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A new control law of an input parallel output serie dc–ac multicell converter is proposed to cancel the common-mode (CM) noise while keeping the differential-mode (DM) noise low. The control law called interleaved symmetrical unipolar respects the conditions studied and detailed in this article to achieve CM noise cancellation. The conditions are generalized whatever an even number of cells in series. The results are validated against experiments and show reduction of the CM choke volume in comparison to a conventional interleaved bipolar control law.

Les représentations sociales (RS) sont omniprésentes dans notre société actuelle, et celle sur la douleur n’y échappe pas. Elles impactent nos attitudes et comportements. Notre étude a pour but de comprendre comment les RS des MK sur les douleurs chroniques de leurs patients peuvent-elles impacter la rééducation ?

The influential writer talks about frighteningly accurate predictions, the creative act of reading, AI consciousness — and hope.

Glucocorticoids probably improve outcomes in patients hospitalised for community acquired pneumonia (CAP). In this a priori planned exploratory subgroup analysis of the phase 3 randomised controlled Activated Protein C and Corticosteroids for Human Septic Shock (APROCCHSS) trial, we aimed to investigate responses to hydrocortisone plus fludrocortisone between CAP and non-CAP related septic shock.

We previously reported that human muscle-derived stem cells (hMuStem cells) contribute to tissue repair after local administration into injured skeletal muscle or infarcted heart in immunodeficient rodent models. However, extrapolation of these findings to a clinical context is problematic owing to the considerable differences often seen between in vivo findings in humans versus rodents. Therefore, we investigated whether the muscle regenerative behavior of hMuStem cells is maintained in a clinically relevant transplantation context. Human MuStem cells were intramuscularly administered by high-density microinjection matrices into nonhuman primates receiving tacrolimus-based immunosuppression thereby reproducing the protocol that has so far produced the best results in clinical trials of cell therapy in myopathies. Four and 9 weeks after administration, histological analysis of cell injection sites revealed large numbers of hMuStem cell-derived nuclei in all cases. Most graft-derived nuclei were distributed in small myofiber groups in which no signs of a specific immune response were observed. Importantly, hMuStem cells contributed to simian tissue repair by fusing mainly with host myofibers, demonstrating their capacity for myofiber regeneration in this model. Together, these findings obtained in a valid preclinical model provide new insights supporting the potential of hMuStem cells in future cell therapies for muscle diseases.

Microneedle patches (MNPs) have been ranked as the highest global priority innovation for overcoming immunisation barriers in low-income and middle-income countries. This trial aimed to provide the first data on the tolerability, safety, and immunogenicity of a measles and rubella vaccine (MRV)-MNP in children.

Les pathologies respiratoires représentent un enjeu majeur de santé publique et impactent tant la qualité que l’espérance de vie des patients concernés.

Mobile element insertions (MEIs) are a known cause of genetic disease but have been underexplored due to technical limitations of genetic testing methods. Various bioinformatic tools have been developed to identify MEIs in Next Generation Sequencing data. However, most tools have been developed specifically for genome sequencing (GS) data rather than exome sequencing (ES) data, which remains more widely used for routine diagnostic testing. In this study, we benchmarked six MEI detection tools (ERVcaller, MELT, Mobster, SCRAMble, TEMP2 and xTea) on ES data and on GS data from publicly available genomic samples (HG002, NA12878). For all the tools we evaluated sensitivity and precision of different filtering strategies. Results show that there were substantial differences in tool performance between ES and GS data. MELT performed best with ES data and its combination with SCRAMble increased substantially the detection rate of MEIs. By applying both tools to 10,890 ES samples from Solve-RD and 52,624 samples from Radboudumc we were able to diagnose 10 patients who had remained undiagnosed by conventional ES analysis until now. Our study shows that MELT and SCRAMble can be used reliably to identify clinically relevant MEIs in ES data. This may lead to an additional diagnosis for 1 in 3000 to 4000 patients in routine clinical ES.

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 101 carriers of (likely) pathogenic variants in ten different genes, 57 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 NSD1signatures displayed a 100% sensitivity, CREBBP-RSTSand one of the CHD8signatures reached <40% sensitivity on our dataset. Remaining Cornelia de Lange syndrome, KMT2A, KDM5Cand CHD7signatures reached 70–100% sensitivity 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.

