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Jakarta, a megacity in Indonesia, experiences recurrent floods associated with heavy rainfall. Characteristics of subdaily rainfall and the local factors influencing rainfall around Jakarta have not been thoroughly investigated, primarily because of data limitations. In this study, we examine the frequency and intensity of hourly and daily rain rate, including spatial characteristics and variations across time scales. We use 6-min C-band Doppler radar and 1-min in situ data during 2009–12 to resolve spatial rain-rate characteristics at higher resolution than previous studies. A reflectivity–rain rate (Z–R) relationship is derived (Z = 102.7R1.75) and applied to estimate hourly rain rate. Our results show that rain rate around Jakarta is spatially inhomogeneous. In the rainy season [December–February (DJF)], rain rate exhibits statistical properties markedly different from other seasons, with much higher frequency of rain, but, on average, less intense rain rate. In all seasons, there is a persistent higher hourly and daily mean rain rate found over mountainous areas, indicating the importance of local orographic effects. In contrast, for hourly rain-rate extremes, peaks are observed mostly over the coastal land and lowland areas. For the diurnal cycle of mean rain rate, a distinct afternoon peak is found developing earlier in DJF and later in the dry season. This study has implications for other analyses of mesoscale rain-rate extremes in areas of complex topography and suggests that coarse-grain products may miss major features of the rain-rate variability identified in our study. Significance Statement For many years, Jakarta and its surrounding regions have been repeatedly inundated by flooding triggered by short-duration heavy rainfall or rainfall accumulated over multiple days. Little is known about the distribution of local rainfall and how it differs between seasons. In this study, we used high-resolution C-band Doppler radar during 2009–12 to understand the characteristics of rainfall over this complex topography. The results demonstrate that the rainfall features vary spatially and seasonally. In the wet season, rainfall is more frequent but, on average, lighter relative to other seasons. In all seasons, the highest hourly and daily mean rain rate persistently occurs over the mountains, indicating the vital role of topography in generating rainfall in the region.

Research on the interaction between the Madden–Julian oscillation (MJO) and rainfall around Jakarta is limited, although the influence of the MJO on increased rainfall is acknowledged as one of the primary causes of flooding in the region. This paper investigates the local rainfall response around Jakarta to the MJO. We used C-band Doppler radar in October–April during 2009–12 to study rain-rate characteristics at much higher resolution than previous analyses. Results show that the MJO strongly modulates rain rates over the region; however, its effect varies depending on topography. During active phases, MJO induces a high rain rate over the ocean and coast, meanwhile during suppressed phases, it generates a high rain rate mainly over the mountains. In phase 2 of the MJO we find the strongest increase in mean and extreme rain rate, which is earlier in the MJO cycle than most studies reported, based on lower-resolution data. This higher rain rate is likely due to increases in convective and stratiform activities. The MJO promotes more stratiform rain once it resides over Indonesia. In phase 5, over the northwestern coast and western part of the radar domain, the MJO might bring forward the peak of the hourly rain rate that occurs in the early morning. This is likely due to a strong westerly flow arising from MJO superimposed westerly monsoonal flow, blocked by the mountains, inducing a strong wind propagating offshore resulting in convection near the coast in the morning. Our study demonstrates the benefits of using high-resolution radar for capturing local responses to the larger-scale forcing of the MJO in Indonesia. Significance Statement Rainfall in Jakarta and its surroundings is highly variable and often heavy resulting in devastating floods. In this region, in the wet season, rainfall is influenced by large-scale climate variability including the Madden–Julian oscillation (MJO) characterized by eastward propagation of clouds near the equatorial regions on intraseasonal time scales. The MJO has been known to increase the probability of rainfall occurrence and its magnitude, but we show that the impact differs in varying topography. The frequency and intensity of rainfall increase over land areas including mountains even when MJO has not arrived in Indonesia. Meanwhile, once MJO moves through Indonesia, the frequency and magnitude of the rainfall increases over the northern coast and ocean as well as in the west of the radar domain.

Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) is an inherited late-onset neurological disease caused by bi-allelic AAGGG pentanucleotide expansions within intron 2 of RFC1. Despite extensive studies, the pathophysiological mechanism of these intronic expansions remains elusive. We screened by clinical exome sequencing two unrelated patients presenting with late-onset ataxia. A repeat-primer polymerase chain reaction was used for RFC1 AAGGG intronic expansion identification. RFC1 mRNA expression was assessed by quantitative reverse transcription–polymerase chain reaction. We identified the first two CANVAS affected patients who are compound heterozygous for RFC1 truncating variants (p.Arg388* and c.575delA, respectively) and a pathological AAGGG expansion. RFC1 expression studies in whole blood showed a significant reduction of RFC1 mRNA for both patients compared to three patients with bi-allelic RFC1 expansions. In conclusion, this observation provides clues that suggest bi-allelic RFC1 conditional loss-of-function as the cause of the disease.

