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Ultrasonic signals can be conveniently recorded using modern high-speed analog-to-digital converters and analyzed through digital signal processing algorithms. Sometimes, in some applications, such as in bioacoustics, it is necessary to convert digital data to analog signals with a special transformation that allows compressing and translating the spectrum toward audible frequencies. The process is called time expansion and can be conveniently achieved by slowing down the frequency clock of a digital-to-analog converter. This paper analyzes in detail the spectral characteristics of a time-expanded signal.

Variants of uncertain significance (VUS) are a significant issue for the molecular diagnosis of rare diseases. The publication of episignatures as effective biomarkers of certain Mendelian neurodevelopmental disorders has raised hopes to help classify VUS. However, prediction abilities of most published episignatures have not been independently investigated yet, which is a prerequisite for an informed and rigorous use in a diagnostic setting. We generated DNA methylation data from 102 carriers of (likely) pathogenic variants in ten different genes, 58 VUS carriers, and 25 healthy controls. Combining published episignature information and new validation data with a k-nearest-neighbour classifier within a leave-one-out scheme, we provide unbiased specificity and sensitivity estimates for each of the signatures. Our procedure reached 100% specificity, but the sensitivities unexpectedly spanned a very large spectrum. While ATRX, DNMT3A, KMT2D, and NSD1 signatures displayed a 100% sensitivity, CREBBP-RSTS and one of the CHD8 signatures reached less than 40% sensitivity on our dataset. Remaining Cornelia de Lange syndrome, KMT2A, KDM5C and CHD7 signatures reached 70%-100% sensibility at best with unstable performances, suffering from heterogeneous methylation profiles among cases and rare discordant samples. Our results call for cautiousness and demonstrate that episignatures do not perform equally well. Some signatures are ready for confident use in a diagnostic setting. Yet, it is imperative to characterise the actual validity perimeter and interpretation of each episignature with the help of larger validation sample sizes and in a broader set of episignatures.

In this work, we provide a systematic theoretical and experimental characterization of bias errors in defocusing particle tracking (DPT) methods based on a single calibration function, with respect to microfluidic applications, in which it is not possible to use calibration targets inside the measurement volume. This approach is widely used in microfluidic experiments, but bias errors are often neglected and to date only few works reported empirical procedures to compensate for that. A systematic characterization of the impact of such error in DPT measurements is still lacking. We show that the field curvature aberration and the refractive index mismatch are the main sources of bias error in these applications. We present a correction methodology for the bias error based on the determination of a reference surface, and in addition we propose a procedure based on a reference measurement of a Poiseuille flow to determine the reference surface on microfluidic channels with constant cross section. We discuss the impact of the refractive index mismatch and how to correctly compensate for it. We validated our methodology and quantified the bias errors on 10 different experimental setups, using different working fluids, materials, geometries, and microscope objective lenses ranging from 5$$\times$$ × to 40$$\times$$ × magnification. Our results indicate that the impact of this type of bias errors is in general not predictable and must be evaluated case by case. The proposed methodology allows to estimate and minimize the bias error in most microfluidic setups and is suitable for any single-camera DPT approach.

We report two series of individuals with DDX3X variations, one (48 individuals) from physicians and one (44 individuals) from caregivers. These two series include several symptoms in common, with fairly similar distribution, which suggests that caregivers’ data are close to physicians’ data. For example, both series identified early childhood symptoms that were not previously described: feeding difficulties, mean walking age and age at first words. Each of the two datasets provide complementary knowledge. We confirmed that symptoms are similar to those in the literature and provide more details on feeding difficulties. Caregivers considered that the symptom attention-deficit/hyperactivity disorder was most worrisome. Both series also reported sleep disturbance. Recently, anxiety has been reported in individuals with DDX3X variants. We strongly suggest that attention-deficit/hyperactivity disorder, anxiety and sleep disorders need to be treated. In addition, we demonstrate preliminary evidence of a mild genome-wide DNA methylation profile in patients carrying mutations in DDX3X.

To characterize natural history and early changes of craniovertebral junction stenosis in achondroplasia correlating with clinical and radiological outcome.Retrospective measures on craniovertebral junction were performed blindly, on sagittal T2-weighted images, in 21 patients with achondroplasia referred from 2008 to 2020. Clinical and polysomnography data were retrospectively collected. Each patient was paired for age and gender with four controls. Wilcoxon means comparison or Student's t-tests were applied.Twenty-one patients (11 females, from 0.1 to 39 years of age) were analyzed and paired with 84 controls. A craniovertebral junction stenosis was found in 11/21 patients (52.4%), all before the age of 2 years. Despite a significant reduction of the foramen magnum diameter (mean ± SD: patients 13.6 ± 6.2 mm, controls 28.5 ± 4.7 mm, p .001), craniovertebral junction stenosis resulted from the narrowing of C2 dens-opisthion antero-posterior diameter (8.7 ± 3.9 mm vs 24.6 ± 5.1 mm, p .001). Other significant changes were opisthion anterior placement (-0.4 ± 2.8 mm vs 9.4 ± 2.3 mm, p .001), posterior tilt of C2 (46.2 ± 13.7° vs 31.6 ± 7.9°, p .001) and of C1 (15.1 ± 4.3° vs 11.9 ± 5.0°, p = 0.01), and dens thickening (9.4 ± 2.2 mm vs 8.5 ± 2.1 mm, p = 0.03), allowing to define three distinguishable early craniovertebral junction patterns in achondroplasia. All children with C2-opisthion antero-posterior diameter of more than 6 mm had a better clinical and radiological outcome.Craniovertebral junction in achondroplasia results from narrowing between C2 dens and opisthion related to anterior placement of opisthion, thickening of C2 dens, and posterior tilt of C1-C2. A threshold of 6 mm for dens-opisthion sagittal diameter seems to correlate with clinical and radiological outcome.