ObjectiveTo investigate the tobacco-attributable burden on disease, medical costs, productivity losses and informal caregiving; and to estimate the health and economic gains that can be achieved if the main tobacco control measures (raising taxes on tobacco, plain packaging, advertising bans and smoke-free environments) are fully implemented in eight countries that encompass 80% of the Latin American population.DesignMarkov probabilistic microsimulation economic model of the natural history, costs and quality of life associated with the main tobacco-related diseases. Model inputs and data on labour productivity, informal caregivers’ burden and interventions’ effectiveness were obtained through literature review, surveys, civil registrations, vital statistics and hospital databases. Epidemiological and economic data from January to October 2020 were used to populate the model.FindingsIn these eight countries, smoking is responsible each year for 351 000 deaths, 2.25 million disease events, 12.2 million healthy years of life lost, US$22.8 billion in direct medical costs, US$16.2 billion in lost productivity and US$10.8 billion in caregiver costs. These economic losses represent 1.4% of countries’ aggregated gross domestic products. The full implementation and enforcement of the four strategies: taxes, plain packaging, advertising bans and smoke-free environments would avert 271 000, 78 000, 71 000 and 39 000 deaths, respectively, in the next 10 years, and result in US$63.8, US$12.3, US$11.4 and US$5.7 billions in economic gains, respectively, on top of the benefits being achieved today by the current level of implementation of these measures.ConclusionsSmoking represents a substantial burden in Latin America. The full implementation of tobacco control measures could successfully avert deaths and disability, reduce healthcare spending and caregiver and productivity losses, likely resulting in large net economic benefits.

Abstract: Purpose: Liver cancer can be treated by transcatheter hepatic arterial embolization. Selective embolizations are desirable as they impact tumors and with limited damage to the surrounding healthy liver. These interventions are typically performed under fluoroscopy guidance. The advent of modern C-arms allows for the acquisition of three-dimensional images that offer a very detailed, unambiguous view of the hepatic arterial network. Methods: We developed a software specifically for planning selective liver tumor embolization from three-dimensional fluoroscopy. Based on the geometry of the vasculature around a targeted tumor, feeding vessels are inferred and highlighted. This accelerates and simplifies the determination of selective treatment points. Results: A retrospective study on nine patients (15 tumors) in two centers showed that the proposed software detected 89% of tumor feeding vessels (unaided radiologists detected 69% based on two-dimensional fluoroscopy) with a positive predictive value of 94% (90% for radiologists). Processing time was 142 s. Conclusion: The current report describes a feasibility analysis of a treatment planning software specifically geared to selective transcatheter delivery procedures in interventional oncology. This software takes advantage of recent advances in three-dimensional rotational angiography and vascular segmentation algorithms. It is likely that in the near term these types of tools will become integral parts of transcatheter therapies.

Translation elongation factor eEF1A2 constitutes the alpha subunit of the elongation factor-1 complex, responsible for the enzymatic binding of aminoacyl-tRNA to the ribosome. Since 2012, 21 pathogenic missense variants affecting EEF1A2have been described in 42 individuals with a severe neurodevelopmental phenotype including epileptic encephalopathy and moderate to profound intellectual disability (ID), with neurological regression in some patients. Through international collaborative call, we collected 26 patients with EEF1A2variants and compared them to the literature. Our cohort shows a significantly milder phenotype. 83% of the patients are walking (vs. 29% in the literature), and 84% of the patients have language skills (vs. 15%). Three of our patients do not have ID. Epilepsy is present in 63% (vs. 93%). Neurological examination shows a less severe phenotype with significantly less hypotonia (58% vs. 96%), and pyramidal signs (24% vs. 68%). Cognitive regression was noted in 4% (vs. 56% in the literature). Among individuals over 10 years, 56% disclosed neurocognitive regression, with a mean age of onset at 2 years. We describe 8 novel missense variants of EEF1A2. Modeling of the different amino-acid sites shows that the variants associated with a severe phenotype, and the majority of those associated with a moderate phenotype, cluster within the switch II region of the protein and thus may affect GTP exchange. In contrast, variants associated with milder phenotypes may impact secondary functions such as actin binding. We report the largest cohort of individuals with EEF1A2variants thus far, allowing us to expand the phenotype spectrum and reveal genotype-phenotype correlations.

BackgroundMolecular diagnosis of neurodevelopmental disorders (NDDs) is mainly based on exome sequencing (ES), with a diagnostic yield of 31% for isolated and 53% for syndromic NDD. As sequencing costs decrease, genome sequencing (GS) is gradually replacing ES for genome-wide molecular testing. As many variants detected by GS only are in deep intronic or non-coding regions, the interpretation of their impact may be difficult. Here, we showed that integrating RNA-Seq into the GS workflow can enhance the analysis of the molecular causes of NDD, especially structural variants (SVs), by providing valuable complementary information such as aberrant splicing, aberrant expression and monoallelic expression.MethodsWe performed trio-GS on a cohort of 33 individuals with NDD for whom ES was inconclusive. RNA-Seq on skin fibroblasts was then performed in nine individuals for whom GS was inconclusive and optical genome mapping (OGM) was performed in two individuals with an SV of unknown significance.ResultsWe identified pathogenic or likely pathogenic variants in 16 individuals (48%) and six variants of uncertain significance. RNA-Seq contributed to the interpretation in three individuals, and OGM helped to characterise two SVs.ConclusionOur study confirmed that GS significantly improves the diagnostic performance of NDDs. However, most variants detectable by GS alone are structural or located in non-coding regions, which can pose challenges for interpretation. Integration of RNA-Seq data overcame this limitation by confirming the impact of variants at the transcriptional or regulatory level. This result paves the way for new routinely applicable diagnostic protocols.