Tobias, Joseph A., Sheard, Catherine, Pigot, Alex L., Devenish, Adam J. M., Yang, Jingyi, Sayol, Ferran, Neate‐Clegg, Montague H. C., Alioravainen, Nico, Weeks, Thomas L., Barber, Robert A., Walkden, Patrick A., MacGregor, Hannah E. A., Jones, Samuel E. I., Vincent, Claire, Phillips, Anna G., Marples, Nicola M., Montaño‐Centellas, Flavia A., Leandro‐Silva, Victor, Claramunt, Santiago, Darski, Bianca, Freeman, Benjamin G., Bregman, Tom P., Cooney, Christopher R., Hughes, Emma C., Capp, Elliot J. R., Varley, Zoë K., Friedman, Nicholas R., Korntheuer, Heiko, Corrales‐Vargas, Andrea, Trisos, Christopher H., Weeks, Brian C., Hanz, Dagmar M., Töpfer, Till, Bravo, Gustavo A., Remeš, Vladimír, Nowak, Larissa, Carneiro, Lincoln S., Moncada R., Amilkar J., Matysioková, Beata, Baldassarre, Daniel T., Martínez‐Salinas, Alejandra, Wolfe, Jared D., Chapman, Philip M., Daly, Benjamin G., Sorensen, Marjorie C., Neu, Alexander, Ford, Michael A., Mayhew, Rebekah J., Fabio Silveira, Luis, Kelly, David J., Annorbah, Nathaniel N. D., Pollock, Henry S., Grabowska‐Zhang, Ada M., McEntee, Jay P., Carlos T. Gonzalez, Juan, Meneses, Camila G., Muñoz, Marcia C., Powell, Luke L., Jamie, Gabriel A., Matthews, Thomas J., Johnson, Oscar, Brito, Guilherme R. R., Zyskowski, Kristof, Crates, Ross, Harvey, Michael G., Jurado Zevallos, Maura, Hosner, Peter A., Bradfer‐Lawrence, Tom, Maley, James M., Stiles, F. Gary, Lima, Hevana S., Provost, Kaiya L., Chibesa, Moses, Mashao, Mmatjie, Howard, Jeffrey T., Mlamba, Edson, Chua, Marcus A. H., Li, Bicheng, Gómez, M. Isabel, García, Natalia C., Päckert, Martin, Fuchs, Jérôme, Ali, Jarome R., Derryberry, Elizabeth P., Carlson, Monica L., Urriza, Rolly C., Brzeski, Kristin E., Prawiradilaga, Dewi M., Rayner, Matt J., Miller, Eliot T., Bowie, Rauri C. K., Lafontaine, René‐Marie, Scofield, R. Paul, Lou, Yingqiang, Somarathna, Lankani, Lepage, Denis, Illif, Marshall, Neuschulz, Eike Lena, Templin, Mathias, Dehling, D. Matthias, Cooper, Jacob C., Pauwels, Olivier S. G., Analuddin, Kangkuso, Fjeldså, Jon, Seddon, Nathalie, Sweet, Paul R., DeClerck, Fabrice A. J., Naka, Luciano N., Brawn, Jeffrey D., Aleixo, Alexandre, Böhning‐Gaese, Katrin, Rahbek, Carsten, Fritz, Susanne A., Thomas, Gavin H., Schleuning, Matthias (2022): AVONET: morphological, ecological and geographical data for all birds. Ecology Letters 25 (3): 581-597, DOI: 10.1111/ele.13898, URL: http://dx.doi.org/10.1111/ele.13898

Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a recessively inherited multisystem ataxia compromising cerebellar, vestibular, and sensory nerves, which has been associated to a pathogenic AAGGG(n) biallelic expansion repeat in the RFC1 gene. Our objective was to assess its prevalence in a French cohort of patients with idiopathic sporadic late-onset ataxia (ILOA), idiopathic early-onset ataxia (IEOA), or Multiple System Atrophy of Cerebellar type (MSA-C). 163 patients were recruited in 3 French tertiary centers: 100 ILOA, 21 IEOA, and 42 patients with possible or probable MSA-C. A pathogenic biallelic RFC1 AAGGG(n) repeat expansion was found in 15 patients: 15/100 in the ILOA group, but none in the IEOA and MSA-C subgroups. 14/15 patients had a CANVAS phenotype. Only 1/15 had isolated cerebellar ataxia, but also shorter biallelic expansions. Two RFC1 AAGGG(n) alleles were found in 78% of patients with a CANVAS phenotype. In one post-mortem case, the pathophysiological involvement of cerebellum and medullar posterior columns was found. Our study confirms the genetic heterogeneity of the CANVAS and that RFC1 repeat expansions should be searched for preferentially in case of unexplained ILOA associated with a sensory neuronopathy, but not particularly in patients classified as MSA-C.