Unique or multiple congenital facial skin polyps are features of several rare syndromes, from the most well-known Pai syndrome (PS), to the less recognized oculoauriculofrontonasal syndrome (OAFNS), encephalocraniocutaneous lipomatosis (ECCL), or Sakoda complex (SC). We set up a research project aiming to identify the molecular bases of PS. We reviewed 27 individuals presenting with a syndromic frontonasal polyp and initially referred for PS. Based on strict clinical classification criteria, we could confirm only nine (33%) typical and two (7%) atypical PS individuals. The remaining ones were either OAFNS (11/27-41%) or presenting with an overlapping syndrome (5/27-19%). Because of the phenotypic overlap between these entities, OAFNS, ECCL, and SC can be either considered as differential diagnosis of PS or part of the same spectrum. Exome and/or genome sequencing from blood DNA in 12 patients and from affected tissue in one patient failed to identify any replication in candidate genes. Taken together, our data suggest that conventional approaches routinely utilized for the identification of molecular etiologies responsible for Mendelian disorders are inconclusive. Future studies on affected tissues and multiomics studies will thus be required in order to address either the contribution of mosaic or noncoding variation in these diseases.

ARIEL, the Atmospheric Remote-sensing Infrared Exoplanet Large-survey, was selected as the fourth medium-class mission in ESA’s Cosmic Vision program. ARIEL is based on a 1 m class telescope optimized for spectroscopy in the waveband between 1.95 and 7.8 micron and operating in cryogenic conditions. Fabrication of the 1.1 m aluminum primary mirror for the ARIEL telescope requires technological advances in the three areas of substrate thermal stabilization, optical surface polishing and coating. This article describes the qualification of the three procedures that have been set up and tested to demonstrate the readiness level of the technological processes employed. Substrate thermal stabilization is required to avoid deformations of the optical surface during cool down of the telescope to the operating temperature below 50 K. Purpose of the process is to release internal stress in the substrate that can cause such shape deformations. Polishing of large aluminum surfaces to optical quality is notoriously difficult due to softness of the material, and required setup and test of a specific polishing recipe capable of reducing residual surface shape errors while maintaining surface roughness below 10 nm RMS. Finally, optical coating with protected silver must be qualified for environmental stability, particularly at cryogenic temperatures, and uniformity. All processes described in this article have been applied to aluminum samples of up to 150 mm of diameter, leading the way to the planned final test on a full size demonstrator of the ARIEL primary mirror.

Recently, Gagie et al. proposed a version of the FM-index, called the r-index, that can store thousands of human genomes on a commodity computer. Then Kuhnle et al. showed how to build the r-index efficiently via a technique called prefix-free parsing (PFP) and demonstrated its effectiveness for exact pattern matching. Exact pattern matching can be leveraged to support approximate pattern matching, but the r-index itself cannot support efficiently popular and important queries such as finding maximal exact matches (MEMs). To address this shortcoming, Bannai et al. introduced the concept of thresholds, and showed that storing them together with the r-index enables efficient MEM finding—but they did not say how to find those thresholds. We present a novel algorithm that applies PFP to build the r-index and find the thresholds simultaneously and in linear time and space with respect to the size of the prefix-free parse. Our implementation called [Formula: see text] can rapidly find MEMs between reads and large-sequence collections of highly repetitive sequences. Compared with other read aligners—PuffAligner, Bowtie2, BWA-MEM, and CHIC— MONI used 2–11 times less memory and was 2–32 times faster for index construction. Moreover, MONI was less than one thousandth the size of competing indexes for large collections of human chromosomes. Thus, MONI represents a major advance in our ability to perform MEM finding against very large collections of related references.

