The K20 survey. VI. The Distribution of the Stellar Masses in Galaxies up to z~2

We present a detailed analysis of the stellar mass content of galaxies up to z=2.5 in the K20 galaxy sample, that has a 92% spectroscopic completeness and a complete $UBVRIzJK_s$ multicolor coverage. We find that the M/L ratio decreases with redshift: in particular, the average M/L ratio of early type galaxies decreases with $z$, with a scatter that is indicative of a range of star--formation time-scales and redshift of formation. More important, the typical M/L of massive early type galaxies is larger than that of less massive ones, suggesting that their stellar population formed at higher z. The final K20 galaxy sample spans a range of stellar masses from M*=10^9Msun to M*=10^12Msun, with massive galaxies ($M*>10^11Msun) detected up to z~2. We compute the Galaxy Stellar Mass Function at various z, of which we observe only a mild evolution (i.e. by 20-30%) up to z~1. At z>1, the evolution of the GSMF appears to be much faster: at z~2, about 35% of the present day stellar mass in objects with M*~10^11Msun appear to have assembled. We also detect a change in the physical nature of the most massive galaxies, since at z>1 a population of massive star--forming galaxies progressively appears. We finally analyze our results in the framework of Lambda-CDM hierarchical models. First, we show that the large number of massive galaxies detected at high z does not violate any fundamental Lambda-CDM constraint based on the number of massive DM halos. Then, we compare our results with the predictions of renditions of both semianalytic and hydro-dynamical models, that range from severe underestimates to slight overestimates of the observed mass density at z<~2. We discuss how the differences among these models are due to the different implementation of the main physical processes. (Abridged)Comment: Accepted for publication on Astronomy & Astrophysic

Norovirus Regulation of the Innate Immune Response and Apoptosis Occurs via the Product of the Alternative Open Reading Frame 4

Small RNA viruses have evolved many mechanisms to increase the capacity of their short genomes. Here we describe the identification and characterization of a novel open reading frame (ORF4) encoded by the murine norovirus (MNV) subgenomic RNA, in an alternative reading frame overlapping the VP1 coding region. ORF4 is translated during virus infection and the resultant protein localizes predominantly to the mitochondria. Using reverse genetics we demonstrated that expression of ORF4 is not required for virus replication in tissue culture but its loss results in a fitness cost since viruses lacking the ability to express ORF4 restore expression upon repeated passage in tissue culture. Functional analysis indicated that the protein produced from ORF4 antagonizes the innate immune response to infection by delaying the upregulation of a number of cellular genes activated by the innate pathway, including IFN-Beta. Apoptosis in the RAW264.7 macrophage cell line was also increased during virus infection in the absence of ORF4 expression. In vivo analysis of the WT and mutant virus lacking the ability to express ORF4 demonstrated an important role for ORF4 expression in infection and virulence. STAT1-/- mice infected with a virus lacking the ability to express ORF4 showed a delay in the onset of clinical signs when compared to mice infected with WT virus. Quantitative PCR and histopathological analysis of samples from these infected mice demonstrated that infection with a virus not expressing ORF4 results in a delayed infection in this system. In light of these findings we propose the name virulence factor 1, VF1 for this protein. The identification of VF1 represents the first characterization of an alternative open reading frame protein for the calicivirus family. The immune regulatory function of the MNV VF1 protein provide important perspectives for future research into norovirus biology and pathogenesis

A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.

This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ng.3448Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.We thank all participants of all the studies included for enabling this research by their participation in these studies. Computer resources for this project have been provided by the high-performance computing centers of the University of Michigan and the University of Regensburg. Group-specific acknowledgments can be found in the Supplementary Note. The Center for Inherited Diseases Research (CIDR) Program contract number is HHSN268201200008I. This and the main consortium work were predominantly funded by 1X01HG006934-01 to G.R.A. and R01 EY022310 to J.L.H

The Human Phenotype Ontology in 2024: phenotypes around the world.

The Human Phenotype Ontology (HPO) is a widely used resource that comprehensively organizes and defines the phenotypic features of human disease, enabling computational inference and supporting genomic and phenotypic analyses through semantic similarity and machine learning algorithms. The HPO has widespread applications in clinical diagnostics and translational research, including genomic diagnostics, gene-disease discovery, and cohort analytics. In recent years, groups around the world have developed translations of the HPO from English to other languages, and the HPO browser has been internationalized, allowing users to view HPO term labels and in many cases synonyms and definitions in ten languages in addition to English. Since our last report, a total of 2239 new HPO terms and 49235 new HPO annotations were developed, many in collaboration with external groups in the fields of psychiatry, arthrogryposis, immunology and cardiology. The Medical Action Ontology (MAxO) is a new effort to model treatments and other measures taken for clinical management. Finally, the HPO consortium is contributing to efforts to integrate the HPO and the GA4GH Phenopacket Schema into electronic health records (EHRs) with the goal of more standardized and computable integration of rare disease data in EHRs

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

The Messina Strait Bridge: A Challenge and a Dream

This book describes the enormous depth of work carried out since the early seventies on the Messina Strait Bridge, up to the recent award of the detailed design and construction contract. This important work has included extensive studies, concepts and design developments, with far reaching applications, which have all confirmed the feasibility of this huge endeavour and have led to the optimisation of costs and expected performance levels. Attention is focused not only on the design itself, but also on the context for the project (e.g. historical, geological, seismo-tectonic and wind conditions; structural and mechanical properties; project management and financial aspects; and environmental considerations), and on the great challenges involved. Thus, considering the innovations and specific solutions adopted in overcoming the challenges presented by constructing a world record span of 3,300 metres at this site, it becomes clear how the Messina Strait Crossing will take its place as a masterpiece in bridge engineering history. This book will be of interest to bridge and structural engineers, geotechnical and wind engineers, mechanical and earthquake engineers, graduate students in all these areas and all others with a broad interest in bridge design and engineering

Professional differences in interprofessional working

UK government policy is encouraging healthcare staff to blur traditional roles, in the drive to increase joint working between practitioners. However, there is currently a lack of clarity regarding the impact that changes to traditional working practice might have on staff delivering the services, or on patient care. In this article, we report findings from three qualitative case studies examining interprofessional practice in stroke care, in which the influence of professional differences emerged as a significant theme. We draw on findings from individual semi-structured interviews, as well as fieldwork observations, to describe the influence of professional knowledge and skills, role and identity, and power and status considerations in interprofessional working. The insights that were gained contribute to the understanding of how professional differences impact on healthcare staff joint working, and suggest that the elements identified need to be fully considered in drives towards changed working practice