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Bryant-Li-Bhoj syndrome (BLBS), which became OMIM-classified in 2022 (OMIM: 619720, 619721), is caused by germline variants in the two genes that encode histone H3.3 (H3-3A/H3F3Aand H3-3B/H3F3B) [1–4]. This syndrome is characterized by developmental delay/intellectual disability, craniofacial anomalies, hyper/hypotonia, and abnormal neuroimaging [1, 5]. BLBS was initially categorized as a progressive neurodegenerative syndrome caused by de novo heterozygous variants in either H3-3Aor H3-3B[1–4]. Here, we analyze the data of the 58 previously published individuals along 38 unpublished, unrelated individuals. In this larger cohort of 96 people, we identify causative missense, synonymous, and stop-loss variants. We also expand upon the phenotypic characterization by elaborating on the neurodevelopmental component of BLBS. Notably, phenotypic heterogeneity was present even amongst individuals harboring the same variant. To explore the complex phenotypic variation in this expanded cohort, the relationships between syndromic phenotypes with three variables of interest were interrogated: sex, gene containing the causative variant, and variant location in the H3.3 protein. While specific genotype-phenotype correlations have not been conclusively delineated, the results presented here suggest that the location of the variants within the H3.3 protein and the affected gene (H3-3Aor H3-3B)contribute more to the severity of distinct phenotypes than sex. Since these variables do not account for all BLBS phenotypic variability, these findings suggest that additional factors may play a role in modifying the phenotypes of affected individuals. Histones are poised at the interface of genetics and epigenetics, highlighting the potential role for gene-environment interactions and the importance of future research.

One of the key parameters in assessing the production potential of unconventional oil and gas reservoirs is the quantification of organic matter, which is generally determined by pyrolysis. Laboratory nuclear magnetic resonance (NMR) is widely used in the oil industry; being a nondestructive method, it enables the possibility to perform several analyses on the same sample, which is desirable due to the heterogeneity of these types of geological formations. 13C spectra provide much information, from speciation to maturity determination. The main drawback of this technique is the inherently low signal obtained for these nuclei, rendering extremely long experimental times. A solution is using cross-polarization schemes that transfer the high polarization of nearby 1H nuclei to 13C ones, with the penalty that quantification is a priori not feasible. In this work, we analyze the cross-polarization evolution and conclude that quantifying the total organic content (TOC) is possible for a wide range of organic matter content and maturities for rock samples corresponding to the Neuquén and Cuyo basins in Argentina.

This study aimed to uncover novel genes associated with neurodevelopmental disorders (NDD) by leveraging recent large-scale de novo burden analysis studies to enhance a virtual gene panel used in a diagnostic setting. We re-analyzed historical trio-exome sequencing data from 745 individuals with NDD according to the most recent diagnostic standards, resulting in a cohort of 567 unsolved individuals. Next, we designed a virtual gene panel containing candidate genes from three large de novo burden analysis studies in NDD and prioritized candidate genes by stringent filtering for ultra-rare de novo variants with high pathogenicity scores. Our analysis revealed an increased burden of de novo variants in our selected candidate genes within the unsolved NDD cohort and identified qualifying de novo variants in seven candidate genes: RIF1, CAMK2D, RAB11FIP4, AGO3, PCBP2, LEO1, and VCP. Clinical data were collected from six new individuals with de novo or inherited LEO1variants and three new individuals with de novo PCBP2variants. Our findings add additional evidence for LEO1as a risk gene for autism and intellectual disability. Furthermore, we prioritize PCBP2as a candidate gene for NDD associated with motor and language delay. In summary, by leveraging de novo burden analysis studies, employing a stringent variant filtering pipeline, and engaging in targeted patient recruitment, our study contributes to the identification of novel genes implicated in NDDs.

