Probing the Local Velocity Distribution of WIMP Dark Matter with Directional Detectors

We explore the ability of directional nuclear-recoil detectors to constrain the local velocity distribution of weakly interacting massive particle (WIMP) dark matter by performing Bayesian parameter estimation on simulated recoil-event data sets. We discuss in detail how directional information, when combined with measurements of the recoil-energy spectrum, helps break degeneracies in the velocity-distribution parameters. We also consider the possibility that velocity structures such as cold tidal streams or a dark disk may also be present in addition to the Galactic halo. Assuming a carbon-tetrafluoride detector with a 30-kg-yr exposure, a 50-GeV WIMP mass, and a WIMP-nucleon spin-dependent cross-section of 0.001 pb, we show that the properties of a cold tidal stream may be well constrained. However, measurement of the parameters of a dark-disk component with a low lag speed of ~50 km/s may be challenging unless energy thresholds are improved.Comment: 38 pages, 15 figure

Stable long-term outcomes after cochlear implantation in subjects with TMPRSS3 associated hearing loss: a retrospective multicentre study

Background The spiral ganglion hypothesis suggests that pathogenic variants in genes preferentially expressed in the spiral ganglion nerves (SGN), may lead to poor cochlear implant (CI) performance. It was long thought that TMPRSS3 was particularly expressed in the SGNs. However, this is not in line with recent reviews evaluating CI performance in subjects with TMPRSS3-associated sensorineural hearing loss (SNHL) reporting overall beneficial outcomes. These outcomes are, however, based on variable follow-up times of, in general, 1 year or less. Therefore, we aimed to 1. evaluate long-term outcomes after CI implantation of speech recognition in quiet in subjects with TMPRSS3-associated SNHL, and 2. test the spiral ganglion hypothesis using the TMPRSS3-group. Methods This retrospective, multicentre study evaluated long-term CI performance in a Dutch population with TMPRSS3-associated SNHL. The phoneme scores at 70 dB with CI in the TMPRSS3-group were compared to a control group of fully genotyped cochlear implant users with post-lingual SNHL without genes affecting the SGN, or severe anatomical inner ear malformations. CI-recipients with a phoneme score <= 70% at least 1-year post-implantation were considered poor performers and were evaluated in more detail. Results The TMPRSS3 group consisted of 29 subjects (N = 33 ears), and the control group of 62 subjects (N = 67 ears). For the TMPRSS3-group, we found an average phoneme score of 89% after 5 years, which remained stable up to 10 years post-implantation. At both 5 and 10-year follow-up, no difference was found in speech recognition in quiet between both groups (p = 0.830 and p = 0.987, respectively). Despite these overall adequate CI outcomes, six CI recipients had a phoneme score of <= 70% and were considered poor performers. The latter was observed in subjects with residual hearing post-implantation or older age at implantation. Conclusion Subjects with TMPRSS3-associated SNHL have adequate and stable long-term outcomes after cochlear implantation, equal to the performance of genotyped patient with affected genes not expressed in the SGN. These findings are not in line with the spiral ganglion hypothesis. However, more recent studies showed that TMPRSS3 is mainly expressed in the hair cells with only limited SGN expression. Therefore, we cannot confirm nor refute the spiral ganglion hypothesis.Otorhinolaryngolog

A RIPOR2 in-frame deletion is a frequent and highly penetrant cause of adult-onset hearing loss

BackgroundHearing loss is one of the most prevalent disabilities worldwide, and has a significant impact on quality of life. The adult-onset type of the condition is highly heritable but the genetic causes are largely unknown, which is in contrast to childhood-onset hearing loss.MethodsFamily and cohort studies included exome sequencing and characterisation of the hearing phenotype. Ex vivo protein expression addressed the functional effect of a DNA variant.ResultsAn in-frame deletion of 12 nucleotides in RIPOR2 was identified as a highly penetrant cause of adult-onset progressive hearing loss that segregated as an autosomal dominant trait in 12 families from the Netherlands. Hearing loss associated with the deletion in 63 subjects displayed variable audiometric characteristics and an average (SD) age of onset of 30.6 (14.9) years (range 0-70 years). A functional effect of the RIPOR2 variant was demonstrated by aberrant localisation of the mutant RIPOR2 in the stereocilia of cochlear hair cells and failure to rescue morphological defects in RIPOR2-deficient hair cells, in contrast to the wild-type protein. Strikingly, the RIPOR2 variant is present in 18 of 22 952 individuals not selected for hearing loss in the Southeast Netherlands.ConclusionCollectively, the presented data demonstrate that an inherited form of adult-onset hearing loss is relatively common, with potentially thousands of individuals at risk in the Netherlands and beyond, which makes it an attractive target for developing a (genetic) therapy.Otorhinolaryngolog

Heterozygous missense variants of LMX1A lead to nonsyndromic hearing impairment and vestibular dysfunction

