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Cyclin-dependent kinase-like 5 (CDKL5) is a serine-threonine kinase enriched in the forebrain to regulate neuronal development and function. Patients with CDKL5 deficiency disorder (CDD), a severe neurodevelopmental condition caused by mutations of CDKL5 gene, present early-onset epilepsy as the most prominent feature. However, spontaneous seizures have not been reported in mouse models of CDD, raising vital questions on the human-mouse differences and the roles of CDKL5 in early postnatal brains. Here, we firstly measured electroencephalographic (EEG) activities via a wireless telemetry system coupled with video-recording in neonatal mice. We found that mice lacking CDKL5 exhibited spontaneous epileptic EEG discharges, accompanied with increased burst activities and ictal behaviors, specifically at postnatal day 12 (P12). Intriguingly, those epileptic spikes disappeared after P14. We next performed an unbiased transcriptome profiling in the dorsal hippocampus and motor cortex of Cdkl5 null mice at different developmental timepoints, uncovering a set of age-dependent and brain region-specific alterations of gene expression in parallel with the transient display of epileptic activities. Finally, we validated multiple differentially expressed genes, such as glycine receptor alpha 2 and cholecystokinin, at the transcript or protein levels, supporting the relevance of these genes to CDKL5-regulated excitability. Our findings reveal early-onset neuronal hyperexcitability in mouse model of CDD, providing new insights into CDD etiology and potential molecular targets to ameliorate intractable neonatal epilepsy.
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Epilepsia Refractaria , Epilepsia , Espasmos Infantiles , Humanos , Animales , Ratones , Transcriptoma/genética , Espasmos Infantiles/genética , Espasmos Infantiles/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Epilepsia/genética , Prosencéfalo/metabolismo , Ratones NoqueadosRESUMEN
Encasements formed around haustoria and biotrophic hyphae as well as hypersensitive reaction (HR) cell death are essential plant immune responses to filamentous pathogens. In this study we examine the components that may contribute to the absence of these responses in susceptible barley attacked by the powdery mildew fungus. We find that the effector CSEP0162 from this pathogen targets plant MONENSIN SENSITIVITY1 (MON1), which is important for the fusion of multivesicular bodies to their target membranes. Overexpression of CSEP0162 and silencing of barley MON1 both inhibit encasement formation. We find that the Arabidopsis ecotype No-0 has resistance to powdery mildew, and that this is partially dependent on MON1. Surprisingly, we find the MON1-dependent resistance in No-0 not only includes an encasement response, but also an effective HR. Similarly, silencing of MON1 in barley also blocks Mla3-mediated HR-based powdery mildew resistance. Our results indicate that MON1 is a vital plant immunity component, and we speculate that the barley powdery mildew fungus introduces the effector CSEP0162 to target MON1 and hence reduce encasement formation and HR.
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Arabidopsis , Ascomicetos , Hordeum , Ascomicetos/fisiología , Hordeum/genética , Hordeum/metabolismo , Monensina/metabolismo , Inmunidad de la Planta , Arabidopsis/metabolismo , Enfermedades de las Plantas/microbiología , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismoRESUMEN
Cyclin-dependent kinase-like 5 (CDKL5), a serine-threonine kinase encoded by an X-linked gene, is highly expressed in the mammalian forebrain. Mutations in this gene cause CDKL5 deficiency disorder, a neurodevelopmental encephalopathy characterized by early-onset seizures, motor dysfunction, and intellectual disability. We previously found that mice lacking CDKL5 exhibit hyperlocomotion and increased impulsivity, resembling the core symptoms in attention-deficit hyperactivity disorder (ADHD). Here, we report the potential neural mechanisms and treatment for hyperlocomotion induced by CDKL5 deficiency. Our results showed that loss of CDKL5 decreases the proportion of phosphorylated dopamine transporter (DAT) in the rostral striatum, leading to increased levels of extracellular dopamine and hyperlocomotion. Administration of methylphenidate (MPH), a DAT inhibitor clinically effective to improve symptoms in ADHD, significantly alleviated the hyperlocomotion phenotype in Cdkl5 null mice. In addition, the improved behavioral effects of MPH were accompanied by a region-specific restoration of phosphorylated dopamine- and cAMP-regulated phosphoprotein Mr 32 kDa, a key signaling protein for striatal motor output. Finally, mice carrying a Cdkl5 deletion selectively in DAT-expressing dopaminergic neurons, but not dopamine receptive neurons, recapitulated the hyperlocomotion phenotype found in Cdkl5 null mice. Our findings suggest that CDKL5 is essential to control locomotor behavior by regulating region-specific dopamine content and phosphorylation of dopamine signaling proteins in the striatum. The direct, as well as indirect, target proteins regulated by CDKL5 may play a key role in movement control and the therapeutic development for hyperactivity disorders.
