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Variants in RAC3, encoding a small GTPase RAC3 which is critical for the regulation of actin cytoskeleton and intracellular signal transduction, are associated with a rare neurodevelopmental disorder with structural brain anomalies and facial dysmorphism. We investigated a cohort of 10 unrelated participants presenting with global psychomotor delay, hypotonia, behavioural disturbances, stereotyped movements, dysmorphic features, seizures and musculoskeletal abnormalities. MRI of brain revealed a complex pattern of variable brain malformations, including callosal abnormalities, white matter thinning, grey matter heterotopia, polymicrogyria/dysgyria, brainstem anomalies and cerebellar dysplasia. These patients harboured eight distinct de novo RAC3 variants, including six novel variants (NM_005052.3): c.34G > C p.G12R, c.179G > A p.G60D, c.186_188delGGA p.E62del, c.187G > A p.D63N, c.191A > G p.Y64C and c.348G > C p.K116N. We then examined the pathophysiological significance of these novel and previously reported pathogenic variants p.P29L, p.P34R, p.A59G, p.Q61L and p.E62K. In vitro analyses revealed that all tested RAC3 variants were biochemically and biologically active to variable extent, and exhibited a spectrum of different affinities to downstream effectors including p21-activated kinase 1. We then focused on the four variants p.Q61L, p.E62del, p.D63N and p.Y64C in the Switch II region, which is essential for the biochemical activity of small GTPases and also a variation hot spot common to other Rho family genes, RAC1 and CDC42. Acute expression of the four variants in embryonic mouse brain using in utero electroporation caused defects in cortical neuron morphology and migration ending up with cluster formation during corticogenesis. Notably, defective migration by p.E62del, p.D63N and p.Y64C were rescued by a dominant negative version of p21-activated kinase 1. Our results indicate that RAC3 variants result in morphological and functional defects in cortical neurons during brain development through variant-specific mechanisms, eventually leading to heterogeneous neurodevelopmental phenotypes. Scala et al. identify six de novo variants in RAC3, which encodes a small GTPase, in 10 unrelated subjects with neurodevelopmental phenotypes. In vivo and in vitro analyses in mice reveal that RAC3 variants cause morpho-functional defects in cortical neurons through variant-specific mechanisms, disrupting corticogenesis.

A linear argument must be consumed exactly once in the body of its function. A linear type system can verify the correct usage of resources such as file handles and manually managed memory. But this verification requires bureaucracy. This paper presents linear constraints, a front-end feature for linear typing that decreases the bureaucracy of working with linear types. Linear constraints are implicit linear arguments that are to be filled in automatically by the compiler. Linear constraints are presented as a qualified type system, together with an inference algorithm which extends OutsideIn, GHC's existing constraint solver algorithm. Soundness of linear constraints is ensured by the fact that they desugar into Linear Haskell.