PurposeWide access to clinical exome/genome sequencing (ES/GS) enables the identification of multiple molecular diagnoses (MMDs), being a long-standing but underestimated concept, defined by two or more causal loci implicated in the phenotype of an individual with a rare disease. Only few series report MMDs rates (1.8% to 7.1%). This study highlights the increasing role of MMDs in a large cohort of individuals addressed for congenital anomalies/intellectual disability (CA/ID).MethodsFrom 2014 to 2021, our diagnostic laboratory rendered 880/2658 positive ES diagnoses for CA/ID aetiology. Exhaustive search on MMDs from ES data was performed prospectively (January 2019 to December 2021) and retrospectively (March 2014 to December 2018).ResultsMMDs were identified in 31/880 individuals (3.5%), responsible for distinct (9/31) or overlapping (22/31) phenotypes, and potential MMDs in 39/880 additional individuals (4.4%).ConclusionMMDs are frequent in CA/ID and remain a strong challenge. Reanalysis of positive ES data appears essential when phenotypes are partially explained by the initial diagnosis or atypically enriched overtime. Up-to-date clinical data, clinical expertise from the referring physician, strong interactions between clinicians and biologists, and increasing gene discoveries and improved ES bioinformatics tools appear all the more fundamental to enhance chances of identifying MMDs. It is essential to provide appropriate patient care and genetic counselling.

BackgroundPathogenic variants in the zinc finger protein coding genes are rare causes of intellectual disability and congenital malformations. Mutations in the ZNF148gene causing GDACCF syndrome (global developmental delay, absent or hypoplastic corpus callosum, dysmorphic facies; MIM #617260) have been reported in five individuals so far.MethodsAs a result of an international collaboration using GeneMatcher Phenome Central Repository and personal communications, here we describe the clinical and molecular genetic characteristics of 22 previously unreported individuals.ResultsThe core clinical phenotype is characterised by developmental delay particularly in the domain of speech development, postnatal growth retardation, microcephaly and facial dysmorphism. Corpus callosum abnormalities appear less frequently than suggested by previous observations. The identified mutations concerned nonsense or frameshift variants that were mainly located in the last exon of the ZNF148gene. Heterozygous deletion including the entire ZNF148gene was found in only one case. Most mutations occurred de novo, but were inherited from an affected parent in two families.ConclusionThe GDACCF syndrome is clinically diverse, and a genotype-first approach, that is, exome sequencing is recommended for establishing a genetic diagnosis rather than a phenotype-first approach. However, the syndrome may be suspected based on some recurrent, recognisable features. Corpus callosum anomalies were not as constant as previously suggested, we therefore recommend to replace the term ‘GDACCF syndrome’ with ‘ZNF148-related neurodevelopmental disorder’.

Generation and subsequently accessibility of secondary findings (SF) in diagnostic practice is a subject of debate around the world and particularly in Europe. The French FIND study has been set up to assess patient/parent expectations regarding SF from exome sequencing (ES) and to collect their real-life experience until 1 year after the delivery of results. 340 patients who had ES for undiagnosed developmental disorders were included in this multicenter mixed study (quantitative N= 340; qualitative N= 26). Three groups of actionable SF were rendered: predisposition to late-onset actionable diseases; genetic counseling; pharmacogenomics. Participants expressed strong interest in obtaining SF and a high satisfaction level when a SF is reported. The medical actionability of the SF reinforced parents’ sense of taking action for their child and was seen as an opportunity. While we observed no serious psychological concerns, we showed that these results could have psychological consequences, in particular for late-onset actionable diseases SF, within families already dealing with rare diseases. This study shows that participants remain in favor of accessing SF despite the potential psychological, care, and lifestyle impacts, which are difficult to anticipate. The establishment of a management protocol, including the support of a multidisciplinary team, would be necessary if national policy allows the reporting of these data.

This article presents the development of an adaptive sampling strategy for building surrogate models of complex electromagnetic systems. Accurate sensitivity analysis is crucial to electromagnetic compatibility but usually requires a few thousand calls of the numerical model if performed using classical Monte Carlo sampling. In the case of an expensive computational model, this results in extremely long computation. Hence, with only a few calls of the numerical model, surrogate models are built to approximate the behavior of the system. This accurate predictor can then be used instead of the expensive computational model for various analyses. The active learning sampling strategy has been tested successfully on a realistic finite-element method model.

This article demonstrates the interest of topology optimization in designing the ferrite plate used in an inductive power transfer system for electric vehicles. The solid isotropic material with the penalization (SIMP) method is used to optimize the ferrite plate, and it modifies the topology of the ferrite shape iteratively. This SIMP method can lead to novel structures compared with usual existing shapes. In this article, it is found that a part of the ferrite from the center and the edges of the predefined ferrite plate can be removed to save the ferrite volume while achieving a minimal reduction of transmission efficiency. Moreover, the results from topology optimization are influenced by the aluminum shielding plate near the ferrite plate. Hence, the ferrite on the receiver side has to be larger than the one on the transmitter side. These results give some design guidelines on arranging the ferrite placement for the system, and the approach could be generalized for shielding sheets/walls.