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Síndromes Epilépticos/genética , Hipercinesia/genética , Proteínas Serina-Treonina Quinasas/genética , Espasmos Infantiles/genética , Animales , Cuerpo Estriado/metabolismo , Cuerpo Estriado/patología , Modelos Animales de Enfermedad , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/patología , Síndromes Epilépticos/patología , Trastornos Neurológicos de la Marcha/genética , Trastornos Neurológicos de la Marcha/metabolismo , Trastornos Neurológicos de la Marcha/patología , Humanos , Hipercinesia/metabolismo , Hipercinesia/patología , Metilfenidato/metabolismo , Ratones , Ratones Noqueados , Espasmos Infantiles/patologíaRESUMEN
Neurodevelopmental disorders frequently share common clinical features and appear high rate of comorbidity, such as those present in patients with attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorders (ASD). While characterizing behavioral phenotypes in the mouse model of cyclin-dependent kinase-like 5 (CDKL5) disorder, a neurodevelopmental disorder caused by mutations in the X-linked gene encoding CDKL5, we found that these mice manifested behavioral phenotypes mimicking multiple key features of ASD, such as impaired social interaction and communication, as well as increased stereotypic digging behaviors. These mice also displayed hyper-locomotion, increased aggressiveness and impulsivity, plus deficits in motor and associative learning, resembling primary symptoms of ADHD. Through brain region-specific biochemical analysis, we uncovered that loss of CDKL5 disrupts dopamine synthesis and the expression of social communication-related key genes, such as forkhead-box P2 and mu-opioid receptor, in the corticostriatal circuit. Together, our findings support that CDKL5 plays a role in the comorbid features of autism and ADHD, and mice lacking CDKL5 may serve as an animal model to study the molecular and circuit mechanisms underlying autism-ADHD comorbidity.
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Trastorno por Déficit de Atención con Hiperactividad/enzimología , Proteínas Serina-Treonina Quinasas/deficiencia , Proteínas Serina-Treonina Quinasas/metabolismo , Animales , Trastorno por Déficit de Atención con Hiperactividad/genética , Trastorno por Déficit de Atención con Hiperactividad/metabolismo , Trastorno del Espectro Autista/enzimología , Trastorno del Espectro Autista/genética , Trastorno Autístico/enzimología , Trastorno Autístico/genética , Encéfalo/enzimología , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Dopamina/metabolismo , Genes Ligados a X , Hipercinesia/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Serina-Treonina Quinasas/genéticaRESUMEN
Soybean mosaic virus (SMV) is one of the most prevalent and important pathogens of soybean, which produces 11 proteins, and the third protein, P3, was suggested to be involved in virus movement and replication, as well as host infection. During the virus infection, host proteins are essential in the virus cycle. However, there is no comprehensive report on the network of host proteins that interact with P3. Fifty-one interactors were identified by using the P3 protein as the bait against the SMV SC15 strain-challenged soybean cDNA library. These proteins were classified into five groups, including transport and protein transport-related proteins, defense and disease-related proteins, photosynthesis proteins, cellular metabolic proteins, and unknown proteins. Among these proteins, the protein defined as hypersensitive response-like lesion-inducing (HRLI) appeared multiple times and showed strong affinity with P3, which indicated its important role in SMV infection. Thus, it was chosen for further investigation. Phylogenetic classification showed that paralog proteins GmHRLI-1 and GmHRLI-2 clustered together and shared 90% homologous identity. Bimolecular fluorescence complementation (BiFC) assay was carried out to confirm the interaction, and fluorescence was detected at the cell periplasmic as well as at the nucleus. Subcellular localization showed that GmHRLI was localized to the cell periplasmic, while the co-localization of GmHRLI and P3 signals was also observed in the nucleus, suggesting that GmHRLI could interact with P3 and promoted the translation of P3 to the nucleus. Moreover, the gene expression of GmHRLI was abundant in the roots, leaves, and flowers, and could be induced by SMV infection, suggesting its involvement in SMV infection. Our results together lay the foundation to explore the mechanisms of P3 in the HR process and the HRLI protein function in SMV response.
