Showing papers by "University of Basel published in 2016"
TL;DR: In this paper, the authors present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macro-autophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes.
Abstract: In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes.
For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure flux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy.
Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation, it is imperative to target by gene knockout or RNA interference more than one autophagy-related protein. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways implying that not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular assays, we hope to encourage technical innovation in the field.
5,187 citations
TL;DR: The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 (GBD 2015) as discussed by the authors was used to estimate the incidence, prevalence, and years lived with disability for diseases and injuries at the global, regional, and national scale over the period of 1990 to 2015.
5,050 citations
TL;DR: The Global Burden of Disease 2015 Study provides a comprehensive assessment of all-cause and cause-specific mortality for 249 causes in 195 countries and territories from 1980 to 2015, finding several countries in sub-Saharan Africa had very large gains in life expectancy, rebounding from an era of exceedingly high loss of life due to HIV/AIDS.
4,804 citations
TL;DR: This Review discusses the recent developments in inflammasome research with a focus on the molecular mechanisms that govern inflammaome assembly, signalling and regulation.
Abstract: Inflammasomes are multiprotein signalling platforms that control the inflammatory response and coordinate antimicrobial host defences. They are assembled by pattern-recognition receptors following the detection of pathogenic microorganisms and danger signals in the cytosol of host cells, and they activate inflammatory caspases to produce cytokines and to induce pyroptotic cell death. The clinical importance of inflammasomes reaches beyond infectious disease, as dysregulated inflammasome activity is associated with numerous hereditary and acquired inflammatory disorders. In this Review, we discuss the recent developments in inflammasome research with a focus on the molecular mechanisms that govern inflammasome assembly, signalling and regulation.
2,084 citations
Nicholas J Kassebaum1, Megha Arora1, Ryan M Barber1, Zulfiqar A Bhutta2 +679 more•Institutions (268)
TL;DR: In this paper, the authors used the Global Burden of Diseases, Injuries, and Risk Factors Study 2015 (GBD 2015) for all-cause mortality, cause-specific mortality, and non-fatal disease burden to derive HALE and DALYs by sex for 195 countries and territories from 1990 to 2015.
1,533 citations
Ghent University1, Forschungszentrum Jülich2, Åbo Akademi University3, Aalto University4, Vienna University of Technology5, Duke University6, University of Grenoble7, École Polytechnique Fédérale de Lausanne8, Durham University9, International School for Advanced Studies10, Max Planck Society11, Uppsala University12, Fritz Haber Institute of the Max Planck Society13, Humboldt University of Berlin14, Technical University of Denmark15, National Institute of Standards and Technology16, University of Udine17, Université catholique de Louvain18, University of Basel19, Harvard University20, University of California, Davis21, Rutgers University22, University of York23, Wake Forest University24, Science and Technology Facilities Council25, University of Oxford26, University of Vienna27, Leibniz Institute for Neurobiology28, Dresden University of Technology29, Radboud University Nijmegen30, University of Tokyo31, Centre national de la recherche scientifique32, University of Cambridge33, Royal Holloway, University of London34, University of California, Santa Barbara35, University of Luxembourg36, Los Alamos National Laboratory37, Harbin Institute of Technology38
TL;DR: A procedure to assess the precision of DFT methods was devised and used to demonstrate reproducibility among many of the most widely used DFT codes, demonstrating that the precisionof DFT implementations can be determined, even in the absence of one absolute reference code.
Abstract: The widespread popularity of density functional theory has given rise to an extensive range of dedicated codes for predicting molecular and crystalline properties. However, each code implements the formalism in a different way, raising questions about the reproducibility of such predictions. We report the results of a community-wide effort that compared 15 solid-state codes, using 40 different potentials or basis set types, to assess the quality of the Perdew-Burke-Ernzerhof equations of state for 71 elemental crystals. We conclude that predictions from recent codes and pseudopotentials agree very well, with pairwise differences that are comparable to those between different high-precision experiments. Older methods, however, have less precise agreement. Our benchmark provides a framework for users and developers to document the precision of new applications and methodological improvements.
1,141 citations
TL;DR: Sleep appears to have not only a short‐term, use‐dependent function; it also serves to enforce rest and fasting, thereby supporting the optimization of metabolic processes at the appropriate phase of the 24‐h cycle.