Organic thin-film transistors (OTFTs) with pentacene active layer were fabricated and analyzed. The electrical parameters were deduced, with the adjusted threshold voltage by modified Y-function method. The derivative field effect mobility was adopted to extract the mobility enhancement factor, which is consistent with the characteristic temperature deduced from density of states (DOS) calculation. The electrical properties of pentacene thin-film transistors were modeled based on variable range hopping (VRH) mechanism, and active layer morphologies were also provided to verify the transport mechanism.

Nonviral transfection of mammalian cells can be performed with electrostatic complexes (polyplexes) between a plasmid DNA (pDNA) encoding a foreign gene and a cationic polymer. However, an excess of the cationic polymer is required for pDNA condensation and polyplexes formation, which generate in vivo toxicity. Here, we present a new concept of polyplexes preparation aiming to reduce the polymer quantity. pDNA was functionalized with 3,6,9-trioxaundecan-1- {4 - [(2-chloroethyl) ethylamino)] - benzylamino}, 11-azide, and polyethyleneimine (lPEI) with reducible dibenzocyclooctyl (SS-DBCO) groups allowing azide-alkyne cycloaddition between pDNA and lPEI after condensation. The size of polyplexes with DBCO-SS-lPEI was smaller than with lPEI due to a stronger DNA condensation thanks to linkages between polymer and pDNA preventing dissociation until disulfide bridges reduction. In vitro transfection showed that the amount of DBCO-SS-lPEI leading to the most efficient polyplexes was three times lower than lPEI. As expected, toxicity in mice was significantly reduced upon intravenous injection of DBCO-SS-lPEI polyplexes at doses where the lPEI polyplexes killed mice. This is probably due to the high stability of the DBCO-SS-lPEI polyplexes which prevented their aggregation in the pulmonary capillaries. Overall, this new concept of polyplexes with DBCO-SS-lPEI offering the possibility of administering higher doses of polyplexes than lPEI and their ability to pass the pulmonary barrier could be favorably exploited for transfection of distant organs or tissues, such as tumors.

A significant challenge in power electronics lifetime modeling is to implement physics-based models using state-of-health indicators specific to the different interconnection aging mechanisms: solders fatigue, metallization reconstruction, wire heel crack, and liftoff. In this work, the focus is put in the latter mechanism. The ON-state voltage as a state-of-health indicator is considered a package-level health indicator, and it includes the aging effects of both interconnections: metallization and wirebond; thus, it is not convenient to characterize the wirebond state-of-health. In this work, new methods are proposed to measure the equivalent bond radius as a specific wirebond state-of-health indicator. For validation, a simplified configuration is considered where the silicon chip is electrically connected with the terminal using a single wire. An electrical method is proposed, where a local voltage drop measurement is done at a position on the metallization close to the bond of interest to monitor the bond resistance change. Analytical and finite element modeling (FEM) models are developed to give the relationship between the bond resistance increase and the bond radius reduction as the wirebond crack progresses. A thermal imaging method is also proposed, where a temperature increase at the bond is measured, due to the bond aging and its increase in the electrical and thermal resistances. Models are proposed to establish a relationship between the temperature measurements and the bond radius. Both electrical and thermal methods show good agreement with direct measurements using scanning electron microscopy (SEM). In addition, in the studied configuration, it is shown that both the wirebond degradation and the metallization (including the connections between metallization pads) contribute significantly to the Vce increase.

During the COVID-19 pandemic, Latin American and Caribbean countries implemented stringent public health and social measures that disrupted economic and social activities. This study used an integrated model to evaluate the epidemiological, economic, and social trade-offs in Argentina, Brazil, Jamaica, and Mexico throughout 2021. Argentina and Mexico displayed a higher gross domestic product (GDP) loss and lower deaths per million compared with Brazil. The magnitude of the trade-offs differed across countries. Reducing GDP loss at the margin by 1 percent would have increased daily deaths by 0.5 per million in Argentina but only 0.3 per million in Brazil. We observed an increase in poverty rates related to the stringency of public health and social measures but no significant income-loss differences by sex. Our results indicate that the economic impact of COVID-19 was uneven across countries as a result of different pandemic trajectories, public health and social measures, and vaccination uptake, as well as socioeconomic differences and fiscal responses. Policy makers need to be informed about the trade-offs to make strategic decisions to save lives and livelihoods.