Work on the post‐2020 global biodiversity framework is now well advanced and will outline a vision, goals, and targets for the next decade of biodiversity conservation and beyond. For the effectiveness of Protected areas and Other Effective area‐based Conservation Measures, an indicator has been proposed for “areas meeting their documented ecological objectives.” However, the Convention on Biological Diversity (CBD) has not identified or agreed on what data should inform this indicator. Here we draw on experiences from the assessment of protected area effectiveness in the CBD's previous strategic plan to provide recommendations on the essential elements related to biodiversity outcomes and management that need to be captured in this updated indicator as well as how this could be done. Our proposed protected area effectiveness indicators include a combination of remotely derived products for all protected areas, combined with data from monitoring of both protected area management and trends in species and ecosystems based on field observations. Additionally, we highlight the need for creating a digital infrastructure to operationalize national‐level data‐capture. We believe these steps are critical and urge the adoption of suitable protected area effectiveness indicators before the post‐2020 framework is agreed in 2021.

Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a recessively inherited multisystem ataxia compromising cerebellar, vestibular, and sensory nerves, which has been associated to a pathogenic AAGGG(n) biallelic expansion repeat in the RFC1 gene. Our objective was to assess its prevalence in a French cohort of patients with idiopathic sporadic late-onset ataxia (ILOA), idiopathic early-onset ataxia (IEOA), or Multiple System Atrophy of Cerebellar type (MSA-C).163 patients were recruited in 3 French tertiary centers: 100 ILOA, 21 IEOA, and 42 patients with possible or probable MSA-C.A pathogenic biallelic RFC1 AAGGG(n) repeat expansion was found in 15 patients: 15/100 in the ILOA group, but none in the IEOA and MSA-C subgroups. 14/15 patients had a CANVAS phenotype. Only 1/15 had isolated cerebellar ataxia, but also shorter biallelic expansions. Two RFC1 AAGGG(n) alleles were found in 78% of patients with a CANVAS phenotype. In one post-mortem case, the pathophysiological involvement of cerebellum and medullar posterior columns was found.Our study confirms the genetic heterogeneity of the CANVAS and that RFC1 repeat expansions should be searched for preferentially in case of unexplained ILOA associated with a sensory neuronopathy, but not particularly in patients classified as MSA-C.

Tout processus de reconnaissance est marqué par une lutte de sens : il est, par définition, le lieu de confrontation entre des énoncés, des procédés définitionnels, que ce soit au moment des mobilisations, des demandes, de l’octroi ou de l’obtention d’une reconnaissance. Comment distinguer, au sein des pratiques de reconnaissance, celles qui produisent des effets émancipateurs pour les individus ou les groupes, de celles qui produisent au contraire des effets de concurrence, de minorisation ou de subordination ? Ces ambiguïtés se manifestent à plusieurs niveaux et elles sont analysées par les deux autrices à partir d’un terrain d’enquête conduit entre 2012 et 2017 où se joue particulièrement la reconnaissance d’identités minorisées : une enquête menée auprès des OSIM, Organisations de Solidarité Internationales issues des Migrations, et particulièrement auprès de leur plate-forme nationale, le FORIM, Forum des Organisations Issues des Migrations. Ce cas d’étude permet d’une part de considérer les formulations ambigües de demandes de reconnaissance des associations de migrants, qui sont envisagées par les autrices comme des luttes de visibilité ; d’autre part d’analyser l’ambiguïté des réponses institutionnelles et des modes d’accès à la reconnaissance dans l’espace public démocratique français. Soulignant la permanence d’un idéal républicain universaliste, l’analyse interroge la frontière entre formes « idéologiques » et formes émancipatrices de reconnaissance. Elle démontre qu’un processus de reconnaissance ambigüe, marqué par l’existence de catégorisations et de pratiques associatives essentialisantes, peut permettre des transformations de la représentation politique pertinentes pour le débat démocratique.

Non-Invasive Prenatal Diagnosis (NIPD), based on the analysis of circulating cell-free fetal DNA (cff-DNA), is successfully implemented for an increasing number of monogenic diseases. However, technical issues related to cff-DNA characteristics remain, and not all mutations can be screened with this method, particularly triplet expansion mutations that frequently concern prenatal diagnosis requests. The objective of this study was to develop an approach to isolate and analyze Circulating Trophoblastic Fetal Cells (CFTCs) for NIPD of monogenic diseases caused by triplet repeat expansion or point mutations. We developed a method for CFTC isolation based on DEPArray sorting and used Huntington’s disease as the clinical model for CFTC-based NIPD. Then, we investigated whether CFTC isolation and Whole Genome Amplification (WGA) could be used for NIPD in couples at risk of transmitting different monogenic diseases. Our data show that the allele drop-out rate was 3-fold higher in CFTCs than in maternal cells processed in the same way. Moreover, we give new insights into CFTCs by compiling data obtained by extensive molecular testing by microsatellite multiplex PCR genotyping and by WGA followed by mini-exome sequencing. CFTCs appear to be often characterized by a random state of genomic degradation.