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Proteínas Portadoras/metabolismo , Potyvirus/metabolismo , Proteínas Virales/metabolismo , Secuencia de Aminoácidos , Perfilación de la Expresión Génica , Orden Génico , Vectores Genéticos/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Interacciones Huésped-Patógeno/genética , Filogenia , Enfermedades de las Plantas/virología , Potyvirus/clasificación , Potyvirus/genética , Unión Proteica , Mapeo de Interacción de Proteínas , Mapas de Interacción de Proteínas , Proteínas Virales/genéticaRESUMEN
Ultrasmooth surfaces with sub-nanometer roughness and low damage are a great challenge for optical fabrication. Ion beam sputtering (IBS) has obvious advantages on the improvement of surface quality and the removal of surface defects. However, surface defects with different properties and structures display different evolution laws during the IBS process, which affects the roughness change and needs classification studies. In this paper, classification experiments are carried out to study the surface topography evolution of plastic scratches, brittle scratches, and micro-particles during the IBS process. The plastic scratches and micro-particles can be removed, while the brittle scratches can be passivated, so that surface defects can be reduced and surface quality improved. The corresponding evolution mechanisms are discussed in depth, and we show that micro-topography characteristics and material properties are important factors affecting the evolution of surface topography. Through the summary of evolution laws of different surface states, the Gaussian distribution law of surface roughness is established. The evolution regularity and mechanism of surface roughness during the IBS process are expounded upon from the perspective of microscopic morphology, which lays a foundation for ultra-smooth surface manufacturing with low damage.
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Methyl-CpG binding protein 2 (MeCP2) is a chromatin regulator highly expressed in mature neurons. Mutations of MECP2 gene cause >90% cases of Rett syndrome, a neurodevelopmental disorder featured by striking psychomotor dysfunction. In Mecp2-null mice, the motor deficits are associated with reduction of dopamine content in the striatum, the input nucleus of basal ganglia mostly composed of GABAergic neurons. Here we investigated the causal role of MeCP2 in modulation of striatal dopamine content and psychomotor function. We found that mice with selective removal of MeCP2 in forebrain GABAergic neurons, predominantly in the striatum, phenocopied Mecp2-null mice in dopamine deregulation and motor dysfunction. Selective expression of MeCP2 in the striatum preserved dopamine content and psychomotor function in both males and females. Notably, the dopamine deregulation was primarily confined to the rostral striatum, and focal deletion or reactivation of MeCP2 expression in the rostral striatum through adeno-associated virus effectively disrupted or restored dopamine content and locomotor activity, respectively. Together, these findings demonstrate that striatal MeCP2 maintains local dopamine content in a non-cell autonomous manner in the rostral striatum and that is critical for psychomotor control.
