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Autism spectrum disorder (ASD) is a neurodevelopmental disorder (NDD) that affects approximately 4% of males and 1% of females in the United States. While causes of ASD are multi-factorial, single rare genetic variants contribute to around 20% of cases. Here, we report a case series of seven unrelated probands (6 males, 1 female) with ASD or another variable NDD phenotype attributed to de novo heterozygous loss of function or missense variants in the gene LARP1 (La ribonucleoprotein 1). LARP1 encodes an RNA-binding protein that post-transcriptionally regulates the stability and translation of thousands of mRNAs, including those regulating cellular metabolism and metabolic plasticity. Using lymphocytes collected and immortalized from an index proband who carries a truncating variant in one allele of LARP1, we demonstrated that lower cellular levels of LARP1 protein cause reduced rates of aerobic respiration and glycolysis. As expression of LARP1 increases during neurodevelopment, with higher levels in neurons and astrocytes, we propose that LARP1 haploinsufficiency contributes to ASD or related NDDs through attenuated metabolic activity in the developing fetal brain.

BACKGROUND: Monoamine oxidase (MAO) inhibitors can interact with selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs). There is clinical interest surrounding use of ozanimod with SSRIs/SNRIs because the major metabolites of ozanimod are weak inhibitors of MAO-B in vitro. OBJECTIVE: To evaluate the incidence of treatment-emergent adverse events (TEAEs) potentially related to serotonin accumulation (SA) during concomitant ozanimod and SSRI/SNRI use by performing analyses of data from an open-label, oral ozanimod 0.92 mg trial (DAYBREAK; NCT02576717). METHODS: SA narrow (serotonin syndrome, neuroleptic malignant syndrome, and hyperthermia malignant) and broad (terms potentially associated with SA) MedDRA v24.0 searches were performed using TEAE data from participants with relapsing multiple sclerosis who entered DAYBREAK from phase 3 studies (cutoff February 1, 2022). Incidences of TEAEs matching terms from each search were stratified by SSRI/SNRI use. RESULTS: Of 2257 DAYBREAK participants, 274 (12.1%) used an SSRI/SNRI. No participants had TEAEs matching the SA narrow search terms. There was no significant difference in the percentage of participants with ⩾1 TEAE matching the SA broad search for those on versus off SSRIs/SNRIs (on: 12.4%, n = 34/274; off: 15.6%, n = 310/1982, nominal p = 0.1630). CONCLUSION: MedDRA searches showed no increase in TEAEs potentially associated with SA with concomitant SSRI/SNRI and ozanimod use.

Objectives: The pathogenesis of Graves’ orbitopathy (GO) remains to be fully elucidated. Here, we reviewed the role of genetics and epigenetics. Design: We conducted a PubMed search with the following keywords: GO, thyroid eye disease; or Graves’ ophthalmopathy; or thyroid-associated ophthalmopathy; and: genetic, or epigenetic, or gene expression, or gene mutation, or gene variant, or gene polymorphism, or DNA methylation, or DNA acetylation. Articles in which whole DNA and/or RNA sequencing, proteome, and methylome analyses were performed were chosen. Results: The different prevalence of GO in the two sexes, as well as racial differences, suggest that genetics play a role in GO pathogenesis. In addition, the long-lasting phenotype of GO and patient-derived orbital fibroblasts suggests a genetic or epigenetic mechanism. Although no genes have been found to confer a specific risk for GO, differential gene expression has been reported in orbital fibroblasts from GO patients vs control fibroblasts, suggesting that an epigenetic mechanism may be involved. In this regard, a different degree of DNA methylation, which affects gene expression, has been found between GO and control fibroblasts, which was confirmed by whole methylome analysis. Histone acetylation and deacetylation, which also affect gene expression, remain to be investigated. Conclusions: Although no pathogenic gene variants have been reported, epigenetic mechanisms elicited by an initial autoimmune insult seem to be needed for differential gene expression to occur and, thus, for GO to develop and persist over time.

Abstract We consider 3d N $$ \mathcal{N} $$ = 2 non-abelian Hanany-Witten brane setups with chiral flavor symmetry. We propose that the associated field theories are quivers with improved bifundamentals, instead of standard bifundamentals. The improved bifundamental is a strongly coupled SCFT that carries one more U(1) global symmetry than the standard bifundamental. As a consequence, our proposal overcomes the long standing challenge of associating to each N $$ \mathcal{N} $$ = 2 brane setup a gauge theory with the full rank global symmetry, allowing the study of all the usual supersymmetric observables, such as superconformal index, sphere partition function, chiral ring and moduli space. The construction passes many non-trivial tests, for instance we algorithmically prove that any two improved quivers associated to S $$ \mathcal{S} $$ -dual brane setups are infrared dual. The 3d N $$ \mathcal{N} $$ = 2 mirror dualities can be uplifted to 4d dualities with 4d improved bifundamentals connecting USp(2N) nodes.

