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Certain mutations can cause proteins to accumulate in neurons, leading to neurodegeneration. We recently showed, however, that upregulation of a wild-type protein, Ataxin1, caused by haploinsufficiency of its repressor, the RNA-binding protein Pumilio1 (PUM1), also causes neurodegeneration in mice. We therefore searched for human patients with PUM1 mutations. We identified eleven individuals with either PUM1 deletions or de novo missense variants who suffer a developmental syndrome (Pumilio1-associated developmental disability, ataxia, and seizure; PADDAS). We also identified a milder missense mutation in a family with adult-onset ataxia with incomplete penetrance (Pumilio1-related cerebellar ataxia, PRCA). Studies in patient-derived cells revealed that the missense mutations reduced PUM1 protein levels by â¼25% in the adult-onset cases and by â¼50% in the infantile-onset cases; levels of known PUM1 targets increased accordingly. Changes in protein levels thus track with phenotypic severity, and identifying posttranscriptional modulators of protein expression should identify new candidate disease genes.
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Discapacidades del Desarrollo/genética , Predisposición Genética a la Enfermedad , Haploinsuficiencia/genética , Mutación/genética , Proteínas de Unión al ARN/genética , Convulsiones/genética , Adolescente , Adulto , Edad de Inicio , Anciano de 80 o más Años , Animales , Secuencia de Bases , Niño , Preescolar , Discapacidades del Desarrollo/diagnóstico por imagen , Evolución Molecular , Femenino , Eliminación de Gen , Células HEK293 , Humanos , Lactante , Masculino , Ratones , Persona de Mediana Edad , Mutación Missense/genética , Neuronas/metabolismo , Neuronas/patología , Linaje , Estabilidad Proteica , Convulsiones/diagnóstico por imagenRESUMEN
The change in the power balance, temporal dynamics, emission weighted size, temperature, mass, and areal density of inertially confined fusion plasmas have been quantified for experiments that reach target gains up to 0.72. It is observed that as the target gain rises, increased rates of self-heating initially overcome expansion power losses. This leads to reacting plasmas that reach peak fusion production at later times with increased size, temperature, mass and with lower emission weighted areal densities. Analytic models are consistent with the observations and inferences for how these quantities evolve as the rate of fusion self-heating, fusion yield, and target gain increase. At peak fusion production, it is found that as temperatures and target gains rise, the expansion power loss increases to a near constant ratio of the fusion self-heating power. This is consistent with models that indicate that the expansion losses dominate the dynamics in this regime.
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Phelan-McDermid syndrome (PMS) is a genetic condition caused by SHANK3 haploinsufficiency and characterized by a wide range of neurodevelopmental and systemic manifestations. The first practice parameters for assessment and monitoring in individuals with PMS were published in 2014; recently, knowledge about PMS has grown significantly based on data from longitudinal phenotyping studies and large-scale genotype-phenotype investigations. The objective of these updated clinical management guidelines was to: (1) reflect the latest in knowledge in PMS and (2) provide guidance for clinicians, researchers, and the general community. A taskforce was established with clinical experts in PMS and representatives from the parent community. Experts joined subgroups based on their areas of specialty, including genetics, neurology, neurodevelopment, gastroenterology, primary care, physiatry, nephrology, endocrinology, cardiology, gynecology, and dentistry. Taskforce members convened regularly between 2021 and 2022 and produced specialty-specific guidelines based on iterative feedback and discussion. Taskforce leaders then established consensus within their respective specialty group and harmonized the guidelines. The knowledge gained over the past decade allows for improved guidelines to assess and monitor individuals with PMS. Since there is limited evidence specific to PMS, intervention mostly follows general guidelines for treating individuals with developmental disorders. Significant evidence has been amassed to guide the management of comorbid neuropsychiatric conditions in PMS, albeit mainly from caregiver report and the experience of clinical experts. These updated consensus guidelines on the management of PMS represent an advance for the field and will improve care in the community. Several areas for future research are also highlighted and will contribute to subsequent updates with more refined and specific recommendations as new knowledge accumulates.