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Corteza Cerebral/metabolismo , Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Proteína 2 de Unión a Metil-CpG/metabolismo , Desempeño Psicomotor/fisiología , Análisis de Varianza , Animales , Cromatografía Líquida de Alta Presión , Conducta Exploratoria/fisiología , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Masculino , Aprendizaje por Laberinto/fisiología , Proteína 2 de Unión a Metil-CpG/genética , Ratones , Ratones Transgénicos , Actividad Motora/genética , Mutación/genética , Transducción GenéticaRESUMEN
Formation of subsurface damage has an inseparable relationship with microscopic material behaviors. In this work, our research results indicate that the formation process of subsurface damage often accompanies with the local densification effect of fused silica material, which seriously influences microscopic material properties. Interestingly, we find ion beam sputtering (IBS) is very sensitive to the local densification, and this microscopic phenomenon makes IBS as a promising technique for the detection of nanoscale subsurface damages. Additionally, to control the densification effect and subsurface damage during the fabrication of high-performance optical components, a combined polishing technology integrating chemical-mechanical polishing (CMP) and ion beam figuring (IBF) is proposed. With this combined technology, fused silica without subsurface damage is obtained through the final experimental investigation, which demonstrates the feasibility of our proposed method.
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A translation-reduced ion beam figuring (TRIBF) technique for five-axis ion beam figuring (IBF) plants is proposed to process large size components which cannot be processed in the traditional way. This novel technique enhances the capability of five-axis IBF plants by taking advantage of their rotation axes. The IBF kinematic model is described and the TRIBF processing technique is established by solving the motion parameters. Verification experiments are conducted on a 150 mm diameter planar mirror. This mirror was processed by TRIBF technique with only a 100 mm translation stage. The surface error was reduced from initial 10.7 nm rms to 1.3 nm rms within 97 minute processing time. The result indicates that the TRIBF processing technique is feasible and effective.
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KEY MESSAGE: Soybean mosaic virus resistance was significantly improved in multiple soybean cultivars through genetic transformation induced by inverted repeat-SMV- HC - Pro genes based on RNAi and post-transcriptional gene silencing. Here, we demonstrate Soybean mosaic virus (SMV) resistance in transgenic soybean plants. Transformation of five soybean genotypes with a construct containing inverted repeat-SMV-HC-Pro genes-induced high-level SMV resistance. Through leaf-painting assays, polymerase chain reaction (PCR) verification and LibertyLink(®) strip detection, 105 T0 and 1059 T1 plants were confirmed as transgene-positive. Southern blotting confirmed insertion of the T-DNA into the genomic DNA and revealed a low-copy integration pattern. Most T0 plants were fertile and transmitted the exogenous genes to their progenies (ratios of 3:1 or 15:1). In the T1 generation, virus resistance was evaluated visually after inoculation with SMV (strain SC3) and 441 plants were highly resistant (HR). SMV disease rating was classified on a scale with 0 = symptomless and 4 = mosaic symptoms with severe leaf curl. In the positive T1 plants, the disease rating on average was 1.42 (range 0.45-2.14) versus 3.2 (range 2-4) for the nontransformed plants. With the T2 generation, 75 transgene-positive plants were inoculated with SC3, and 57 HR plants were identified. Virus-induced seed coat mottling was eliminated in the resistant lines. Analysis of SMV levels in the plants was performed using quantitative real-time PCR and double-antibody sandwich enzyme-linked immunosorbent assays; the results revealed no virus or a gradual reduction over time in the viral content, thereby supporting the visual examination results. This is the first report demonstrating pathogen-derived resistance to SMV induced by inverted repeat-SMV-HC-Pro genes in multiple soybean cultivars. Our findings contribute positively to the study of transgenic SMV-resistance using RNA interference.
