Search Results (393)

Rubinstein–Taybi Syndrome type 1 (RSTS1) is an uncommon autosomal dominant genetic disorder associated with neurodevelopmental impairments and multiple congenital anomalies, with an incidence of 1:100,000–125,000 live births. The syndrome, caused by de novo mutations in the CREBBP gene, is characterized by phenotypic variability, including intellectual disability, facial dysmorphisms, and systemic abnormalities. The current case report describes a 15-year-old Brazilian female diagnosed with RSTS1 through whole-exome sequencing, which identified a de novo heterozygous missense mutation in the CREBBP gene (NM_004380.3; c.4393G > C; p.Gly1465Arg), classified as pathogenic. The patient’s clinical presentation included facial dysmorphisms, skeletal abnormalities, neurodevelopmental delay, psychiatric conditions, and other systemic manifestations. A comprehensive genetic counseling process facilitated the differential diagnosis and management strategies, emphasizing the importance of early and precise diagnosis for improving clinical outcomes. This report contributes to the growing knowledge of the genotype–phenotype correlations in RSTS1, aiding in the understanding and management of this uncommon condition. Full article

Background: Spectrin proteins are critical cytoskeleton components that maintain cellular structure and mediate intracellular transport. Pathogenic variants in SPTBN1, encoding βII-spectrin, have been associated with various neurodevelopmental disorders, including developmental delay, intellectual disability, autism spectrum disorder, and epilepsy. Here we report a Korean infant with infantile epileptic spasms syndrome (IESS) and an SPTBN1 mutation and provide a review of this mutation. Methods: The genomic data of the patient were analyzed by whole exome sequencing. A comprehensive literature review was conducted to identify and analyze all reported SPTBN1 variants, resulting in a dataset of 60 unique mutations associated with neurodevelopmental phenotypes. Case Presentation: A 10-month-old Korean female presented with IESS associated with a de novo heterozygous SPTBN1 mutation (c.785A>T; p.Asp262Val). The patient exhibited global developmental delay, microcephaly, hypotonia, spasticity, and MRI findings of diffuse cerebral atrophy and corpus callosum hypoplasia. Electroencephalography revealed hypsarrhythmia, confirming the diagnosis of IESS. Seizures persisted despite initial treatment with vigabatrin and steroids. Genetic analysis identified a likely pathogenic variant within the calponin homology 2 (CH2) domain of SPTBN1. Conclusions: This is the first report of an association between IESS and an SPTBN1 CH2 domain mutation in a Korean infant. This finding expands the clinical spectrum of SPTBN1-related disorders and suggests domain-specific effects may critically influence phenotypic severity. Further functional studies are warranted to elucidate the pathogenic mechanisms of domain-specific variants. Full article

New approach methodologies (NAMs), including microphysiological systems (MPSs), can recapitulate structural and functional complexities of organs. Vanoxerine was reported to induce cardiac adverse events, including torsade de points (TdP), in a Phase III clinical trial. Despite earlier nonclinical animal models and Phase I–II clinical trials, events of QT prolongation or proarrhythmia were not observed. Here, we utilized cardiac NAMs to evaluate the functional consequences of vanoxerine treatment on human cardiac excitation–contraction coupling. The cardiac MPS used in this study was a microfabricated fluidic culture platform with human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) capable of evaluating voltage, intracellular calcium handling, and contractility. Likewise, the hiPSC-CM comprehensive in vitro proarrhythmia assay (CiPA) was employed based on multielectrode array (MEA). Vanoxerine treatment delayed repolarization in a concentration-dependent manner and induced proarrhythmic events in both NAM platforms. The complex cardiac MPS displayed a frequency-dependent vanoxerine response such that EADs were eliminated at a faster pacing rate (1.5 Hz). Moreover, exposure analysis revealed a 99% vanoxerine loss in the cardiac MPS. TdP risk analysis demonstrated high to intermediate TdP risk at clinically relevant concentrations of vanoxerine and frequency-independent EAD events in the hiPSC-CM CiPA model. These findings demonstrate that nonclinical cardiac NAMs can recapitulate clinical outcomes, including detection of vanoxerine-induced delayed repolarization and proarrhythmic effects. Moreover, this work provides a foundation to evaluate the safety and efficacy of novel compounds to reduce the dependence on animal studies. Full article

