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This deliverable addresses EOSC-Life WP1's objectives related to publication of data and data resources in cloud repositories by making available resources in EOSC-Life's registries; the implementation of FAIR services and standards, by development of FAIR registries in collaboration with WP6; and evolution of repository infrastructure by making available registry entries deriving from WP3 demonstrators. Use cases for EOSC-Life registries have been defined for general and clinical research data use and the 'EOSC-Life' collection in FAIRsharing has been populated and released comprising more than 100 data resources and standards. A clinical MetaData Repository has also been developed to address challenges of clinical data sharing in Europe. We have engaged with EOSC, sister projects such as FAIRsFAIR and ENVRI to consider the features of registries, cross registry interoperability and use cases which link EOSC projects. We will continue to update the registries as the project progresses and as new dataset and resources are made available and will engage with pan-EOSC registry planning based on our work to date.

Motivation High-throughput phenomic projects generate complex data from small treatment and large control groups that increase the power of the analyses but introduce variation over time. A method is needed to utlize a set of temporally local controls that maximizes analytic power while minimizing noise from unspecified environmental factors. Results Here we introduce ‘soft windowing’, a methodological approach that selects a window of time that includes the most appropriate controls for analysis. Using phenotype data from the International Mouse Phenotyping Consortium (IMPC), adaptive windows were applied such that control data collected proximally to mutants were assigned the maximal weight, while data collected earlier or later had less weight. We applied this method to IMPC data and compared the results with those obtained from a standard non-windowed approach. Validation was performed using a resampling approach in which we demonstrate a 10% reduction of false positives from 2.5 million analyses. We applied the method to our production analysis pipeline that establishes genotype–phenotype associations by comparing mutant versus control data. We report an increase of 30% in significant P-values, as well as linkage to 106 versus 99 disease models via phenotype overlap with the soft-windowed and non-windowed approaches, respectively, from a set of 2082 mutant mouse lines. Our method is generalizable and can benefit large-scale human phenomic projects such as the UK Biobank and the All of Us resources. Availability and implementation The method is freely available in the R package SmoothWin, available on CRAN http://CRAN.R-project.org/package=SmoothWin. Supplementary information Supplementary data are available at Bioinformatics online.

Resume Introduction Bien qu’utilisees couramment, le resultat a long terme des protheses de genou (PTG) a contrainte augmentee (CCK) n’est pas connu avec precision. Cette serie porte sur des PTG CCK au recul minimal theorique de 10 ans afin de preciser : (1) les effets secondaires (osteolyse, descellement, faillite du mecanisme de contrainte) ; (2) le resultat fonctionnel et particulierement la mobilite ; (3) le taux de survie. Hypothese L’augmentation de contrainte par cage type CCK n’augmente pas les taux d’osteolyse et de descellement mecanique a long terme. Materiel et methodes Quarante-trois PTG Legacy CCK primaires ont ete analysees. L’indication etait une deformation importante (n = 20), une laxite preoperatoire (n = 6) ou une impossibilite d’equilibrage peroperatoire (n = 17). Il s’agissait de 41 patients âges en moyenne de 66 ans (21–88). Vingt-sept genoux (63 %) avaient deja eu au moins une intervention. Les resultats etaient evalues au moyen des scores HSS et Knee Society Score (KSS), et sur la variation des angles HKA. La survie etait mesuree avec comme censure une reintervention pour toutes causes hors et avec infection. Resultats Hormis les thromboses veineuses, le taux de complication etait de 16 % dont 3 revisions (2 descellements septiques, 1 instabilite majeure lorsque la PTG CCK avait ete implantee sous une arthrodese de hanche). Il n’y avait aucune osteolyse, ni descellement aseptique. Le recul moyen etait de 12,7 ans (10–14). Le score HSS passait de 53 (26–83) en preoperatoire a 80 (55–93) au recul, le score KSS genou de 42 (16–77) a 90 (77–99) et KSS fonction de 31 (0–80) a 61 (10–90) (p Discussion L’amelioration fonctionnelle obtenue etait comparable a celles des PTG posterostabilisees standard, sans defaillance de la came ni osteolyse. Le taux de complication etait plus important, donnant une survie inferieure aux PTG standard, mais il s’agissait de genoux particulierement deformes et/ou instables et dont 2/3 avaient deja subi au moins une intervention. Niveau de preuve Niveau IV. Serie retrospective.

