Inelastic collisions of fast charged particles with atoms: Bethe asymptotic formulas and shell corrections

The relativistic plane-wave Born approximation is applied to the study of inelastic collisions of charged particles with atoms, by considering atomic wave functions calculated from the independent-electron approximation with the self-consistent Dirac-Hartree-Fock-Slater potential. A database of longitudinal and transverse generalized oscillator strengths (GOSs) has been computed by using accurate numerical methods for all the subshells of the ground-state configurations of the elements with atomic numbers from 1 (hydrogen) to 99 (einsteinium). The calculated GOS do not satisfy the Bethe sum rule; departures from the sum rule are in accordance with previous theoretical estimates. Asymptotic high-energy formulas for the total cross section, the stopping cross section, and the energy-straggling cross section are derived with proper account of the relativistic departure from the Bethe sum rule. The shell correction is calculated as the energy-dependent term that, when added to the asymptotic formula, reproduces the value of the atomic cross section calculated by integrating the energy-loss differential cross section. Shell corrections to the stopping cross section obtained from the present approach are presented and compared with previous estimates

Paradigmatic de novo GRIN1 variants recapitulate pathophysiological mechanisms underlying GRIN1-related disorder clinical spectrum

Background: GRIN-related disorders (GRD), the so-called grinpathies, is a group of rare encephalopathies caused by mutations affecting GRIN genes (mostly GRIN1, GRIN2A and GRIN2B genes), which encode for the GluN subunit of the N-methyl D-aspartate (NMDA) type ionotropic glutamate receptors. A growing number of functional studies indicate that GRIN-encoded GluN1 subunit disturbances can be dichotomically classified into gain- and loss-of-function, although intermediate complex scenarios are often present. Methods: In this study, we aimed to delineate the structural and functional alterations of GRIN1 disease-associated variants, and their correlations with clinical symptoms in a Spanish cohort of 15 paediatric encephalopathy patients harbouring these variants. Results: Patients harbouring GRIN1 disease-associated variants have been clinically deeplyphenotyped. Further, using computational and in vitro approaches, we identified different critical checkpoints affecting GluN1 biogenesis (protein stability, subunit assembly and surface trafficking) and/or NMDAR biophysical properties, and their association with GRD clinical symptoms. Conclusions: Our findings show a strong correlation between GRIN1 variants-associated structural and functional outcomes. This structural-functional stratification provides relevant insights of genotypephenotype association, contributing to future precision medicine of GRIN1-related encephalo

Hallazgos clínicos en pacientes neuropediátricos con mutaciones en la región crítica de la lisencefalia

El retraso psicomotor, la epilepsia y en general los trastornos del neurodesarrollo, son entidades muy prevalentes en la edad pediátrica y suponen un reto profesional para el pediatra y un importante desafío epidiológico y ético para los sistemas sanitarios La gran angustia que genera este tipo de entidades, el importante impacto social y económico que supone en la dinámica familiar, junto con los problemas diagnósticos, los pronósticos inciertos y los escasos recursos terapéuticos disponibles, hacen que sea imprescindible intentar aproximarnos a la identificación y el conocimiento de las bases etiológicas de estas patologías. Dado que todos estos trastornos tienen su base fisiopatológica total o parcialmente localizada en la corteza cerebral, el conocimiento de la misma y su asociación con el neurodesarrollo, se hace indispensable. La proliferación de los precursores neuronales y la migración de las neuronas son probablemente los procesos más decisivos en el desarrollo cerebral, y por tanto, de su corteza. Como consecuencia de ello, diferentes grados de alteración de las mismas pueden producir alteraciones estructurales con disfunciones cerebrales muy dispares y cuadros clínicos muy diversos, desde retraso psicomotor y trastornos de conducta, hasta cuadros de epilepsia y microcefalia. Se han identificado varios genes involucrados en las principales etapas del desarrollo cortical TUBA1A1, DCX, ARX... destacando el LIS (17p13.3), que codifica para la proteína PAFAH1B1, regula la dineína citoplasmática e influye en la función de los microtúbulos, actuando tanto en la proliferación como en la migración neuronal. Así pues, la mutación del gen LIS1, así como de la región cromosómica en la que se encuentra, la Región Crítica de la Lisencefalia (RCL), producen diferentes grados de alteración del desarrollo de la corteza cerebral, que se pueden manifestar como diferentes tipos de anomalías congénitas. Se realiza un estudio observacional de casos y controles de un área sanitaria de la provincia de Alicante, el departamento 17, desde marzo de 2006 hasta diciembre de 2013, donde se incluyen 115 pacientes de la Unidad de Neuropediatría del Hospital Universitario de San Juan con retraso psicomotor y/o epilepsia y alteraciones en la neuroimagen y 400 voluntarios sanos de entre 23 y 45 años. Se lleva a cabo un estudio genético mediante técnicas de PCR donde se estudian 635 kb de la región genómica localizada en la RCL 34 en 17p13.3, analizando también la región codificante de LIS1 buscando alteraciones de transcripción, añadiendo el estudio de otros genes relacionados con LIS1 y la RCL, así como el de otros genes implicados en el neurodesarrollo, haciendo un análisis estadístico con el módulo "Statcalc" de Epiinfo 7.2.1 de los resultados obtenidos. En el estudio se puede observar un reagrupamiento de ciertas mutaciones genéticas en un área determinada y con una clínica y unos hallazgos radiológicos característicos, que pueden suponer un avance importante en el conocimiento y manejo de determinadas patologías. Se deduce que las alteraciones en la RCL pueden explicar la etiología de casi un 50% de los pacientes con retraso psicomotor y/o epilepsia con anomalías estructurales en el SNC, ya que los pacientes con esta patología y alteraciones inespecíficas estructurales del SNC, tienen casi 350 veces más de riesgo de presentar alteraciones en dicha región, que un grupo control. Por lo tanto, se puede concluir que la RCL es una de las zonas del genoma que más repercusión tiene sobre el neurodesarrollo, por lo que su estudio puede llegar a ser muy relevante para dar explicación causal de diferentes problemas neurológicos, así como servir de importante herramienta ya no solo diagnóstica, sino también pronóstica e incluso terapéutica