Background: SET domain-containing 5 (SETD5) is a member of the protein lysine-methyltransferase family. SETD5 gene mutations cause disorders of the epigenetic machinery which determinate phenotypic overlap characterized by several abnormalities. SEDT5 gene variants have been described in patients with KBG and Cornelia de Lange (CdL) syndromes. Case description: A female patient with severe short stature and intellectual disability had been followed since she was 9 years old. Several causes of short stature were ruled out. At the age of 12 years, her height was 114 cm (−5.22 SDS), weight 19 kg (−5.88 SDS), BMI 14.6 kg/m² (−2.26 SDS), and was Tanner stage 1. The target height for the proband was 151.65 cm (−1.80 SDS). The bone age (BA) was delayed by 3 years compared to chronological age. The growth rate was persistently deficient (<<2 SDS). Physical examination revealed dysmorphic features. Genetic analysis documented a de novo SETD5 gene mutation (c.890_891delTT), responsible for phenotypes in the context of an overlap syndrome between the phenotype of MDR23, CdL and KBG syndromes. Recombinant growth hormone therapy (rhGH) was started at the age of 12 years. After both one year (+3.16 SDS) and two years (+2.9 SDS), the growth rate significantly increased compared with the pre-therapy period. Conclusion: This is the first case of a patient with overlap syndrome due to SETD5 mutation treated with rhGH. The review of the scientific literature highlighted the clinical and molecular features of SETD5 gene mutation and the use of rhGH therapy in patients suffering from CdL and KBG syndromes. Full article

This research is part of a broader investigation into innovative simulation-based approaches for improving traffic efficiency and road safety in roundabout corridors. These corridors, composed of successive roundabouts along arterials, present systemic challenges due to the dynamic interactions between adjacent intersections. While previous studies have addressed localized inefficiencies or proposed isolated interventions, this paper introduces possible replicable methodology based on a microsimulation and surrogate safety analysis to evaluate roundabout corridors as integrated systems. In this context, efficiency refers to the ability of a road corridor to maintain stable traffic conditions under a given demand scenario, with low delay times corresponding to acceptable levels of service. Safety is interpreted as the minimization of vehicle conflicts and critical interactions, evaluated through surrogate measures derived from simulated vehicle trajectories. The proposed approach—implemented through Aimsun Next and the SSAM tool—is tested on two real-world corridors: Via Aurelia Nord in Pisa (Italy) and Route de Marseille in Avignon (France), assessing multiple intersection configurations that combine roundabouts and signal-controlled junctions. Results show how certain layouts can produce unexpected performance outcomes, underlining the importance of system-wide evaluations. The proposed framework aims to support engineers and planners in identifying optimal corridor configurations under realistic operating conditions. Full article

Low-latency and robust beamforming are vital for sustaining signal quality and spectral efficiency in emerging high-mobility 5G and future 6G wireless networks. Conventional beam management approaches, which rely on periodic Channel State Information feedback and static codebooks, as outlined in 3GPP standards, are insufficient in rapidly varying propagation environments. In this work, we propose a Dominance-Enforced Adaptive Clustered Sliding Window Regression (DE-ACSW-R) framework for predictive beamforming in O-RAN Split 7-2x architectures. DE-ACSW-R leverages a sliding window of recent angle of arrival (AoA) estimates, applying in-window change-point detection to segment user trajectories and performing both Linear Regression (LR) and curvature-adaptive Support Vector Regression (SVR) for short-term and non-linear prediction. A confidence-weighted fusion mechanism adaptively blends LR and SVR outputs, incorporating robust outlier detection and a dominance-enforced selection regime to address strong disagreements. The Open Radio Unit (O-RU) autonomously triggers localised MUSIC scans when prediction confidence degrades, minimising unnecessary full-spectrum searches and saving delay. Simulation results demonstrate that the proposed DE-ACSW-R approach significantly enhances AoA tracking accuracy, beamforming gain, and adaptability under realistic high-mobility conditions, surpassing conventional LR/SVR baselines. This AI-native modular pipeline aligns with O-RAN architectural principles, enabling scalable and real-time beam management for next-generation wireless deployments. Full article

