coupling of specifically designed molecular building blocks, the fabrication of regular two-dimensional polyphenylene networks with single-atom wide pores and sub-nanometer periodicity is demonstrated.
Pasteur Institute1, Leipzig University2, French Institute of Health and Medical Research3, University of Oulu4, University of Bern5, Paris Diderot University6, National Institute for Health Research7, Wellcome Trust Centre for Human Genetics8, University of Oxford9, Imperial College London10, McGill University11
TL;DR: In addition to FTO and MC4R, genome-wide association data from 1,380 Europeans with early-onset and morbid adult obesity and 1,416 age-matched normal-weight controls detected significant association of obesity with three new risk loci in NPC1, near MAF and near PTER.
Abstract: We analyzed genome-wide association data from 1,380 Europeans with early-onset and morbid adult obesity and 1,416 age-matched normal-weight controls. Thirty-eight markers showing strong association were further evaluated in 14,186 European subjects. In addition to FTO and MC4R, we detected significant association of obesity with three new risk loci in NPC1 (endosomal/lysosomal Niemann-Pick C1 gene, P = 2.9 x 10(-7)), near MAF (encoding the transcription factor c-MAF, P = 3.8 x 10(-13)) and near PTER (phosphotriesterase-related gene, P = 2.1 x 10(-7)).
TL;DR: Current knowledge on the cellular and molecular basis of the functional and dysfunctional blood–CNS barriers with focus on CNS autoimmune inflammation is described.
Abstract: The central nervous system (CNS) is tightly sealed from the changeable milieu of blood by the blood-brain barrier (BBB) and the blood-cerebrospinal fluid (CSF) barrier (BCSFB). While the BBB is considered to be localized at the level of the endothelial cells within CNS microvessels, the BCSFB is established by choroid plexus epithelial cells. The BBB inhibits the free paracellular diffusion of water-soluble molecules by an elaborate network of complex tight junctions (TJs) that interconnects the endothelial cells. Combined with the absence of fenestrae and an extremely low pinocytotic activity, which inhibit transcellular passage of molecules across the barrier, these morphological peculiarities establish the physical permeability barrier of the BBB. In addition, a functional BBB is manifested by a number of permanently active transport mechanisms, specifically expressed by brain capillary endothelial cells that ensure the transport of nutrients into the CNS and exclusion of blood-borne molecules that could be detrimental to the milieu required for neural transmission. Finally, while the endothelial cells constitute the physical and metabolic barrier per se, interactions with adjacent cellular and acellular layers are prerequisites for barrier function. The fully differentiated BBB consists of a complex system comprising the highly specialized endothelial cells and their underlying basement membrane in which a large number of pericytes are embedded, perivascular antigen-presenting cells, and an ensheathment of astrocytic endfeet and associated parenchymal basement membrane. Endothelial cell morphology, biochemistry, and function thus make these brain microvascular endothelial cells unique and distinguishable from all other endothelial cells in the body. Similar to the endothelial barrier, the morphological correlate of the BCSFB is found at the level of unique apical tight junctions between the choroid plexus epithelial cells inhibiting paracellular diffusion of water-soluble molecules across this barrier. Besides its barrier function, choroid plexus epithelial cells have a secretory function and produce the CSF. The barrier and secretory function of the choroid plexus epithelial cells are maintained by the expression of numerous transport systems allowing the directed transport of ions and nutrients into the CSF and the removal of toxic agents out of the CSF. In the event of CNS pathology, barrier characteristics of the blood-CNS barriers are altered, leading to edema formation and recruitment of inflammatory cells into the CNS. In this review we will describe current knowledge on the cellular and molecular basis of the functional and dysfunctional blood-CNS barriers with focus on CNS autoimmune inflammation.