Since July 2014, the Gaia mission has been engaged in a high-spatial-resolution, time-resolved, precise, accurate astrometric, and photometric survey of the entire sky. Aims: We present the Gaia Science Alerts project, which has been in operation since 1 June 2016. We describe the system which has been developed to enable the discovery and publication of transient photometric events as seen by Gaia. Methods: We outline the data handling, timings, and performances, and we describe the transient detection algorithms and filtering procedures needed to manage the high false alarm rate. We identify two classes of events: (1) sources which are new to Gaia and (2) Gaia sources which have undergone a significant brightening or fading. Validation of the Gaia transit astrometry and photometry was performed, followed by testing of the source environment to minimise contamination from Solar System objects, bright stars, and fainter near-neighbours. Results: We show that the Gaia Science Alerts project suffers from very low contamination, that is there are very few false-positives. We find that the external completeness for supernovae, $C_E=0.46$, is dominated by the Gaia scanning law and the requirement of detections from both fields-of-view. Where we have two or more scans the internal completeness is $C_I=0.79$ at 3 arcsec or larger from the centres of galaxies, but it drops closer in, especially within 1 arcsec. Conclusions: The per-transit photometry for Gaia transients is precise to 1 per cent at $G=13$, and 3 per cent at $G=19$. The per-transit astrometry is accurate to 55 milliarcseconds when compared to Gaia DR2. The Gaia Science Alerts project is one of the most homogeneous and productive transient surveys in operation, and it is the only survey which covers the whole sky at high spatial resolution (subarcsecond), including the Galactic plane and bulge., This work has made use of data from the European Space Agency (ESA) mission \gaia\ (\url{https://www.cosmos.esa.int/gaia}), processed by the \gaia\ Data Processing and Analysis Consortium (DPAC, \url{https://www.cosmos.esa.int/web/gaia/dpac/consortium}). Funding for the DPAC has been provided by national institutions, in particular the institutions participating in the \gaia\ Multilateral Agreement. Further details of funding authorities and individuals contributing to the success of the mission is shown at \url{https://gea.esac.esa.int/archive/documentation/GEDR3/Miscellaneous/sec_acknowl/}. We thank the United Kingdom Particle Physics and Astronomy Research Council (PPARC), the United Kingdom Science and Technology Facilities Council (STFC), and the United Kingdom Space Agency (UKSA) through the following grants to the University of Bristol, the University of Cambridge, the University of Edinburgh, the University of Leicester, the Mullard Space Sciences Laboratory of University College London, and the United Kingdom Rutherford Appleton Laboratory (RAL): PP/D006511/1, PP/D006546/1, PP/D006570/1, ST/I000852/1, ST/J005045/1, ST/K00056X/1, ST/K000209/1, ST/K000756/1, ST/L006561/1, ST/N000595/1, ST/S000623/1, ST/N000641/1, ST/N000978/1, ST/N001117/1, ST/S000089/1, ST/S000976/1, ST/S001123/1, ST/S001948/1, ST/S002103/1, and ST/V000969/1. This paper made use of the Whole Sky Database (WSDB) created by Sergey Koposov and maintained at the Institute of Astronomy, Cambridge with financial support from the Science and Technology Facilities Council (STFC) and the European Research Council (ERC). We thank the William Herschel and Isaac Newton Telescopes on the Roque de los Muchachos Observatory, La Palma, Spain, as well as the Optical Infrared Coordination Network for Astronomy (OPTICON) for their support of this project through telescope time, especially during the commissioning and verification phases. We thank the Copernico 1.82m telescope (Mt. Ekar, Asiago Italy) operated by INAF Padova for supporting the project through telescope time (under the Large Programme Tomasella-SNe) during the verification phases. We acknowledge observations taken as part of the PESSTO project collected at the European Organisation for Astronomical Research in the Southern Hemisphere under ESO programme 199.D-0143. Authors at the ICCUB were supported by the Spanish Ministry of Science, Innovation and University (MICIU/FEDER, UE) through grant RTI2018-095076-B-C21, and the Institute of Cosmos Sciences University of Barcelona (ICCUB, Unidad de Excelencia ’Mar\'{\i}a de Maeztu’) through grant CEX2019-000918-M. This work is supported by Polish NCN grants: Daina No. 2017/27/L/ST9/03221, Harmonia No. 2018/30/M/ST9/00311, Preludium No. 2017/25/N/ST9/01253 and MNiSW grant DIR/WK/2018/12 as well as the European Commission's Horizon2020 OPTICON grant No. 730890. The Authors would like to thank the Warsaw University OGLE project for their continuous support in this work. AB acknowledges financial support from the Netherlands Research School for Astronomy (NOVA). AG acknowledges the financial support from the Slovenian Research Agency (grants P1-0031, I0-0033, J1-8136, J1-2460). AH was funded in part by the Leverhulme Trust through grant RPG-2012-541 and by the European Research Council grant 320360. AP acknowledges support from the NCN grant No.~2016/21/B/ST9/01126. CM acknowledges support from Jim and Hiroko Sherwin. DAK acknowledges support from the Spanish research projects AYA 2014-58381-P, AYA2017-89384-P, from Juan de la Cierva Incorporaci\'on fellowship IJCI-2015-26153, and from Spanish National Research Project RTI2018-098104-J-I00 (GRBPhot). EB and STH are funded by the Science and Technology Facilities Council grant ST/S000623/1. TW was funded in part by European Research Council grant 320360 and by European Commission grant 730980. GC acknowledges the Agenzia Spaziale Italiana (ASI) for its continuing support through contract 2018-24-HH.0 to the Italian Istituto Nazionale di Astrofisica (INAF). GD acknowledges the observing grant support from the Institute of Astronomy and Rozhen NAO BAS through the bilateral joint research project "Gaia Celestial Reference Frame (CRF) and fast variable astronomical objects" (during 2020-2022, leader is G.Damljanovic), and support by the Ministry of Education, Science and Technological Development of the Republic of Serbia (contract No 451-03-68/2020-14/200002). G. Marton acknowledges support from the EC Horizon 2020 project OPTICON (730890) and the ESA PRODEX contract nr. 4000129910. MF is supported by a Royal Society - Science Foundation Ireland University Research Fellowship NB acknowledges support from the research programme VENI, with project number 016.192.277, which is (partly) financed by the Netherlands Organisation for Scientific Research (NWO). NI is partially supported by Polish NCN DAINA grant No. 2017/27/L/ST9/03221. PAW acknowledges research funding from the South African National Research Foundation. RWW was funded by the Science and Technology Facilities Council grant ST/P000541/1. V.A.R.M.R.\ acknowledges financial support from Radboud Excellence Initiative, the Funda\c{c}\~{a}o para a Ci\^encia e a Tecnologia (FCT) in the form of an exploratory project of reference IF/00498/2015/CP1302/CT0001, FCT and the Minist\'erio da Ci\^encia, Tecnologia e Ensino Superior (MCTES) through national funds and when applicable co-funded EU funds under the project UIDB/EEA/50008/2020, and supported by Enabling Green E-science for the Square Kilometre Array Research Infrastructure (ENGAGE-SKA), POCI-01-0145-FEDER-022217, and PHOBOS, POCI-01-0145-FEDER-029932, funded by Programa Operacional Competitividade e Internacionaliza\c{c}\~ao (COMPETE 2020) and FCT, Portugal. ZKR acknowledges funding from the Netherlands Research School for Astronomy (NOVA). ZN acknowledges support from the ESA PRODEX contract nr. 4000129910.