BackgroundAlthough constrained condylar knee (CCK) inserts are widely used for total knee arthroplasty (TKA), their long-term outcomes remain unclear. We sought to evaluate patients with at least 10 years’ follow-up after CCK TKA to identify potential adverse events (osteolysis, loosening, constraint-mechanism failure), assess functional outcomes with special emphasis on range of motion, and determine prosthesis survival.HypothesisIncreasing constraint by implantation of a CCK insert does not increase the long-term frequencies of osteolysis or mechanical loosening.Material and methodsWe studied 43 knees after Legacy® CCK TKA. The indication was severe deformity (n=20), pre-operative laxity (n=6), or failure to achieve intra-operative balancing (n=17). There were 41 patients with a mean age of 66 years (21–88). A history of one or more surgical procedures was noted for 27 (63%) knees. Outcome measures were the Hospital for Special Surgery (HSS) knee score, Knee Society Score (KSS), and change in the hip-knee-ankle (HKA) angle. Prosthesis survival was assessed using revision surgery for any reason or for reasons other than infection as the censoring criterion.ResultsComplications other than venous thrombosis occurred in 16% of patients, including 3 who required revision surgery (septic loosening, n=2; and major instability in a patient with ipsilateral hip arthrodesis). No cases of osteolysis or aseptic loosening were recorded. Mean follow-up was 12.7 years (range, 10–14). At last follow-up, the HSS score had improved from 53 (26–83) pre-operatively to 80 (55–93), the KSS knee component from 42 (16–77) to 90 (77–99), and the KSS function component from 31 (0–80) to 61 (10–90) (P

Introduction Although Charnley-Kerboull metal-on-polyethylene 22.2 mm cemented total hip arthroplasty (THA) is considered to be the gold standard in France, results with this prosthesis are conflicting, in particular in relation to Scandinavian registers. The goal of this retrospective study was to confirm the validity of this prosthesis at a minimum of 10 years follow-up. Hypothesis Survival of this type of THA would fulfill NICE conditions (survival at 10 years of at least 90%). Materials and methods One hundred and five primary THA were performed in 93 patients (30 men and 63 women) mean age 72.6 years old (60–86) between January 1998 and March 2001. After a mean follow-up of 10.6 years (10–13 years), 21 patients (23 THA) were lost to follow-up and 32 (35 THA) had died leaving 40 patients (47 THA) for clinical analysis (Merle d’Aubigne and Oxford scores) and X-ray assessment. Survival was calculated with revision for any cause and radiological loosening with or without revision as end-points. Results The mean Oxford score at the final follow-up was 22/60 (13–45), the PMA score was 14.2 (11–17). Eight patients underwent revision surgery after a mean 7.5 years (2–11) (1 early dislocation and 7 acetabular cup loosenings). Survival at 10 years was 89.4% (CI95%: 78–95) for all causes of revision and 78% (CI95%: 61–91) for loosening with ( n = 7) or without ( n = 3) revision. No cases of septic or femoral loosening were observed. Twelve of the 47 revised hip replacements (25.5%) presented wear ≥ 2 mm. Discussion Although functional results were acceptable for this elderly population, survival did not reach the NICE value and was lower than results in the literature for this type of implant. Cup loosening and wear were the main causes of revision. Level of evidence IV: retrospective.

