Presentation of DNA Methyltransferase 3 Beta Mutation with Immune Deficiency and Dilation of Aorta and Esophagus

Background: Immunodeficiency, Centromeric region instability, and Facial anomalies syndrome (ICF) is a rare autosomal recessive disorder with Centromeric instability as a hallmark. Method: In this case report, we describe an Iranian 6-year-old male who was diagnosed with ICF syndrome. He had a history of recurrent infections, hydrocephalus report in pregnancy, failure to thrive, facial anomalies, global developmental delay, and umbilical hernia. Results: The investigation showed esophageal dilatation in barium swallow, ascending aortic dilatation in echocardiography and cutis laxa in skin biopsy. In laboratory data, impaired antibody function was observed. Finally, to find the probable causative genetic variant, a whole exome sequencing was performed. The data analysis using bioinformatics tools revealed c.1592G>A mutation in the exon 15 of DNMT3B. With respect to the diagnosis of ICF syndrome, our patient was treated with intravenous immunoglobulin (IVIG). Conclusion: It is necessary to perform periodic neurologic and ophthalmologic examinations. Echocardiography must be done annually. In addition, the possibility of HSCT should be evaluate

Longitudinal diffusion changes in prodromal and early HD: Evidence of white-matter tract deterioration

INTRODUCTION: Huntington's disease (HD) is a genetic neurodegenerative disorder that primarily affects striatal neurons. Striatal volume loss is present years before clinical diagnosis; however, white matter degradation may also occur prior to diagnosis. Diffusion-weighted imaging (DWI) can measure microstructural changes associated with degeneration that precede macrostructural changes. DWI derived measures enhance understanding of degeneration in prodromal HD (pre-HD). METHODS: As part of the PREDICT-HD study, N = 191 pre-HD individuals and 70 healthy controls underwent two or more (baseline and 1-5 year follow-up) DWI, with n = 649 total sessions. Images were processed using cutting-edge DWI analysis methods for large multicenter studies. Diffusion tensor imaging (DTI) metrics were computed in selected tracts connecting the primary motor, primary somato-sensory, and premotor areas of the cortex with the subcortical caudate and putamen. Pre-HD participants were divided into three CAG-Age Product (CAP) score groups reflecting clinical diagnosis probability (low, medium, or high probabilities). Baseline and longitudinal group differences were examined using linear mixed models. RESULTS: Cross-sectional and longitudinal differences in DTI measures were present in all three CAP groups compared with controls. The high CAP group was most affected. CONCLUSIONS: This is the largest longitudinal DWI study of pre-HD to date. Findings showed DTI differences, consistent with white matter degeneration, were present up to a decade before predicted HD diagnosis. Our findings indicate a unique role for disrupted connectivity between the premotor area and the putamen, which may be closely tied to the onset of motor symptoms in HD. Hum Brain Mapp 38:1460-1477, 2017. © 2017 Wiley Periodicals, Inc

Understanding pore formation and the effect on mechanical properties of high speed sintered polyamide-12 parts: A focus on energy input

High Speed Sintering is a novel powder-bed fusion Additive Manufacturing technique that uses an infrared lamp to provide intensive thermal energy to sinter polymer powders. The amount of thermal energy is critical to particle coalescence related defects such as porosity. This study investigates the effect of energy input on porosity and the resulting mechanical properties of polyamide-12 parts. Samples were produced at different lamp speeds, generating varying amount of energy input from a low to a high level. They were then scanned using X-ray Computed Tomography technique, following which they were subject to tensile testing. A strong correlation between energy input, porosity and mechanical properties was found, whereby pore formation was fundamentally caused by insufficient energy input. A greater amount of energy input resulted in a reduced porosity level, which in turn led to improved mechanical properties. The porosity, ultimate tensile strength and elongation achieved were 0.58%, 42.4 MPa and 10.0%, respectively, by using the standard parameters. Further increasing the energy input resulted in the lowest porosity of 0.14% and the highest ultimate tensile strength and elongation of 44.4 MPa and 13.5%, respectively. Pore morphology, volume, number density and spatial distribution were investigated, which were found to be closely linked with energy input and mechanical properties