The 26S proteasome is a large, ATP-dependent proteolytic complex responsible for degrading ubiquitinated proteins in eukaryotic cells. It plays a crucial role in maintaining cellular protein homeostasis by selectively eliminating misfolded, damaged, or regulatory proteins marked for degradation. In this study, whole-exome sequencing (WES) was performed on an individual presenting with developmental delay and mild intellectual disability, as well as on both of his unaffected parents. This analysis identified a de novo variant, c.959C>G (p.Pro320Arg), in the PSMC5 gene. As predicted, this gene shows a very likely autosomal dominant inheritance pattern. Notably, PSMC5 has not previously been associated with any phenotype in the OMIM database. This variant was recently submitted to the ClinVar database as a variant of uncertain significance (VUS) and remains absent in both gnomAD and dbSNP. Notably, it has been identified in six unrelated individuals presenting with clinical features comparable to those observed in the patient described in this study. Multiple in silico prediction tools classified the variant as pathogenic, and a PhyloP conservation score supports strong evolutionary conservation of the mutated nucleotide. Protein structure predictions using the AlphaFold3 algorithm revealed notable structural differences between the mutant and wild-type PSMC5 proteins. We hypothesize that the p.Pro320Arg substitution alters the structure and function of PSMC5 as a regulatory subunit of the 26S proteasome, potentially impairing the stability and activity of the entire complex. Although functional studies are imperative, this study contributes to a deeper understanding of PSMC5, expands the spectrum of associated neurodevelopmental phenotypes, and highlights its potential as a therapeutic target. Furthermore, this study resulted in the submission of the identified variant to the ClinVar database (SCV006083352), where it was classified as pathogenic. Full article

The integration of distributed big data analytics into modern industrial environments has become increasingly critical, particularly with the rise of data-intensive applications and the need for real-time processing at the edge. While High-Performance Computing (HPC) systems offer robust petabyte-scale capabilities for efficient big data analytics, the performance of big data frameworks, especially on ARM-based HPC systems, remains underexplored. This paper presents an extensive experimental study on deploying Apache Spark 3.0.2, the de facto standard in-memory processing system, on an ARM-based HPC system. This study conducts a comprehensive performance evaluation of Apache Spark through representative big data workloads, including K-means clustering, to assess the effects of latency variations, such as those induced by network delays, memory bottlenecks, or computational overheads, on application performance in industrial IoT and edge computing environments. Our findings contribute to an understanding of how big data frameworks like Apache Spark can be effectively deployed and optimized on ARM-based HPC systems, particularly when leveraging vectorized instruction sets such as SVE, contributing to the broader goal of enhancing the integration of cloud–edge computing paradigms in modern industrial environments. We also discuss potential improvements and strategies for leveraging ARM-based architectures to support scalable, efficient, and real-time data processing in Industry 4.0 and beyond. Full article

Guardrail concrete in cold regions frequently suffers from corrosion due to icing and solutions, significantly shortening the service life of the guardrail. This paper proposed a cement-based composite coating for concrete protection. The hydrophobic agent was synthesized using nano-silica, tetraethyl orthosilicate and perfluorodecyltrimethoxysilane and used for coating modification as an additive or by impregnation. Also, a commercial hydrophobic agent was used for comparison. The modified coating was characterized by wettability, mechanical properties, chemical stability and icephobicity tests. The results showed that the coating prepared with the synthetic hydrophobic agent presented a higher contact angle than that prepared with the commercial one during the above tests. Moreover, it featured excellent icephobicity by effectively delaying the time of icing on concrete and reducing the icing mass and ice adhesion strength. In addition, the hydrophobic agent used by impregnation was a better choice for concrete surface protection. Chemical composition and morphology analysis of the coating showed that hydrophobicity and icephobicity were mainly attributed to F-containing functional groups and rough structure with low surface energy. This study provided an application potential of modified cement-based composite coating for anti-/de-icing of guardrail concrete. Full article