Abstract: In the last three decades the two-process model of sleep regulation has served as a major conceptual framework in sleep research. It has been applied widely in studies on fatigue and performance and to dissect individual differences in sleep regulation. The model posits that a homeostatic process (Process S) interacts with a process controlled by the circadian pacemaker (Process C), with time-courses derived from physiological and behavioural variables. The model simulates successfully the timing and intensity of sleep in diverse experimental protocols. Electrophysiological recordings from the suprachiasmatic nuclei (SCN) suggest that S and C interact continuously. Oscillators outside the SCN that are linked to energy metabolism are evident in SCN-lesioned arrhythmic animals subjected to restricted feeding or methamphetamine administration, as well as in human subjects during internal desynchronization. In intact animals these peripheral oscillators may dissociate from the central pacemaker rhythm. A sleep/fast and wake/feed phase segregate antagonistic anabolic and catabolic metabolic processes in peripheral tissues. A deficiency of Process S was proposed to account for both depressive sleep disturbances and the antidepressant effect of sleep deprivation. The model supported the development of novel non-pharmacological treatment paradigms in psychiatry, based on manipulating circadian phase, sleep and light exposure. In conclusion, the model remains conceptually useful for promoting the integration of sleep and circadian rhythm research. Sleep appears to have not only a short-term, use-dependent function; it also serves to enforce rest and fasting, thereby supporting the optimization of metabolic processes at the appropriate phase of the 24-h cycle.
986 citations
Christian Fuchsberger1, Christian Fuchsberger2, Jason Flannick3, Jason Flannick4 +346 more•Institutions (77)
TL;DR: In this paper, the authors performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing for 12,940 individuals from five ancestry groups.
Abstract: The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.
866 citations
Christian R. Marshall1, Daniel P. Howrigan2, Daniele Merico1, Bhooma Thiruvahindrapuram1 +252 more•Institutions (87)
TL;DR: A collaborative effort in which a centralized analysis pipeline is applied to a SCZ cohort, finding support at a suggestive level for nine additional candidate susceptibility and protective loci, which consist predominantly of CNVs mediated by non-allelic homologous recombination (NAHR).
Abstract: Genomic copy number variants (CNVs) have been strongly implicated in the etiology of schizophrenia (SCZ). However, apart from a small number of risk variants, elucidation of the CNV contribution to risk has been difficult due to the rarity of risk alleles, all occurring in less than 1% of cases. We sought to address this obstacle through a collaborative effort in which we applied a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. We observed a global enrichment of CNV burden in cases (OR=1.11, P=5.7e-15), which persisted after excluding loci implicated in previous studies (OR=1.07, P=1.7e-6). CNV burden is also enriched for genes associated with synaptic function (OR = 1.68, P = 2.8e-11) and neurobehavioral phenotypes in mouse (OR = 1.18, P= 7.3e-5). We identified genome-wide significant support for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. We find support at a suggestive level for nine additional candidate susceptibility and protective loci, which consist predominantly of CNVs mediated by non-allelic homologous recombination (NAHR).
764 citations
TL;DR: Overall, these data demonstrate that GSDMD is the direct and final executor of pyroptotic cell death.
Abstract: Pyroptosis is a lytic type of cell death that is initiated by inflammatory caspases. These caspases are activated within multi-protein inflammasome complexes that assemble in response to pathogens and endogenous danger signals. Pyroptotic cell death has been proposed to proceed via the formation of a plasma membrane pore, but the underlying molecular mechanism has remained unclear. Recently, gasdermin D (GSDMD), a member of the ill-characterized gasdermin protein family, was identified as a caspase substrate and an essential mediator of pyroptosis. GSDMD is thus a candidate for pyroptotic pore formation. Here, we characterize GSDMD function in live cells and in vitro We show that the N-terminal fragment of caspase-1-cleaved GSDMD rapidly targets the membrane fraction of macrophages and that it induces the formation of a plasma membrane pore. In vitro, the N-terminal fragment of caspase-1-cleaved recombinant GSDMD tightly binds liposomes and forms large permeability pores. Visualization of liposome-inserted GSDMD at nanometer resolution by cryo-electron and atomic force microscopy shows circular pores with variable ring diameters around 20 nm. Overall, these data demonstrate that GSDMD is the direct and final executor of pyroptotic cell death.