Work has begun in earnest to formulate a post-2020 Global Biodiversity Framework which will outline the vision and targets for the next decade of biodiversity conservation and beyond. However, the performance of the 2011-2020 Strategic Plan for Biodiversity suggests that even a meaningful target can fail to deliver if not accompanied by fit-for-purpose indicators. Here we provide a review of how ‘protected area’ effectiveness was addressed in the 2011-2020 plan and based on this, provide recommendations for fit-for-purpose indicators that will measure how such efforts contribute to the conservation of biodiversity. Indicators need to be built on quantitative data from site-level biodiversity monitoring of species and ecosystems combined with measurements of the state of nature in near-time, informed by remote-sensed products and other technologies. Additionally, indicators need to capture whether the essential elements of good management are in place including the identification of ecological values, threats, and objectives, equitable governance, and sufficient management resources and capacity. These fit-for-purpose indicators will require multilateral collaboration to galvanize support for, and resources to develop, the necessary infrastructure to collate and store information from countries.

An organism’s ability to disperse influences many fundamental processes in ecology. However, standardised estimates of dispersal ability are rarely available, and thus the patterns and drivers of broad-scale variation in dispersal ability remain unclear. Here we present a global dataset of avian hand-wing index (HWI), an estimate of wingtip pointedness widely adopted as a proxy for flight efficiency and dispersal in birds. We show that HWI is correlated with geography and ecology across 10,391 (>99 %) bird species, increasing at higher latitudes and in migratory and/or non-territorial species. After controlling for these effects, the strongest predictor of HWI is temperature variability (i.e. seasonality), with secondary effects of diet and habitat type. Our analyses (1) reveal a prominent latitudinal gradient in HWI shaped by ecological and environmental factors, and (2) provide a global index of avian dispersal ability for wider use in community ecology, macroecology, and macroevolution.Statement of authorshipThe study was conceived by CS and JAT. Data collection was led by JAT, SC, and CS, with contributions from CS, MNC, NA, SEIJ, CV, HEAM, TPB, and SC. CS performed the analyses. CS and JAT wrote the manuscript and all authors revised the text.

Les leaders associatifs migrants constituent un objet d’étude privilégié pour la recherche sur la mobilité et le transnationalisme. Nos enquêtes révèlent cependant que leurs trajectoires ne sont pas marquées par une continuité circulatoire mais par des ruptures de mobilité et des périodes d’immobilité. La création d’associations de solidarité tournées vers le développement du pays natal permet à ces acteurs de retrouver une mobilité. Ces nouvelles circulations entrent alors dans un processus de réaffiliation vis-à-vis du « pays d’origine » et participent à l’acquisition d’un capital mobilitaire. Si nos résultats confirment la relation indiscutable, dans les représentations individuelles et collectives des migrants, entre la mobilité transnationale, comme pratique sociale, et la migration, comme expérience, ils montrent que ce lien est un construit social. L’engagement associatif dans une OSIM participe à des stratégies d’ascension sociale, selon lesquelles la mobilité transnationale est l’aboutissement du parcours migratoire.

Background: Analysis of cell-free fetal DNA in maternal plasma is very promising for early diagnosis of monogenic diseases. However, it has been limited by the need to set up patient- or disease-specific custom-made approaches. Here we propose a universal test based on fluorescent multiplex PCR and size fragment analysis for an indirect diagnosis of cystic fibrosis (CF). Methods: The test, based on haplotyping, includes nine intra- and extragenic short tandem repeats of the CFTR locus, the coamplification of p.Phe508del (the most frequent mutation in CF patients worldwide), and a specific SRY sequence. The assay is able to determine the inherited paternal allele. Results: Our simple approach was successfully applied to 30 couples and provided clear results from the maternal plasma. The mean rate of informative markers was sufficient to propose it for use in indirect diagnosis. Conclusions: This noninvasive prenatal diagnosis test, focused on indirect diagnosis of CF, offers many advantages over current methods: it is simple, rapid, and cost-effective. It allows for the testing of a large number of couples with high risk of CF, whatever the familial mutation of the CFTR gene. It provides an alternative method to reduce the number of invasive tests.

Protected areas (PAs) play a critical role in conserving biodiversity and maintaining viable populations of threatened species. Yet, as global change could reduce the future effectiveness of existing PAs in covering high species richness, updating the boundaries of existing PAs or creating new ones might become necessary to uphold conservation goals. Modelling tools are increasingly used by policymakers to support the spatial prioritization of biodiversity conservation, enabling the inclusion of scenarios of environmental changes to achieve specific targets. Here, using the Western Swiss Alps as a case study, we show how integrating species richness derived from species distribution model predictions for four taxonomic groups under present and future climate and land-use conditions into two conservation prioritization schemes can help optimize extant and future PAs. The first scheme, the “Priority Scores Method” identified priority areas for the expansion of the existing PA network. The second scheme, using the zonation software, allowed identifying priority conservation areas while incorporating global change scenarios and political costs. We found that existing mountain PAs are currently not situated in the most environmentally nor politically suitable locations when maximizing alpha diversity for the studied taxonomic groups and that current PAs could become even less optimum under the future climate and land-use change scenarios. This analysis has focused on general areas of high species richness or species of conservation concern and did not account for special habitats or functional groups that could have been used to create the existing network. We conclude that such an integrated framework could support more effective conservation planning and could be similarly applied to other landscapes or other biodiversity conservation indices., Global Ecology and Conservation, 17