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Trastornos de los Cromosomas , Humanos , Fenotipo , Trastornos de los Cromosomas/diagnóstico , Trastornos de los Cromosomas/epidemiología , Trastornos de los Cromosomas/genética , Deleción Cromosómica , Proteínas del Tejido Nervioso/genética , Cromosomas Humanos Par 22/genéticaRESUMEN
SYNGAP1 is a major genetic risk factor for global developmental delay, autism spectrum disorder, and epileptic encephalopathy. De novo loss-of-function variants in this gene cause a neurodevelopmental disorder defined by cognitive impairment, social-communication disorder, and early-onset seizures. Cell biological studies in mouse and rat neurons have shown that Syngap1 regulates developing excitatory synapse structure and function, with loss-of-function variants driving formation of larger dendritic spines and stronger glutamatergic transmission. However, studies to date have been limited to mouse and rat neurons. Therefore, it remains unknown how SYNGAP1 loss of function impacts the development and function of human neurons. To address this, we used CRISPR/Cas9 technology to ablate SYNGAP1 protein expression in neurons derived from a commercially available induced pluripotent stem cell line (hiPSC) obtained from a human female donor. Reducing SynGAP protein expression in developing hiPSC-derived neurons enhanced dendritic morphogenesis, leading to larger neurons compared with those derived from isogenic controls. Consistent with larger dendritic fields, we also observed a greater number of morphologically defined excitatory synapses in cultures containing these neurons. Moreover, neurons with reduced SynGAP protein had stronger excitatory synapses and expressed synaptic activity earlier in development. Finally, distributed network spiking activity appeared earlier, was substantially elevated, and exhibited greater bursting behavior in SYNGAP1 null neurons. We conclude that SYNGAP1 regulates the postmitotic maturation of human neurons made from hiPSCs, which influences how activity develops within nascent neural networks. Alterations to this fundamental neurodevelopmental process may contribute to the etiology of SYNGAP1-related disorders.SIGNIFICANCE STATEMENTSYNGAP1 is a major genetic risk factor for global developmental delay, autism spectrum disorder, and epileptic encephalopathy. While this gene is well studied in rodent neurons, its function in human neurons remains unknown. We used CRISPR/Cas9 technology to disrupt SYNGAP1 protein expression in neurons derived from an induced pluripotent stem cell line. We found that induced neurons lacking SynGAP expression exhibited accelerated dendritic morphogenesis, increased accumulation of postsynaptic markers, early expression of synapse activity, enhanced excitatory synaptic strength, and early onset of neural network activity. We conclude that SYNGAP1 regulates the postmitotic differentiation rate of developing human neurons and disrupting this process impacts the function of nascent neural networks. These altered developmental processes may contribute to the etiology of SYNGAP1 disorders.
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Dendritas/fisiología , Red Nerviosa/fisiología , Sistema Nervioso/crecimiento & desarrollo , Sinapsis/fisiología , Proteínas Activadoras de ras GTPasa/genética , Proteínas Activadoras de ras GTPasa/fisiología , Sistemas CRISPR-Cas , Diferenciación Celular/genética , Tamaño de la Célula , Células Cultivadas , Potenciales Postsinápticos Excitadores/genética , Femenino , Eliminación de Gen , Humanos , Trastornos del Neurodesarrollo/genética , Células Madre PluripotentesRESUMEN
Neurons are sensitive to changes in the dosage of many genes, especially those regulating synaptic functions. Haploinsufficiency of SHANK3 causes Phelan-McDermid syndrome and autism, whereas duplication of the same gene leads to SHANK3 duplication syndrome, a disorder characterized by neuropsychiatric phenotypes including hyperactivity and bipolar disorder as well as epilepsy. We recently demonstrated the functional modularity of Shank3, which suggests that normalizing levels of Shank3 itself might be more fruitful than correcting pathways that function downstream of it for treatment of disorders caused by alterations in SHANK3 dosage. To identify upstream regulators of Shank3 abundance, we performed a kinome-wide siRNA screen and identified multiple kinases that potentially regulate Shank3 protein stability. Interestingly, we discovered that several kinases in the MEK/ERK2 pathway destabilize Shank3 and that genetic deletion and pharmacological inhibition of ERK2 increases Shank3 abundance in vivo. Mechanistically, we show that ERK2 binds Shank3 and phosphorylates it at three residues to promote its poly-ubiquitination-dependent degradation. Altogether, our findings uncover a druggable pathway as a potential therapeutic target for disorders with reduced SHANK3 dosage, provide a rich resource for studying Shank3 regulation, and demonstrate the feasibility of this approach for identifying regulators of dosage-sensitive genes.