MotivationThe positional Burrows-Wheeler Transform (PBWT) has been introduced as a key data structure for indexing haplotype sequences with the main purpose of finding maximal haplotype matches inhsequences containingwvariation sites in-time with a significant improvement over classical quadratic time approaches. However the original PBWT data structure does not allow queries over the modern biobank panels of haplotypes consisting of several millions of haplotypes, as they must be kept entirely in memory.ResultsIn this paper, we present a method for constructing the run-length encoded PBWT for memory efficient haplotype matching. We implement our method, which we refer to asμ-PBWT, and evaluate it on datasets of 1000 Genome Project and UK Biobank data. Our experiments demonstrate that theμ-PBWTreduces the memory usage up to a factor of 25 compared to the best current PBWT-based indexing. In particular,μ-PBWTproduces an index that stores high-coverage whole genome sequencing data of chromosome 20 in half the space of its BCF file. In addition,μ-PBWTis able to index a dataset with 2 million haplotypes and 2.3 million sites in 4 GB of space, which can be uploaded in 20 seconds on a commodity laptop.μ-PBWTis an adaptation of techniques for the run-length compressed BWT for the PBWT (RLPBWT) and it is based on keeping in memory only a small representation of the RLPBWT that still allows the efficient computation of set maximal matches (SMEMs) over the original panel.AvailabilityOur implementation is open source and available athttps://github.com/dlcgold/muPBWT. The binary is available athttps://bioconda.github.io/recipes/mupbwt/README.htmlContactPaola Bonizzonipaola.bonizzoni@unimib.it

Efficiently finding maximal exact matches (MEMs) between a sequence read and a database of genomes is a key first step in read alignment. But until recently, it was unknown how to build a data structure in [Image: see text] space that supports efficient MEM finding, where r is the number of runs in the Burrows–Wheeler Transform. In 2021, Rossi et al. showed how to build a small auxiliary data structure called thresholds in addition to the r-index in [Image: see text] space. This addition enables efficient MEM finding using the r-index. In this article, we present the tool that implements this solution, which we call MONI. Namely, we give a high-level view of the main components of the data structure and show how the source code can be downloaded, compiled, and used to find MEMs between a set of sequence reads and a set of genomes.

SUMMARY We present a solution for long-term direct current resistivity and time-domain induced polarization (DCIP) monitoring, which consists of a monitoring system and the associated software that automates the data collection and processing. This paper describes the acquisition system that is used for remote data collection and then introduces the routines that have been developed for pre-processing of the monitoring data set. The collected data set is pre-processed using digital signal processing algorithms for outlier detection and removal; the resulting data set is then used for the inversion procedure. The suggested processing workflow is tested against a simulated time-lapse experiment and then applied to field data. The results from the simulation show that the suggested approach is very efficient for detecting changes in the subsurface; however, there are some limitations when no a priori information is used. Furthermore, the mean weekly data sets that are generated from the daily collected data can resolve low-frequency changes, making the approach a good option for monitoring experiments where slow changes occur (i.e. leachates in landfills, internal erosion in dams, bioremediation). The workflow is then used to process a large data set containing 20 months of daily monitoring data from a field site where a pilot test of in situ bioremediation is taking place. Based on the time-series analysis of the inverted data sets, we can detect two portions of the ground that show different geophysical properties and that coincide with the locations where the different fluids were injected. The approach that we used in this paper provides consistency in the data processing and has the possibility to be applied to further real-time geophysical monitoring in the future.

Congenital combined vitamin K-dependent clotting factors deficiency (VKCFD) is a rare autosomal recessive disease resulting in hemorrhagic symptoms usually associated with developmental disorders and bone abnormalities. Pathogenic variants in two genes encoding enzymes of the vitamin K cycle, GGCX and VKORC1, can lead to this disorder. We present the case of a male fetus with a brachytelephalangic chondrodysplasia punctata (CDP), absence of nasal bone, growth restriction, and bilateral ventriculomegaly at 18 weeks of gestation. Pathological examination showed a Binder phenotype, hypoplastic distal phalanges, stippled epiphyses, and brain abnormalities suggestive of a brain hemorrhage. Two GGCX pathogenic variants inherited respectively from the mother and the father were identified. To our knowledge, this is the first prenatal description of VKCFD. Even if it remains a rare etiology, which is mostly described in children or adult patients, VKCFD should be considered in fetuses with CDP.

Supplying a piezoelectric transducer with constant voltage or constant power during a frequency sweep can lead to different results in the determination of the acoustofluidic resonance frequencies, which are observed when studying the acoustophoretic displacements and velocities of particles suspended in a liquid-filled microchannel. In this work, three cases are considered: (1) Constant input voltage into the power amplifier, (2) constant voltage across the piezoelectric transducer, and (3) constant average power dissipation in the transducer. For each case, the measured and the simulated responses are compared, and good agreement is obtained. It is shown that Case 1, the simplest and most frequently used approach, is largely affected by the impedance of the used amplifier and wiring, so it is therefore not suitable for a reproducible characterization of the intrinsic properties of the acoustofluidic device. Case 2 strongly favors resonances at frequencies yielding the lowest impedance of the piezoelectric transducer, so small details in the acoustic response at frequencies far from the transducer resonance can easily be missed. Case 3 provides the most reliable approach, revealing both the resonant frequency, where the power-efficiency is the highest, as well as other secondary resonances across the spectrum., 16 pages, 6 pdf-figures, RevTeX