The fibrin matrix of thrombi is intertwined with neutrophil extracellular traps (NETs) containing histones that render resistance to fibrinolysis. During NET formation, histones are citrullinated. Our study addresses the question of whether citrullination modifies the fibrin-stabilizing effects of histones. We studied the structure and viscoelastic properties of fibrin formed in the presence of native or citrullinated H1 and core histones by scanning electron microscopy, clot permeation, and oscillation rheometry. The kinetics of fibrin formation and its dissolution were followed by turbidimetry and thromboelastometry. Co-polymerizing H1 with fibrin enhanced the mechanical strength of the clots, thickened the fibrin fibers, and enlarged the gel pores. In contrast, the addition of core histones resulted in a reduction in the fiber diameter, and the pores were only slightly larger, whereas the mechanical stability was not modified. Plasmin-mediated fibrinogen degradation was delayed by native and citrullinated core histones, but not by H1, and the action of des-kringle1-4-plasmin was not affected. Plasmin-mediated fibrinolysis was inhibited by native and citrullinated core histones, and this effect was moderated when the kringle domains of plasmin were blocked or deleted. These findings suggest that in NET-containing thrombi that are rich in core histones, alternative fibrinolytic enzymes lacking kringle domains are more efficient lytic agents than the classic plasmin-dependent fibrinolysis. Full article

The macrolide class of antibiotics are widely utilized in clinical settings for a broad range of bacterial infections and have additional roles as immunomodulatory agents. Although efficacious with a good safety profile overall, they have been associated with prolongation of the QT interval and development of the polymorphic ventricular tachycardia, Torsades de pointes (TdP). In a 2020 scientific statement, the American Heart Association (AHA) classified azithromycin, clarithromycin and erythromycin as QT-prolonging drugs known to cause TdP and the online database, CredibleMeds, that maintains a list of drugs known to cause QT prolongation classifies these drugs as having an increased risk of QT prolongation. The mechanism of this risk has been delineated to involve macrolide binding to and a blockade of delayed rectifier potassium channels that conduct rapid potassium current, I_kr, during repolarization, leading to prolonged repolarization and subsequent QT prolongation. Studies investigating this association have revealed variable results, with several suggesting that the risk of QT prolongation and TdP with macrolide use may be highly dependent on underlying patient risk factors and comorbidities. In the present investigation, we summarize current evidence on association of macrolide antibiotics, azithromycin, clarithromycin and erythromycin, with the development of QT prolongation and TdP, pathophysiology of and risk factors predisposing to development of these events, the role of implementation of strategies to reduce this risk and highlight emerging research. Full article

Background/Objectives: Cowden syndrome (or PTEN hamartoma tumor syndrome) (CS/PHTS) belongs to a group of inherited disorders associated with the development of multiple hamartomas. The clinical presentation of patients may include dysmorphic facial features, macrocephaly, developmental delay, and multiple benign and malignant tumors of various localizations. At the same time, only thyroid cancer is thought to have an increased risk in childhood. Skin lesions in CS/PHTS occur in 90–100% of patients and include multiple tricholemmoma, papilloma, acral keratosis, pigmentation changes, as well as rarer forms like vascular malformations, fibromas, neuromas, melanoma, and basal cell carcinoma. Methods: Next-generation sequencing and Sanger sequencing were used to search for PTEN genetic variants. A histological and immunohistochemical examination of tumor biopsies and skin lesions was performed. Results: A total of 13 patients from six families with CS/PHTS, including 10 children, were described. Seven pediatric patients belonged to families with paternal transmission of the PTEN pathogenic variants, while three others were de novo cases. Atypical manifestations in CS/PHTS were diffuse large B-cell lymphoma in one adult, a renal cell carcinoma, three germ cell tumors, and a linear epidermal nevus in pediatric patients. A literature review of the identified pathogenic variants in the PTEN gene was performed, assessing their clinical significance and analyzing the traditional and modified diagnostic criteria as applied to the pediatric population. Conclusions: Taking into account the low incidence of CS/PHTS, the data presented significantly expand our current understanding of this disease and guide physicians to consider a wider range of possible malignant neoplasms in pediatric patients with CS/PHTS. Full article