Purpose: Our aim is to automatically align digital subtraction angiography (DSA) series, recorded before and after endovascular thrombectomy. Such alignment may enable quantification of procedural success. Methods: Firstly, we examine the inherent limitations for image registration, caused by the projective characteristics of DSA imaging, in a representative set of image pairs from thrombectomy procedures. Secondly, we develop and assess various image registration methods (SIFT, ORB). We assess these methods using manually annotated point correspondences for thrombectomy image pairs. Results: Linear transformations that account for scale differences are effective in aligning DSA sequences. Two anatomical landmarks can be reliably identified for registration using a U-net. Point-based registration using SIFT and ORB proves to be most effective for DSA registration and are applicable to recordings for all patient sub-types. Image-based techniques are less effective and did not refine the results of the best point-based registration method. Conclusion: We developed and assessed an automated image registration approach for cerebral DSA sequences, recorded before and after endovascular thrombectomy. Accurate results were obtained for approximately 85% of our image pairs.

Tethering a metal complex to its phosphate counterion via a phosphine ligand enables a new strategy in asymmetric counteranion-directed catalysis (ACDC). A straightforward, scalable synthetic route gives access to the gold(I) complex of a phosphine displaying a chiral phosphoric acid function. The complex generates a catalytically active species with an unprecedented intramolecular relationship between the cationic Au(I) center and the phosphate counterion. The benefits of tethering the two functions of the catalyst are demonstrated here in a tandem cycloisomerization/nucleophilic addition reaction, by attaining high enantioselectivity levels (up to 97% ee) at an unusually low 0.2 mol % catalyst loading. Remarkably, the method is also compatible with a silver-free protocol.

The article presents an interview with film director Kevin Smith. Topics include his partnership with the manufacturing and distributing company Chemesis International to start a legal cannabis brand titled Jay and Silent Bob's Private Stash which is named after two characters from several of his films, and his opinion regarding the gentrification of cannabis.

The purpose of the present study was to analyse the contents of calcium, magnesium, potassium, and sodium in bottom sediments of two water reservoirs. The chemical composition of the bottom sediments and the ratios between the studied macronutrients were assessed, taking into account the nutritional requirements of plants, to determine whether the sediments were suitable for use in natural/agricultural settings.

The safety systems include the functioning of the institutions of a state, central, and local government, businesses, and social organizations. Research in this discipline should contribute to the development of the theoretical foundations and systems of national and international security and operating systems in the area of technical safety. Technical safety engineering should deal with a design, build, operation, and decommissioning of technical measures in order to minimize the opportunities and the size of their negative impact on the environment, people, and the good of civilization. With this in mind, the main purpose of the research was to evaluate the safety of technical manufacturing company that uses a wide machine park. A plant manufacturing parts and components for automobiles was the audited company.

This analysis describes the results of three Cell Tracking Challenge editions for examining the performance of cell segmentation and tracking algorithms and provides practical feedback for users and developers.

•This study is the first to present asphaltene precipitation onsets for crude oils produced in Argentina.•Two light oils and two medium viscous oils were studied in the lab, following the “Indirect Method” with some variations.•In agreement with previous publications, it was found that n-pentane anticipates the onset in comparison to n-heptane.•An onset was detected for one of the two light oils from the Vaca Muerta formation, only with n-pentane as precipitant.•When tuning a model based on an onset, the characterization of heavy fractions can have a high impact on predicting AOP’s.

A study was made of the possibility of producing composites based on natural ‘Kvaliteks’ latex that are filled (20–30 parts) with shungite (‘Karelit’). The possibility of producing such composites had been shown earlier for the natural latex ‘Revultex’ containing a vulcanising group. Therefore, all the composites investigated in the present work contained a vulcanising group (sulphur, ethyl zimate, zinc oxide), and vulcanisation was carried out at a temperature of 125°C. Into the latex was introduced an aqueous dispersion of ‘Karelit’ with dispersing agent NF. The filler content was the same as in the formulation for gloves resistant to aggressive media. The mechanical properties of films of these composites were on a par with or even slightly superior to those for the standard composites, while the acid and alkali resistances were far higher. Acid- and alkali-resistant gloves manufactured from ‘Kvaliteks’ latex filled with ‘Karelit’ shungite satisfy the specifications fully and are considerably superior to standard gloves in terms of resistance to aggressive media in long-term tests.