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Proteína Quinasa 1 Activada por Mitógenos/antagonistas & inhibidores , Proteína Quinasa 1 Activada por Mitógenos/genética , Proteínas del Tejido Nervioso/metabolismo , Estabilidad Proteica , Interferencia de ARN , Animales , Línea Celular Tumoral , Trastornos de los Cromosomas/genética , Femenino , Eliminación de Gen , Haploinsuficiencia , Humanos , Masculino , Ratones , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteínas del Tejido Nervioso/deficiencia , Proteínas del Tejido Nervioso/genética , Neuronas/metabolismo , Fosforilación/efectos de los fármacos , Estabilidad Proteica/efectos de los fármacosRESUMEN
Genome sequencing has revealed an increasing number of genetic variations that are associated with neuropsychiatric disorders. Frequently, studies limit their focus to likely gene-disrupting mutations because they are relatively easy to interpret. Missense variants, instead, have often been undervalued. However, some missense variants can be informative for developing a more profound understanding of disease pathogenesis and ultimately targeted therapies. Here we present an example of this by studying a missense variant in a well-known autism spectrum disorder (ASD) causing gene SHANK3. We analyzed Shank3's in vivo phosphorylation profile and identified S685 as one phosphorylation site where one ASD-linked variant has been reported. Detailed analysis of this variant revealed a novel function of Shank3 in recruiting Abelson interactor 1 (ABI1) and the WAVE complex to the post-synaptic density (PSD), which is critical for synapse and dendritic spine development. This function was found to be independent of Shank3's other functions such as binding to GKAP and Homer. Introduction of this human ASD mutation into mice resulted in a small subset of phenotypes seen previously in constitutive Shank3 knockout mice, including increased allogrooming, increased social dominance, and reduced pup USV. Together, these findings demonstrate the modularity of Shank3 function in vivo. This modularity further indicates that there is more than one independent pathogenic pathway downstream of Shank3 and correcting a single downstream pathway is unlikely to be sufficient for clear clinical improvement. In addition, this study illustrates the value of deep biological analysis of select missense mutations in elucidating the pathogenesis of neuropsychiatric phenotypes.
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Trastorno del Espectro Autista/genética , Proteínas de Microfilamentos/genética , Proteínas de Microfilamentos/metabolismo , Mutación Missense/genética , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Trastorno Autístico/genética , Proteínas del Citoesqueleto/metabolismo , Femenino , Humanos , Masculino , Ratones , Densidad Postsináptica/metabolismo , RatasRESUMEN
The implosion efficiency in inertial confinement fusion depends on the degree of stagnated fuel compression, density uniformity, sphericity, and minimum residual kinetic energy achieved. Compton scattering-mediated 50-200 keV x-ray radiographs of indirect-drive cryogenic implosions at the National Ignition Facility capture the dynamic evolution of the fuel as it goes through peak compression, revealing low-mode 3D nonuniformities and thicker fuel with lower peak density than simulated. By differencing two radiographs taken at different times during the same implosion, we also measure the residual kinetic energy not transferred to the hot spot and quantify its impact on the implosion performance.
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Mutations in SHANK3 and large duplications of the region spanning SHANK3 both cause a spectrum of neuropsychiatric disorders, indicating that proper SHANK3 dosage is critical for normal brain function. However, SHANK3 overexpression per se has not been established as a cause of human disorders because 22q13 duplications involve several genes. Here we report that Shank3 transgenic mice modelling a human SHANK3 duplication exhibit manic-like behaviour and seizures consistent with synaptic excitatory/inhibitory imbalance. We also identified two patients with hyperkinetic disorders carrying the smallest SHANK3-spanning duplications reported so far. These findings indicate that SHANK3 overexpression causes a hyperkinetic neuropsychiatric disorder. To probe the mechanism underlying the phenotype, we generated a Shank3 in vivo interactome and found that Shank3 directly interacts with the Arp2/3 complex to increase F-actin levels in Shank3 transgenic mice. The mood-stabilizing drug valproate, but not lithium, rescues the manic-like behaviour of Shank3 transgenic mice raising the possibility that this hyperkinetic disorder has a unique pharmacogenetic profile.