Characterisation and correlation of areal surface texture with processing parameters and porosity of High Speed Sintered parts

High Speed Sintering is an advanced powder bed fusion polymer Additive Manufacturing technique aimed at economical production of end-use parts in series manufacture. Surface finish is thus of high importance to end users. This study investigates the surface topography of High Speed Sintered parts produced using a range of different energy-related process parameters including sinter speed, lamp power and ink grey level. Areal surface texture was measured using Focus Variation microscopy and the sample porosity was systematically examined by the X-ray Computed Tomography technique. Surface topography was further characterised by Scanning Electron Microscopy, following which the samples were subject to tensile testing. Results showed that areal surface texture is strongly correlated with porosity, which can be further linked with mechanical properties. Certain texture parameters i.e. arithmetic mean height Sa, root-mean-square Sq and maximum valley depth Sv were identified as good indicators that can be used to compare porosity and/or mechanical properties between different samples, as well as distinguish up-, down-skins and side surfaces. Sa, Sq and Sv for up- and down-skins were found to correlate with the above energy-related process parameters. It was also revealed that skewness Ssk and kurtosis Sku are related to sphere-like protrusions, sub-surface porosity and re-entrant features. Energy input is the fundamental reason that causes varying porosity levels and consequently different surface topographies and mechanical properties, with a 10.07 μm and a 30.21 % difference in Sa and porosity, respectively, between the ‘low’ and ‘high’ energy input

Bi-allelic genetic variants in the translational GTPases GTPBP1 and GTPBP2 cause a distinct identical neurodevelopmental syndrome

: The homologous genes GTPBP1 and GTPBP2 encode GTP-binding proteins 1 and 2, which are involved in ribosomal homeostasis. Pathogenic variants in GTPBP2 were recently shown to be an ultra-rare cause of neurodegenerative or neurodevelopmental disorders (NDDs). Until now, no human phenotype has been linked to GTPBP1. Here, we describe individuals carrying bi-allelic GTPBP1 variants that display an identical phenotype with GTPBP2 and characterize the overall spectrum of GTP-binding protein (1/2)-related disorders. In this study, 20 individuals from 16 families with distinct NDDs and syndromic facial features were investigated by whole-exome (WES) or whole-genome (WGS) sequencing. To assess the functional impact of the identified genetic variants, semi-quantitative PCR, western blot, and ribosome profiling assays were performed in fibroblasts from affected individuals. We also investigated the effect of reducing expression of CG2017, an ortholog of human GTPBP1/2, in the fruit fly Drosophila melanogaster. Individuals with bi-allelic GTPBP1 or GTPBP2 variants presented with microcephaly, profound neurodevelopmental impairment, pathognomonic craniofacial features, and ectodermal defects. Abnormal vision and/or hearing, progressive spasticity, choreoathetoid movements, refractory epilepsy, and brain atrophy were part of the core phenotype of this syndrome. Cell line studies identified a loss-of-function (LoF) impact of the disease-associated variants but no significant abnormalities on ribosome profiling. Reduced expression of CG2017 isoforms was associated with locomotor impairment in Drosophila. In conclusion, bi-allelic GTPBP1 and GTPBP2 LoF variants cause an identical, distinct neurodevelopmental syndrome. Mutant CG2017 knockout flies display motor impairment, highlighting the conserved role for GTP-binding proteins in CNS development across species

Biallelic MED27 variants lead to variable ponto-cerebello-lental degeneration with movement disorders