Resume Introduction La prothese totale de hanche (PTH) cimentee metal-polyethylene en calibre 22,2 mm de type Charnley-Kerboull est consideree comme le gold standard en France, mais fait l’objet de resultats discordants notamment dans les registres scandinaves. Cette etude retrospective avait pour but de verifier la validite de ce concept au recul minimal de 10 ans. Hypothese La survie de ce modele d’arthroplastie remplit les conditions du NICE (survie a 10 ans depassant 90 %). Patients et methodes Cent cinq arthroplasties primaires ont ete effectuees chez 93 patients (30 hommes et 63 femmes) âges en moyenne de 72,6 ans (60–86) entre janvier 1998 et mars 2001. Au recul moyen de 10,6 ans (10–13 ans), 21 patients (23 PTH) etaient perdus de vue et 32 (35 PTH) decedes laissant 40 patients (47 PTH) pour l’analyse clinique (score de Merle d’Aubigne et d’Oxford) et radiographique. La survie a ete calculee avec pour censure les reprises toutes causes confondues et les descellements radiologiques repris ou non. Resultats Le score d’Oxford moyen au recul etait de 22 (13–45), le score PMA de 14,2 (11–17). Huit patients ont ete repris au recul moyen de 7,5 ans (2–11) (1 luxation precoce et 7 descellements acetabulaires). La survie a 10 ans etait 89,4 % (IC95 % : 78–95) pour toute cause de reprise et 78 % (IC95 % : 61–91) pour les descellements repris ( n = 7) ou non ( n = 3). Aucun descellement septique ni femoral n’etait observe. Douze des 47 protheses revues (25,5 %) presentaient des usures ≥ 2 mm. Discussion Bien que les resultats fonctionnels soient acceptables compte tenu de l’âge eleve de la population, la survie n’atteignait pas la valeur du NICE et etait inferieure aux taux habituellement retrouves dans la litterature pour ce type d’implant. Les descellements des cupules et l’usure etaient les principales causes de revision. Niveau de preuve IV : retrospectif.

Background: We previously reported the outcomes of a case-control study, at a minimum of five years of follow-up, comparing metal-on-metal and ceramic-on-polyethylene bearings for cementless primary hip arthroplasty in active patients below the age of fifty years. This report is an update on these groups after a minimum duration of follow-up of twelve years. Methods: Thirty-nine metal-on-metal cementless hip replacements with a 28-mm-diameter Metasul articulation were compared with a control group that included thirty-nine cementless ceramic-on-polyethylene hip replacements performed with a 28-mm-diameter head. The Metasul group included thirty patients with a mean age of forty years (range, twenty-three to forty-nine years), and the control group included thirty-two patients with a mean age of forty-one years (range, fifteen to forty-nine years). The groups were matched for age, activity level, preoperative Harris hip score, acetabular cup diameter, and indication for hip arthroplasty. All patients had a high level of activity, with 82% rated as grade IV or V according to the Devane scale. Results: After a mean duration of follow-up of thirteen years (twelve to fourteen years), only one hip (3%) had asymptomatic acetabular osteolysis and no hip (0%) had been revised in the metal-on-metal group, whereas eighteen hips (46%) had osteolysis and eleven hips (28%) had been revised because of wear or osteolysis in the ceramic-on-polyethylene group (p < 0.003). In the metal-on-metal group, the median Co concentration in the whole blood was 0.95 μg/L (0.4 to 4.8 μg/L) and the median Cr concentration was 1.2 μg/L (0.1 to 5.6 μg/L). The twelve-year survival rate (with reoperation for any reason as the end point) was 100% in the metal-on-metal group and 70% (95% confidence interval, 63% to 77%) in the ceramic-on-polyethylene group (p = 0.003). Conclusions: After twelve to fourteen years of follow-up, metal-on-metal implants demonstrated better radiographic and survival results than ceramic-on-polyethylene implants in young, very active patients. Current wrought metal-on-metal implants with a 28-mm-diameter head and high carbide concentration did not produce the high rates of osteolysis and allergic reactions that may be observed with cast low-carbide metal-on-metal bearings after a shorter duration of follow-up. Level of Evidence: Therapeutic Level III. See Instructions to Authors for a complete description of levels of evidence.