Utrecht University1, Stanford University2, University Hospital of Lausanne3, University of Duisburg-Essen4, University of Bern5, University Hospital of Basel6, Sheba Medical Center7, University of Glasgow8, Katholieke Universiteit Leuven9, Charité10, Ludwig Maximilian University of Munich11, Heidelberg University12, Helsinki University Central Hospital13, Federal University of Rio de Janeiro14
TL;DR: The results do not support unequivocal superiority of IAT over IVT, and the efficacy of I AT versus IVT in patients with an acute BAO needs to be assessed in a randomised controlled trial.
Abstract: Summary Background Treatment strategies for acute basilar artery occlusion (BAO) are based on case series and data that have been extrapolated from stroke intervention trials in other cerebrovascular territories, and information on the efficacy of different treatments in unselected patients with BAO is scarce. We therefore assessed outcomes and differences in treatment response after BAO. Methods The Basilar Artery International Cooperation Study (BASICS) is a prospective, observational registry of consecutive patients who presented with an acute symptomatic and radiologically confirmed BAO between November 1, 2002, and October 1, 2007. Stroke severity at time of treatment was dichotomised as severe (coma, locked-in state, or tetraplegia) or mild to moderate (any deficit that was less than severe). Outcome was assessed at 1 month. Poor outcome was defined as a modified Rankin scale score of 4 or 5, or death. Patients were divided into three groups according to the treatment they received: antithrombotic treatment only (AT), which comprised antiplatelet drugs or systemic anticoagulation; primary intravenous thrombolysis (IVT), including subsequent intra-arterial thrombolysis; or intra-arterial therapy (IAT), which comprised thrombolysis, mechanical thrombectomy, stenting, or a combination of these approaches. Risk ratios (RR) for treatment effects were adjusted for age, the severity of neurological deficits at the time of treatment, time to treatment, prodromal minor stroke, location of the occlusion, and diabetes. Findings 619 patients were entered in the registry. 27 patients were excluded from the analyses because they did not receive AT, IVT, or IAT, and all had a poor outcome. Of the 592 patients who were analysed, 183 were treated with only AT, 121 with IVT, and 288 with IAT. Overall, 402 (68%) of the analysed patients had a poor outcome. No statistically significant superiority was found for any treatment strategy. Compared with outcome after AT, patients with a mild-to-moderate deficit (n=245) had about the same risk of poor outcome after IVT (adjusted RR 0·94, 95% CI 0·60–1·45) or after IAT (adjusted RR 1·29, 0·97–1·72) but had a worse outcome after IAT compared with IVT (adjusted RR 1·49, 1·00–2·23). Compared with AT, patients with a severe deficit (n=347) had a lower risk of poor outcome after IVT (adjusted RR 0·88, 0·76–1·01) or IAT (adjusted RR 0·94, 0·86–1·02), whereas outcomes were similar after treatment with IAT or IVT (adjusted RR 1·06, 0·91–1·22). Interpretation Most patients in the BASICS registry received IAT. Our results do not support unequivocal superiority of IAT over IVT, and the efficacy of IAT versus IVT in patients with an acute BAO needs to be assessed in a randomised controlled trial. Funding Department of Neurology, University Medical Center Utrecht.
TL;DR: Both direct measurements and computer simulations showed that NMDA spikes are the dominant mechanism by which distal synaptic input leads to firing of the neuron and provide the substrate for complex parallel processing of top-down input arriving at the tuft.
Abstract: Tuft dendrites are the main target for feedback inputs innervating neocortical layer 5 pyramidal neurons, but their properties remain obscure. We report the existence of N-methyl-D-aspartate (NMDA) spikes in the fine distal tuft dendrites that otherwise did not support the initiation of calcium spikes. Both direct measurements and computer simulations showed that NMDA spikes are the dominant mechanism by which distal synaptic input leads to firing of the neuron and provide the substrate for complex parallel processing of top-down input arriving at the tuft. These data lead to a new unifying view of integration in pyramidal neurons in which all fine dendrites, basal and tuft, integrate inputs locally through the recruitment of NMDA receptor channels relative to the fixed apical calcium and axosomatic sodium integration points.