Introduction:Pulmonary arterial hypertension (PAH) causes right heart failure (HF) and mainly affects females, but males have worse survival. Atrial Natriuretic Peptide (ANP) and Brain Natriuretic Peptide (BNP), along with N-terminal BNP (NTproBNP), are secreted from cardiomyocytes upon stretch and are important biomarkers in HF. Sex differences are observed in NTproBNP levels and prognostic value in left HF, but unknown in right HF. The aim was to assess sex differences in NTproBNP levels and prognostic value in PAH from a translational perspective.Methods:We screened patients with baseline NTproBNP measurements and right heart catheterization between 2002 and 2020. Induced pluripotent stem cells (iPSCs) from 1 male and 1 female PAH-patients were differentiated into cardiomyocytes (iPSC-CMs), and stretched for 24h at 1Hz and 10% on the Flexcell FX-6000 system (N=2). Gene expression analyses were performed on static and stretched samples.Results:266 patients (N=106 male, N=166 female) were included. Median baseline NTproBNP levels were similar in male and female patients (1118 vs832 ng/ml, P=0.58). We risk stratified patients on NTproBNP according to the guidelines and assessed differences in 1-year survival. In males highest 1-year mortality was observed in low and low-intermediate risk groups (16,4% and 7.7%, respectively) vsfemales (4.7% and 4.2%, respectively) (Figure1 A,B). Preliminary results indicate ~2x higher BNP mRNA expressions on male vsfemale patients (0.80 vs0.37, N=3 male and N=3 female, P=0.018), after mechanical stretch (Figure1 C).Conclusions:Although no sex differences were observed in NTproBNP plasma levels, it had different prognostic value in male and female patients. Furthermore, in vitromale iPSC-CMs had higher BNP levels after stretch compared to female iPSC-CMs.

Currently, effective treatment options for heart failure are lacking. Methods to monitor cardiac function longitudinally can accelerate preclinical and clinical research into disease progression and novel drugs. However, manual image analysis of cardiac substructures is resource-intensive and error-prone. While automated methods exist for clinical CT images, translating these to preclinical μCT data is challenging. We aimed at employing deep-learning to automatically extract quantitative data on cardiac functional parameters, developing a uniform method for both μCT and CT images. For this, we collected 110 contrast-enhanced μCT images of wild-type and accelerated aging (Ercc1Δ/-) mice, as well as a public dataset of 60 segmented cardiac CT images. Substructures, i.e., the left ventricle, left myocardium and right ventricle, were manually segmented in 24 μCT images to create a training set. After template-based heart detection, two separate segmentation neural network architectures were trained using the nnU-Net framework. Automatic and manual segmentations of the μCT training set were nearly identical (mean Dice score 0.983). The estimated median Dice score (0.940) of the test set results was comparable to existing methods for μCT image segmentation. Also, the automatic volume metrics were similar to manual observations by an expert. In Ercc1Δ/-mice, ejection fractions had significantly decreased, and myocardial mass increased by age 24 weeks. The mean Dice score of the CT segmentation results (0.925 ± 0.019, n = 40) was superior to those achieved by state-of-the-art algorithms. While further optimization and validation of the models is recommended, automated data extraction expands the use application of (μ)CT imaging, while reducing subjectivity and workload. In conclusion, the proposed method offers a pipeline to efficiently monitor disease progression in animals and humans, allowing uniform translation from preclinical to clinical studies.