Large-scale systemic mouse phenotyping, as performed by mouse clinics for more than a decade, requires thousands of mice from a multitude of different mutant lines to be bred, individually tracked and subjected to phenotyping procedures according to a standardised schedule. All these efforts are typically organised in overlapping projects, running in parallel. In terms of logistics, data capture, data analysis, result visualisation and reporting, new challenges have emerged from such projects. These challenges could hardly be met with traditional methods such as pen & paper colony management, spreadsheet-based data management and manual data analysis. Hence, different Laboratory Information Management Systems (LIMS) have been developed in mouse clinics to facilitate or even enable mouse and data management in the described order of magnitude. This review shows that general principles of LIMS can be empirically deduced from LIMS used by different mouse clinics, although these have evolved differently. Supported by LIMS descriptions and lessons learned from seven mouse clinics, this review also shows that the unique LIMS environment in a particular facility strongly influences strategic LIMS decisions and LIMS development. As a major conclusion, this review states that there is no universal LIMS for the mouse research domain that fits all requirements. Still, empirically deduced general LIMS principles can serve as a master decision support template, which is provided as a hands-on tool for mouse research facilities looking for a LIMS. Electronic supplementary material The online version of this article (doi:10.1007/s00335-015-9586-7) contains supplementary material, which is available to authorized users.

Cup design has been incriminated as the source of groin pain after hip resurfacing but has not been well described; thus, it was assessed in a prospective study looking at three implant types.A group-match was done between three groups of hip resurfacing devices according to age, sex, body mass index, activity level, osteoarthritis aetiology and pre-operative scores.The global groin pain rate was 5.7 % at six months and 2.7 % at last follow-up. Groin pain rate was significantly different between the three groups (p = 0.004) and had a strong influence on the subjective results (p = 0.04). No groin pain emerged between six months and last follow-up. No clinical differences were noted in Harris hip score and Merle d'Aubigné-Postel score at last follow-up. However, the Oxford hip score and Devane activity score were significantly lower for cups with macrostructures.The low groin pain rate in this prospective cohort was probably secondary to the specific surgical technique used and seems to be correlated with cup design. Macrostructures on the external part of the cup could be significantly harmful.

Recent studies have recommended the discontinuation of metal-on-metal (MoM) components in total hip arthroplasty (THA) because of adverse effects reported with large-diameter MoM THA. This is despite favorable long-term results observed with 28 and 32 mm MoM bearings.The aim of this study was to assess the value of calls for an end to MoM bearings as THA components. Specifically, we wish to address the risks associated with MoM bearings including adverse soft tissue reactions, metal ion release, and carcinogenic risk.The study evaluates the arguments in the literature reporting on MoM (adverse soft tissue reactions, metal ion release, and carcinogenic risk) and the experience of the current authors who re-introduced these bearings in 1995. They are balanced by a benefit-risk review of the literature and the authors' experience with MoM use.Adverse reactions to metallic debris as well as metal ion release are predictable and can be prevented by adequate design (arc of coverage, clearance), metallurgy (forged instead of cast alloy, high-carbide content), and appropriate component orientation. There is no scientific evidence that carcinogenicity is increased in subjects with MoM hip prostheses. MoM articulations appear to be attractive allowing safe hip resurfacing, decreasing the risk of THA revision in active patients, and providing secure THA fixation with cement in cages in severely deformed hips. MoM bearings in women of child-bearing age are controversial, but long-term data on metallic devices in adolescents undergoing spinal surgery seem reassuring.Adequate selection of MoM articulations ensures their safe use. These articulations are sensitive to orientation. Fifteen years of safe experience with 28- and 32-mm bearings of forged alloy and high-carbide content is the main reason for retaining them in primary and revision THA.