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Trastorno Bipolar/tratamiento farmacológico , Trastorno Bipolar/fisiopatología , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Complejo 2-3 Proteico Relacionado con la Actina/metabolismo , Actinas/metabolismo , Adulto , Animales , Conducta Animal , Trastorno Bipolar/genética , Cromosomas Humanos Par 22/genética , Modelos Animales de Enfermedad , Potenciales Postsinápticos Excitadores , Femenino , Dosificación de Gen/genética , Expresión Génica/genética , Genes Duplicados/genética , Humanos , Hipercinesia/genética , Hipercinesia/fisiopatología , Potenciales Postsinápticos Inhibidores , Litio/farmacología , Masculino , Ratones , Ratones Transgénicos , Proteínas de Microfilamentos , Convulsiones/genética , Ácido Valproico/farmacología , Ácido Valproico/uso terapéuticoRESUMEN
SHANK3 encodes for a scaffolding protein that links neurotransmitter receptors to the cytoskeleton and is enriched in postsynaptic densities of excitatory synapses. Deletions or mutations in one copy of the SHANK3 gene cause Phelan-McDermid syndrome, also called 22q13.3 deletion syndrome, a neurodevelopmental disorder with common features including global developmental delay, absent to severely impaired language, autistic behavior, and minor dysmorphic features. By whole exome sequencing, we identified two de novo novel variants including one frameshift pathogenic variant and one missense variant of unknown significance in a 14-year-old boy with delayed motor milestones, delayed language acquisition, autism, intellectual disability, ataxia, progressively worsening spasticity of the lower extremities, dysmorphic features, short stature, microcephaly, failure to thrive, chronic constipation, intrauterine growth restriction, and bilateral inguinal hernias. Both changes are within the CpG island in exon 21, separated by a 375 bp sequence. Next generation sequencing of PCR products revealed that the two variants are most frequently associated with each other. Sanger sequencing of the cloned PCR products further confirmed that both changes were on a single allele. The clinical presentation in this individual is consistent with other patients with a truncating mutation in exon 21, suggesting that the missense change contributes none or minimally to the phenotypes. This is the first report of two de novo mutations in one SHANK3 allele.
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Alelos , Trastorno Autístico/diagnóstico , Trastorno Autístico/genética , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Mutación , Proteínas del Tejido Nervioso/genética , Adolescente , Análisis Mutacional de ADN , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Masculino , Fenotipo , Secuenciación del ExomaRESUMEN
Acoustic manipulation has emerged as a versatile method for microfluidic separation and concentration of particles and cells. Most recent demonstrations of the technology use piezoelectric actuators to excite resonant modes in silicon or glass microchannels. Here, we focus on acoustic manipulation in disposable, plastic microchannels in order to enable a low-cost processing tool for point-of-care diagnostics. Unfortunately, the performance of resonant acoustofluidic devices in plastic is hampered by a lack of a predictive model. In this paper, we build and test a plastic blood-bacteria separation device informed by a design of experiments approach, parametric rapid prototyping, and screening by image-processing. We demonstrate that the new device geometry can separate bacteria from blood while operating at 275% greater flow rate as well as reduce the power requirement by 82%, while maintaining equivalent separation performance and resolution when compared to the previously published plastic acoustofluidic separation device.