BACKGROUND In older patients, sarcopenia is a prevalent disease associated with negative outcomes. Sarcopenia has been investigated in patients undergoing transcatheter aortic valve implantation (TAVI), but the criteria for diagnosis of the disease are heterogeneous. This systematic review of the current literature aims to evaluate the prevalence of sarcopenia in patients undergoing TAVI and to analyse the impact of sarcopenia on clinical outcomes. METHODS A comprehensive search of the literature has been performed in electronic databases from the date of initiation until March 2020. Using a pre-defined search strategy, we identified studies assessing skeletal muscle mass, muscle quality and muscle function as measures for sarcopenia in patients undergoing TAVI. We evaluated how sarcopenia affects the outcomes mortality at ≥1 year, prolonged length of hospital stay, and functional decline. RESULTS We identified 18 observational studies, enrolling a total number of 9'513 patients. For assessment of skeletal muscle mass, all included studies used data from computed tomography. Cut-off points for definition of low muscle mass were heterogeneous, and prevalence of sarcopenia varied between 21.0% and 70.2%. In uni- or multivariate regression analysis of different studies, low muscle mass was found to be a significant predictor of mortality, prolonged length of hospital stay, and functional decline. No interventional study was identified measuring the effect of nutritional or physiotherapy interventions on sarcopenia in TAVI patients. CONCLUSIONS Sarcopenia is highly prevalent among patients undergoing TAVI, and negatively affects important outcomes. Early diagnosis of this condition might allow a timely start of nutritional and physiotherapy interventions to prevent negative outcomes in TAVI patients.