Introduction Les patients presentant une instabilite ligamentaire peripherique peuvent necessiter une prothese totale de genou (PTG) a contrainte augmentee quand la laxite parait incompatible avec la pose d’une PTG standard. Pour apprecier l’influence de cette augmentation de contrainte, nous avons effectue une revue clinique et radiographique des patients ayant beneficie d’une prothese de ce type a plus de 10 ans de recul. Materiel et methode La mise en place d’une prothese a contrainte augmentee pour le controle d’une laxite peripherique fait modifier le montage prothetique avec mise en place d’une came tibiale de taille augmentee associee a des tiges intra-medullaires. Il existe peu d’etudes sur ce type de protheses surtout utilise en chirurgie de reprise. Nous avons revu dans cette etude monocentrique retrospective multi-operateur 41 patients (43 protheses) ayant beneficie d’une PTG primaire a contrainte augmentee de 2eme generation (Legacy LCCKy, Zimmery) entre 1997 et 2002. Le recul moyen est de 12,7 ans. Methodes L’evaluation clinique a compare en pre- et post-operatoire le score HSS et le Knee Society Score. L’evaluation radiographique a porte sur la variation des angles HKA, HKS, alpha, beta, la bascule et la hauteur patellaire (Blackburn and Peel). La survie a ete appreciee en prenant comme critere le changement de la prothese. Resultats Le gain du score HSS etait de 27, celui du KSS genou de 48 et celui du KSS fonction de 30. Ils ont montre une difference significative (respectivement p p p = 0,0003). En postoperatoire la flexion moyenne etait de 112° (90°–130°), l’axe mecanique de 179,5° (174°–184°) et l’indice de Blackburn and Peel de 0,73. Le taux de complication etait de 16 % dont 3 revisions pour 1 descellement mecanique et 2 septiques. Au recul moyen de 12,7 ans, la survie globale selon Kaplan–Meyer est de 88,5 ± 7 %. Discussion L’amelioration fonctionnelle obtenue chez ces patients est importante et comparable aux resultats de la litterature. L’axe mecanique au recul est reste satisfaisant, ne revelant pas de faillite de la came en polyethylene. Par contre on deplore un taux de complication, et un nombre de descellement notamment infectieux plus important, donnant une survie inferieure a une serie de PTG standard. Conclusion L’utilisation d’une prothese totale de genou a contrainte augmentee en primaire chez des patients presentant une laxite ou une deformation necessitant une liberation ligamentaire importante est satisfaisante sur le plan mecanique et clinique, au prix d’un taux de complications plus important qu’une PTG standard.

Understanding the functions encoded in the mouse genome will be central to an understanding of the genetic basis of human disease. To achieve this it will be essential to be able to characterise the phenotypic consequences of variation and alterations in individual genes. Data on the phenotypes of mouse strains are currently held in a number of different forms (detailed descriptions of mouse lines, first line phenotyping data on novel mutations, data on the normal features of inbred lines, etc.) at many sites worldwide. For the most efficient use of these data sets, we have initiated a process to develop standards for the description of phenotypes (using ontologies), and file formats for the description of phenotyping protocols and phenotype data sets. This process is ongoing, and needs to be supported by the wider mouse genetics and phenotyping communities to succeed. We invite interested parties to contact us as we develop this process further.

The French Military Robotic Study Program (introduced in Aerosense 2003), sponsored by the French Defense Procurement Agency and managed by Thales as the prime contractor, focuses on about 15 robotic themes which can provide an immediate "operational add-on value". The paper details the "constrained navigation" study (named TEL2), which main goal is to identify and test a well-balanced task sharing between man and machine to accomplish a robotic task that cannot be performed autonomously at the moment because of technological limitations. The chosen function is "obstacle avoidance" on rough ground and quite high speed (40 km/h). State of the art algorithms have been implemented to perform autonomous obstacle avoidance and following of forest borders, using scanner laser sensor and standard localization functions. Such an "obstacle avoidance" function works well most of the time, BUT fails sometimes. The study analyzed how the remote operator can manage such failures so that the system remains fully operationally reliable; he can act according to two ways: a) finely adjust the vehicle current heading; b) take the control of the vehicle "on the fly" (without stopping) and bring it back to autonomous behavior when motion is secured again. The paper also presents the results got from the military acceptance tests performed on French 4x4 DARDS ATD.© (2005) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

The French Military Robotic Study Program (introduced in Aerosense 2003), sponsored by the French Defense Procurement Agency and managed by Thales Airborne Systems as the prime contractor, focuses on about 15 robotic themes which can provide an immediate "operational added value." The paper details the "robotic convoy" theme (named TEL1), which main purpose is to develop a robotic leader-follower function so that several unmanned vehicles can autonomously follow teleoperated, autonomous or on-board driven leader. Two modes have been implemented: Perceptive follower: each autonomous follower anticipates the trajectory of the vehicle in front of it, thanks to a dedicated perception equipment. This mode is mainly based on the use of perceptive data, without any communication link between leader and follower (to lower the cost of future mass development and extend the operational capabilities). Delayed follower: the leader records its path and transmits it to the follower; the follower is able to follow the recorded trajectory again at any delayed time. This mode uses localization data got from inertial measurements. The paper presents both modes with detailed algorithms and the results got from the military acceptance tests performed on wheeled 4x4 vehicles (DARDS French ATD).© (2004) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