762 citations
University of California, Berkeley1, United States Department of Energy2, Nagoya University3, University of Texas at Austin4, Ulsan National Institute of Science and Technology5, National Institute of Genetics6, Hiroshima University7, Hokkaido University8, University of Tokyo9, Radboud University Nijmegen10, Salk Institute for Biological Studies11, Nagahama Institute of Bio-Science and Technology12, Yamagata University13, Okinawa Institute of Science and Technology14, Tokyo Institute of Technology15, University of Tokushima16, Harry Perkins Institute of Medical Research17, Rikkyo University18, University of Maryland, Baltimore19, Kitasato University20, University of Chicago21, National Institute of Advanced Industrial Science and Technology22, National Institutes of Natural Sciences, Japan23, Illumina24, University of Washington25, University of Virginia26, Niigata University27, University of Rochester28, Cincinnati Children's Hospital Medical Center29, University of Calgary30, University of Iowa31, University of Basel32, Graduate University for Advanced Studies33, National Institute of Informatics34
TL;DR: The Xenopus laevis genome is sequenced and it is estimated that the two diploid progenitor species diverged around 34 million years ago and combined to form an allotetraploid around 17–18 Ma, where more than 56% of all genes were retained in two homoeologous copies.
Abstract: To explore the origins and consequences of tetraploidy in the African clawed frog, we sequenced the Xenopus laevis genome and compared it to the related diploid X. tropicalis genome. We characterize the allotetraploid origin of X. laevis by partitioning its genome into two homoeologous subgenomes, marked by distinct families of 'fossil' transposable elements. On the basis of the activity of these elements and the age of hundreds of unitary pseudogenes, we estimate that the two diploid progenitor species diverged around 34 million years ago (Ma) and combined to form an allotetraploid around 17-18 Ma. More than 56% of all genes were retained in two homoeologous copies. Protein function, gene expression, and the amount of conserved flanking sequence all correlate with retention rates. The subgenomes have evolved asymmetrically, with one chromosome set more often preserving the ancestral state and the other experiencing more gene loss, deletion, rearrangement, and reduced gene expression.
TL;DR: The Gviz package offers a flexible framework to visualize genomic data in the context of a variety of different genome annotation features, and greatly facilitates the production of publication-ready figures of genomic loci.
Abstract: The Gviz package offers a flexible framework to visualize genomic data in the context of a variety of different genome annotation features. Being tightly embedded in the Bioconductor genomics landscape, it nicely integrates with the existing infrastructure, but also provides direct data retrieval from external sources like Ensembl and UCSC and supports most of the commonly used annotation file types. Through carefully chosen default settings the package greatly facilitates the production of publication-ready figures of genomic loci, while still maintaining high flexibility due to its ample customization options.
TL;DR: The most potent neutralizing antibodies were ZIKV-specific and targeted EDIII or quaternary epitopes on infectious virus, and an EDIII-targeted antibody protected mice against lethal infection, illustrating the potential for antibody-based therapy.
Abstract: Zika virus (ZIKV), a mosquito-borne flavivirus with homology to Dengue virus (DENV), has become a public health emergency. By characterizing memory lymphocytes from ZIKV-infected patients, we dissected ZIKV-specific and DENV–cross-reactive immune responses. Antibodies to nonstructural protein 1 (NS1) were largely ZIKV-specific and were used to develop a serological diagnostic tool. In contrast, antibodies against E protein domain I/II (EDI/II) were cross-reactive and, although poorly neutralizing, potently enhanced ZIKV and DENV infection in vitro and lethally enhanced DENV disease in mice. Memory T cells against NS1 or E proteins were poorly cross-reactive, even in donors preexposed to DENV. The most potent neutralizing antibodies were ZIKV-specific and targeted EDIII or quaternary epitopes on infectious virus. An EDIII-specific antibody protected mice from lethal ZIKV infection, illustrating the potential for antibody-based therapy.