Type family applications in Haskell must be fully saturated. This means that all type-level functions haveto be first-order, leading to code that is both messy and longwinded. In this paper we detail an extension toGHC that removes this restriction. We augment Haskell’s existing type arrow,→, with anunmatchablearrow,↠, that supports partial application of type families without compromising soundness. A soundness proof isprovided. We show how the techniques described can lead to substantial code-size reduction (circa 80%) inthe type-level logic of commonly-used type-level libraries whilst simultaneously improving code quality and readability.

There are few data exploring clustering of osteoporotic fractures within families. The aim of this study was to determine the influence of maternal and paternal history of hip fracture on the risk of vertebral deformity. 12,816 men and women aged 50 to 75 years were recruited from population based sampling frames across Europe. Subjects were invited to attend by letter of invitation for an interviewer administered questionnaire and lateral spinal radiographs. Vertebral deformity was defined morphometrically using the McCloskey-Kanis method. 6.4% of men and 7.1% of women reported that their mother had suffered a hip fracture, while 1.7% of both men and women reported that their father had suffered a hip fracture. A maternal history of hip fracture was associated with a modest increased risk of vertebral deformity in men [odds ratio (OR) 1.3, 95% confidence interval (CI) 1.0-1.8], the risk being greater among those aged 65 years and over (OR = 1.5; 95% CI 1.0-2.4) and in those from low prevalence areas. There was no increased risk in women. Paternal history of hip fracture was not associated with vertebral deformity in either sex. In conclusion, maternal history of hip fracture appears to be a risk factor for vertebral deformity, particularly in men.

International audience; Aims. Trans-Neptunian objects (TNOs) are bodies populating the Kuiper belt and they are believed to retain the most pristine and least altered material of the solar system. The Herschel open time key programme entitled “TNOs are Cool: A survey of the trans-Neptunian region” has been awarded 373 h to investigate the albedo, size distribution and thermal properties of TNOs and Centaurs. Here we focus on the brightest targets observed by both the PACS and SPIRE multiband photometers: the dwarf planet Haumea, six TNOs (Huya, Orcus, Quaoar, Salacia, 2002 UX25, and 2002 TC302), and two Centaurs (Chiron and Chariklo).Methods. Flux densities are derived from PACS and SPIRE instruments using optimised data reduction methods. The spectral energy distribution obtained with the Herschel PACS and SPIRE instruments over 6 bands (centred at 70, 100, 160, 250, 350, and 500 μm), with Spitzer-MIPS at 23.7 and 71.4 μm, and with WISE at 11.6 and 22.1 μm in the case of 10199 Chariklo, has been modelled with the NEATM thermal model in order to derive the albedo, diameter, and beaming factor. For the Centaurs Chiron and Chariklo and for the 1000 km sized Orcus and Quaoar, a thermophysical model was also run to better constrain their thermal properties.Results. We derive the size, albedo, and thermal properties, including thermal inertia and surface emissivity, for the 9 TNOs and Centaurs. Several targets show a significant decrease in their spectral emissivity longwards of ~300 μm and especially at 500 μm. Using our size estimations and the mass values available in the literature, we also derive the bulk densities for the binaries Quaoar/Weywot (2.18-0.36+0.43 g/cm3), Orcus/Vanth (1.53-0.13+0.15 g/cm3), and Salacia/Actea (1.29-0.23+0.29 g/cm3). Quaoar’s density is similar to that of the other dwarf planets Pluto and Haumea, and its value implies high contents of refractory materials mixed with ices.

In this paper we briefly summarize the design concepts of the Fly's Eye Camera System, a proposed high resolution all-sky monitoring device which intends to perform high cadence time domain astronomy in multiple optical passbands while still accomplish a high étendue. Funding has already been accepted by the Hungarian Academy of Sciences in order to design and build a Fly's Eye device unit. Beyond the technical details and the actual scientific goals, this paper also discusses the possibilities and yields of a network operation involving ˜10 sites distributed geographically in a nearly homogeneous manner. Currently, we expect to finalize the mount assembly - that performs the sidereal tracking during the exposures - until the end of 2012 and to have a working prototype with a reduced number of individual cameras sometime in the spring or summer of 2013.