International research attention on evacuation issues has increased significantly following the human and natural disasters at the turn of the century, such as 9/11, Hurricane Katrina, Cyclones Idai and Kenneth, the Black Saturday forest fires and tsunamis in Japan. The main problem concerning when a disaster can occur involves studying the risk reduction. Risk, following all the theoretical and experimental studies, is determined by the product of three components: occurrence, vulnerability and exposure. Vulnerability can be improved over time through major infrastructure actions, but absolute security cannot be achieved. When the event will occur with certainty, only exposure remains to reduce the risk to people before the effect hits them. Exposure can be improved, under fixed conditions of occurrence and vulnerability, by improving evacuation. The main problem in terms of evacuating the population from an area is the available transport system, which must be used to its fullest. So, if the system is well managed, the evacuation improves (shorter times), meaning the exposure is reduced, and therefore, the risk is reduced. A key factor in the analysis of transport systems under emergency conditions is the behavior of the user, and therefore, the study of demand. This work identifies the main research lines that are useful for studying demand under exposure-related risk conditions. The classification of demand models that simulate evacuation conditions in relation to the effect on the transportation system is summarized. The contribution proposes a model for updating choice in relation to emergency conditions and utility. The contribution of emerging ICTs to actualization is formally introduced into the models. Intelligent technologies make it possible to improve user decisions, reducing exposure and therefore risk. The proposed model moves within the two approaches of the literature: it is an inter-period dynamic model with the probability expressed within the discrete choice theory; furthermore, it is a sequential dynamic model with the probability dependent on the previous choices. The contribution presents an example of application of the model, developing a transition matrix considering the case of choice updating under two extreme conditions.

Parkinson’s disease (PD) affects more than one million people in the EU. It currently has no definitive cure, meaning that patients rely only on symptomatic treatments, which themselves are burdened by side effects. The need for advancements in both knowledge and available treatments is thus strongly felt by patients, caregivers, and health operators. This unmet need sparked the idea of orchestrating a collaborative effort via a common network – IMMUPARKNET (The role of IMMUnity in tackling PARKinson’s disease through a Translational NETwork). The IMMUPARKNET COST Action focuses on challenges in PD and its related crosstalk with immune response. Although widely recognized, the role of immunity in the onset and development of PD is still unclear. The main goal of IMMUPARKNET is to fill this knowledge gap by establishing an innovative, interdisciplinary research network and fostering exchanges of expertise among specialists from different countries and institutions. As we gather scientists and clinicians who study immunity in PD and related fields, IMMUPARKNET will establish the first nucleus of a multidisciplinary ecosystem that aims to harmonize efforts and approaches, both in research and clinical practice, to boost the development of ground-breaking treatments for PD. Through meetings, training schools, webinars, position papers, and review manuscripts, IMMUPARKNET will lead fruitful exchanges of know-how among experts in the field. The IMMUPARKNET structure revolves around 5 working groups, with a total of 157 active members from 34 different countries. Of these active members, 58.5% are young researchers, while 67.5% come from Inclusiveness Target Countries (ITC - less research-intensive COST Members; https://www.cost.eu/about/members/). IMMUPARKNET output will facilitate the improved sharing and development of research resources, straightening the road to novel treatments and identifying where existing ones can be repurposed, all, ultimately and hopefully, finding a cure for PD.

Myotonia congenita, both in a dominant (Thomsen disease) and recessive form (Becker disease), is caused by molecular defects in CLCN1 that encodes the major skeletal muscle chloride channel, ClC-1. This channel is important for the normal repolarization of muscle action potentials and consequent relaxation of the muscle, and its dysfunction leads to impaired muscle relaxation after voluntary or evoked contraction and muscle stiffness. More than 300 CLCN1 pathogenic variants have been found in association with congenital myotonia, inherited as recessive or dominant traits (with complete or incomplete penetrance). In this study, we describe the case of a 44-year-old woman complaining of “leg stiffness” since the age of 20 years and presenting with transient muscle weakness, especially after sitting for several minutes, with grip myotonia and feet myotonia, cold-sensitive and warm-up. The strength was normal, but muscle hypertrophy in the lower limbs was evident. EMG myotonia was detected in all explored muscles. The patient’s father had precocious cataract correction but did not show myotonic discharges at EMG. Examination of the patient’s sons (aged 18 years and 12 years) was unremarkable. The patient started treatment with mexiletine, with improvement in grip myotonia and limb stiffness, but it was soon interrupted due to gastrointestinal disturbances. Direct sequencing of CLCN1 identified the previously described heterozygous intronic variant c.1471 + 1G > A, which resulted in the skipping of exon 13 in the CLCN1 muscle transcript. In addition, the rare heterozygous synonymous nucleotide change c.762C > T p.Cys254Cys was identified and predicted to alter physiological splicing. The detection of multiple splicing abnormalities leading to premature termination codons supported the in silico prediction. We developed a Western blot assay to assess the ClC-1 protein in muscle biopsy, and we observed that ClC-1 levels were consistently reduced in the patient’s muscle, supporting the pathogenic behavior of the variants disclosed. Overall, we report a novel case of Becker myotonia and highlight the importance of multiple levels of analysis to achieve a firm molecular diagnosis.