Heidelberg University1, German Cancer Research Center2, St. Jude Children's Research Hospital3, Ontario Institute for Cancer Research4, University of Toronto5, Institute of Cancer Research6, University of California, San Francisco7, Cincinnati Children's Hospital Medical Center8, Sapienza University of Rome9, University of Warsaw10, Boston Children's Hospital11, University of Bonn12, University of Hamburg13, Medical University of Vienna14, French Institute of Health and Medical Research15, Karolinska Institutet16, University of Freiburg17, Cork University Hospital18, Hadassah Medical Center19, Otto-von-Guericke University Magdeburg20, Copenhagen University Hospital21, Vanderbilt University Medical Center22, Children's Hospital of Philadelphia23, Washington University in St. Louis24, University of Göttingen25, Augsburg College26, University of Münster27, Radboud University Nijmegen28, VU University Medical Center29, University Medical Center Freiburg30, Ludwig Maximilian University of Munich31, University of Tübingen32, University of Basel33, Masaryk University34, University of Cambridge35, University of Amsterdam36, Necker-Enfants Malades Hospital37, Institut Gustave Roussy38, Aix-Marseille University39, University of Düsseldorf40, Virginia Commonwealth University41, University of Würzburg42, New York University43, Henry Ford Hospital44, University of Texas MD Anderson Cancer Center45, University of Queensland46, McGill University47
TL;DR: It is demonstrated that a significant proportion of institutionally diagnosed CNS-PNETs display molecular profiles indistinguishable from those of various other well-defined CNS tumor entities, facilitating diagnosis and appropriate therapy for patients with these tumors.
United States Department of Health and Human Services1, Erasmus University Rotterdam2, University of California, Berkeley3, Johns Hopkins University4, Icahn School of Medicine at Mount Sinai5, University of Southern California6, Duke University7, University of Bristol8, University Medical Center Groningen9, University of California, San Francisco10, North Carolina State University11, Karolinska Institutet12, Pompeu Fabra University13, University of Paris14, University of Memphis15, Centre Hospitalier Universitaire de Grenoble16, University of Bergen17, Isfahan University of Medical Sciences18, Brigham and Women's Hospital19, Oslo University Hospital20, Utrecht University21, French Institute of Health and Medical Research22, Norwegian Institute of Public Health23, Johns Hopkins University School of Medicine24, Harvard University25, International Agency for Research on Cancer26, Paris Descartes University27, Michigan State University28, Centre national de la recherche scientifique29, Fred Hutchinson Cancer Research Center30, University of Basel31, Swiss Tropical and Public Health Institute32, Stockholm County Council33, University of Southampton34
TL;DR: This large scale meta-analysis of methylation data identified numerous loci involved in response to maternal smoking in pregnancy with persistence into later childhood and provide insights into mechanisms underlying effects of this important exposure.
Abstract: Epigenetic modifications, including DNA methylation, represent a potential mechanism for environmental impacts on human disease. Maternal smoking in pregnancy remains an important public health problem that impacts child health in a myriad of ways and has potential lifelong consequences. The mechanisms are largely unknown, but epigenetics most likely plays a role. We formed the Pregnancy And Childhood Epigenetics (PACE) consortium and meta-analyzed, across 13 cohorts (n = 6,685), the association between maternal smoking in pregnancy and newborn blood DNA methylation at over 450,000 CpG sites (CpGs) by using the Illumina 450K BeadChip. Over 6,000 CpGs were differentially methylated in relation to maternal smoking at genome-wide statistical significance (false discovery rate, 5%), including 2,965 CpGs corresponding to 2,017 genes not previously related to smoking and methylation in either newborns or adults. Several genes are relevant to diseases that can be caused by maternal smoking (e.g., orofacial clefts and asthma) or adult smoking (e.g., certain cancers). A number of differentially methylated CpGs were associated with gene expression. We observed enrichment in pathways and processes critical to development. In older children (5 cohorts, n = 3,187), 100% of CpGs gave at least nominal levels of significance, far more than expected by chance (p value < 2.2 × 10(-16)). Results were robust to different normalization methods used across studies and cell type adjustment. In this large scale meta-analysis of methylation data, we identified numerous loci involved in response to maternal smoking in pregnancy with persistence into later childhood and provide insights into mechanisms underlying effects of this important exposure.
TL;DR: The abundance and composition of microplastics at the surface of the Rhine, one of the largest European rivers, is reported and measures should be implemented to avoid and reduce the pollution with anthropogenic litter in aquatic ecosystems.