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Acústica , Sangre/microbiología , Dispositivos Laboratorio en un Chip , Plásticos , Pseudomonas aeruginosa/aislamiento & purificación , Diseño de Equipo , Humanos , Sistemas de Atención de Punto , Factores de TiempoRESUMEN
OBJECTIVE: The coincidence of autism with epilepsy is 27% in those individuals with intellectual disability.1 Individuals with loss-of-function mutations in SHANK3 have intellectual disability, autism, and variably, epilepsy.2-5 The spectrum of seizure semiologies and electroencephalography (EEG) abnormalities has never been investigated in detail. With the recent report that SHANK3 mutations are present in approximately 2% of individuals with moderate to severe intellectual disabilities and 1% of individuals with autism, determining the spectrum of seizure semiologies and electrographic abnormalities will be critical for medical practitioners to appropriately counsel the families of patients with SHANK3 mutations. METHODS: A retrospective chart review was performed of all individuals treated at the Blue Bird Circle Clinic for Child Neurology who have been identified as having either a chromosome 22q13 microdeletion encompassing SHANK3 or a loss-of-function mutation in SHANK3 identified through whole-exome sequencing. For each subject, the presence or absence of seizures, seizure semiology, frequency, age of onset, and efficacy of therapy were determined. Electroencephalography studies were reviewed by a board certified neurophysiologist. Neuroimaging was reviewed by both a board certified pediatric neuroradiologist and child neurologist. RESULTS: There is a wide spectrum of seizure semiologies, frequencies, and severity in individuals with SHANK3 mutations. There are no specific EEG abnormalities found in our cohort, and EEG abnormalities were present in individuals diagnosed with epilepsy and those without history of a clinical seizure. SIGNIFICANCE: All individuals with a mutation in SHANK3 should be evaluated for epilepsy due to the high prevalence of seizures in this population. The most common semiology is atypical absence seizure, which can be challenging to identify due to comorbid intellectual disability in individuals with SHANK3 mutations; however, no consistent seizure semiology, neuroimaging findings, or EEG findings were present in the majority of individuals with SHANK3 mutations.
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Ondas Encefálicas/genética , Epilepsia/genética , Epilepsia/fisiopatología , Mutación/genética , Proteínas del Tejido Nervioso/genética , Adolescente , Anticonvulsivantes/uso terapéutico , Niño , Preescolar , Aberraciones Cromosómicas , Deleción Cromosómica , Trastornos de los Cromosomas/complicaciones , Trastornos de los Cromosomas/diagnóstico por imagen , Trastornos de los Cromosomas/genética , Cromosomas Humanos Par 22/genética , Electroencefalografía , Epilepsia/diagnóstico por imagen , Epilepsia/tratamiento farmacológico , Femenino , Humanos , Estudios Longitudinales , Imagen por Resonancia Magnética , Masculino , Estudios Retrospectivos , Adulto JovenRESUMEN
Individuals with deletions of chromosome 5q12-13 have rarely been reported and have a range of phenotypes including postnatal growth restriction, intellectual disability, hyperactivity, and ocular abnormalities. Most individuals reported have large deletions or complex rearrangements which have made identifying genes responsible for these phenotypes challenging. Here we report an individual with a chromosome 5q12-13 deletion with intellectual disability, hyperactivity and restricted linear growth. Based on the location of our patient's deletion in relation to the previously reported deletions, we have narrowed the locus for postnatal growth restriction to less than 1 megabase. Further refinement of this locus with reports of additional individuals with deletions of this region will allow for better understanding of the gene(s) responsible for this phenotype.
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Deleción Cromosómica , Cromosomas Humanos Par 5/genética , Sitios Genéticos , Crecimiento y Desarrollo/genética , Adolescente , Niño , Preescolar , Hibridación Genómica Comparativa , Humanos , Hibridación Fluorescente in Situ , Lactante , Recién Nacido , Masculino , FenotipoRESUMEN
Many efforts are underway to develop selective inhibitors of the voltage-gated sodium channel NaV1.7 as new analgesics. Thus far, however, in vitro selectivity has proved difficult for small molecules, and peptides generally lack appropriate pharmacokinetic properties. We previously identified the NaV1.7 inhibitory peptide GpTx-1 from tarantula venom and optimized its potency and selectivity via structure-guided analoging. To further understand GpTx-1 binding to NaV1.7, we have mapped the binding site to transmembrane segments 1-4 of the second pseudosubunit internal repeat (commonly referred to as Site 4) using NaV1.5/NaV1.7 chimeric protein constructs. We also report that select GpTx-1 amino acid residues apparently not contacting NaV1.7 can be derivatized with a hydrophilic polymer without adversely affecting peptide potency. Homodimerization of GpTx-1 with a bifunctional polyethylene glycol (PEG) linker resulted in a compound with increased potency and a significantly reduced off-rate, demonstrating the ability to modulate the function and properties of GpTx-1 by linking to additional molecules.