Dysregulated expression of nuclear receptor superfamily 4 group A member 2 (NR4A2) has recently been associated with autistic spectrum disorder (ASD), speech impairment, and neurodevelopmental delay (NDD); however, its precise role in the prevalence and etiopathogenesis of ASD has not been fully elucidated. Herein, we aimed to explore the role of NR4A2 variants in the genetic underpinnings of ASD among Saudi children of different age ranges and phenotype severities. A total of 338 children with ASD from 315 unrelated families (293 simplex, 2 quads, and 1 quintet) were screened for NR4A2 variants via exome sequencing (ES) of the genomic DNA extracted from peripheral blood mononuclear cells (PBMCs), after which the probands with identified NR4A2 variants were further subjected to trio genetic analyses. ES analysis revealed 10 de novo NR4A2 variants (5 indels/nonsense, 2 missense, and 3 variants affecting splicing) in 8 unrelated probands (2.37%) and 2 affected siblings from 8 unrelated families (6 simplex (2.04%) and 2 quads (8.7%)). Three NR4A2 variants were notably recurrent among both affected and unaffected carriers. All identified indels and two splicing variants met the criteria for pathogenic/loss-of-function (LoF) variants according to the ACMG classification (PVS1), whereas the missense variants were classified as of uncertain significance (VUS). This study is among the first to identify such a high frequency of recurrent variants in an ASD cohort, suggesting their significant contribution to the etiopathogenesis of ASD within this population. Full article

As high-performance computing (HPC) platforms continue to scale up, communication costs have become a critical bottleneck affecting overall application performance. An effective strategy to overcome this limitation is to overlap communication with computation. The Message Passing Interface (MPI), as the de facto standard for communication in HPC, provides non-blocking communication primitives that make such overlapping feasible. By enabling asynchronous communication, non-blocking operations reduce idle time of cores caused by data transfer delays, thereby improving resource utilization. Overlapping communication with computation is particularly important for enhancing the performance of large-scale scientific applications, such as numerical simulations, climate modeling, and other data-intensive tasks. However, achieving efficient overlapping is non-trivial and depends not only on advances in hardware technologies such as Remote Direct Memory Access (RDMA), but also on well-designed and optimized MPI implementations. This paper presents a comprehensive survey on the principles of MPI non-blocking communication, the core techniques for achieving computation–communication overlap, and some representative applications in scientific computing. Alongside the survey, we include a preliminary experimental study evaluating the effectiveness of asynchronous progress mechanism on modern HPC platforms to support the development of parallel programs for HPC researchers and practitioners. Full article

This case study presents the long-term management of a 14-year-old male diagnosed with 18q deletion syndrome, also known as de Grouchy Syndrome, highlighting the challenges of treating rare chromosomal disorders in rural Romania. Background and Clinical Significance: 18q deletion syndrome, also known as de Grouchy syndrome, is a chromosomal disorder caused by the deletion of a part of the long arm of chromosome 18. This syndrome is seen in one out of 10,000 live births. The main features of the syndrome are short stature, hearing loss, hypotonia, mental retardation, endocrine disorders, and autoimmunity. Case Presentation: The patient’s condition was initially suspected at birth due to abnormal features and was later confirmed through genetic testing, revealing a 46,XY,del(18) karyotype. Key clinical features include craniofacial dysmorphism, delayed growth, congenital cardiac anomalies, developmental delay, severe neurological impairment, and multiple comorbidities such as endocrine dysfunction, dental anomalies, and orthopedic deformities. Despite early interventions such as cardiac surgery, the patient’s management has been challenged by limited access to specialized care. Conclusions: The case underscores the importance of timely genetic testing, early multidisciplinary care, and the role of family support in managing complex disorders. This report also addresses the gaps in healthcare accessibility in rural settings and emphasizes the need for improved infrastructure and genetic services. By comparing this case with the existing literature, the study explores the variability in clinical presentations of 18q deletion syndrome and advocates for more precise genetic testing to better understand its phenotypic spectrum. The patient’s ongoing challenges with medical and socio-economic factors emphasize the critical need for coordinated care and family support in managing rare genetic conditions. Full article