As anthropogenic degradation of biodiversity and ecosystems increases, so does the potential threat to the supply of ecosystem services, a key contribution of nature to people. Biodiversity has often been used in spatial conservation planning and has been regarded as one among multiple services delivered by ecosystems. Hence, biodiversity conservation planning should be integrated in a framework of prioritizing services in order to inform decision-making. Here, we propose a prioritization approach based on scenarios maximising both the provision of ecosystem services and the conservation of biodiversity hotspots. Different weighting scenarios for the α-diversity in four taxonomic groups and 10 mapped ecosystem services were used to simulate varying priorities of policymakers in a mountain region. Our results illustrate how increasing priorities to ecosystem services can be disadvantageous to biodiversity. Moreover, the analysis to identify priority areas that best compromise the conservation of α-diversity and ecosystem services are predominantly not located within the current protected area network. Our analyses stress the need for an appropriate weighting of biodiversity within decision making that seek to integrate multiple ecosystem services. Our study paves the way toward further integration of multiple biodiversity groups and components, ecosystem services and various socio-economic scenarios, ultimately fuelling the development of more informed, evidence-based spatial planning decisions for conservation.

Le livre de Thomas Lacroix est appele a devenir un ouvrage de reference sur le transnationalisme villageois. A mi-chemin entre l’etude empirique et la reflexion epistemologique, il demontre que l’engagement transnational est une reponse collective faite par des migrants a la question « qu’est-ce qu’etre un villageois ? » (p. 178). L’ouvrage tente de saisir le point de jonction entre les processus de developpement et les associations villageoises transnationales en trois temps. Tout d’abord, l...

In the city of Lyon, two competing local authorities have been taking opposite political stances on whether to include local migrant organizations to international cooperation and decentralized cooperation programmes. The Metropole de Lyon refuses to consider them while Region Rhone-Alpes warmly supports their participation. However, despite a clear opposition on ideological positions and governance practices, both of these perspectives are rooted in the same conventional and long-lasting French integrationist paradigm, and the same technical vision of development processes. Secondly, drawing on two case studies, this chapter looks at the impact of this political and institutional frame on migrant organizations inclusion into local networks of cooperation for development. It has very weak consequences because of overlapping and interlaced governance levels, the active presence of public-private partnerships, and the network density. Therefore, despite the absence of shared governance, there is a growing experience of migrant organization presence in development networks, which in turn may lead to higher participation claims.

The early use of risk stratification scores is recommended for patients presenting with acute non-variceal upper gastrointestinal (GI) bleeds (ANVGIB). AIMS65 is a novel, recently derived scoring system, which has been proposed as an alternative to the more established Glasgow-Blatchford score (GBS).To validate the AIMS65 scoring system in a predominantly Caucasian population from Scotland and compare it with the GBS.Retrospective study of patients presenting to a district general hospital in Scotland with a suspected diagnosis of ANVGIB who underwent inpatient upper GI endoscopy between March 2008 and March 2013.The primary outcome measure was 30-day mortality. Secondary outcome measures were requirement for endoscopic intervention, endoscopy refractory bleeding, blood transfusion, rebleeding and admission to high dependency unit (HDU) and intensive care unit (ICU). The area under the receiver operating characteristic (AUROC) curve was calculated for each score.328 patients were included. Of these 65.9% (n=216) were men and 34.1% (n=112) women. The mean age was 65.2 years and 30-day mortality 5.2%. AIMS65 was superior to the GBS in predicting mortality, with an AUROC of 0.87 versus 0.70 (p0.05). The GBS was superior for blood transfusion (AUROC 0.84 vs 0.62, p0.05) and admission to HDU (AUROC 0.73 vs 0.62, p0.05). There were no significant differences between the scores with respect to requirement for endoscopic intervention, endoscopy refractory bleeding, rebleeding and admission to ICU.AIMS65 accurately predicted mortality in a Scottish population of patients with ANVGIB. Large prospective studies are now required to establish the exact role of AIMS65 in triaging patients with ANVGIB.