Introduction:Pulmonary Hypertension (PH) is characterized by increased right atrial (RA) stretch and pressure. The major genetic predisposing risk factor for PH involves mutations in the bone morphogenetic protein (BMP) receptor 2 (BMPR2), for which BMP9 and BMP10 are ligands. Although BMP9 is mostly produced by hepatocytes, BMP10 is predominantly produced by adult RA cardiomyocytes. Therefore, its role is of interest in PH despite an elusive BMP10 release mechanism.Hypothesis:Increased RA wall stress in PH may be a trigger for BMP10 secretion.Methods:We first investigated BMP10 gene and protein expressions, as well as BMP activity, in RA tissue samples from control (N=5) and PH-patients (N=4). We also quantified BMP10, BMP9, IL-6 and active TGF-β plasma levels in controls (N=16) and PH-patients (N=48) by ELISA. We studied BMP10 and BMP9 activities, using a BMP-inducible reporter assay. Last, we established correlations between BMP10 activity and PH clinical parameters.Results:BMP10 mRNA, protein and activity (pSMAD1/5/8 and ID3) were increased in RA tissue of PH-patients compared to controls (Figure1 A-E). BMP10, BMP9 and IL-6 plasma levels were also augmented (Figure1 F-H); while TGF-β plasma levels, and BMP10 and BMP9 activities between PH-patients and controls were preserved. Finally, we divided the PH cohort on median BMP10-activity (0.33 AU). Higher BMP10 activity in PH-patients was associated with diminished RA compliance, reduced right ventricular function, lower stroke volume and elevated NT-proBNP (Figure1 I).Conclusions:Although BMP10 plasma levels were increased, BMP10 activity was preserved in PH-patients, probably because of high inflammatory cytokines, such as IL-6. High BMP10 activity was associated with increased RA pressure and worse disease severity in PH-patients.

Introduction:Pulmonary arterial hypertension (PAH) is associated with increased right atrial (RA) pressure and volume. We hypothesized that these patients have RA hypertrophy, increased stroke work, fibrosis and stiffness and that RA adaptation falls short in severe right ventricular (RV) diastolic stiffness (end-diastolic elastance; Eed).Methods:RA pressure-volume loops were created through a novel method in controls (N=9) and patients (N=27). RA volume was measured on a magnetic resonance transverse stack of slices and pressure with catheterization. In a larger cohort of controls (N=20) and PAH patients with low (N=39) or high Eed(N=41), RA volume was measured on a 4-chamber view and stroke work estimated through multiplying active emptying by A-wave pressure. Atriovenous stiffness was measured as the slope from minimal pressure and volume and V-wave. In PAH-patients (N=4) and controls (N=5) that died or underwent heart- and lung-transplantation, we collected RA tissue to study hypertrophy and capillarization (CD31 and wheat germ agglutinin staining) and fibrosis (Masson’s trichrome staining).Results:Averaged pressure-volume loops show RA dilatation in patients and elevated pressure, especially during atrial contraction. Atriovenous stiffness was similar in PAH and controls, but higher in high Eedwhen compared to low Eedpatients. RA stroke work and pressure rise during atrial contraction were higher in PAH. However, when corrected for Eed, these parameters were decreased in high Eedpatients, indicating RA-RV uncoupling. Histological analysis showed increased RA hypertrophy, number of capillaries per cardiomyocyte and perivascular/interstitial fibrosis in PAH patients.Conclusions:In PAH patients there is RA hypertrophy and increased stroke work. In severe RV diastolic stiffness, RA adaptation falls short and RA-RV uncoupling occurs. Although there is increased fibrosis, atriovenous stiffness is not different between PAH and controls.

This paper presents a fluid flow analytical model of a micro check valve based on an ortho-planar spring. The comparison with a coupled fluid-structure finite-element model shows that the analytical model gives results very close to the finite-element model (FEM). These models are then validated using flow rate measurements on valve prototypes.