The positional Burrows–Wheeler Transform (PBWT) was presented in 2014 by Durbin as a means to find all maximal haplotype matches inhsequences containingwvariation sites in 𝒪(hw)-time. This time complexity of finding maximal haplotype matches using the PBWT is a significant improvement over the naïve pattern-matching algorithm that requires 𝒪(h2w)-time. Compared to the more famous Burrows-Wheeler Transform (BWT), however, a relatively little amount of attention has been paid to the PBWT. This has resulted in less space-efficient data structures for building and storing the PBWT. Given the increasing size of available haplotype datasets, and the applicability of the PBWT to pangenomics, the time is ripe for identifying efficient data structures that can be constructed for large datasets. Here, we present a comprehensive study of the memory footprint of data structures supporting maximal haplotype matching in conjunction with the PBWT. In particular, we present several data structure components that act as building blocks for constructing six different data structures that store the PBWT in a manner that supports efficiently finding the maximal haplotype matches. We estimate the memory usage of the data structures by bounding the space usage with respect to the input size. In light of this experimental analysis, we implement the solutions that are deemed to be superior with respect to the memory usage and show the performance on haplotype datasets taken from the 1000 Genomes Project data.

Genomics analyses often use a large sequence collection as a reference, like a pangenome or taxonomic database. We previously described SPUMONI, which performs binary classification of nanopore reads using pangenomic matching statistics. Here we describe SPUMONI 2, an improved version that is faster, more memory efficient, works effectively for both short and long reads, and can solve multi-class classification problems with the aid of a novel sampled document array structure. By incorporating minimizers, SPUMONI 2 reduces index size by a factor of 2 compared to SPUMONI, yielding an index more than 65 times smaller than minimap2’s for a mock community pangenome. SPUMONI 2 also achieves a speed improvement of 3-fold compared to SPUMONI and 15-fold compared to minimap2. We show SPUMONI 2 achieves an advantageous mix of accuracy and efficiency for short and long reads, including in an adaptive sampling scenario. We further demonstrate that SPUMONI 2 can detect contaminated contigs in genome assemblies, and can perform multi-class metagenomic read classification.

Tests of quantum mechanics on a macroscopic scale require extreme control over mechanical motion and its decoherence. Quantum control of mechanical motion has been achieved by engineering the radiation–pressure coupling between a micromechanical oscillator and the electromagnetic field in a resonator. Furthermore, measurement-based feedback control relying on cavity-enhanced detection schemes has been used to cool micromechanical oscillators to their quantum ground states8. In contrast to mechanically tethered systems, optically levitated nanoparticles are particularly promising candidates for matter-wave experiments with massive objects, since their trapping potential is fully controllable. Here we optically levitate a femtogram (10−15 grams) dielectric particle in cryogenic free space, which suppresses thermal effects sufficiently to make the measurement backaction the dominant decoherence mechanism. With an efficient quantum measurement, we exert quantum control over the dynamics of the particle. We cool its centre-of-mass motion by measurement-based feedback to an average occupancy of 0.65 motional quanta, corresponding to a state purity of 0.43. The absence of an optical resonator and its bandwidth limitations holds promise to transfer the full quantum control available for electromagnetic fields to a mechanical system. Together with the fact that the optical trapping potential is highly controllable, our experimental platform offers a route to investigating quantum mechanics at macroscopic scales., Nature, 595 (7867), ISSN:0028-0836, ISSN:1476-4687

Tools that classify sequencing reads against a database of reference sequences require efficient index data structures. Ther-index is a compressed full-text index that answers substring presence/absence, count and locate queries in space proportional to the amount of distinct sequence in the database:O(r)space whereris the number of Burrows-Wheeler runs. To date, ther-index has lacked the ability to quickly classify matches according to which reference sequences (or sequence groupings, i.e.~taxa) a match overlaps. We present new algorithms and methods for solving this problem. Specifically, given a collectionDofddocumentsD = {T_1, T_2, ..., T_d }over an alphabet of size sigma, we extend ther-index withO(rd)additional words to support document listing queries for a patternS[1..m]that occurs inndocdocuments inDinO(m log log_w(sigma + n/r) + ndoc)time andO(rd)space, wherewis the machine word size. Applied in a bacterial mock community experiment, our method is up to 3 times faster than a comparable method that uses the standardr-index locate queries. We show that our method classifies both simulated and real nanopore reads at the strain level with higher accuracy compared to other approaches. Finally, we present strategies for compacting this structure in applications where read lengths or match lengths can be bounded.

The analysis of surface wave dispersion curves is a way to infer the vertical distribution of shear-wave velocity. The range of applicability is extremely wide going, for example, from seismological studies to geotechnical characterizations and exploration geophysics. However, the inversion of the dispersion curves is severely ill-posed and only limited efforts have been put into the development of effective regularization strategies. In particular, relatively simple smoothing regularization terms are commonly used, even when this is in contrast with the expected features of the investigated targets. To tackle this problem, stochastic approaches can be utilized, but they are too computationally expensive to be practical, at least, in the case of large surveys. Instead, within a deterministic framework, we evaluate the applicability of a regularizer capable of providing reconstructions characterized by tunable levels of sparsity. This adjustable stabilizer is based on the minimum support regularization, applied before on other kinds of geophysical measurements, but never on surface wave data. We demonstrate the effectiveness of this stabilizer on i) two benchmark - publicly available - datasets at crustal and near-surface scales, ii) an experimental dataset collected on a well-characterized site. In addition, we discuss a possible strategy for the estimation of the depth of investigation. This strategy relies on the integrated sensitivity kernel used for the inversion and calculated for each individual propagation mode. Moreover, we discuss the reliability, and possible caveats, of the direct interpretation of this particular estimation of the depth of investigation, especially in the presence of sharp boundary reconstructions., Accepted for publication by Geophysical Journal International

Salt stress represents one of the most problematic abiotic stress affecting plants worldwide. In saline soils, plants try to counteract the consequences of salt stress by physiological changes, lea...