Understanding the functions encoded in the mouse genome will be central to an understanding of the genetic basis of human disease. To achieve this it will be essential to be able to characterise the phenotypic consequences of variation and alterations in individual genes. Data on the phenotypes of mouse strains are currently held in a number of different forms (detailed descriptions of mouse lines, first line phenotyping data on novel mutations, data on the normal features of inbred lines, etc.) at many sites worldwide. For the most efficient use of these data sets, we have set in train a process to develop standards for the description of phenotypes (using ontologies), and file formats for the description of phenotyping protocols and phenotype data sets. This process is ongoing, and needs to be supported by the wider mouse genetics and phenotyping communities to succeed. We invite interested parties to contact us as we develop this process further.

Two large-scale phenotyping efforts, the European Mouse Disease Clinic (EUMODIC) and the Wellcome Trust Sanger Institute Mouse Genetics Project (SANGER-MGP), started during the late 2000s with the aim to deliver a comprehensive assessment of phenotypes or to screen for robust indicators of diseases in mouse mutants. They both took advantage of available mouse mutant lines but predominantly of the embryonic stem (ES) cells resources derived from the European Conditional Mouse Mutagenesis programme (EUCOMM) and the Knockout Mouse Project (KOMP) to produce and study 799 mouse models that were systematically analysed with a comprehensive set of physiological and behavioural paradigms. They captured more than 400 variables and an additional panel of metadata describing the conditions of the tests. All the data are now available through EuroPhenome database ( www.europhenome.org ) and the WTSI mouse portal ( http://www.sanger.ac.uk/mouseportal/ ), and the corresponding mouse lines are available through the European Mouse Mutant Archive (EMMA), the International Knockout Mouse Consortium (IKMC), or the Knockout Mouse Project (KOMP) Repository. Overall conclusions from both studies converged, with at least one phenotype scored in at least 80% of the mutant lines. In addition, 57% of the lines were viable, 13% subviable, 30% embryonic lethal, and 7% displayed fertility impairments. These efforts provide an important underpinning for a future global programme that will undertake the complete functional annotation of the mammalian genome in the mouse model.

SummaryIntroductionSecuring femoral offset should in theory improve hip stability and abductor muscles moment arms. As problems arise mainly in case of originally increased offset (>40mm), a range of extra-offset stems is available; the exact impact in terms of fixation, however, is not known.HypothesisExtra-offset stems should more reliably reestablish original femoral offsets exceeding 40mm than standard femoral components, limiting instability risk without possible adverse effect on fixation.ObjectiveTo compare the ability of five commonly available femoral stem designs to restitute offset exceeding 40mm, and to assess function and cement fixation at a minimum 6 years’ follow-up in a stem conceived to reproduce such offset.Patients and methodsA continuous series of 74 total hip replacements (THR) in hips with increased (>40mm) femoral offset was studied. All underwent preoperative X-ray templating on Imagika™ software to assess offset reproduction by five models of stem: four standard, and one Lubinus SP2™ extra-offset stem. A retrospective clinical and X-ray study was conducted with a minimum 6 years’ follow-up on the Lubinus SP2™ 117° stems used to try to reproduce offset in the 74 THRs.ResultsApart from the increased (>40mm) offset, the cervicodiaphyseal angle was consistently 5mm femoral offset reduction in 50–83% of cases, versus only 25% with the Lubinus SP2™ 117°). All 74 hips received Lubinus SP2™ 117° stems: at a mean 78 months FU (range, 70–94mo), their mean Postel-Merle d’Aubigné score was 17±1.8 (range, 13–18). Five of the 74 THRs underwent surgical revision: three cases of loosening, in which the stem was replaced, and two of instability, without change of stem. Loosening was not related to offset reproduction quality; two of the three cases were due to initial cementing defect, and the third occurred in a femur with previous history of two osteotomies. There were four cases of dislocation (5.4%: two primary, which were not operated on, and two recurrent, managed by acetabular revision), despite good reproduction of the preoperative offset in three of the four cases. Mean 7-year implant survivorship was 95.1% (±4.8).Discussion and conclusionThe anatomic form of the Lubinus™ SP2 117° should in theory provide a uniform cement mantle. Survivorship, however, is less good than for regular offset versions (126° or 135°). On the other hand, it does reproduce anatomy in case of >40mm offset, providing extra offset of more than 51mm. The slightly shorter survivorship requires more long-term surveillance.Level of evidenceLevel IV, retrospective study.