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Canal de Sodio Activado por Voltaje NAV1.7/metabolismo , Péptidos/química , Péptidos/farmacología , Ingeniería de Proteínas , Bloqueadores del Canal de Sodio Activado por Voltaje/farmacología , Dimerización , Relación Dosis-Respuesta a Droga , Humanos , Conformación Molecular , Unión Proteica , Estructura Terciaria de Proteína , Relación Estructura-Actividad , Bloqueadores del Canal de Sodio Activado por Voltaje/químicaRESUMEN
Hardened gated x-ray detectors use photographic film as the data recording medium due to its low sensitivity to the high-yield neutron environments at the National Ignition Facility (NIF). The photographic film is digitized with a Photometric Data Systems (PDS) microdensitometer, which measures the film's optical density. The PDS scanner is able to measure a dynamic range of 0-5 OD; however, raster scanning the film is time consuming and maintenance of the instrument is challenging due to legacy technology. Since film usage at NIF is expected to continue in the foreseeable future, a digitization platform that is faster and more maintainable would benefit the NIF's current and future operations. This work presents the characterization of the digital transitions (DT) atom, a CMOS camera-based digitization platform that records film data in a single image capture very quickly and has widely available user support. The preliminary results suggest that the DT atom is able to reconstruct exposures accurately enough to be a competitive alternative to the PDS Scanner.
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BACKGROUND: Phelan-McDermid syndrome (PMS) is a genetic neurodevelopmental disorder caused by SHANK3 haploinsufficiency and is associated with an increased risk for seizures. Previous literature indicates that around one third of individuals with PMS also have epilepsy or seizures, with a wide range of types and ages of onset. Investigating the impact of seizures on intellectual and adaptive functioning for PMS is a primary concern for caregivers and is important to understanding the natural history of this syndrome. METHODS: We report on results from 98 individuals enrolled in a prospective, longitudinal study. We detailed seizure frequency, type, and age of onset, and we analyzed seizure occurrence with best estimate IQ, adaptive functioning, clinical features, and genotype. We conducted multiple linear regression analyses to assess the relationship between the presence of seizures and the Vineland Adaptive Behavior Scale, Second Edition (VABS-II) Adaptive Behavior Composite score and the best estimate full-scale IQ. We also performed Chi-square tests to explore associations between seizure prevalence and genetic groupings. Finally, we performed Chi-square tests and t-tests to explore the relationship between seizures and demographic features, features that manifest in infancy, and medical features. RESULTS: Seizures were present in 41% of the cohort, and age of onset was widely variable. The presence of seizures was associated with significantly lower adaptive and intellectual functioning. Genotype-phenotype analyses were discrepant, with no differences in seizure prevalence across genetic classes, but with more genes included in deletions of participants with 22q13 deletions and seizures compared to those with 22q13 deletions and no seizures. No clinical associations were found between the presence of seizures and sex, history of pre- or neonatal complications, early infancy, or medical features. In this cohort, generalized seizures were associated with developmental regression, which is a top concern for PMS caregivers. CONCLUSIONS: These results begin to eludicate correlates of seizures in individuals with PMS and highlight the importance of early seizure management. Importantly, presence of seizures was associated with adaptive and cognitive functioning. A larger cohort might be able to identify additional associations with medical features. Genetic findings suggest an increased capability to realize genotype-phenotype relationships when deletion size is taken into account.
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Deleción Cromosómica , Trastornos de los Cromosomas , Cromosomas Humanos Par 22 , Convulsiones , Humanos , Masculino , Femenino , Convulsiones/genética , Trastornos de los Cromosomas/complicaciones , Trastornos de los Cromosomas/genética , Trastornos de los Cromosomas/fisiopatología , Cromosomas Humanos Par 22/genética , Niño , Preescolar , Adolescente , Estudios Longitudinales , Adulto Joven , Adulto , Estudios Prospectivos , Lactante , Proteínas del Tejido Nervioso/genéticaRESUMEN
Inertial confinement fusion experiments taking place at the National Ignition Facility are generating ever increasing amounts of fusion energy, with the deuterium tritium fusion neutron yield growing a hundredfold over the past ten years. Strategies must be developed to mitigate this harsh environment's deleterious effects on the operation and the performance of the time-resolved x-ray imagers deployed in the National Ignition Facility target bay to record the dynamics of the implosions. We review the evolution of these imagers in recent years and detail some of the past and present efforts undertaken to maintain or improve the quality of the experimental data collected on high neutron yield experiments. These include the use of a dump-and-read electronic backend, the selection of photographic film with a low background sensitivity, and the optical filtering of Cherenkov radiation.