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Cisteína Endopeptidasas/genética , Resistencia a la Enfermedad/genética , Glycine max/genética , Virus del Mosaico/patogenicidad , Enfermedades de las Plantas/virología , Proteínas Virales/genética , Agrobacterium tumefaciens , ADN Bacteriano/genética , ADN de Plantas/genética , Genotipo , Enfermedades de las Plantas/genética , Plantas Modificadas Genéticamente/genética , Plantas Modificadas Genéticamente/virología , Interferencia de ARN , Glycine max/virología , Transformación GenéticaRESUMEN
Ultraprecise and ultrasmooth surfaces become critical requirements for some high-performance optical systems. Ion-beam figuring (IBF) is a good and highly deterministic method for the final precision optical figuring. However, the uniform convergences of all spatial frequency surface errors are strongly dependent on the dynamic performance and ion-beam stability of the IBF machine. In this paper, only the dynamic performance is discussed, which is limited by the acceleration and velocity of the motion system. So we discuss these problems and their influences on figuring optical surfaces in detail. The structure optimization principle is based on the fabricating capability of ultraprecise surface errors in all spatial frequency ranges. With this requirement, the structure optimization of a quick-response platform is performed to improve its dynamic performance. Manufacturing experiments on a fused silica spherical concave surface (Φ135.7 mm, radius of curvature 340.5 mm) are accomplished, and the IBF machine can effectively correct the figure errors and improve the surface quality simultaneously. The IBF process realizes the uniform convergence of surface errors in all spatial frequency ranges, which is reduced down to 0.368 nm RMS, 0.204 nm RMS, and 0.087 nm RMS, respectively. The final results indicate that the performance of the new designed IBF machine meets the requirements well for the fabrication of a subnanometer optical surface.
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Ion sputtering of Zerodur material often results in the formation of nanoscale microstructures on the surfaces, which seriously influences optical surface quality. In this paper, we describe the microscopic morphology evolution during ion sputtering of Zerodur surfaces through experimental researches and theoretical analysis, which shows that preferential sputtering together with curvature-dependent sputtering overcomes ion-induced smoothing mechanisms leading to granular nanopatterns formation in morphology and the coarsening of the surface. Consequently, we propose a new method for ion beam smoothing (IBS) of Zerodur optics assisted by deterministic ion beam material adding (IBA) technology. With this method, Zerodur optics with surface roughness down to 0.15 nm root mean square (RMS) level is obtained through the experimental investigation, which demonstrates the feasibility of our proposed method.
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Morphology evolution at microscopic scales has an inseparable relationship with surface material behaviors, especially during ultrasmooth surface fabrication. In this work, the influence of initially existing local densification on ion nanopatterning of a fused-silica surface is investigated. Our research results indicate that fused-silica surfaces will easily densify permanently under a compressive load, exhibiting an anisotropic surface at the nanoscale. During the subsequent ion-beam sputtering process, the densification-dependent sputtering would influence and even dominate surface morphology evolution, which is identified as being an important evolution mechanism. However, ion-induced relaxation mechanisms will overcome surface roughening in the absence of local densification, and an ultrasmooth surface with root mean square roughness down to 0.06 nm is obtained in our experiment.
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Ion beam figuring (IBF) is established for the final precision figuring of high-performance optical components, where the figuring accuracy is guaranteed by the stability of the removal function and the solution accuracy of the dwell time. In this deterministic method, the figuring process can be represented by a two-dimensional (2D) convolution operation of a constant removal function and the dwell time. However, we have found that the current 2D convolution operation cannot factually describe the IBF process of curved surfaces, which neglects the influences of the projection distortion and the workpiece geometry on the removal function. Consequently, the current 2D convolution algorithm would influence the solution accuracy for the dwell time and reduce the convergence of the figuring process. In this part, based on the material removal characteristics of IBF, a mathematical model of the removal function is developed theoretically and verified experimentally. Research results show that the removal function during IBF of a curved surface is actually a dynamic function in the 2D convolution algorithm. The mathematical modeling of the dynamic removal function provides theoretical foundations for our proposed new algorithm in the next part, and final verification experiments indicate that this algorithm can effectively improve the accuracy of the dwell time solution for the IBF of curved surfaces.
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Ion beam figuring (IBF) is established for the final precision figuring of optical components. In this deterministic method, the figuring process is represented by a two-dimensional (2D) convolution operation of a constant removal function and the dwell time, where the figuring precision is guaranteed by the stability of the removal function as well as the solution accuracy of the dwell time. However, the current 2D convolution equation cannot factually reflect the IBF process of curved surfaces, which neglects the influence of the projection distortion and the workpiece geometry. Consequently, the current convolution algorithm for the IBF process would influence the solution accuracy for the dwell time and reduce the convergence of the figuring process. In this part, we propose an improved algorithm based on the mathematical modeling of the dynamic removal function in Part A, which provides a more accurate dwell time for IBF of a curved surface. Additionally, simulation analysis and figuring experiments are carried out to verify the feasibility of our proposed algorithm. The final experimental results indicate that the figuring precision and efficiency can be simultaneously improved by this method.