Le xxie siecle signe l’entree dans l’ere de la medecine genomique qui vehicule la promesse d’une medecine personnalisee susceptible de transformer le paradigme medical et d’offrir a l’avenir des soins sur mesure, a la fois en termes de diagnostic, de pronostic et de traitement.Aujourd’hui, le sequencage de l’integralite de l’adn d’un individu ne posant plus de problemes techniques ni economiques, sa finalite devient un sujet societal engageant une reflexion ethique citoyenne. Nous souhaitons ici discuter de l’emergence de nouvelles pratiques en genetique qui concernent les donnees dites secondaires issues des analyses genomiques ou exomiques. L’acces a ces donnees pourrait a l’avenir etre propose, par exemple, a une famille dont l’enfant presente des troubles du neurodeveloppement. Ces donnees seraient susceptibles de reveler au sein de la famille l’existence de facteurs de predisposition a des maladies cardiaques ou oncologiques, pour lesquelles des mesures preventives ou curatives pourraient eventuellement etre proposees. Ces pratiques sont d’actualite aux Etats-Unis, mais font encore debat en Europe.Nous souhaitons interroger ici comment les resultats des donnees secondaires peuvent etre subjectives par le consultant et sa famille, et s’ils offrent veritablement au patient et a ses apparentes les conditions necessaires pour un avenir plus ouvert ou a l’inverse davantage subi. Cela nous amenera a distinguer la notion de destin non modifiable de celle de destinee qui, a l’inverse, est toujours a creer dans une temporalite ouverte a l’irreductible contingence de l’avenir.

Megalencephaly-CApillary malformation-Polymicrogyria (MCAP) syndrome results from somatic mosaic gain-of-function variants in PIK3CA. Main features are macrocephaly, somatic overgrowth, cutaneous vascular malformations, connective tissue dysplasia, neurodevelopmental delay, and brain anomalies. The objectives of this study were to describe the clinical and radiological features of MCAP, to suggest relevant clinical endpoints applicable in future trials of targeted drug therapy. Based on a French collaboration, we collected clinical features of 33 patients (21 females, 12 males, median age of 9.9 years) with MCAP carrying mosaic PIK3CA pathogenic variants. MRI images were reviewed for 21 patients. The main clinical features reported were macrocephaly at birth (20/31), postnatal macrocephaly (31/32), body/facial asymmetry (21/33), cutaneous capillary malformations (naevus flammeus 28/33, cutis marmorata 17/33). Intellectual disability was present in 15 patients. Among the MRI images reviewed, the neuroimaging findings were megalencephaly (20/21), thickening of corpus callosum (16/21), Chiari malformation (12/21), ventriculomegaly/hydrocephaly (10/21), cerebral asymmetry (6/21) and polymicrogyria (2/21). This study confirms the main known clinical features that defines MCAP syndrome. Taking into account the phenotypic heterogeneity in MCAP patients, in the context of emerging clinical trials, we suggest that patients should be evaluated based on the main neurocognitive expression on each patient.

Contains fulltext : 231688.pdf (Publisher’s version ) (Closed access) PURPOSE: Pathogenic variants in the X-linked gene NEXMIF (previously KIAA2022) are associated with intellectual disability (ID), autism spectrum disorder, and epilepsy. We aimed to delineate the female and male phenotypic spectrum of NEXMIF encephalopathy. METHODS: Through an international collaboration, we analyzed the phenotypes and genotypes of 87 patients with NEXMIF encephalopathy. RESULTS: Sixty-three females and 24 males (46 new patients) with NEXMIF encephalopathy were studied, with 30 novel variants. Phenotypic features included developmental delay/ID in 86/87 (99%), seizures in 71/86 (83%) and multiple comorbidities. Generalized seizures predominated including myoclonic seizures and absence seizures (both 46/70, 66%), absence with eyelid myoclonia (17/70, 24%), and atonic seizures (30/70, 43%). Males had more severe developmental impairment; females had epilepsy more frequently, and varied from unaffected to severely affected. All NEXMIF pathogenic variants led to a premature stop codon or were deleterious structural variants. Most arose de novo, although X-linked segregation occurred for both sexes. Somatic mosaicism occurred in two males and a family with suspected parental mosaicism. CONCLUSION: NEXMIF encephalopathy is an X-linked, generalized developmental and epileptic encephalopathy characterized by myoclonic-atonic epilepsy overlapping with eyelid myoclonia with absence. Some patients have developmental encephalopathy without epilepsy. Males have more severe developmental impairment. NEXMIF encephalopathy arises due to loss-of-function variants.