International audience; BACKGROUND:Analysis of cell-free foetal DNA (cff-DNA) in maternal plasma is very promising for early diagnosis of monogenic diseases; in particular, cystic fibrosis (CF). However, NIPD of single-gene disorders has been limited by the availability of suitable technical platforms and the need to set up patient or disease-specific custom-made approaches.METHODS:To make research applications more readily accessible to the clinic, we offer a simple assay combining two independent methods to determine the presence or absence of paternally inherited foetal allele p.Phe508del (the most frequent mutation in CF patients worldwide). The first method detects the presence or absence of a p.Phe508del allele by Mutant Enrichment with 3'-Modified Oligonucleotide PCR coupled to Fragment Length Analysis (MEMO-PCR-FLA). The second method detects the p.Phe508del allele with classical Multiplex Fluorescent PCR including five intragenic and extragenic STR markers of the CFTR locus and a specific SRY sequence.RESULTS:We collected 24 plasma samples from 23 women carrying foetuses at risk for CF and tested each sample using both methods. Our new procedures were successfully applied to 10 couples where fathers carried the p.Phe508del mutation and mothers were carrying a different mutation in the CFTR gene. These simple tests provided clear positive or negative results from the maternal plasma of the pregnant women. We confirmed the presence of cff-DNA in the studied samples by the identification of a tri-allelic DNA profile using a miniSTR kit. All results were correlated with chorionic villus sampling or amniocentesis analyses.CONCLUSIONS:This NIPD approach, easily set up in any clinical laboratory where prenatal diagnosis is routinely performed, offers many advantages over current methods: it is simple, rapid, and cost-effective. It opens up the possibility for testing a large number of couples with offspring at risk for CF.

Hearing loss is the most common sensory disorder and because of its high genetic heterogeneity, implementation of Massively Parallel Sequencing (MPS) in diagnostic laboratories is greatly improving the possibilities of offering optimal care to patients. We present the results of a two-year period of molecular diagnosis that included 207 French families referred for non-syndromic hearing loss. Our multi-step strategy involved (i) DFNB1 locus analysis, (ii) MPS of 74 genes, and (iii) additional approaches including Copy Number Variations, in silico analyses, minigene studies coupled when appropriate with complete gene sequencing, and a specific assay for STRC. This comprehensive screening yielded an overall diagnostic rate of 48%, equally distributed between DFNB1 (24%) and the other genes (24%). Pathogenic genotypes were identified in 19 different genes, with a high prevalence of GJB2, STRC, MYO15A, OTOF, TMC1, MYO7A and USH2A. Involvement of an Usher gene was reported in 16% of the genotyped cohort. Four de novo variants were identified. This study highlights the need to develop several molecular approaches for efficient molecular diagnosis of hearing loss, as this is crucial for genetic counselling, audiological rehabilitation and the detection of syndromic forms.

International audience; We report on the effectiveness of a custom-designed oligonucleotide-based comparative genomic hybridization microarray (array-CGH) to interrogate copy number across the entire 2.2-Mb genomic region of the DMD gene and its applicability in diagnosis. The high-resolution array-CGH, we developed, successfully detected a series of 42 previously characterized large rearrangements of various size, localization and type (simple or complex deletions, duplications, triplications) and known intronic CNVs/Indels. Moreover, the technique succeeded in identifying a small duplication of only 191 bp in one patient previously negative for DMD mutation. Accurate intronic breakpoints localization by the technique enabled subsequent junction fragments identification by sequencing in 86% of cases (all deletion cases and 62.5% of duplication cases). Sequence examination of the junctions supports a role of microhomology-mediated processes in the occurrence of DMD large rearrangements. In addition, the precise knowledge of the sequence context at the breakpoints and analysis of the resulting consequences on maturation of pre-mRNA contribute to elucidating the cause of discrepancies in phenotype/genotype correlations in some patients. Thereby, the array-CGH proved to be a highly efficient and reliable diagnostic tool, and the new data it provides will have many potential implications in both, clinics and research.

Introduction La dystonie est definie par une contraction musculaire anormale responsable de mouvements ou de postures anormales. La forme monogenique la plus frequente est la DYT1 liee au gene TOR1A. Objectifs Determiner la frequence de la dystonie DYT1 chez des patients algeriens. Patients et methodes Nous rapportons une serie de 9 patients âges de 12 a 43 ans presentant une dystonie isolee ou combinee, a debut precoce, d’allure primitive. Tous les patients ont beneficie d’une etude moleculaire a la recherche de la mutation recurrente du gene DYT1 et d’une prise en charge therapeutique medicale notamment une substitution dopaminergique et ou un traitement chirurgicale (stimulation pallidale). Resultats La dystonie etait generalisee isolee dans 6 cas, associant une dystonie crânienne et ou laryngee dans 4 cas. Elle etait combinee dans 3 cas. L’etude moleculaire a revele l’absence chez tous les patients de la mutation recurrente c.907delGAG dans l’exon 5 du gene DYT1 (TOR1A). Sur le plan therapeutique la sustitution dopaminergique a ete spectaculaire dans 2 cas sur 9 et la stimulation pallidale dans 1 cas sur 4. Discussion Devant toute dystonie isolee, il convient toujours de rechercher en premiere intention la mutation du gene DYT1 du fait de sa relative frequence. Toutefois, le tableau clinique est non specifique et souvent comparable a celui des formes non DYT1 notamment la DYT6 caracterisee par une dystonie crânienne et laryngee associee, ceci rend compte de l’heterogeneite genetique des dystonies primitives non dopa sensibles. Conclusion La DYT1 est decrite comme la plus frequente des dystonies monogeniques mais cela ne semble pas etre le cas de notre cohorte. Une serie plus importante est necessaire pour juger de sa frequence en Algerie.