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BACKGROUND: Kawasaki disease (KD) patients who experience a cardiovascular complication known as a coronary artery aneurysm (CAA) are at high risk of developing ischemic heart disease, which may lead to sudden death. The etiology of CAA in KD patients is unclear, and this study aims to clarify the relationship between steroid receptor coactivator-1 (SRC-1) gene polymorphisms and CAA pathogenesis. METHODS: We investigated four SRC-1 gene polymorphisms (rs11894248, rs17791703, rs7572475, and rs9309308) and their correlation with KD with CAA susceptibility in 327 Taiwanese people (279 KD patients without CAA and 48 KD patients with CAA). RESULTS: The results indicated a statistically significant difference in genotype and allele frequency distributions at the SRC-1 four single nucleotide polymorphisms (SNPs) between KD patients with and without CAA (P < 0.01). Additionally, Smad3 gene polymorphism (rs12901071) is well known to be associated with KD patients. In our results, Smad3 SNP did not provide a statistically significant difference between KD patients with and without CAA. CONCLUSION: Our data show that SRC-1 polymorphisms may be the underlying cause of CAA; therefore, the polymorphisms examined in this study warrant further investigation.
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Aneurisma Coronario/genética , Predisposición Genética a la Enfermedad , Síndrome Mucocutáneo Linfonodular/complicaciones , Coactivador 1 de Receptor Nuclear/genética , Polimorfismo Genético , Pueblo Asiatico , Preescolar , Aneurisma Coronario/complicaciones , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Masculino , Síndrome Mucocutáneo Linfonodular/genética , TaiwánRESUMEN
Although ion beam figuring (IBF) provides a highly deterministic method for the precision figuring of optical components, several problems still need to be addressed, such as the limited correcting capability for mid-to-high spatial frequency surface errors and low machining efficiency for pit defects on surfaces. We propose a figuring method named deterministic ion beam material adding (IBA) technology to solve those problems in IBF. The current deterministic optical figuring mechanism, which is dedicated to removing local protuberances on optical surfaces, is enriched and developed by the IBA technology. Compared with IBF, this method can realize the uniform convergence of surface errors, where the particle transferring effect generated in the IBA process can effectively correct the mid-to-high spatial frequency errors. In addition, IBA can rapidly correct the pit defects on the surface and greatly improve the machining efficiency of the figuring process. The verification experiments are accomplished on our experimental installation to validate the feasibility of the IBA method. First, a fused silica sample with a rectangular pit defect is figured by using IBA. Through two iterations within only 47.5 min, this highly steep pit is effectively corrected, and the surface error is improved from the original 24.69 nm root mean square (RMS) to the final 3.68 nm RMS. Then another experiment is carried out to demonstrate the correcting capability of IBA for mid-to-high spatial frequency surface errors, and the final results indicate that the surface accuracy and surface quality can be simultaneously improved.
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Ultra-precision and ultra-smooth surfaces are vitally important for some high performance optical systems. Ion beam figuring (IBF) is a well-established, highly deterministic method for the final precision figuring of extremely high quality optical surfaces, whereas ion sputtering induced smoothing, or roughening for nanoscale surface morphology, strongly depends on the processing conditions. Usually, an improper machining method would arouse the production of nanoscale patterns leading to the coarsening of the optical surface. In this paper, the morphology evolution mechanism on a fused silica surface during IBF of high-slope optical components has been investigated by means of atomic force microscopy. Figuring experiments are implemented on two convex spherical surfaces by using different IBF methods. Both of their surface errors are rapidly reduced to 1.2 nm root mean square (RMS) after removing similar deep material, but their surfaces are characterized with obviously different nanoscale morphologies. The experimental results indicate that the ion incidence angle dominates the microscopic morphology during the IBF process. At near-normal incidence, fused silica achieves an ultra-smooth surface with an RMS roughness value R(q) down to 0.1 nm, whereas nanoscale ripple patterns are observed at a large incidence angle with an R(q) value increasing to more than 0.9 nm. Additionally, the difference of incidence angles on various machined areas would influence the uniformity of surface quality, resulting from the interplay between the smoothing and roughening effects induced by ion sputtering.