Item does not contain fulltext SETBP1 haploinsufficiency disorder (MIM#616078) is caused by haploinsufficiency of SETBP1 on chromosome 18q12.3, but there has not yet been any systematic evaluation of the major features of this monogenic syndrome, assessing penetrance and expressivity. We describe the first comprehensive study to delineate the associated clinical phenotype, with findings from 34 individuals, including 24 novel cases, all of whom have a SETBP1 loss-of-function variant or single (coding) gene deletion, confirmed by molecular diagnostics. The most commonly reported clinical features included mild motor developmental delay, speech impairment, intellectual disability, hypotonia, vision impairment, attention/concentration deficits, and hyperactivity. Although there is a mild overlap in certain facial features, the disorder does not lead to a distinctive recognizable facial gestalt. As well as providing insight into the clinical spectrum of SETBP1 haploinsufficiency disorder, this reports puts forward care recommendations for patient management.

Mutations in the PQBP1 gene (polyglutamine-binding protein 1) are responsible for a syndromic X-linked form of intellectual disability (XLID), the Renpenning syndrome. PQBP1 encodes a protein that plays a role in the regulation of gene expression, splicing and mRNA translation. To investigate the consequences of variants in PQBP1, we performed transcriptomic studies in 1) patients’ lymphoblastoid cell lines (LCL) carrying pathogenic variants in PQBP1 and 2) in human neural stem cells (hNSC) knocked-down (KD) for PQBP1. This led to the identification of a hundred dysregulated genes. In particular, we identified an increase in the expression of a non-canonical isoform of another XLID gene, UPF3B. UPF3B plays a crucial role during neurodevelopment by coding for an important actor of the nonsense mRNA mediated decay (NMD) system involved in regulation of protein translation, however, the exact function of the non-canonical isoform,UPF3B_S, is currently unknown. In order to investigate the role of UPF3B_S isoform, we compared the protein interactome of UPF3B_S to the canonical isoform (UPF3B_L). We confirmed that, on the contrary to UPF3B_L, UPF3B_S does not interact with the UPF2/UPF1 complex while it still interacts with exon junction complexes (EJC). However, no notable decrease of NMD pathways was observed in patient’s LCL or in hNSC KD for PQBP1. We identified several additional protein interactors specific to UPF3B_S. Moreover, we used the increase of UPF3B_S mRNA as a molecular marker to test the pathogenicity of variants of unknown clinical significance identified in individuals with ID in PQPB1. We analyzed patients’ LCL mRNA as well as blood mRNA samples and performed complementation studies in HeLa cells by overexpressing Wild-type and mutant PQBP1 cDNA. We showed that all these three approaches were efficient to test the effect of variants, at least for variants affecting the CTD domain of the protein. In conclusion, our study provides information on how PQBP1 deficiency may affect the expression of genes and isoforms, such as UPF3B. This informs about the pathological mechanisms involved in Renpenning syndrome but also allows to propose a functional test for variants of unknown significance identified in PQBP1.

Les progres vertigineux des biotechnologies font emerger la promesse d’une medecine genomique personnalisee du XXIe siecle dont nous decrirons les enjeux societaux, ethiques et psychologiques. A partir d’un cas clinique, nous montrerons que l’information genetique predictive issue de l’analyse de l’exome est a l’origine de reactions impredictibles chez les sujets. Nous concluons que, quelles que soient les avancees scientifiques, la vulnerabilite ontologique de l’etre humain et la radicale contingence de l’avenir peuvent toujours laisser une place a l’inattendu, permettant au sujet de rester acteur de sa destinee.

The mutual correlations between spatially separated optical fields can be controlled employing an optical linear port. By shaping the wavefront of the light transmitted through a complex medium, we realize this port for three beams.

ARID1B mutations in Coffin-Siris syndrome are a cause of intellectual disability (0.5-1%), with various degrees of autism and agenesis of the corpus callosum (10%). Little is known regarding the cognitive and motor consequences of ARID1B mutations in humans and no link has been made between corpus callosum anomalies and visuospatial and neuromotor dysfunctions. We have investigated the visuospatial and neuromotor phenotype in eight patients with ARID1B mutations. A paramedian sagittal section of the brain MRI was selected, and corpus callosum was measured in anteroposterior length, genu and trunk width. Spearman's rank order coefficients were used to explore correlations between visuospatial and social cognitive variables and dimensions of the corpus callosum. A significant correlation between genu width size and visual cognition was observed. Retrocerebellar cysts were associated with corpus callosum anomalies. Here, we show that corpus callosum anomalies caused in ARID1B mutations may be predictive of the visuospatial and motor phenotype in Coffin-Siris syndrome.

