Fast iterative boundary element methods for high-frequency scattering problems in 3D elastodynamics

International audienceThe fast multipole method is an efficient technique to accelerate the solution of large scale 3D scattering problems with boundary integral equations. However, the fast multipole accelerated boundary element method (FM-BEM) is intrinsically based on an iterative solver. It has been shown that the number of iterations can significantly hinder the overall efficiency of the FM-BEM. The derivation of robust preconditioners for FM-BEM is now inevitable to increase the size of the problems that can be considered. The main constraint in the context of the FM-BEM is that the complete system is not assembled to reduce computational times and memory requirements. Analytic preconditioners offer a very interesting strategy by improving the spectral properties of the boundary integral equations ahead from the discretization. The main contribution of this paper is to combine an approximate adjoint Dirichlet to Neumann (DtN) map as an analytic preconditioner with a FM-BEM solver to treat Dirichlet exterior scattering problems in 3D elasticity. The approximations of the adjoint DtN map are derived using tools proposed in [40]. The resulting boundary integral equations are preconditioned Combined Field Integral Equations (CFIEs). We provide various numerical illustrations of the efficiency of the method for different smooth and non smooth geometries. In particular, the number of iterations is shown to be completely independent of the number of degrees of freedom and of the frequency for convex obstacles

Retention of the virus-derived sequences in the nuclear genome of grapevine as a potential pathway to virus resistance

<p>Abstract</p> <p>Background</p> <p>Previous studies have revealed a wide-spread occurence of the partial and complete genomes of the reverse-transcribing pararetroviruses in the nuclear genomes of herbaceous plants. Although the absence of the virus-encoded integrases attests to the random and incidental incorporation of the viral sequences, their presence could have functional implications for the virus-host interactions.</p> <p>Hypothesis</p> <p>Analyses of two nuclear genomes of grapevine revealed multiple events of horizontal gene transfer from pararetroviruses. The ~200–800 bp inserts that corresponded to partial ORFs encoding reverse transcriptase apparently derived from unknown or extinct caulimoviruses and tungroviruses, were found in 11 grapevine chromosomes. In contrast to the previous reports, no reliable cases of the inserts derived from the positive-strand RNA viruses were found. Because grapevine is known to be infected by the diverse positive-strand RNA viruses, but not pararetroviruses, we hypothesize that pararetroviral inserts have conferred host resistance to these viruses. Furthermore, we propose that such resistance involves RNA interference-related mechanisms acting via small RNA-mediated methylation of pararetroviral DNAs and/or via degradation of the viral mRNAs.</p> <p>Conclusion</p> <p>The pararetroviral sequences in plant genomes may be maintained due to the benefits of virus resistance to this class of viruses conferred by their presence. Such resistance could be particularly significant for the woody plants that must withstand years- to centuries-long virus assault. Experimental research into the RNA interference pathways involving the integrated pararetroviral inserts is required to test this hypothesis.</p> <p>Reviewers</p> <p>This article was reviewed by Arcady R. Mushegian, I. King Jordan, and Eugene V. Koonin.</p

Latest Altimetry-Based Sea Ice Freeboard and Volume Inter-Annual Variability in the Antarctic over 2003–2020

The relatively stable conditions of the sea ice cover in the Antarctic, observed for almost 40 years, seem to be changing recently. Therefore, it is essential to provide sea ice thickness (SIT) and volume (SIV) estimates in order to anticipate potential multi-scale changes in the Antarctic sea ice. For that purpose, the main objectives of this work are: (1) to assess a new sea ice freeboard, thickness and volume altimetry dataset over 2003–2020 and (2) to identify first order impacts of the sea ice recent conditions. To produce these series, we use a neuronal network to calibrate Envisat radar freeboards onto CryoSat-2 (CS2). This method addresses the impacts of surface roughness on Low Resolution Mode (LRM) measurements. During the 2011 common flight period, we found a mean deviation between Envisat and CryoSat-2 radar freeboards by about 0.5 cm. Using the Advanced Microwave Scanning Radiometer (AMSR) and the dual-frequency Altimetric Snow Depth (ASD) data, our solutions are compared with the Upward looking sonar (ULS) draft data, some in-situ measurement of the SIMBA campaign, the total freeboards of 6 Operation Ice Bridge (OIB) missions and ICESat-2 total freeboards. Over 2003–2020, the global mean radar freeboard decreased by about −14% per decade and the SIT and SIV by about −10% per decade (considering a snow depth climatology). This is marked by a slight increase through 2015, which is directly followed by a strong decrease in 2016. Thereafter, freeboards generally remained low and even continued to decrease in some regions such as the Weddell sea. Considering the 2013–2020 period, for which the ASD data are available, radar freeboards and SIT decreased by about −40% per decade. The SIV decreased by about −60% per decade. After 2016, the low SIT values contrast with the sea ice extent that has rather increased again, reaching near-average values in winter 2020. The regional analysis underlines that such thinning (from 2016) occurs in all regions except the Amundsen-Bellingshausen sea sector. Meanwhile, we observed a reversal of the main regional trends from 2016, which may be the signature of significant ongoing changes in the Antarctic sea ice