Summary Background Hypohidrotic ectodermal dysplasia (HED) is characterized by abnormal development of the eccrine sweat glands, hair and teeth. The X-linked form of the disease, caused by mutations in the EDA gene, represents the majority of HED cases. Autosomal dominant and recessive forms occasionally occur and result from mutations in at least two other genes: EDAR and EDARADD. EDARADD interacts with the TAB2/TRAF6/TAK1 complex, which is necessary for NF-κB activation by EDAR. Objectives To determine frequency of EDARADD, TRAF6, TAB2 and TAK1 mutations in HED. Materials and methods We have screened 28 familial or sporadic HED cases with no mutations in the EDA and EDAR genes for EDARADD, TRAF6, TAB2 and TAK1 mutations. Results We identified one EDARADD 6-bp homozygous in-frame deletion (c.402-407del, p.Thr135-Val136del) in a patient born to consanguineous parents. Functional studies showed that the p.Thr135-Val136del impaired the EDAR–EDARADD interaction and then severely inhibited NF-κB activity. In the remaining 27 patients, we failed to find causative mutations in EDARADD, or in TRAF6, TAB2 or TAK1. Conclusions Our study demonstrates that EDARADD mutations are not a frequent cause of HED, while mutations in TRAF6, TAB2 and TAK1 may not be implicated in this disease.

Hypohidrotic ectodermal dysplasia (HED) is characterized by abnormal development of ectodermal structures and its molecular etiology corresponds to mutations of EDA-EDAR genes. The aim of this study was first to investigate the genotype and dental phenotype associated with HED and second, to explore possible correlations between dental features and molecular defects. A total of 27 patients from 24 unrelated families exhibiting clinical signs of HED (22 XLHED males, 5 autosomal recessive forms) were retrospectively included. In the sample, 25 different mutations on EDA and EDAR genes were detected; 10 were not previously described. EDA and EDAR mutations corresponded respectively to 80.0% and 20.0% of the mutations. The dental phenotype analysis revealed a mean number of primary and permanent missing teeth ranging respectively from 14.5 (4-20) to 22.5 (10-28); the majority of the patients exhibited dysmorphic teeth. Overall, no differential expression in the degree of oligodontia according to either the mutated gene, the mutated functional sub-domains, or the mutation type, could be observed. Nevertheless, the furin group exhibited severe phenotypes unobserved in the TNF group. Significant differences in the number of some primary missing teeth (incisor and canine) related to EDA-EDAR genes defects were detected for the first time between XLHED and autosomal recessive HED, suggesting differential local effects of EDA-EDAR genes during odontogenesis. The present genotypic-phenotypic findings may add to the knowledge of the consequences of the molecular dysfunction of EDA-NF-kB in odontogenesis, and could be helpful in genetic counseling to distinguish autosomal forms from other HED syndromes.

Analysis of circulating cell-free fetal DNA (cffDNA) in maternal plasma is very promising for early diagnosis of monogenic diseases. However, this approach is not yet available for routine use and remains technically challenging because of the low concentration of cffDNA, which is swamped by the overwhelming maternal DNA.To make clinical applications more readily accessible, we propose a new approach based on mutant enrichment with 3′-modified oligonucleotides (MEMO) PCR along with real-time PCR to selectively amplify from the maternal blood the paternally inherited fetal allele that is not present in the maternal genome.The first proof of concept of this strategy was displayed for cystic fibrosis by the accuracy of our detection of the p.Gly542* mutation used as the initial developmental model. Subsequently, a retrospective study of plasmas originating from two pregnant women carrying a fetus with private mutation confirmed the effectiveness of our method. We confirmed the presence of cffDNA in the studied samples by the identification of a tri-allelic DNA profile using a miniSTR kit.This new non-invasive prenatal diagnosis test offers numerous advantages over current methods: it is simple, cost effective, time efficient and does not require complex equipment or bioinformatics settings. Moreover, our assays for different private mutations demonstrate the viability of this approach in clinical settings for monogenic disorders.

We report on 23 years old discordant monozygotic (MZ) twins, one with minor anomalies and mental delay, the other one being normal. Both had 46,XX,dup(11)(p12p15)/46,XX mosaicism in blood, with a similar proportion of abnormal cells (respectively, 16% and 17%). However, interphase fluorescence in situ hybridization (FISH) analysis performed on buccal smear and urinary sediment using specific probes located at the duplicated region showed that mosaicism was only present in the abnormal twin, with 68% abnormal cells. We hypothesize that the postzygotic chromosomal rearrangement may have occurred early in one embryo after the twinning event, and the blood mosaicism observed in both twins would have resulted from blood exchanges via placental anastomoses. This hypothesis of chimerism is strongly supported by twin-to-twin transfusion syndrome observed during fetal life of our twins. This case and those previously reported lead us to suggest that blood is particularly unsuitable for cytogenetic investigations of twins.