Abstract: Microplastics result from fragmentation of plastic debris or are released to the environment as pre-production pellets or components of consumer and industrial products. In the oceans, they contribute to the 'great garbage patches'. They are ingested by many organisms, from protozoa to baleen whales, and pose a threat to the aquatic fauna. Although as much as 80% of marine debris originates from land, little attention was given to the role of rivers as debris pathways to the sea. Worldwide, not a single great river has yet been studied for the surface microplastics load over its length. We report the abundance and composition of microplastics at the surface of the Rhine, one of the largest European rivers. Measurements were made at 11 locations over a stretch of 820 km. Microplastics were found in all samples, with 892,777 particles km (-2) on average. In the Rhine-Ruhr metropolitan area, a peak concentration of 3.9 million particles km (-2) was measured. Microplastics concentrations were diverse along and across the river, reflecting various sources and sinks such as waste water treatment plants, tributaries and weirs. Measures should be implemented to avoid and reduce the pollution with anthropogenic litter in aquatic ecosystems.
TL;DR: This work uses efficient protein extraction and sample fractionation, as well as state-of-the-art quantitative mass spectrometry techniques to generate a comprehensive, condition-dependent protein-abundance map for Escherichia coli, uncovering system-wide proteome allocation, expression regulation and post-translational adaptations.
Abstract: Measuring precise concentrations of proteins can provide insights into biological processes. Here we use efficient protein extraction and sample fractionation, as well as state-of-the-art quantitative mass spectrometry techniques to generate a comprehensive, condition-dependent protein-abundance map for Escherichia coli. We measure cellular protein concentrations for 55% of predicted E. coli genes (>2,300 proteins) under 22 different experimental conditions and identify methylation and N-terminal protein acetylations previously not known to be prevalent in bacteria. We uncover system-wide proteome allocation, expression regulation and post-translational adaptations. These data provide a valuable resource for the systems biology and broader E. coli research communities.
Nicholas J Kassebaum1, Ryan M Barber1, Zulfiqar A Bhutta2, Zulfiqar A Bhutta3 +613 more•Institutions (272)
TL;DR: In this article, the authors quantified maternal mortality throughout the world by underlying cause and age from 1990 to 2015 for ages 10-54 years by systematically compiling and processing all available data sources from 186 of 195 countries and territories.
Vita-Salute San Raffaele University1, National Institute for Health Research2, UCL Institute of Neurology3, University of Siena4, University of Nottingham5, University of Basel6, Autonomous University of Barcelona7, University of Copenhagen8, University of Oxford9, National Institutes of Health10, Children's Hospital of Philadelphia11, VU University Amsterdam12
TL;DR: State-of-the-art MRI findings in patients presenting with a clinically isolated syndrome were discussed in a MAGNIMS workshop, the goal of which was to provide an evidence-based and expert-opinion consensus on diagnostic MRI criteria modifications.
Abstract: In patients presenting with a clinically isolated syndrome, MRI can support and substitute clinical information in the diagnosis of multiple sclerosis by showing disease dissemination in space and time and by helping to exclude disorders that can mimic multiple sclerosis. MRI criteria were first included in the diagnostic work-up for multiple sclerosis in 2001, and since then several modifications to the criteria have been proposed in an attempt to simplify lesion-count models for showing disease dissemination in space, change the timing of MRI scanning to show dissemination in time, and increase the value of spinal cord imaging. Since the last update of these criteria, new data on the use of MRI to establish dissemination in space and time have become available, and MRI technology has improved. State-of-the-art MRI findings in these patients were discussed in a MAGNIMS workshop, the goal of which was to provide an evidence-based and expert-opinion consensus on proposed modifications to MRI criteria for the diagnosis of multiple sclerosis.
Haidong Wang1, Zulfiqar A Bhutta2, Zulfiqar A Bhutta3, Matthew M Coates1 +610 more•Institutions (263)
TL;DR: The Global Burden of Disease 2015 Study provides an analytical framework to comprehensively assess trends for under-5 mortality, age-specific and cause-specific mortality among children under 5 years, and stillbirths by geography over time and decomposed the changes in under- 5 mortality to changes in SDI at the global level.
TL;DR: This work uses circuit-based optogenetic, in vivo and in vitro electrophysiological, and neuroanatomical tracing methods to define midbrain periaqueductal grey circuits for specific defensive behaviours and defines the neuronal circuitry underlying the execution of freezing, an evolutionarily conserved defensive behaviour.