Elevated plasma reelin levels in children with autism

Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders involving age-dependent gene dysregulation. Reelin is a glycoprotein that varies its expression throughout lifetime and controls cortical patterning and synaptogenesis. Brain and plasma reelin levels have been reported to be low in adults with autism; as well as in children with autism, but only when compared to control adults. Therefore, reelin expression levels in children with autism are unclear. For this reason, we compared plasma reelin levels in children with autism and children without autism (non-ASD) of similar ages to evaluate reelin expression in ASD during childhood. Plasma samples from 19 non-ASD (8.9 ± 0.8 years) and 40 children with autism (7.5 ± 0.5 years) were analyzed. We found that 50% of the children with autism displayed similar plasma reelin levels to the non-ASD group. However, the remaining 50% expressed more than 30 times more reelin compared to non-ASD levels. We also show that male children with autism displayed significantly higher reelin levels than females. The clinical presentation of this subgroup could not be distinguished from that of children with autism. Epilepsy or attention-deficit/hyperactivity disorder (ADHD) was not associated to reelin levels. We conclude that the high levels of plasma reelin might be an important hallmark in a subset of children with autism, previously unnoticed. As we could not find any correlation between reelin levels and ASD clinical presentations, our results may indicate transient reelin increases in the plasma or the characterization of a group of ASD individuals with a different pathophysiology.This work was supported by grants from Fondo de Investigaciones Sanitarias (PI15/00665 and PI19-01359, co-funded by the Fondo Europeo de Desarrollo Regional, FEDER "Investing in your future"), by the Direcció General d’Universitat, Investigació i Ciència, GVA (AICO/2018/090) and through CIBERNED (Instituto de Salud Carlos III, Spain). We also acknowledge financial support from the Spanish Ministerio de Economía y Competitividad, through the “Severo Ochoa” Programme for Centres of Excellence in R&D (SEV-2017-0723).Peer reviewe

Clinical Phenotypes Associated to Engrailed 2 Gene Alterations in a Series of Neuropediatric Patients

The engrailed homeobox protein (EN) plays an important role in the regionalization of the neural tube. EN distribution regulates the cerebellum and midbrain morphogenesis, as well as retinotectal synaptogenesis. In humans, the EN1 and EN2 genes code for the EN family of transcription factors. Genetic alterations in the expression of EN2 have been related to different neurologic conditions and more particularly to autism spectrum disorders (ASD). We aimed to study and compare the phenotypes of three series of patients: (1) patients with encephalic structural anomalies (ESA) and abnormalities in the genomic (DNA) and/or transcriptomic (RNAm) of EN2 (EN2-g), (2) ESA patients having other gene mutations (OG-g), and (3) ESA patients free of these mutations (NM-g).Subjects and Methods: We have performed a descriptive study on 109 patients who suffer from mental retardation (MR), cerebral palsy (CP), epilepsy (EP), and behavioral disorders (BD), showing also ESA in their encephalic MRI. We studied genomic DNA and transcriptional analysis (cDNA) on EN2 gene (EN2), and in other genes (OG): LIS1, PTAFR, PAFAH1B2, PAFAH1B3, FGF8, PAX2, D17S379, D17S1866, and SMG6 (D17S5), as a routine genetic diagnosis in ESA patients.Results: From 109 patients, fifteen meet the exclusion criteria. From the remaining 94 patients, 12 (12.8%) showed mutations in EN2 (EN2-g), 20 showed mutations in other studied genes (OG-g), and 62 did not showed any mutation (NM-g). All EN2-g patients, suffered from MR, nine EP, seven BD and four CP. The proportions of these phenotypes in EN2-g did not differ from those in the OG-g, but it was significantly higher when comparing EN2-g with NM-g (MR: p = 0.013; EP: p = 0.001; BD: p = 0.0001; CP: p = 0.07, ns). Groups EN2-g and OG-g showed a 100 and a 70% of comorbidity, respectively, being significantly (p = 0.04) greater than NM-group (62.9%).Conclusion: Our series reflects a significant effect of EN2 gene alterations in neurodevelopmental abnormalities associated to ESA. Conversely, although these EN2 related anomalies might represent a predisposition to develop brain diseases, our results did not support direct relationship between EN2 mutations and specific clinical phenotypes