Thirty patients have been described with cytogenetically visible deletion of the short arm of chromosome 6. However, subtelomeric 6p deletion detected by subtelomeric specific probes has been reported only twice. We report two new patients with terminal 6p deletion detected by subtelomeric screening using fluorescence in situ hybridization (FISH). The two patients exhibited mental retardation, ocular abnormalities, hearing loss, and a characteristic facial appearance. Detailed FISH analyses with probes covering the distal 6p25 region estimated the size of the terminal deletions to approximately 5.5 Mb and approximately 4.8 Mb. Array-based comparative genomic hybridization (array CGH) was used to confirm the cryptic deletions. Most patients with subtelomeric defects lack a characteristic phenotype. However, some of the subtelomeric deletions result in a specific phenotype, which can direct the clinician towards the diagnosis. Submicroscopic 6p deletion appears to be a recognizable clinical phenotype, and this region should be thoroughly investigated with FISH probes, including at least a subtelomeric 6p probe and a probe covering FOXC1, for patients presenting with a characteristic facial appearance, ocular abnormalities, predominantly anterior-chamber eye defects, hearing loss, and mental retardation.

PAX6, a paired box transcriptional factor, is considered as the master control gene for morphogenesis of the eye. Human PAX6 mutations have been associated with a range of eye abnormalities, including aniridia, various anterior segment defects and foveal hypoplasia. We carried out a mutational analysis of the PAX6 gene in 54 unrelated patients with aniridia or related syndromes. A deleterious variation was evidenced in 17 sporadic cases (50%) and in 13 (72%) familial cases. Twenty-four different mutations, 17 of which are novel, were found. The spectrum of PAX6 mutations was highly homogeneous: 23 mutations (96%) leading to premature stop codons (eight nonsense and four splice site mutations, 11 insertions and deletions) and only one (4%) missense mutation. Twenty-two mutations were associated with aniridia phenotypes whereas two were associated with atypical phenotypes. These latter encompassed a missense mutation (R19P) in an individual with a microphthalmia-sclerocornea and a splice site mutation (IVS4+5G > C) in a family presenting with a congenital nystagmus. Both represented the most probably hypomorphic alleles. Aniridia cases were associated with nonsense or frameshifting mutations. A careful examination of the phenotypes did not make it possible to recognise significant differences whenever the predicted protein was deprived of one or another of its functional domains. This strongly suggested that most of the truncating mutations generated null alleles by nonsense mediated mRNA decay. Our observations support the concept of dosage effects of the PAX6 mutations as well as presenting evidence for variable expressivity.

The aim of this study was to find out if field boundaries are refuges for earthworms from where they can spread out into the agricultural fields, thereby keeping up their abundance and biodiversity. The earthworm community was studied in: (1) a 640 m long field boundary; (2) the adjacent arable field at different distances from the boundary; (3) a pasture adjoining to the opposite side of the field near Uppsala in Sweden. Sampling was done in May and September. In contradiction to what was preconceived, the abundance and biomass of earthworms, both in the boundary and the pasture, was significantly lower than that in the agricultural field. The density increased towards the centre of the field. The trends were similar for both spring and autumn. The same species were found in the field, boundary and pasture, but Aporrectodea caliginosa was more dominant in the field than in the other habitats. The conclusion is that agriculture with manure, fertilisers, moderate soil cultivation and varying crops, in general, is favourable for earthworms, except for certain species. However, situations can occur when the earthworm populations in the field decline, and then boundaries may serve as sources from where re-immigration can take place.

Lenalidomide in combination with dexamethasone is a treatment for patients with relapsed or refractory myeloma. Although this combination demonstrates a high level of efficacy, it further exacerbates the hypercoaguable state that exists within myeloma. Thromboprophylactic regimen require careful selection and if warfarin is chosen, assiduous monitoring is required to ensure it will be clinically effective. We report the case of one patient who experienced multiple thrombotic events despite anticoagulant or antiplatelet thromboprophylaxis and review the contributing factors.

Testicular cancer is the most common neoplasia occurring in the young male population. The PEB (cisplatin, etoposide and bleomycin) adjuvant chemotherapy usually proposed after orchidectomy in non seminomatous tumours, and in metastatic seminomas, has improved the long-term survival of these patients. Following an azoospermic period, sperm cell recovery is generally observed after treatment delivery, but little is known about the genetic consequences on these new spermatozoa. To estimate the chromosomal consequences of this chemotherapy on sperm cells during the period of recovery of spermatogenesis, sperm cell aneuploidy was studied in testicular cancer patients, at 6-18 months after PEB adjuvant chemotherapy delivery, using fluorescence in-situ hybridization (FISH) of chromosomes 7, 16, 18, X and Y with specific DNA probes. A significant increase in the frequency of diploidy and disomy for chromosomes 16, 18 and XY was observed in treated patients compared with a healthy control group. Spermatozoa aneuploidy occurring during the spermatogenesis recovery period might be a possible side effect of the PEB regimen. Thus, practitioners should be advised to provide counselling about the need for an appropriate duration of contraception. Moreover, genetic counselling should be offered in cases of pregnancy occurring soon after the end of chemotherapy.