Protein arylation has attracted much attention for developing new classes of bioconjugates with improved properties. Here, we have evaluated 2-sulfonylpyrimidines as covalent warheads for the mild, chemoselective, and metal free cysteine S-arylation. 2-Sulfonylpyrimidines react rapidly with cysteine, resulting in stable S-heteroarylated adducts at neutral pH. Fine tuning the heterocyclic core and exocyclic leaving group allowed predictable SNAr reactivity in vitro, covering >9 orders of magnitude. Finally, we achieved fast chemo- and regiospecific arylation of a mutant p53 protein and confirmed arylation sites by protein X-ray crystallography. Hence, we report the first example of a protein site specifically S-arylated with iodo-aromatic motifs. Overall, this study provides the most comprehensive structure–reactivity relationship to date on heteroaryl sulfones and highlights 2-sulfonylpyrimidine as a synthetically tractable and protein compatible covalent motif for targeting reactive cysteines, expanding the arsenal of tunable warheads for modern covalent ligand discovery.

The increase in the number of newcomer students in countries across the world has underscored the importance of effective transition strategies in education. Many students encounter difficulties in acquiring academic knowledge due to initial limited language skills in the school language. Implementing appropriate strategies to facilitate this transition has shown positive outcomes. However, some obstacles remain to be addressed for newcomer students. In the Netherlands, standardized tests are utilised to monitor the academic progress of all students and determine the appropriate educational pathway. Our study, based on longitudinal assessment data from 51 newcomer elementary school students and 74 of their classmates, sheds light on how this system interacts with the transitions of newcomers. While newcomer students made greater progress compared to their peers, we found that their results were influenced by the application of test norms designed for younger age groups. The insights from this study provide valuable perspectives on educational pathways for newcomer students and prompt us to reconsider the implications of norm accommodation for these students. It highlights the needs to implement practices that enable newcomer students to effectively pursue their academic aspirations.

About 0.3% of all variants are due to de novo mobile element insertions (MEIs). The massive development of next-generation sequencing has made it possible to identify MEIs on a large scale. We analyzed exome sequencing (ES) data from 3232 individuals (2410 probands) with developmental and/or neurological abnormalities, with MELT, a tool designed to identify MEIs. The results were filtered by frequency, impacted region and gene function. Following phenotype comparison, two candidates were identified in two unrelated probands. The first mobile element (ME) was found in a patient referred for poikilodermia. A homozygous insertion was identified in the FERMT1gene involved in Kindler syndrome. RNA study confirmed its pathological impact on splicing. The second ME was a de novo Alu insertion in the GRIN2Bgene involved in intellectual disability, and detected in a patient with a developmental disorder. The frequency of de novo exonic MEIs in our study is concordant with previous studies on ES data. This project, which aimed to identify pathological MEIs in the coding sequence of genes, confirms that including detection of MEs in the ES pipeline can increase the diagnostic rate. This work provides additional evidence that ES could be used alone as a diagnostic exam.

Patients with chronic obstructive pulmonary disease (COPD) with impaired postural control had a poorer QoL, lower Pao2, and higher anxiety scores compared with patients with normal postural control. Predictors of impaired postural control in patients with COPD were symptom-related QoL, Pao2, inspiratory muscle strength, and body mass index.

This study aimed to investigate renal replacement therapy (RRT) practices in a representative nationwide sample of French intensive care units (ICUs).

In nonviral gene therapy approaches, the linkage of signal molecules to plasmid DNA (pDNA) is of interest for guiding its delivery to the nucleus. Here, we report its linkage to a peptide (P79–98) mediating migration on microtubules by using a triplex-forming oligonucleotide (TFO). pDNA of 5 kbp and 21 kbp containing 6 and 36 oligopurine • oligopyrimidine sites (TH), respectively, inserted outside the luciferase gene sequence were used. TFO with a dibenzocyclooctyl (DBCO) group in 3’ end comprising some Bridged Nucleic Acid bases was conjugated by click chemistry with the peptide carrying an azide function in the C-terminal end. We found the formation of 6 and 18 triplex with pDNA of 5 kbp and 21 kbp, respectively. A twofold increase of the transfection efficiency was observed in the hind-limbs upon Hydrodynamic Limb Vein (HLV) injection in mice of naked P79–98–pDNA of 21 kbp. This work paves the way for the selective equipping of pDNA with intracellular targeting molecules while preserving the full expression of the encoded gene.

Haploinsufficiency of TRIP12causes a neurodevelopmental disorder characterized by intellectual disability associated with epilepsy, autism spectrum disorder and dysmorphic features, also named Clark-Baraitser syndrome. Only a limited number of cases have been reported to date. We aimed to further delineate the TRIP12-associated phenotype and objectify characteristic facial traits through GestaltMatcher image analysis based on deep-learning algorithms in order to establish a TRIP12gestalt. 38 individuals between 3 and 66 years (F= 20, M= 18) - 1 previously published and 37 novel individuals - were recruited through an ERN ITHACA call for collaboration. 35 TRIP12variants were identified, including frameshift (n= 15) and nonsense (n= 6) variants, as well as missense (n= 5) and splice (n= 3) variants, intragenic deletions (n= 4) and two multigene deletions disrupting TRIP12. Though variable in severity, global developmental delay was noted in all individuals, with language deficit most pronounced. About half showed autistic features and susceptibility to obesity seemed inherent to this disorder. A more severe expression was noted in individuals with a missense variant. Facial analysis showed a clear gestalt including deep-set eyes with narrow palpebral fissures and fullness of the upper eyelids, downturned corners of the mouth and large, often low-set ears with prominent earlobes. We report the largest cohort to date of individuals with TRIP12variants, further delineating the associated phenotype and introducing a facial gestalt. These findings will improve future counseling and patient guidance.