Abstract: Survival in threatening situations depends on the selection and rapid execution of an appropriate active or passive defensive response, yet the underlying brain circuitry is not understood. Here we use circuit-based optogenetic, in vivo and in vitro electrophysiological, and neuroanatomical tracing methods to define midbrain periaqueductal grey circuits for specific defensive behaviours. We identify an inhibitory pathway from the central nucleus of the amygdala to the ventrolateral periaqueductal grey that produces freezing by disinhibition of ventrolateral periaqueductal grey excitatory outputs to pre-motor targets in the magnocellular nucleus of the medulla. In addition, we provide evidence for anatomical and functional interaction of this freezing pathway with long-range and local circuits mediating flight. Our data define the neuronal circuitry underlying the execution of freezing, an evolutionarily conserved defensive behaviour, which is expressed by many species including fish, rodents and primates. In humans, dysregulation of this 'survival circuit' has been implicated in anxiety-related disorders.
TL;DR: In this article, it was shown that all radial eigenvalues of the corresponding fractional Schrodinger operator H = (−Δ)^s+V are simple, provided that the potential V is radial and non-decreasing.
Abstract: We prove general uniqueness results for radial solutions of linear and nonlinear equations involving the fractional Laplacian (−Δ)^s with s ∊ (0,1) for any space dimensions N ≥ 1. By extending a monotonicity formula found by Cabre and Sire , we show that the linear equation
(−Δ)^s u + Vu=0 in R^N
has at most one radial and bounded solution vanishing at infinity, provided that the potential V is radial and nondecreasing. In particular, this result implies that all radial eigenvalues of the corresponding fractional Schrodinger operator H = (−Δ)^s + V are simple. Furthermore, by combining these findings on linear equations with topological bounds for a related problem on the upper half-space R^N_+^(+1), we show uniqueness and nondegeneracy of ground state solutions for the nonlinear equation
(−Δ)^s Q + Q- │Q│^ɑ Q=0 in R^N
for arbitrary space dimensions N ≥ 1 and all admissible exponents α > 0. This generalizes the nondegeneracy and uniqueness result for dimension N = 1 recently obtained by the first two authors and, in particular, the uniqueness result for solitary waves of the Benjamin-Ono equation found by Amick and Toland.
TL;DR: This work presents supramolecular polymer assemblies resulting from self-assembly of mostly amphiphilic copolymers either as 3D compartments either as polymersomes, PICsomes, peptosomes, or as planar membranes as candidates in applications ranging from drug delivery systems, up to artificial organelles, or active surfaces.
Abstract: Biological membranes play an essential role in living organisms by providing stable and functional compartments, preserving cell architecture, whilst supporting signalling and selective transport that are mediated by a variety of proteins embedded in the membrane. However, mimicking cell membranes – to be applied in artificial systems – is very challenging because of the vast complexity of biological structures. In this respect a highly promising strategy to designing multifunctional hybrid materials/systems is to combine biological molecules with polymer membranes or to design membranes with intrinsic stimuli-responsive properties. Here we present supramolecular polymer assemblies resulting from self-assembly of mostly amphiphilic copolymers either as 3D compartments (polymersomes, PICsomes, peptosomes), or as planar membranes (free-standing films, solid-supported membranes, membrane-mimetic brushes). In a bioinspired strategy, such synthetic assemblies decorated with biomolecules by insertion/encapsulation/attachment, serve for development of multifunctional systems. In addition, when the assemblies are stimuli-responsive, their architecture and properties change in the presence of stimuli, and release a cargo or allow “on demand” a specific in situ reaction. Relevant examples are included for an overview of bioinspired polymer compartments with nanometre sizes and membranes as candidates in applications ranging from drug delivery systems, up to artificial organelles, or active surfaces. Both the advantages of using polymer supramolecular assemblies and their present limitations are included to serve as a basis for future improvements.
TL;DR: A meta-analysis of genome-wide association studies for estimated glomerular filtration rate suggests that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.
Abstract: Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.
TL;DR: This work has assigned several nonredundant in vivo functions to distinct DC lineages, consisting of plasmacytoid DCs and several subsets of classical DCs that promote different immune effector modules in response to pathogens.
Abstract: The dendritic cells (DCs) of the immune system function in innate and adaptive responses by directing activity of various effector cells rather than serving as effectors themselves. DCs and closely related myeloid lineages share expression of many surface receptors, presenting a challenge in distinguishing their unique in vivo functions. Recent work has taken advantage of unique transcriptional programs to identify and manipulate murine DCs in vivo. This work has assigned several nonredundant in vivo functions to distinct DC lineages, consisting of plasmacytoid DCs and several subsets of classical DCs that promote different immune effector modules in response to pathogens. In parallel, a correspondence between human and murine DC subsets has emerged, underlying structural similarities for the DC lineages between these species. Recent work has begun to unravel the transcriptional circuitry that controls the development and diversification of DCs from common progenitors in the bone marrow.