Lean body stature and tallness have both been identified as risk factors for hip fracture. In this study, height and weight data from a multinational multicenter study were used' to compare Oslo, which has some of the highest incidence rates of hip fracture ever reported, to other regions of Europe, with respect to height and body mass index. More than 17, 000 subjects in six age strata (50–54, 55–59, 60–64, 65–69, 70–74, 75+ years) from 36 centers in 19 European countries were enrolled in the European Vertebral Osteoporosis Study (EVOS), which included standardized height and weight measurements. We found that men in Oslo were 4.3 cm taller than men in western Europe, 5.0 cm taller than men in eastern Europe, and 8.6 cm taller than men in southern Europe. Oslo women were also taller, by 2.2 cm compared to women in western Europe, 2.7 cm compared to women in eastern Europe, and 5.2 cm compared to women in southern Europe. In all age groups, except women aged 55–59 years, mean body mass index (BMI) was lowest in Oslo. Nearly twice as many had a BMI less than 22.0 kg/m2 in Oslo compared to the other regions combined (11.1% vs. 6.6% in men and 19.2% vs. 9.9% in women). This study indicates that the people of Oslo are taller and leaner than people in other regions of Europe. This may in part explain the higher incidence of hip fracture in the population of Oslo.

We investigate the effect of the "high-pass filter" data reduction technique on the Herschel PACS PSF and noise of the PACS maps at the 70, 100 and 160 um bands and in medium and fast scan speeds. This branch of the PACS Photometer pipeline is the most used for cosmological observations and for point-source observations.The calibration of the flux loss due to the median removal applied by the PACS pipeline (high-pass filter) is done via dedicated simulations obtained by "polluting" real PACS timelines with fake sources at different flux levels. The effect of the data reduction parameter settings on the final map noise is done by using selected observations of blank fields with high data redundancy. We show that the running median removal can cause significant flux losses at any flux level. We analyse the advantages and disadvantages of several masking strategies and suggest that a mask based on putting circular patches on prior positions is the best solution to reduce the amount of flux loss. We provide a calibration of the point-source flux loss for several masking strategies in a large range of data reduction parameters, and as a function of the source flux. We also show that, for stacking analysis, the impact of the high-pass filtering effect is to reduce significantly the clustering effect. The analysis of the global noise and noise components of the PACS maps shows that the dominant parameter in determining the final noise is the high-pass filter width. We also provide simple fitting functions to build the error map from the coverage map and to estimate the cross-correlation correction factor in a representative portion of the data reduction parameter space., Comment: 32 pages, 28 figures, submitted to A&A

In this paper optimal experimental designs for inverse quadratic regression models are determined. We consider two different parameterizations of the model and investigate local optimal designs with respect to the $c$-, $D$- and $E$-criteria, which reflect various aspects of the precision of the maximum likelihood estimator for the parameters in inverse quadratic regression models. In particular it is demonstrated that for a sufficiently large design space geometric allocation rules are optimal with respect to many optimality criteria. Moreover, in numerous cases the designs with respect to the different criteria are supported at the same points. Finally, the efficiencies of different optimal designs with respect to various optimality criteria are studied, and the efficiency of some commonly used designs are investigated., 24 pages

著者人数: 22名, Accepted: 2013-07-29, 資料番号: SA1004524000

International audience

In this study, acoustic-phonetic analysis of continuous speech and statistical analyses were performed in order to find parameters in depressed speech that show significant differences compared to a healthy reference group. Read speech materials were gathered in the Hungarian and Italian languages from both healthy people and patients diagnosed with different degrees of depression. By statistical examination it was found that there are many parameters in the speech of depressed people that show significant differences compared to a healthy reference group. Moreover, most of those parameters behave similarly in other languages such as in Italian. For classification of the healthy and depressed speech, these parameters were used as an input for the classifiers. Two classification methods were compared: Support Vector Machine (SVM) and a two-layer feed-forward neural network (NN). No difference was found between the results of the two methods when trained and tested on Hungarian language (both SVM and NN classification accuracy was 75 %). In the case of training with Hungarian and testing with Italian healthy and depressed speech both classifiers reached 77 % of accuracy.