Cytotoxic CD8⁺ T lymphocytes expressing ALS-causing SOD1 mutant selectively trigger death of spinal motoneurons.

Adaptive immune response is part of the dynamic changes that accompany motoneuron loss in amyotrophic lateral sclerosis (ALS). CD4 &lt;sup&gt;+&lt;/sup&gt; T cells that regulate a protective immunity during the neurodegenerative process have received the most attention. CD8 &lt;sup&gt;+&lt;/sup&gt; T cells are also observed in the spinal cord of patients and ALS mice although their contribution to the disease still remains elusive. Here, we found that activated CD8 &lt;sup&gt;+&lt;/sup&gt; T lymphocytes infiltrate the central nervous system (CNS) of a mouse model of ALS at the symptomatic stage. Selective ablation of CD8 &lt;sup&gt;+&lt;/sup&gt; T cells in mice expressing the ALS-associated superoxide dismutase-1 (SOD1) &lt;sup&gt;G93A&lt;/sup&gt; mutant decreased spinal motoneuron loss. Using motoneuron-CD8 &lt;sup&gt;+&lt;/sup&gt; T cell coculture systems, we found that mutant SOD1-expressing CD8 &lt;sup&gt;+&lt;/sup&gt; T lymphocytes selectively kill motoneurons. This cytotoxicity activity requires the recognition of the peptide-MHC-I complex (where MHC-I represents major histocompatibility complex class I). Measurement of interaction strength by atomic force microscopy-based single-cell force spectroscopy demonstrated a specific MHC-I-dependent interaction between motoneuron and SOD1 &lt;sup&gt; G93A &lt;/sup&gt; CD8 &lt;sup&gt;+&lt;/sup&gt; T cells. Activated mutant SOD1 CD8 &lt;sup&gt;+&lt;/sup&gt; T cells produce interferon-γ, which elicits the expression of the MHC-I complex in motoneurons and exerts their cytotoxic function through Fas and granzyme pathways. In addition, analysis of the clonal diversity of CD8 &lt;sup&gt;+&lt;/sup&gt; T cells in the periphery and CNS of ALS mice identified an antigen-restricted repertoire of their T cell receptor in the CNS. Our results suggest that self-directed immune response takes place during the course of the disease, contributing to the selective elimination of a subset of motoneurons in ALS

Statement on how to interpret the QPS qualification on ‘acquired antimicrobial resistance genes’

The qualified presumption of safety (QPS) approach was developed to provide a regularly updated generic pre-evaluation of the safety of microorganisms intended for use in the food or feed chains. Safety concerns identified for a taxonomic unit (TU) are, where possible, confirmed at the species/strain or product level and reflected by ‘qualifications’ which should be assessed at strain and/or product level by EFSA's Scientific Panels. The generic qualification ‘the strains should not harbour any acquired antimicrobial resistance (AMR) genes to clinically relevant antimicrobials’ applies to all QPS bacterial TUs. The different EFSA risk assessment areas use the same approach to assess the qualification related to AMR genes. In this statement, the terms ‘intrinsic’ and ‘acquired’ AMR genes were defined for the purpose of EFSA's risk assessments, and they apply to bacteria used in the food and feed chains. A bioinformatic approach is proposed for demonstrating the ‘intrinsic’/’acquired’ nature of an AMR gene. All AMR genes that confer resistance towards ‘critically important’, ‘highly important’ and ‘important’ antimicrobials, as defined by the World Health Organisation (WHO), found as hits, need to be considered as hazards (for humans, animals and environment) and need further assessment. Genes identified as responsible for ‘intrinsic’ resistance could be considered as being of no concern in the frame of the EFSA risk assessment. ‘Acquired’ AMR genes resulting in a resistant phenotype should be considered as a concern. If the presence of the ‘acquired’ AMR gene is not leading to phenotypic resistancinfo:eu-repo/semantics/publishedVersio