The mechanisms of reproductive isolation that cause phenotypic diversification and eventually speciation are a major topic of evolutionary research. Hybrid necrosis is a post-zygotic isolation mechanism in which cell death develops in the absence of pathogens. It is often due to the incompatibility between proteins from two parents. Here we describe a unique case of hybrid necrosis due to an incompatibility between loci on chromosomes 2 and 7 between two pollinator-isolated Petuniaspecies. Typical immune responses as well as endoplasmic reticulum stress responses are induced in the necrotic line. The locus on chromosome 2 encodes ChiA1, a bifunctional GH18 chitinase/lysozyme. The enzymatic activity of ChiA1 is dispensable for the development of necrosis. We propose that the extremely high expression of ChiA1 involves a positive feedback loop between the loci on chromosomes 2 and 7. ChiA1is tightly linked to major genes involved in the adaptation to different pollinators, a form of pre-zygotic isolation. This linkage of pre- and post-zygotic barriers strengthens reproductive isolation and probably contributes to rapid diversification and speciation.

The neuronal SNARE complex drives synaptic vesicle exocytosis. Therefore, one of its core proteins syntaxin 1A (STX1A) has long been suspected to play a role in neurodevelopmental disorders. We assembled eight individuals harboring ultra rare variants in STX1Awho present with a spectrum of intellectual disability, autism and epilepsy. Causative variants comprise a homozygous splice variant, three de novo missense variants and two inframe deletions of a single amino acid. We observed a phenotype mainly driven by epilepsy in the individuals with missense variants in contrast to intellectual disability and autistic behavior in individuals with single amino acid deletions and the splicing variant. In silico modeling of missense variants and single amino acid deletions show different impaired protein-protein interactions. We hypothesize the two phenotypic courses of affected individuals to be dependent on two different pathogenic mechanisms: (1) a weakened inhibitory STX1A-STXBP1 interaction due to missense variants results in an STX1A-related developmental epileptic encephalopathy and (2) a hampered SNARE complex formation due to inframe deletions causes an STX1A-related intellectual disability and autism phenotype. Our description of a STX1A-related neurodevelopmental disorder with or without epilepsy thus expands the group of rare diseases called SNAREopathies.

•Confocal microscopy and texture analysis discriminate tools used to reap cereals near the ground (low) and near the ear (high).•We classify sickle elements from archaeological sites dating from the Natufian, to the Pottery Neolithic.•We show that the transition from high to low harvesting was a long process that took place during the origins of cereal agriculture.•This shift in harvesting techniques was related to the increasing use of straw.

This study is the first systematic survey of a large corpus of zinc white (ZnO) artists’ materials. Zinc white is a white pigment developed within the wave of 19th-century technological developments in the paint industry. The composition, particle morphology and size, and luminescence of 49 zinc white samples from artists’ materials were characterized, including three references of known synthesis methods (indirect and direct) and synthesized by the authors (ZnO nanosmoke). The corpus included historical and modern zinc white pigment powders and paint materials from the leading European and American color manufacturers. The study aims to characterize and evaluate the variability of the properties of zinc white and its paint formulations. The reference materials presented properties in agreement with the literature: indirect ZnO exhibited submicron prismoidal blue-luminescent particles of higher purity than direct ZnO, which had larger acicular green-luminescent particles. ZnO nanosmoke presented acicular (tetrapod-like) blue/green-luminescent nanoparticles. Composition, particle morphology, size, and documentary sources suggested a production via the indirect method for the analyzed corpus. However, the luminescence behavior was more complex to interpret. The fundamental emission of ZnO was not always detected, even in pure ZnO powders. Three trends were identified: smaller ZnO particles for the most recent samples; green luminescence connected to larger particle size; fewer trace elements, and of the same type (i.e., lead, sulfur) for historical materials. Another interesting finding was the detection of hydrozincite in some powders, likely a degradation product of ZnO. In terms of methodology, cathodoluminescence proved a valuable tool for pigment identification. The study provides a database of zinc white references for pigment and artwork analysis.