SummaryNuclear receptors (NRs) compose a large family of transcription factors that operate at the interface between genes and environment, acting as sensors and effectors that translate endocrine and metabolic cues into well-defined gene expression programs. We report here on a systematic quantitative and anatomical expression atlas of the 49 NR genes in 104 regions of the adult mouse brain, organized in the interactive MousePat database. MousePat defines NR expression patterns to cellular resolution, a requirement for functional genomic strategies to understand the function of a highly heterogeneous and complex organ such as the brain. Using MousePat data, NR expression patterns can be clustered into anatomical and regulatory networks that delineate the role of NRs in brain functions, like the control of feeding and learning/memory. Mining the MousePat resource will improve the understanding of NR function in the brain and elucidate hierarchical networks that control behavior and whole body homeostasis.

Opioid receptors are G protein-coupled receptors (GPCRs) that modulate brain function at all levels of neural integration, including autonomic, sensory, emotional and cognitive processing. Mu (MOR) and delta (DOR) opioid receptors functionally interact in vivo, but whether interactions occur at circuitry, cellular or molecular levels remains unsolved. To challenge the hypothesis of MOR/DOR heteromerization in the brain, we generated redMOR/greenDOR double knock-in mice and report dual receptor mapping throughout the nervous system. Data are organized as an interactive database offering an opioid receptor atlas with concomitant MOR/DOR visualization at subcellular resolution, accessible online. We also provide co-immunoprecipitation-based evidence for receptor heteromerization in these mice. In the forebrain, MOR and DOR are mainly detected in separate neurons, suggesting system-level interactions in high-order processing. In contrast, neuronal co-localization is detected in subcortical networks essential for survival involved in eating and sexual behaviors or perception and response to aversive stimuli. In addition, potential MOR/DOR intracellular interactions within the nociceptive pathway offer novel therapeutic perspectives. Electronic supplementary material The online version of this article (doi:10.1007/s00429-014-0717-9) contains supplementary material, which is available to authorized users.

The identification of causal variants in sequencing studies remains a considerable challenge that can be partially addressed by new gene-specific knowledge. Here, we integrate measures of how essential a gene is to supporting life, as inferred from viability and phenotyping screens performed on knockout mice by the International Mouse Phenotyping Consortium and essentiality screens carried out on human cell lines. We propose a cross-species gene classification across the Full Spectrum of Intolerance to Loss-of-function (FUSIL) and demonstrate that genes in five mutually exclusive FUSIL categories have differing biological properties. Most notably, Mendelian disease genes, particularly those associated with developmental disorders, are highly overrepresented among genes non-essential for cell survival but required for organism development. After screening developmental disorder cases from three independent disease sequencing consortia, we identify potentially pathogenic variants in genes not previously associated with rare diseases. We therefore propose FUSIL as an efficient approach for disease gene discovery., Discovery of causal variants for monogenic disorders has been facilitated by whole exome and genome sequencing, but does not provide a diagnosis for all patients. Here, the authors propose a Full Spectrum of Intolerance to Loss-of-Function (FUSIL) categorization that integrates gene essentiality information to aid disease gene discovery.

The role of sex in biomedical studies has often been overlooked, despite evidence of sexually dimorphic effects in some biological studies. Here, we used high-throughput phenotype data from 14,250 wildtype and 40,192 mutant mice (representing 2,186 knockout lines), analysed for up to 234 traits, and found a large proportion of mammalian traits both in wildtype and mutants are influenced by sex. This result has implications for interpreting disease phenotypes in animal models and humans., Systemic dissection of sexually dimorphic phenotypes in mice is lacking. Here, Karp and the International Mouse Phenotype Consortium show that approximately 10% of qualitative traits and 56% of quantitative traits in mice as measured in laboratory setting are sexually dimorphic.