Clinical practice guidelines for BRCA1 and BRCA2 genetic testing

BRCA1 and BRCA2 gene pathogenic variants account for most hereditary breast cancer and are increasingly used to determine eligibility for PARP inhibitor (PARPi) therapy of BRCA-related cancer. Because issues of BRCA testing in clinical practice now overlap with both preventive and therapeutic management, updated and comprehensive practice guidelines for BRCA genotyping are needed. The integrative recommendations for BRCA testing presented here aim to (1) identify individuals who may benefit from genetic counselling and risk-reducing strategies; (2) update germline and tumour-testing indications for PARPi-approved therapies; (3) provide testing recommendations for personalised management of early and metastatic breast cancer; and (4) address the issues of rapid process and tumour analysis. An international group of experts, including geneticists, medical and surgical oncologists, pathologists, ethicists and patient representatives, was commissioned by the French Society of Predictive and Personalised Medicine (SFMPP). The group followed a methodology based on specific formal guidelines development, including (1) evaluating the likelihood of BRCAm from a combined systematic review of the literature, risk assessment models and expert quotations, and (2) therapeutic values of BRCAm status for PARPi therapy in BRCA-related cancer and for management of early and advanced breast cancer. These international guidelines may help clinicians comprehensively update and standardise BRCA testing practices

Establishment of a taxonomic and molecular reference collection to support the identification of species regulated by the Western Australian Prevention List for Introduced Marine Pests

Introduced Marine Pests (IMP, = non-indigenous marine species) prevention, early detection and risk-based management strategies have become the priority for biosecurity operations worldwide, in recognition of the fact that, once established, the effective management of marine pests can rapidly become cost prohibitive or impractical. In Western Australia (WA), biosecurity management is guided by the “Western Australian Prevention List for Introduced Marine Pests” which is a policy tool that details species or genera as being of high risk to the region. This list forms the basis of management efforts to prevent introduction of these species, monitoring efforts to detect them at an early stage, and rapid response should they be detected. It is therefore essential that the species listed can be rapid and confidently identified and discriminated from native species by a range of government and industry stakeholders. Recognising that identification of these species requires very specialist expertise which may be in short supply and not readily accessible in a regulatory environment, and the fact that much publicly available data is not verifiable or suitable for regulatory enforcement, the WA government commissioned the current project to collate a reference collection of these marine pest specimens. In this work, we thus established collaboration with researchers worldwide in order to source representative specimens of the species listed. Our main objective was to build a reference collection of taxonomically vouchered specimens and subsequently to generate species-specific DNA barcodes suited to supporting their future identification. To date, we were able to obtain specimens of 75 species (representative of all but four of the pests listed) which have been identified by experts and placed with the WA Government Department of Fisheries and, where possible, in accessible museums and institutions in Australasia. The reference collection supports the fast and reliable taxonomic and molecular identification of marine pests in WA and constitutes a valuable resource for training of stakeholders with interest in IMP recognition in Australia. The reference collection is also useful in supporting the development of a variety of DNA-based detection strategies such as real-time PCR and metabarcoding of complex environmental samples (e.g. biofouling communities). ThePrevention List is under regular review to ensure its continued relevance and that it remains evidence and risk-based. Similarly, its associated reference collection also remains to some extent a work in progress. In recognition of this fact, this report seeks to provide details of this continually evolving information repository publicly available to the biosecurity management community worldwid

Pooled Analysis of Prognostic Impact of Urokinase-Type Plasminogen Activator and Its Inhibitor PAI-1 in 8377 Breast Cancer Patients