Optical mapping has been largely automated, and first produces single molecule restriction maps, called Rmaps, which are assembled to generate genome wide optical maps. Since the location and orientation of each Rmap is unknown, the first problem in the analysis of this data is finding related Rmaps, i.e., pairs of Rmaps that share the same orientation and have significant overlap in their genomic location. Although heuristics for identifying related Rmaps exist, they all require quantization of the data which leads to a loss in the precision. In this paper, we propose a Gaussian mixture modelling clustering based method, which we refer to as O, that finds overlapping Rmaps without quantization. Using both simulated and real datasets, we show that OMclust substantially improves the precision (from 48.3% to 73.3%) over the state-of-the art methods while also reducing CPU time and memory consumption. Further, we integrated OMclust into the error correction methods (Elmeri and Comet) to demonstrate the increase in the performance of these methods. When OMclust was combined with Comet to error correct Rmap data generated from human DNA, it was able to error correct close to 3x more Ramps, and reduced the CPU time by more than 35x.

Soil salinization, one of the most common causes of soil degradation, negatively affects plant growth, reproduction, and yield in plants. Saline conditions elicit some physiological changes to cope with the imposed osmotic and oxidative stresses. Inoculation of plants with some bacterial species that stimulate their growth, i.e., plant growth-promoting bacteria (PGPB), may help plants to counteract saline stress, thus improving the plant’s fitness. This manuscript reports the effects of the inoculation of a salt-sensitive cultivar of Brassica napus (canola) with five different PGPB species (separately), i.e., Azospirillum brasilense, Arthrobacter globiformis, Burkholderia ambifaria, Herbaspirillum seropedicae, and Pseudomonas sp. on plant salt stress physiological responses. The seeds were sown in saline soil (8 dS/m) and inoculated with bacterial suspensions. Seedlings were grown to the phenological stage of rosetta, when morphological and physiological features were determined. In the presence of the above-mentioned PGPB, salt exposed canola plants grew better than non-inoculated controls. The water loss was reduced in inoculated plants under saline conditions, due to a low level of membrane damage and the enhanced synthesis of the osmolyte proline, the latter depending on the bacterial strain inoculated. The reduction in membrane damage was also due to the increased antioxidant activity (i.e., higher amount of phenolic compounds, enhanced superoxide dismutase, and ascorbate peroxidase activities) in salt-stressed and inoculated Brassica napus. Furthermore, the salt-stressed and inoculated plants did not show detrimental effects to their photosynthetic apparatus, i.e., higher efficiency of PSII and low energy dissipation by heat for photosynthesis were detected. The improvement of the response to salt stress provided by PGPB paves the way to further use of PGPB as inoculants of plants grown in saline soils.

International audience; Inverted duplication deletion 8p [invdupdel(8p)] is a complex and rare chromosomal rearrangement that combines a distal deletion and an inverted interstitial duplication of the short arm of chromosome 8. Carrier patients usually have developmental delay and intellectual disability (ID), associated with various cerebral and extra-cerebral malformations. Invdupdel(8p) is the most common recurrent chromosomal rearrangement in ID patients with anomalies of the corpus callosum (AnCC). Only a minority of invdupdel(8p) cases reported in the literature to date had both brain cerebral imaging and chromosomal microarray (CMA) with precise breakpoints of the rearrangements, making genotype-phenotype correlation studies for AnCC difficult. In this study, we report the clinical, radiological, and molecular data from 36 new invdupdel(8p) cases including three fetuses and five individuals from the same family, with breakpoints characterized by CMA. Among those, 97% (n = 32/33) of patients presented with mild to severe developmental delay/ID and 34% had seizures with mean age of onset of 3.9 years (2 months-9 years). Moreover, out of the 24 patients with brain MRI and 3 fetuses with neuropathology analysis, 63% (n = 17/27) had AnCC. We review additional data from 99 previously published patients with invdupdel(8p) and compare data of 17 patients from the literature with both CMA analysis and brain imaging to refine genotype-phenotype correlations for AnCC. This led us to refine a region of 5.1 Mb common to duplications of patients with AnCC and discuss potential candidate genes within this region.

Computing the matching statistics of patterns with respect to a text is a fundamental task in bioinformatics, but a formidable one when the text is a highly compressed genomic database. Bannai et al. gave an efficient solution for this case, which Rossi et al. recently implemented, but it uses two passes over the patterns and buffers a pointer for each character during the first pass. In this paper, we simplify their solution and make it streaming, at the cost of slowing it down slightly. This means that, first, we can compute the matching statistics of several long patterns (such as whole human chromosomes) in parallel while still using a reasonable amount of RAM; second, we can compute matching statistics online with low latency and thus quickly recognize when a pattern becomes incompressible relative to the database., Our code is available at https://github.com/koeppl/phoni

The dynamics of wetting and dewetting is largely determined by the velocity field near the contact lines. For water drops it has been observed that adding surfactant decreases the dynamic receding contact angle even at a concentration much lower than the critical micelle concentration (CMC). To better understand why surfactants have such a drastic effect on drop dynamics, we constructed a dedicated a setup on an inverted microscope, in which an aqueous drop is held stationary while the transparent substrate is moved horizontally. Using astigmatism particle tracking velocimetry, we track the 3D displacement of the tracer particles in the flow. We study how surfactants alter the flow dynamics near the receding contact line of a moving drop for capillary numbers in the order of $10^{-6}$. Even for surfactant concentrations $c$ far below the critical micelle concentration ($c \ll$ CMC) Marangoni stresses change the flow drastically. We discuss our results first in a 2D model that considers advective and diffusive surfactant transport and deduce estimates of the magnitude and scaling of the Marangoni stress from this. Modeling and experiment agree that a tiny gradient in surface tension of a few $\mu N \, m^{-1}$ is enough to alter the flow profile significantly. The variation of the Marangoni stress with the distance from the contact line suggests that the 2D advection-diffusion model has to be extended to a full 3D model. The effect is ubiquitous, since surfactant is present in many technical and natural dewetting processes either deliberately or as contamination., Comment: 12 pages, 7 figure plus supporting information