Each enantiomer of a chiral pentagonal bipyramidal (PBP) FeIIcomplex ([FeLN5R,RCl(MeOH)]Cl·H2O, 1R, or [FeLN5S,SCl(MeOH)]Cl·H2O, 1S) has been obtained using either the Ror the Sstereoisomer of the macrocyclic pentadentate ligand formed in a template-condensation reaction of the tetraamine N,N′-Bis-{(1R,2R)-[2-(amino)]cyclohexyl}-1,2-diaminoethane, or its (1S,2S) enantiomer, and 2,5-diacetylpyridine, respectively LN5R,Rand LN5S,S. Subsequently, the 1-D coordination polymers [FeLN5R,R{FeCl4}], 2R, and [FeLN5S,S{FeCl4}], 2S, were formed by reacting respectively 1Ror 1Swith 1 equiv of FeCl2(H2O)4. These chain compounds consist of an alternation of PBP and tetrahedral FeIIunits sharing a Cl atom. Theoretical calculations reveal large magnetic anisotropy for each Fe center but of different type with axial zero-field splitting parameter Dof respectively −30 cm–1and 15 cm–1. The magnetic behavior for the 1-D compound revealed canted antiferromagnetic Fe–Fe interactions (J= −6 cm–1) and SCM behavior characterized by Δ/kB= 42 K with pre-exponential factor τ0= 2.17 × 10–10s. It was noted that this SCM behavior was accompanied by a magnetic order leading to a weak ferromagnet (i.e., canted antiferromagnet). The preparations, crystal structures (CCDC references 2214580–2214583), spectroscopic data, magnetic behaviors, and theoretical investigations are reported.

In this work, we studied the effect of a postbonding thermal treatment (TT) on thick aluminum wirebonds lifetime in insulated gate bipolar transistor (IGBT) power modules during power cycling (PC) at different temperature swings. A reliability improvement of up to 44% is demonstrated for the bonds located at the center of the chip and seeing the highest TT temperature. The physical phenomena occurring during the TTs and during PC are studied using microstructure analysis (Scanning Electron Microscopy techniques) and nanoindentation. Softening of the material results from recrystallization and/or recovery during TT, whereas during PC, the thermally treated material hardens due to strain accumulation and defect formation. Despite the hardening, our data suggest a decrease in crack growth rate at the second half of the testing time. We implemented an approach for applying TTs during typical operating conditions in a converter by controlling the OFF-state losses of a device in a multichip configuration. The stability and the limits of this approach are studied experimentally and described by an electrothermal model. This study allows us to conclude on a realistic process window for online TTs, by considering both material constraints and practical temperature control limits.

BRAT1biallelic variants are associated with rigidity and multifocal seizure syndrome, lethal neonatal (RMFSL), and neurodevelopmental disorder associating cerebellar atrophy with or without seizures syndrome (NEDCAS). To date, forty individuals have been reported in the literature. We collected clinical and molecular data from 57 additional cases allowing us to study a large cohort of 97 individuals and draw phenotype-genotype correlations. Fifty-nine individuals presented with BRAT1-related RMFSL phenotype. Most of them had no psychomotor acquisition (100%), epilepsy (100%), microcephaly (91%), limb rigidity (93%), and died prematurely (93%). Thirty-eight individuals presented a non-lethal phenotype of BRAT1-related NEDCAS phenotype. Seventy-six percent of the patients in this group were able to walk and 68% were able to say at least a few words. Most of them had cerebellar ataxia (82%), axial hypotonia (79%) and cerebellar atrophy (100%). Genotype-phenotype correlations in our cohort revealed that biallelic nonsense, frameshift or inframe deletion/insertion variants result in the severe BRAT1-related RMFSL phenotype (46/46; 100%). In contrast, genotypes with at least one missense were more likely associated with NEDCAS (28/34; 82%). The phenotype of patients carrying splice variants was variable: 41% presented with RMFSL (7/17) and 59% with NEDCAS (10/17).

In this article, the scale reduction method is applied to an induction power transfer system for electric vehicle (EV) charging for its rapid and low-cost prototyping. In addition, a co-simulation method is proposed, which is based on the coupling between a circuit analysis and a finite-element (FE) analysis. Then, it is proposed to combine the scale reduction method with the co-simulation method to consider, at the same time, the nonlinearities due to the power electronic converter and the magnetic material characteristics of the system. Finally, a 1 kW experimental IPT system is proposed to validate both methods.

Background: The Southern US is confronting bourgeoning HIV and hepatitis C virus (HCV) epidemics among people who inject drugs (PWID), yet little is known about shared and unique risk factors across the region. We applied an intersectional risk environment framework to understand infectious disease outcomes for sub-groups of PWID that experience multiple axes of social marginalization related to racial and ethnic identity and social and economic vulnerability. Methods: HIV and HCV prevalence was estimated from the first iteration of the CDC’s National HIV Behavioral Surveillance respondent driven sample of PWID in Shelby County, Tennessee in 2018. We ran adjusted multinomial models to test main and interaction effects of race/ethnicity and structural factors on the prevalence of a three-level outcome: HIV-only, HCV-only, and no infection. Results: A total of 564 PWID participated, 558 (99%) completed HIV testing, and 540 (96%) HCV testing. Thirty (5%) were HIV-positive, 224 (40%) HCV-positive, and less than 1% were co-infected. Descriptive differences by race/ethnicity and levels of structural vulnerability for HIV and HCV subpopulations were present; however, there was no evidence for statistical interaction. In the final main effects model, HIV status was positively associated with non-Hispanic Black identity (aRR 4.95, 95% CI 1.19, 20.6), whereas HCV status was associated with non-white identity (aRR 0.11 95% CI 0.07, 0.18). Factors associated with HCV infection were higher scores of structural vulnerability (aRR 2.19 95% CI 1.10, 4.35), and criminal legal involvement (aOR 1.99 95% CI 1.18, 3.37). Conclusion: This is the first study to implement local population-based survey data to evaluate distinctive intersections of ethnic/racial and social factors associated with HIV and HCV status among PWID in the Memphis region. Findings come at an opportune time as harm reduction programs are in development in the South and shed light to the need for socially equitable race conscious resource investment.