TL;DR: Although higher monthly doses of vitamin D were effective in reaching a threshold of at least 30 ng/mL of 25-hydroxyvitamin D, they had no benefit on lower extremity function and were associated with increased risk of falls compared with 24,000 IU.
Abstract: Importance Vitamin D deficiency has been associated with poor physical performance. Objective To determine the effectiveness of high-dose vitamin D in lowering the risk of functional decline. Design, Setting, and Participants One-year, double-blind, randomized clinical trial conducted in Zurich, Switzerland. The screening phase was December 1, 2009, to May 31, 2010, and the last study visit was in May 2011. The dates of our analysis were June 15, 2012, to October 10, 2015. Participants were 200 community-dwelling men and women 70 years and older with a prior fall. Interventions Three study groups with monthly treatments, including a low-dose control group receiving 24 000 IU of vitamin D 3 (24 000 IU group), a group receiving 60 000 IU of vitamin D 3 (60 000 IU group), and a group receiving 24 000 IU of vitamin D 3 plus 300 μg of calcifediol (24 000 IU plus calcifediol group). Main Outcomes and Measures The primary end point was improving lower extremity function (on the Short Physical Performance Battery) and achieving 25-hydroxyvitamin D levels of at least 30 ng/mL at 6 and 12 months. A secondary end point was monthly reported falls. Analyses were adjusted for age, sex, and body mass index. Results The study cohort comprised 200 participants (men and women ≥70 years with a prior fall). Their mean age was 78 years, 67.0% (134 of 200) were female, and 58.0% (116 of 200) were vitamin D deficient ( P = .001), they were not more effective in improving lower extremity function, which did not differ among the treatment groups ( P = .26). However, over the 12-month follow-up, the incidence of falls differed significantly among the treatment groups, with higher incidences in the 60 000 IU group (66.9%; 95% CI, 54.4% to 77.5%) and the 24 000 IU plus calcifediol group (66.1%; 95% CI, 53.5%-76.8%) group compared with the 24 000 IU group (47.9%; 95% CI, 35.8%-60.3%) ( P = .048). Consistent with the incidence of falls, the mean number of falls differed marginally by treatment group. The 60 000 IU group (mean, 1.47) and the 24 000 IU plus calcifediol group (mean, 1.24) had higher mean numbers of falls compared with the 24 000 IU group (mean, 0.94) ( P = .09). Conclusions and Relevance Although higher monthly doses of vitamin D were effective in reaching a threshold of at least 30 ng/mL of 25-hydroxyvitamin D, they had no benefit on lower extremity function and were associated with increased risk of falls compared with 24 000 IU. Trial Registration clinicaltrials.gov Identifier:NCT01017354
TL;DR: In this article, a new global database was assembled to examine broad patterns of seasonal NSC variation across organs (leaves, stems, and belowground), plant functional types (coniferous, drought-deciduous angiosperms, winter deciduous, evergreen, and herbaceous) and biomes (boreal, temperate, Mediterranean, and tropical) under natural conditions.
Abstract: Plants store large amounts of non-structural carbohydrates (NSC). While multiple functions of NSC have long been recognized, the interpretation of NSC seasonal dynamics is often based on the idea that stored NSC is a reservoir of carbon that fluctuates depending on the balance between supply via photosynthesis and demand for growth and respiration (the source–sink dynamics concept). Consequently, relatively high NSC concentrations in some plants have been interpreted to reflect excess supply relative to demand. An alternative view, however, is that NSC accumulation reflects the relatively high NSC levels required for plant survival; an important issue that remains highly controversial. Here, we assembled a new global database to examine broad patterns of seasonal NSC variation across organs (leaves, stems, and belowground), plant functional types (coniferous, drought-deciduous angiosperms, winter deciduous angiosperms, evergreen angiosperms, and herbaceous) and biomes (boreal, temperate, Mediterranean, and tropical). We compiled data from 121 studies, including seasonal measurements for 177 species under natural conditions. Our results showed that, on average, NSC account for ~10% of dry plant biomass and are highest in leaves and lowest in stems, whereas belowground organs show intermediate concentrations. Total NSC, starch, and soluble sugars (SS) varied seasonally, with a strong depletion of starch during the growing season and a general increase during winter months, particularly in boreal and temperate biomes. Across functional types, NSC concentrations were highest and most variable in herbaceous species and in conifer needles. Conifers showed the lowest stem and belowground NSC concentrations. Minimum NSC values were relatively high (46% of seasonal maximums on average for total NSC) and, in contrast to average values, were similar among biomes and functional types. Overall, although starch depletion was relatively common, seasonal depletion of total NSC or SS was rare. These results are consistent with a dual view of NSC function: whereas starch acts mostly as a reservoir for future use, soluble sugars perform immediate functions (e.g., osmoregulation) and are kept above some critical threshold. If confirmed, this dual function of NSC will have important implications for the way we understand and model plant carbon allocation and survival under stress.