IntroductionGraves' Orbitopathy (GO) is an autoimmune disorder characterized by inflammation of orbital tissues, leading to various ocular manifestations, including ocular surface disease. This cross-sectional study aimed to assess the presence of ocular surface disease using the Ocular Surface Disease Index (OSDI) in patients with Graves' disease (GD) and moderate-to-severe active GO compared to those with GD and mild non-active GO. Additionally, we aimed to investigate the correlation between ocular surface disease and the eye features of GO.MethodsConsecutive GD patients with GO referred to the Ophthalmology and Endocrinology Units of the University Hospital of Pisa between June 2022 and February 2023 were enrolled. OSDI scores were obtained from 79 GD patients, categorized into moderate-to-severe active GO and mild non-active GO groups.ResultsOSDI scores were significantly higher in patients with moderate-to-severe active GO compared to those with mild non-active GO (P=0.0006). A cutoff value of 33 for positive tests revealed a higher frequency of pathological OSDI in moderate-to-severe active GO patients compared to mild non-active GO patients (P=0.0221; OR 3.673, CI 1.277-9.531). Within the moderate-to-severe active GO group, a significant positive correlation was found between OSDI and Clinical Activity Score (CAS) (R= 0.3867, 95% CI from 0.1403 to 0.5880; P=0.0030). Using a cutoff value of 55 (the 75th percentile of the study population), patients with CAS ≥ 3 had a significantly higher proportion of pathological OSDI compared to those with CAS

Guillain–Barré syndrome (GBS) and its variants represent a spectrum of acute, immune-mediated polyneuropathies with heterogeneous clinical presentations and underlying etiologies. While infectious triggers are common precursors to these disorders, the association between viral infections and autoimmune neurological conditions remains an area of active investigation. Here, we report a case of GBS/Miller–Fisher syndrome overlap syndrome in an 80-year-old male presenting with dysarthria, dysphonia, ophthalmoplegia, areflexia, and postural instability following an upper respiratory tract infection. Cerebrospinal fluid analysis revealed the unexpected detection of herpes simplex virus type 1 DNA. Treatment with intravenous immunoglobulin therapy and acyclovir resulted in a progressive recovery of neurological symptoms. This case emphasizes the role of viral infections in differential diagnosis or as potential triggers for autoimmune neurological disorders highlighting the efficacy to addressed therapy in such complex cases.

Sturge–Weber syndrome (SWS) is a rare congenital neurovascular disorder that initially presents with a facial port-wine birthmark (PWB) and most commonly associated with a R183Q somatic mosaic mutation in the gene GNAQ. This mutation is enriched in endothelial cells. Contrast-enhanced magnetic resonance imaging (MRI) diagnoses brain abnormalities including leptomeningeal vascular malformation, an enlarged choroid plexus, and abnormal cortical and subcortical blood vessels. Mouse SWS models identify dysregulated proteins important for abnormal vasculogenesis and blood brain barrier permeability. Recent clinical research has focused on early diagnosis, biomarker development, presymptomatic treatment, and development of novel treatment strategies. Prospective pilot clinical drug trials with cannabidiol (Epidiolex) or with sirolimus, an mTOR inhibitor, indicate possible reductions in seizure frequency and improved cognitive outcome. This review connects the most recent molecular research in SWS cell culture and animal models to developing new treatment methods and identifies future areas of research.

Aim: Early biomarkers of phenoconversion to neurodegeneration are crucial to identify individuals at high risk. In patients with idiopathic REM sleep behavior disorder (iRBD), the strongest risk factor for neurodegeneration, CD4+ T cells exhibit a peculiar transcription factor pattern.Objective: To assess transcription factor mRNA levels in CD4+ T cells as predictive biomarkers of phenoconversion in iRBD patients.Methods: iRBD patients were followed prospectively. ROC curve analysis and Kaplan-Meier curves were used to assess the discrimination between converters and non-converters.Results: CD4+ T cells from converters had higher STAT1, and lower GATA3 and FOXP3 mRNA levels. Hazard ratio was 58.3 (95% CI: 6.2–547.1) for higher STAT1, 101.2 (95% CI: 16.8–609.4) for lower GATA3 and 15.7 (2.7–91.4) for lower FOXP3.Conclusion: STAT1, GATA3 and FOXP3 mRNA levels in CD4+ T cells are promising predictive biomarkers of phenoconversion in iRBD patients.