Nonylphenol ethoxylate surfactants find wide applications in various industries. These surfactants could be used mainly as washing agents, pesticides, and in textile and leather manufacturing. However, their presence in aquatic environments has raised significant global health concerns. To address this issue, we conducted a study to investigate the impact of surface chemical groups on the removal of nonylphenol ethoxylate (NPEO) from synthetic laundry wastewater using different samples of coal-based activated carbon. The following treatments were carried out to prepare a series of samples: acid treatment with 10% HCl at 75 °C, heat treatment at 900 °C under N2flow, and oxidation in 10% HNO3at 75 °C. The impact of carbon treatments on the NPEO3–17and COD adsorption were examined by conducting batch adsorption using the modified carbons and synthetic laundry wastewater (SLWW) containing NPEO with the ethoxylate chain in the range of 3 to 17. Unmodified and modified activated carbon samples were characterized in terms of structural, morphological and chemical properties. The samples obtained by thermal treatment under N2flow at 900 °C achieved the highest removal efficiency (of up to 99%) for the adsorption of NPEO3–17. Our results have proven that the highly improved removal efficiency of NPEO3–17is due to the increase of surface hydrophobicity of the heat-treated activated carbon. When the concentrations were below the critical micelle concentration, the ethoxylated surfactants are adsorbed as monomers by their hydrophobic moiety on a hydrophobic surface of activated carbon. Additional experiments were carried out to describe the sorption phenomenon, followed by the determination of the kinetic of NPEO3–17and COD removal using modified activated carbon. The application of Langmuir isotherm provided the best fit for NPEO3–17removal and allowed the determination of the adsorption rate constant (Ka= 0.0506 L μg−1) and the maximum adsorption capacity (Qm= 2168.3 μg g−1). The initial adsorption rate for COD removal was 420 mg g−1min−1. After ten cycles, the COD removal efficiency reduced from 80% to 50%, indicating the presence of unoccupied active sites in the activated carbon.

EHMT1 (also known as GLP) is a multifunctional protein, best known for its role as an H3K9me1 and H3K9me2 methyltransferase through its reportedly obligatory dimerization with EHMT2 (also known as G9A). Here, we investigated the role of EHMT1 in the oocyte in comparison to EHMT2 using oocyte-specific conditional knockout mouse models (Ehmt2cKO, Ehmt1cKO, Ehmt1/2cDKO), with ablation from the early phase of oocyte growth. Loss of EHMT1 in Ehmt1cKO and Ehmt1/2cDKO oocytes recapitulated meiotic defects observed in the Ehmt2cKO; however, there was a significant impairment in oocyte maturation and developmental competence in Ehmt1cKO and Ehmt1/2cDKO oocytes beyond that observed in the Ehmt2cKO. Consequently, loss of EHMT1 in oogenesis results, upon fertilization, in mid-gestation embryonic lethality. To identify H3K9 methylation and other meaningful biological changes in each mutant to explore the molecular functions of EHMT1 and EHMT2, we performed immunofluorescence imaging, multi-omics sequencing, and mass spectrometry (MS)–based proteome analyses in cKO oocytes. Although H3K9me1 was depleted only upon loss of EHMT1, H3K9me2 was decreased, and H3K9me2-enriched domains were eliminated equally upon loss of EHMT1 or EHMT2. Furthermore, there were more significant changes in the transcriptome, DNA methylome, and proteome in Ehmt1/2cDKO than Ehmt2cKO oocytes, with transcriptional derepression leading to increased protein abundance and local changes in genic DNA methylation in Ehmt1/2cDKO oocytes. Together, our findings suggest that EHMT1 contributes to local transcriptional repression in the oocyte, partially independent of EHMT2, and is critical for oogenesis and oocyte developmental competence.

AbstractTitanium alloy Ti6Al4V possesses a range of highly interesting properties such as excellent corrosion resistance, bio-compatibility and high specific stress but suffers from poor wear resistance. The present work addresses plasma assisted surface treatment using various combinations of nitriding and oxidizing treatments for improving the surface properties of this alloy. The response to the surface treatments is investigated by hardness depth profiling in correlation with the chemical and microstructural evolution. It highlights the advantages of combined nitriding and oxidizing treatments compared to single nitriding for improving surface mechanical properties of titanium alloys.