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Compared to male pups, perinatal female rats rely heavily on neuronal glutamine (Gln) transport for sustaining glutamatergic synaptic release in neurons of the ventrolateral ventral media nucleus of the hypothalamus (vlVMH). VMH mainly regulates female sexual behavior and increases glutamate release of perinatal hypothalamic neurons, permanently enhances dendrite spine numbers and is associated with brain and behavioral defeminization. We hypothesized that perinatal interruption of neuronal Gln transport may alter the glutamatergic synaptic transmission during adulthood. Perinatal rats of both sexes received an intracerebroventricular injection of a neuronal Gln uptake blocker, alpha-(methylamino) isobutyric acid (MeAIB, 5 mM), and were raised until adulthood. Whole-cell voltage-clamp recordings of miniature excitatory postsynaptic currents (mEPSCs) and evoked EPSCs (eEPSCs) of vlVMH neurons in adult rats with the perinatal pretreatment were conducted and neuron morphology was subjected to post hoc examination. Perinatal MeAIB treatment sex-differentially increased mEPSC frequency in males, but decreased mEPSC amplitude and synaptic Glu release in females. The pretreatment sex-differentially decreased eEPSC amplitude in males but increased AMPA/NMDA current ratio in females, and changed the morphology of vlVMH neurons of adult rats to that of the opposite sex. Most alterations in the glutamatergic synaptic transmission resembled the changes occurring during MeAIB acute exposure in perinatal rats of both sexes. We conclude that perinatal blockade of neuronal Gln transport mediates changes via different presynaptic and postsynaptic mechanisms to induce sex-differential alterations of the glutamatergic synaptic transmission and organization of vlVMH neurons in adult rats. These changes may be permanent and associated with brain and behavior feminization and/or defeminization in rats.
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Glutamina , Neuronas , Embarazo , Ratas , Animales , Masculino , Femenino , Ratas Sprague-Dawley , Transmisión Sináptica/fisiología , Ácido Glutámico/fisiología , HipotálamoRESUMEN
Impairments in cortical sensory processing have been demonstrated in Rett syndrome (RTT) and Autism Spectrum Disorders (ASD) and are thought to contribute to high-order phenotypic deficits. However, underlying pathophysiological mechanisms for these abnormalities are unknown. This study investigated auditory sensory processing in a mouse model of RTT with a heterozygous loss of MeCP2 function. Cortical abnormalities in a number of neuropsychiatric disorders, including ASD are reflected in auditory evoked potentials and fields measured by EEG and MEG. One of these abnormalities, increased latency of cortically sourced components, is associated with language and developmental delay in autism. Additionally, gamma-band abnormalities have recently been identified as an endophenotype of idiopathic autism. Both of these cortical abnormalities are potential clinical endpoints for assessing treatment. While ascribing similar mechanisms of idiopathic ASD to Rett syndrome (RTT) has been controversial, we sought to determine if mouse models of RTT replicate these intermediate phenotypes. Mice heterozygous for the null mutations of the gene MeCP2, were implanted for EEG. In response to auditory stimulation, these mice recapitulated specific latency differences as well as select gamma and beta band abnormalities associated with ASD. MeCP2 disruption is the predominant cause of RTT, and reductions in MeCP2 expression predominate in ASD. This work further suggests a common cortical pathophysiology for RTT and ASD, and indicates that the MeCP2+/- model may be useful for preclinical development targeting specific cortical processing abnormalities in RTT with potential relevance to ASD.