Tracking the 3D position of tracer particles or small objects like cells or unicellular organisms in miniaturized lab-on-a-chip or biomedical devices is complicated since it is often not possible in these setups to use multi-camera approaches. Most successful single-camera approaches for these applications are based on holography or defocusing. Holographic methods have been used to track complex objects such has bacteria (Bianchi et al. (2019)) and even to estimate their orientation (Wang et al. (2016)). However, these methods require a complex and expensive experimental setup which is not always available in research laboratories. On the other hand, defocusing methods work with conventional microscopic optics, are easy to implement, and have shown excellent results in 3D PTV experiments (Qiu et al. (2019)). One main drawback is that they normally work only with spherical and mono-dispersed tracer particles. A defocusing method that has potential to measure non-spherical particles is the General Defocusing Particle Tracking (Barnkob and Rossi (2020)) which is based on pattern recognition and can be conceptually extended to more complex tasks by extending the reference library of particle images, including not only spherical particles at different depth positions, but also non-spherical particles at different orientations. However, whether this approach could work in practice is still unknown. First, is the information contained in simple defocused images sufficient to reconstruct depth and orientation of non-spherical particles, and eventually under which circumstances? Second, how to practically collect the labelled reference images?

Control over optical spatial coherence is a key requirement in diverse applications including imaging, optical trapping, and communications. Current approaches to controlling spatial coherence are constrained by speed or limited to a single pair of optical fields. Here, we propose a method to achieve single-shot control of the spatial coherence between an arbitrary number of fields. Our method employs a multi-port linear optical device, which we realize by shaping the wavefront of the input light fields and transmitting them through a complex medium. To demonstrate the capabilities of our method, we experimentally realize a 3x3-port system and use it to generate three output beams with desired mutual correlations., Optics Express, 29 (25), ISSN:1094-4087

Background Achondroplasia (ACH), the most common non-lethal form of skeletal dysplasia, is characterized by defective endochondral ossification resulting from gain-of-function mutations in the fibroblast growth factor receptor 3 (FGFR3) gene, a negative regulator of endochondral bone formation. Infigratinib, a selective, orally bioavailable FGFR1–3 tyrosine kinase inhibitor, has been shown to reverse established growth arrest in chondrocytes and improve foramen magnum and long bone length in Fgfr3Y367C/+ mice. Infigratinib is being investigated for the treatment of ACH in the PROPEL program of three clinical trials: 1) PROPEL, designed to collect information on the natural history of ACH; 2) PROPEL2, designed to obtain preliminary evidence of efficacy and safety and to identify the dose of infigratinib to investigate further; 3) PROPEL OLE, which is designed to evaluate the long-term efficacy and safety of infigratinib in children with ACH. Methods PROPEL (NCT04035811) is a non-interventional clinical assessment study designed to characterize the natural history of up to 200 children aged 2.5–10 years with ACH over a 6−24-month period. The primary objective is to collect baseline height velocity measurements in children who may participate in an interventional study with infigratinib. The primary endpoint is the annualized growth velocity (AGV). Further objectives are to collect other baseline growth measurements, evaluate exploratory biomarker indicators of growth, and assess ACH-related medical events reported as medical history, or non-treatment adverse events (AEs). PROPEL2 (NCT04265651) is a phase 2, open-label study of infigratinib in children aged 3−11 years with ACH who completed ≥6 months observation in PROPEL. PROPEL2 includes dose-escalation with an extended dose-finding treatment phase (n≈40), a pharmacokinetics sub-study (n≈18), followed by a dose-expansion phase (n≈20) in which children receive infigratinib for 12 months to confirm the selected dose and provide evidence of efficacy. Primary endpoints are treatment-emergent AEs, change from baseline in AGV, and infigratinib pharmacokinetics. Secondary endpoints include safety/tolerability of infigratinib and changes from baseline in anthropometric parameters, including body proportions. Exploratory outcomes include changes in QoL and other parameters of disease burden. PROPEL OLE (NCT05145010) is a phase 2, open-label extension study in up to 230 children who completed an interventional study with infigratinib and, potentially, in ≤50 who are infigratinib-naive. The primary objectives are to evaluate safety, tolerability, and efficacy of long-term daily doses of infigratinib. Secondary objectives include evaluation of changes in other indicators of growth and development, and evaluation of QoL and disease burden. Children will receive infigratinib until they reach final/near final height. Summary PROPEL, PROPEL2, and PROPEL OLE are currently ongoing. Together, these studies are intended to provide key evidence on the safety and efficacy of oral infigratinib in children with ACH and will inform the design of future studies in this setting. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.