The HRAS, KRAS, and NRASgene products belong to the superfamily of small GTPases. These proteins regulate the cellular response to extracellular stimuli through the activation of different signaling pathways. Although the role of the RASgene mutations in the pathogenesis of various human cancers has been established, the clinical significance of these molecular alterations in bladder cancer remains unclear. The aim of this study was to determine the frequency and spectrum of the HRAS, KRAS, and NRASmutations, to analyze their association with the clinicopathological variables, and to determine the prognostic value of these alterations in terms of recurrence, progression and mortality, in a prospective cohort of 249 bladder cancer patients. The frequency of the RASmutations, detected by the SNaPshot method, was 11.2%, of which the HRASmutations accounted for 64.3%, KRAS, for 28.6%, and NRAS, for 7.1%. We failed to find any correlation between all the RASgene mutations and pathomorphological characteristics. However, when analyzed separately, the opposite association of the HRASand KRASmutations with the clinical parameters of bladder cancer was for the first time shown: the HRASmutations were significantly associated with low stage low grade papillary tumors of a small size (p< 0.05), whereas the KRASmutations were associated with non-papillary urothelial carcinomas and the presence of metastases (p< 0.05). Analysis of the prognostic value of the molecular alterations revealed the association of the KRASmutations with decreased cancer-specific survival in both the total group of patients and the subgroup with nonmuscle invasive disease. The data obtained suggest that the HRASand KRASgene mutations may characterize alternative pathways of bladder cancer pathogenesis: the HRASmutations indicating benign and KRASmutations, aggressive disease course.

A novel mechanism is described for the agrin-mediated focal delivery of acetylcholine receptors (AChRs) to the postsynaptic membrane of the neuromuscular junction. Microtubule capture mediated by CLASP2 and its interaction partner, LL5β, and an intact subsynaptic actin cytoskeleton are both required for focal AChR transport to the synaptic membrane.

Hematopoietic stem cells (HSCs) express a large variety of cell surface receptors that are associated with acquisition of self-renewal and multipotent properties. Correct expression of these receptors depends on a delicate balance between cell surface trafficking, recycling, and degradation and is controlled by the microtubule network and Golgi apparatus, whose roles have hardly been explored during embryonic/fetal hematopoiesis. Here we show that, in the absence of CLASP2, a microtubule-associated protein, the overall production of HSCs is reduced, and the produced HSCs fail to self-renew and maintain their stemness throughout mouse and zebrafish development. This phenotype can be attributed to decreased cell surface expression of the hematopoietic receptor c-Kit, which originates from increased lysosomal degradation in combination with a reduction in trafficking to the plasma membrane. A dysfunctional Golgi apparatus in CLASP2-deficient HSCs seems to be the underlying cause of the c-Kit expression and signaling imbalance.

Typification and quantification of organic matter and fluids in shale rocks are prime topics for the characterization and geochemical evaluation of unconventional oil reservoirs. High field 1H nuclear magnetic resonance is a fast and reliable technique that requires a small amount of sample. The acquisition of T1–T2relaxation correlation maps provide a rich variety of information, where signals arising from solid organic matter may be clearly distinguished from that of water or hydrocarbon. However, quantification is hampered due to the finite echo times used in the multipulse sequence used to determine the T2distribution, where even for the shortest available echo times partial relaxation is unavoidable. In this work, we apply a variation of a sequence developed for fluid typing at low fields in conventional reservoirs to shale mudstones at a high magnetic field. The addition of a Hahn echo with variable echo time applied before the T2determination renders a data set from which extrapolation to time zero is more accurate than with previous methods. We applied this sequence to a sample saturated with a varying degree of heptane and compare our results with gravimetric ones. Furthermore, the evaporation kinetics show a change from a funicular to a pendular regime when the amount of heptane evaporating from inorganic pores reaches a critical level.