TL;DR: In this article, the authors develop modeling and inference tools for counterfactual distributions based on regression methods, which can be used to test functional hypotheses such as no-effect, positive effect, or stochastic dominance.
Abstract: Counterfactual distributions are important ingredients for policy analysis and decomposition analysis in empirical economics. In this article, we develop modeling and inference tools for counterfactual distributions based on regression methods. The counterfactual scenarios that we consider consist of ceteris paribus changes in either the distribution of covariates related to the outcome of interest or the conditional distribution of the outcome given covariates. For either of these scenarios, we derive joint functional central limit theorems and bootstrap validity results for regression-based estimators of the status quo and counterfactual outcome distributions. These results allow us to construct simultaneous confidence sets for function-valued effects of the counterfactual changes, including the effects on the entire distribution and quantile functions of the outcome as well as on related functionals. These confidence sets can be used to test functional hypotheses such as no-effect, positive effect, or stochastic dominance. Our theory applies to general counterfactual changes and covers the main regression methods including classical, quantile, duration, and distribution regressions. We illustrate the results with an empirical application to wage decompositions using data for the United States. As a part of developing the main results, we introduce distribution regression as a comprehensive and flexible tool for modeling and estimating the entire conditional distribution. We show that distribution regression encompasses the Cox duration regression and represents a useful alternative to quantile regression. We establish functional central limit theorems and bootstrap validity results for the empirical distribution regression process and various related functionals. [PUBLICATION ABSTRACT]
University of Bern1, Cochrane Collaboration2, University Medical Center Freiburg3, American Society of Clinical Oncology4, National Institute for Health Research5, Trinity College, Dublin6, Mayo Clinic7, University of South Florida8, Thomas Jefferson University Hospital9, Gynecologic Oncology Group10
TL;DR: Treatment with erythropoiesis-stimulating agents in patients with cancer increased mortality during active study periods and worsened overall survival, and the increased risk of death associated with treatment with these drugs should be balanced against their benefits.
University of Wales, Lampeter1, University of Copenhagen2, Institute of Arctic and Alpine Research3, University of Cambridge4, Utrecht University5, Royal Holloway, University of London6, University of Colorado Boulder7, Lund University8, University of New Brunswick9, Woods Hole Oceanographic Institution10, Monash University11, Heidelberg University12, University of Bonn13, University of Waikato14, University of Newcastle15, University of Plymouth16, University of Bern17
TL;DR: The Greenland ice core from NorthGRIP (NGRIP) contains a proxy climate record across the Pleistocene-Holocene boundary of unprecedented clarity and resolution, which enables the base of the Holocene, as reflected in the first signs of climatic warming at the end of the Younger Dryas/Greenland Stadial 1 cold phase, to be located with a high degree of precision as discussed by the authors.
Abstract: The Greenland ice core from NorthGRIP (NGRIP) contains a proxy climate record across the Pleistocene-Holocene boundary of unprecedented clarity and resolution. Analysis of an array of physical and chemical parameters within the ice enables the base of the Holocene, as reflected in the first signs of climatic warming at the end of the Younger Dryas/Greenland Stadial 1 cold phase, to be located with a high degree of precision. This climatic event is most clearly reflected in an abrupt shift in deuterium excess values, accompanied by more gradual changes in d 18 O, dust concentration, a range of chemical species, and annual layer thickness. A timescale based on multi-parameter annual layer counting provides an age of 11 700 calendar yr b2 k (before AD 2000) for the base of the Holocene, with a maximum counting error of 99 yr. A proposal that an archived core from this unique sequence should constitute the Global Stratotype Section and Point (GSSP) for the base of the Holocene Series/Epoch (Quaternary System/Period) has been ratified by the International Union of Geological Sciences. Five auxiliary stratotypes for the Pleistocene-Holocene boundary have also been recognised. Copyright # 2008 John Wiley & Sons, Ltd.