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An indirect-drive inertial fusion experiment on the National Ignition Facility was driven using 2.05 MJ of laser light at a wavelength of 351 nm and produced 3.1±0.16 MJ of total fusion yield, producing a target gain G=1.5±0.1 exceeding unity for the first time in a laboratory experiment [Phys. Rev. E 109, 025204 (2024)10.1103/PhysRevE.109.025204]. Herein we describe the experimental evidence for the increased drive on the capsule using additional laser energy and control over known degradation mechanisms, which are critical to achieving high performance. Improved fuel compression relative to previous megajoule-yield experiments is observed. Novel signatures of the ignition and burn propagation to high yield can now be studied in the laboratory for the first time.
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On the National Ignition Facility, the hohlraum-driven implosion symmetry is tuned using cross-beam energy transfer (CBET) during peak power, which is controlled by applying a wavelength separation between cones of laser beams. In this Letter, we present early-time measurements of the instantaneous soft x-ray drive at the capsule using reemission spheres, which show that this wavelength separation also leads to significant CBET during the first shock, even though the laser intensities are 30× smaller than during the peak. We demonstrate that the resulting early drive P2/P0 asymmetry can be minimized and tuned to <1% accuracy (well within the ±7.5% requirement for ignition) by varying the relative input powers between different cones of beams. These experiments also provide time-resolved measurements of CBET during the first 2 ns of the laser drive, which are in good agreement with radiation-hydrodynamics calculations including a linear CBET model.
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Osteoarthritis of the hip is a common condition that affects older adults. Total hip replacement is the end-stage treatment to relief pain and improve joint function. Little is known about the mechanical load distribution during the activity of bipedal stance, which is an important daily activity for older adults who need to rest more frequently. This study investigated the distribution of the hip and knee joint moments during bipedal stance in patients with unilateral hip osteoarthritis and how the distribution changed 1 year after total hip replacement. Kinematic and kinetic data from bipedal stance were recorded. External hip and knee adduction moments were calculated and load distribution over both limbs was calculated using the symmetry angle. Preoperatively, the non-affected limb carried 10% more body weight than the affected limb when standing on two legs. Moreover, the mean external hip and knee adduction moments of the non-affected limb were increased compared to the affected limb. At follow-up no significant differences were observed between the patients' limbs. Preoperative and postoperative changes in hip adduction moment were mainly explained by the combination of the vertical ground reaction force and the hip adduction angle. Stance width also explained changes in the hip and knee adduction moments of the affected leg. Furthermore, as with walking, bipedal standing also showed an asymmetric mechanical load distribution in patients with unilateral hip osteoarthritis. Overall, the findings suggest the need for preventive therapy concepts that focus not only on walking but also on optimizing stance towards a balanced load distribution of both legs.
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Introduction: Developmental synaptopathies are neurodevelopmental disorders caused by genetic mutations disrupting the development and function of neuronal synapses. Methods: We administered the validated Social Responsiveness Scale, Second Edition (SRS-2) to investigate the phenotypic presentation of social-behavioral impairments for the developmental synaptopathy-SYNGAP1-related Intellectual Disability (SYNGAP1-ID) (n = 32) compared with a phenotypically similar disorder Phelan-McDermid syndrome (PMD) (n = 27) and healthy controls (n = 43). A short form SRS-2 analysis (n = 85) was also conducted. Results: Both SYNGAP1-ID and PMD had significantly elevated total and subcategory T-scores, with no significant score differences between SYNGAP1-ID and PMD, consistent between the full and short form. Mild to severe deficiencies in reciprocal social behavior were found in 100% of PMD individuals and 87.1% of SYNGAP1-ID individuals. Surprisingly, a positive correlation between age and total score was discovered for SYNGAP1-ID participants and not found in individuals with PMD or healthy controls. Discussion: The short form demonstrated greater utility for SYNGAP1-ID participants due to lower item-omission rates. In conclusion, significant impairment in reciprocal social behaviors is highly prevalent in SYNGAP1-ID.