Context: The study of genome integrity in some genetic disorders has diagnostic and prognostic importance because of the evident relationship between genome instability and both DNA repair deficiencies and cancer predisposition.Objective: The objective was to compare the chromosomal and DNA damage responses in lymphocytes from patients with Nijmegen breakage syndrome (NBS), Fanconi anemia (FA) and Williams–Beuren syndrome (WBS) to find additional biomarkers of genome instability.Methods: The cytogenetic approaches were combined with the alkaline Comet assay to estimate genome integrity in cultured or freshly isolated and H2O2-treated lymphocytes.Results: Basal frequencies of chromosome aberrations were significantly increased in NBS/FA probands and NBS heterozygous carriers. The NBS diagnosis was confirmed by detecting site-specific rearrangements, while the mitomycin C (MMC)-stress test was highly positive in a FA patient. Among patients with suspected WBS, 12 individuals had a 7q11.23 microdeletion. In the Comet assay, genome instability was revealed in all three disorders, impaired capacity to repair oxidative damage being observed in NBS and WBS in contrast to FA and controls.Conclusion: The results indicate that the estimates of DNA damage response may be proposed as efficient biomarkers for detecting and characterizing genome instability in the genetic disorders under study.

Advanced driving-assistance systems (ADAS) have recently received an increasing attention from the car industry. ADAS development represents a considerable effort to obtain efficient and reliable systems. Driving several million kilometers is necessary to validate a system. Thus, there are strong needs to ease the development and validation processes. In this context, computer simulation techniques are a candidate solution to this problem since running digital scenarios saves time, money and human resources. Up until now, several simulators have been developed. In the first part of this paper we present one of these simulators i.e. Pro-SiVICTM, as a tool that is able to simulate and validate different sensors, control and path planning algorithms for ADAS. Pro-SiVICTMconnected with other tools is able to simulate/emulate vehicle components and road environment elements (e.g. perception sensors, wheel-road contacts, chassis characteristics, road side objects including their sensor responses, etc.). However, mainly in ADAS, sound assessment is a difficult task; therefore our paper approaches the related methodology in focusing the effort on defining the assessment criterion. Based on some ADAS developments, assessment examples are given.

Numerical simulation is gradually becoming an advantage in active safety. This is why the development of realistic numerical models enabling to substitute real truth by simulated truth is primordial. Pro-SiVIC™ has been developed to address this issue, and Pro-SiVIC™ simulations can replace real camera test campaigns. An optical analysis of sensors has been achieved by IFSTTAR, allowing the confrontation between real and simulated results. An optical platform has been developed to characterize and validate any camera, permitting to measure their performances. By comparing real and simulated sensors with this platform, this paper demonstrates that Pro-SiVIC™ accurately reproduces real sensors’ behaviour.

EBs, key microtubule (MT) tip–tracking proteins, are elongated molecules with two interacting calponin homology (CH) domains, an arrangement reminiscent of MT- and actin-binding CH proteins. In addition, electrostatic interactions between the C-terminus of EBs and MTs drive the specificity of EBs for growing MT ends.

End-binding proteins (EBs) comprise a conserved family of microtubule plus end–tracking proteins. The concerted action of calponin homology (CH), linker, and C-terminal domains of EBs is important for their autonomous microtubule tip tracking, regulation of microtubule dynamics, and recruitment of numerous partners to microtubule ends. Here we report the detailed structural and biochemical analysis of mammalian EBs. Small-angle X-ray scattering, electron microscopy, and chemical cross-linking in combination with mass spectrometry indicate that EBs are elongated molecules with two interacting CH domains, an arrangement reminiscent of that seen in other microtubule- and actin-binding proteins. Removal of the negatively charged C-terminal tail did not affect the overall conformation of EBs; however, it increased the dwell times of EBs on the microtubule lattice in microtubule tip–tracking reconstitution experiments. An even more stable association with the microtubule lattice was observed when the entire negatively charged C-terminal domain of EBs was replaced by a neutral coiled-coil motif. In contrast, the interaction of EBs with growing microtubule tips was not significantly affected by these C-terminal domain mutations. Our data indicate that long-range electrostatic repulsive interactions between the C-terminus and the microtubule lattice drive the specificity of EBs for growing microtubule ends.

The article presents research comparing the dissocial personality disorder (DPD), antisocial personality disorder (ASPD), and psychopathy among Sesotho-speaking unsentenced prisoners in South Africa. It determines the prevalence of these disorders and their co-morbidity. The differences found in these disorders indicate that they are three distinct disorders, while their similarities suggest an essential degree of overlap.