Neuro Imaging Researc

Genome-wide identification of the genetic basis of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a complex disease that leads to motor neuron death. Despite heritability estimates of 52%, genome-wide association studies (GWASs) have discovered relatively few loci. We developed a machine learning approach called RefMap, which integrates functional genomics with GWAS summary statistics for gene discovery. With transcriptomic and epigenetic profiling of motor neurons derived from induced pluripotent stem cells (iPSCs), RefMap identified 690 ALS-associated genes that represent a 5-fold increase in recovered heritability. Extensive conservation, transcriptome, network, and rare variant analyses demonstrated the functional significance of candidate genes in healthy and diseased motor neurons and brain tissues. Genetic convergence between common and rare variation highlighted KANK1 as a new ALS gene. Reproducing KANK1 patient mutations in human neurons led to neurotoxicity and demonstrated that TDP-43 mislocalization, a hallmark pathology of ALS, is downstream of axonal dysfunction. RefMap can be readily applied to other complex diseases

Discovery of widespread transcription initiation at microsatellites predictable by sequence-based deep neural network

Using the Cap Analysis of Gene Expression (CAGE) technology, the FANTOM5 consortium provided one of the most comprehensive maps of transcription start sites (TSSs) in several species. Strikingly, ~72% of them could not be assigned to a specific gene and initiate at unconventional regions, outside promoters or enhancers. Here, we probe these unassigned TSSs and show that, in all species studied, a significant fraction of CAGE peaks initiate at microsatellites, also called short tandem repeats (STRs). To confirm this transcription, we develop Cap Trap RNA-seq, a technology which combines cap trapping and long read MinION sequencing. We train sequence-based deep learning models able to predict CAGE signal at STRs with high accuracy. These models unveil the importance of STR surrounding sequences not only to distinguish STR classes, but also to predict the level of transcription initiation. Importantly, genetic variants linked to human diseases are preferentially found at STRs with high transcription initiation level, supporting the biological and clinical relevance of transcription initiation at STRs. Together, our results extend the repertoire of non-coding transcription associated with DNA tandem repeats and complexify STR polymorphism

Sulfate-reducing prokaryotic communities in two deep hypersaline anoxic basins in the Eastern Mediterranean deep sea

In the Eastern Mediterranean Sea, deep hypersaline anoxic basins (DHABs) and deep-sea sediment contain anoxic environments where sulfate reduction is an important microbial metabolic process. The objective of this study was to characterize the sulfate-reducing community in the brine and interface of the DHABs L'Atalante and Urania based on a phylogenetic analysis of the dissimilatory sulfite reductase gene (dsrA). Results demonstrated that the sulfate-reducing community was diverse, except for the sulfidogenic brine of the Urania basin. The similarity of the dsrA sequences between different environments was very low demonstrating that each environment had a unique sulfate-reducing community. Sequences had 67.6-93.3% similarity to dsrA sequences from GenBank database and were mostly related to the delta-proteobacteria. Each environment was dominated by a different family within the delta-proteobacteria except for the Urania interface, which was dominated by sequences related to the Gram-positive Peptococcaceae. We conclude that sulfate-reducing communities inhabiting the L'Atalante and Urania basins are highly diverse with low similarities to each other and contain a sulfate-reducing species composition that is very different from sulfate-reducing species compositions in previously studied ecosystems

Targeted sequencing to identify novel genetic risk factors for deep vein thrombosis: a study of 734 genes

International audienceEssentials Deep vein thrombosis (DVT) has a large unknown genetic component. We sequenced coding areas of 734 hemostasis-related genes in 899 DVT patients and 599 controls. Variants in F5, FGA-FGG, CYP4V2-KLKB1-F11, and ABO were associated with DVT risk. Associations in KLKB1 and F5 suggest a more complex genetic architecture than previously thought. SUMMARY: Background Although several genetic risk factors for deep vein thrombosis (DVT) are known, almost all related to hemostasis, a large genetic component remains unexplained. Objectives To identify novel genetic determinants by using targeted DNA sequencing. Patients/Methods We included 899 DVT patients and 599 controls from three case-control studies (DVT-Milan, Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis [MEGA], and the Thrombophilia, Hypercoagulability and Environmental Risks in Venous Thromboembolism [THE-VTE] study) for sequencing of the coding regions of 734 genes involved in hemostasis or related pathways. We performed single-variant association tests for common variants (minor allele frequency [MAF] ≥ 1%) and gene-based tests for rare variants (MAF ≤ 1%), accounting for multiple testing by use of the false discovery rate (FDR). Results Sixty-two of 3617 common variants were associated with DVT risk (FDR 0.2). Conclusions We confirmed associations between DVT and common variants in F5,ABO,FGA-FGG, and CYP4V2-KLKB1-F11, and observed secondary signals in F5 and CYP4V2-KLKB1-F11 that warrant replication and fine-mapping in larger studies