Background: Urokinase-type plasminogen activator (uPA) and its inhibitor (PAI-1) play essential roles in tumor invasion and metastasis. High levels of both uPA and PAI-1 are associated with poor prognosis in breast cancer patients. To confirm the prognostic value of uPA and PAI-1 in primary breast cancer, we reanalyzed individual patient data provided by members of the European Organization for Research and Treatment of Cancer-Receptor and Biomarker Group (EORTC-RBG). Methods: The study included 18 datasets involving 8377 breast cancer patients. During follow-up (median 79 months), 35% of the patients relapsed and 27% died. Levels of uPA and PAI-1 in tumor tissue extracts were determined by different immunoassays; values were ranked within each dataset and divided by the number of patients in that dataset to produce fractional ranks that could be compared directly across datasets. Associations of ranks of uPA and PAI-1 levels with relapse-free survival (RFS) and overall survival (OS) were analyzed by Cox multivariable regression analysis stratified by dataset, including the following traditional prognostic variables: age, menopausal status, lymph node status, tumor size, histologic grade, and steroid hormone-receptor status. All P values were two-sided. Results: Apart from lymph node status, high levels of uPA and PAI-1 were the strongest predictors of both poor RFS and poor OS in the analyses of all patients. Moreover, in both lymph node-positive and lymph node-negative patients, higher uPA and PAI-1 values were independently associated with poor RFS and poor OS. For (untreated) lymph node-negative patients in particular, uPA and PAI-1 included together showed strong prognostic ability (all P<.001). Conclusions: This pooled analysis of the EORTC-RBG datasets confirmed the strong and independent prognostic value of uPA and PAI-1 in primary breast cancer. For patients with lymph node-negative breast cancer, uPA and PAI-1 measurements in primary tumors may be especially useful for designing individualized treatment strategie

Extending the clinical spectrum of X-linked Tonne-Kalscheuer syndrome (TOKAS):new insights from the fetal perspective

INTRODUCTION: Tonne-Kalscheuer syndrome (TOKAS) is a recessive X-linked multiple congenital anomaly disorder caused by RLIM variations. Of the 41 patients reported, only 7 antenatal cases were described.METHOD: After the antenatal diagnosis of TOKAS by exome analysis in a family followed for over 35 years because of multiple congenital anomalies in five male fetuses, a call for collaboration was made, resulting in a cohort of 11 previously unpublished cases.RESULTS: We present a TOKAS antenatal cohort, describing 11 new cases in 6 French families. We report a high frequency of diaphragmatic hernia (9 of 11), differences in sex development (10 of 11) and various visceral malformations. We report some recurrent dysmorphic features, but also pontocerebellar hypoplasia, pre-auricular skin tags and olfactory bulb abnormalities previously unreported in the literature. Although no clear genotype-phenotype correlation has yet emerged, we show that a recurrent p.(Arg611Cys) variant accounts for 66% of fetal TOKAS cases. We also report two new likely pathogenic variants in RLIM, outside of the two previously known mutational hotspots.CONCLUSION: Overall, we present the first fetal cohort of TOKAS, describe the clinical features that made it a recognisable syndrome at fetopathological examination, and extend the phenotypical spectrum and the known genotype of this rare disorder.</p

Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: A Gradient of Severity in Cognitive Impairments.

International audienceSHANK genes code for scaffold proteins located at the post-synaptic density of glutamatergic synapses. In neurons, SHANK2 and SHANK3 have a positive effect on the induction and maturation of dendritic spines, whereas SHANK1 induces the enlargement of spine heads. Mutations in SHANK genes have been associated with autism spectrum disorders (ASD), but their prevalence and clinical relevance remain to be determined. Here, we performed a new screen and a meta-analysis of SHANK copy-number and coding-sequence variants in ASD. Copy-number variants were analyzed in 5,657 patients and 19,163 controls, coding-sequence variants were ascertained in 760 to 2,147 patients and 492 to 1,090 controls (depending on the gene), and, individuals carrying de novo or truncating SHANK mutations underwent an extensive clinical investigation. Copy-number variants and truncating mutations in SHANK genes were present in ∼1% of patients with ASD: mutations in SHANK1 were rare (0.04%) and present in males with normal IQ and autism; mutations in SHANK2 were present in 0.17% of patients with ASD and mild intellectual disability; mutations in SHANK3 were present in 0.69% of patients with ASD and up to 2.12% of the cases with moderate to profound intellectual disability. In summary, mutations of the SHANK genes were detected in the whole spectrum of autism with a gradient of severity in cognitive impairment. Given the rare frequency of SHANK1 and SHANK2 deleterious mutations, the clinical relevance of these genes remains to be ascertained. In contrast, the frequency and the penetrance of SHANK3 mutations in individuals with ASD and intellectual disability-more than 1 in 50-warrant its consideration for mutation screening in clinical practice