TL;DR: The authors discusses the consequences and challenges of putting the body at the center of attention in social interaction, and proposes to consider the involvement of entire bodies in social interactions, overcoming a logo-centric vision of communication, as well as a visuo-centric view of embodiment.
Abstract: This article reflects on recent challenges emerging from the study of language and the body in social interaction. There is a general interest in language and the body across disciplines that has invited a reconceptualization of the broader issues relative to action, cognition, culture, knowledge, social relations and identities, spatiality and temporality. The study of social interaction focuses on how multimodal resources – including language and bodily movements – are holistically and situatedly used in building human action. This article discusses some consequences and challenges of putting the body at the center of attention: it repositions language as one among other modalities, and invites us to consider the involvement of entire bodies in social interaction, overcoming a logo-centric vision of communication, as well as a visuo-centric vision of embodiment. These issues are developed through a series of conversation analytic studies, firstly of classic topics in linguistics like deixis, then of more recent topics, such as mobility and sensoriality.
TL;DR: Better understand the molecular networks underlying the cell plasticity conferred by an EMT or a MET and its functional contribution to malignant tumor progression.
Wesley C. Van Voorhis1, John H. Adams2, Roberto Adelfio3, Roberto Adelfio4 +197 more•Institutions (62)
TL;DR: The results reveal the immense potential for translating the dispersed expertise in biological assays involving human pathogens into drug discovery starting points, by providing open access to new families of molecules, and emphasize how a small additional investment made to help acquire and distribute compounds, and sharing the data, can catalyze drug discovery for dozens of different indications.
Abstract: A major cause of the paucity of new starting points for drug discovery is the lack of interaction between academia and industry. Much of the global resource in biology is present in universities, whereas the focus of medicinal chemistry is still largely within industry. Open source drug discovery, with sharing of information, is clearly a first step towards overcoming this gap. But the interface could especially be bridged through a scale-up of open sharing of physical compounds, which would accelerate the finding of new starting points for drug discovery. The Medicines for Malaria Venture Malaria Box is a collection of over 400 compounds representing families of structures identified in phenotypic screens of pharmaceutical and academic libraries against the Plasmodium falciparum malaria parasite. The set has now been distributed to almost 200 research groups globally in the last two years, with the only stipulation that information from the screens is deposited in the public domain. This paper reports for the first time on 236 screens that have been carried out against the Malaria Box and compares these results with 55 assays that were previously published, in a format that allows a meta-analysis of the combined dataset. The combined biochemical and cellular assays presented here suggest mechanisms of action for 135 (34%) of the compounds active in killing multiple life-cycle stages of the malaria parasite, including asexual blood, liver, gametocyte, gametes and insect ookinete stages. In addition, many compounds demonstrated activity against other pathogens, showing hits in assays with 16 protozoa, 7 helminths, 9 bacterial and mycobacterial species, the dengue fever mosquito vector, and the NCI60 human cancer cell line panel of 60 human tumor cell lines. Toxicological, pharmacokinetic and metabolic properties were collected on all the compounds, assisting in the selection of the most promising candidates for murine proof-of-concept experiments and medicinal chemistry programs. The data for all of these assays are presented and analyzed to show how outstanding leads for many indications can be selected. These results reveal the immense potential for translating the dispersed expertise in biological assays involving human pathogens into drug discovery starting points, by providing open access to new families of molecules, and emphasize how a small additional investment made to help acquire and distribute compounds, and sharing the data, can catalyze drug discovery for dozens of different indications. Another lesson is that when multiple screens from different groups are run on the same library, results can be integrated quickly to select the most valuable starting points for subsequent medicinal chemistry efforts.