MED27 is a subunit of the Mediator multiprotein complex, which is involved in transcriptional regulation. Biallelic MED27 variants have recently been suggested to be responsible for an autosomal recessive neurodevelopmental disorder with spasticity, cataracts and cerebellar hypoplasia. We further delineate the clinical phenotype of MED27-related disease by characterizing the clinical and radiological features of 57 affected individuals from 30 unrelated families with biallelic MED27 variants. Using exome sequencing and extensive international genetic data sharing, 39 unpublished affected individuals from 18 independent families with biallelic missense variants in MED27 have been identified (29 females, mean age at last follow-up 17 ± 12.4 years, range 0.1-45). Follow-up and hitherto unreported clinical features were obtained from the published 12 families. Brain MRI scans from 34 cases were reviewed. MED27-related disease manifests as a broad phenotypic continuum ranging from developmental and epileptic-dyskinetic encephalopathy to variable neurodevelopmental disorder with movement abnormalities. It is characterized by mild to profound global developmental delay/intellectual disability (100%), bilateral cataracts (89%), infantile hypotonia (74%), microcephaly (62%), gait ataxia (63%), dystonia (61%), variably combined with epilepsy (50%), limb spasticity (51%), facial dysmorphism (38%) and death before reaching adulthood (16%). Brain MRI revealed cerebellar atrophy (100%), white matter volume loss (76.4%), pontine hypoplasia (47.2%) and basal ganglia atrophy with signal alterations (44.4%). Previously unreported 39 affected individuals had seven homozygous pathogenic missense MED27 variants, five of which were recurrent. An emerging genotype-phenotype correlation was observed. This study provides a comprehensive clinical-radiological description of MED27-related disease, establishes genotype-phenotype and clinical-radiological correlations and suggests a differential diagnosis with syndromes of cerebello-lental neurodegeneration and other subtypes of 'neuro-MEDopathies'

Numerical Analysis of Hollow Core Slabs in Relation to Pedestrian Traffic

Prefabricated concrete floor slabs are well-established types of flooring and are widely used in the construction industry. Concrete floor slabs have almost never had problems with vibrations caused by pedestrians. It is only in recent times, with modern constructions demanding longer spans and thus slimmer floor slabs, that vibration issues have begun to arise.This thesis has investigated how vibrations caused by pedestrian traffic in hollow-core floor slabs affect individuals according to the requirements and standards in place. The investigation was conducted using simulations in the finite element program RFEM. Various configurations of hollow-core floor slabs were modeled and subjected to different load cases by applying a load function representing the dynamic movement of pedestrians. The slabs were placed adjacent to each other and in succession to attempt a nuanced analysis. An extreme case was also examined to determine when the number of pedestrians became critical. The load function is derived from a Swedish standard, and the load has been reduced according to that standard. Checks with manual calculations were performed to confirm the program's accuracy.The results obtained from this study were presented in terms of maximum accelerations and Root Mean Square (r.m.s.) values, as these evaluation methods were the most recommended. The accelerations were then compared with the requirements from the standard ISO 10137. During the analysis, it was found that the load cases with the highest pedestrian frequencies also exhibited the highest acceleration values. The study also revealed that the lightest floor slab was most affected from a structural dynamic perspective. The simulations also showed that vibrations from a realistic pedestrian scenario posed no risk of disturbance. This is explained by the fact that the required number of pedestrians to generate a risk on the floor slab exceeds the number that can fit on a single floor slab. The number of elements in the width was found to have a negligible impact on the accelerations, provided that the number of pedestrians per slab remained constant

Numerical Analysis of Hollow Core Slabs in Relation to Pedestrian Traffic

Prefabricated concrete floor slabs are well-established types of flooring and are widely used in the construction industry. Concrete floor slabs have almost never had problems with vibrations caused by pedestrians. It is only in recent times, with modern constructions demanding longer spans and thus slimmer floor slabs, that vibration issues have begun to arise.This thesis has investigated how vibrations caused by pedestrian traffic in hollow-core floor slabs affect individuals according to the requirements and standards in place. The investigation was conducted using simulations in the finite element program RFEM. Various configurations of hollow-core floor slabs were modeled and subjected to different load cases by applying a load function representing the dynamic movement of pedestrians. The slabs were placed adjacent to each other and in succession to attempt a nuanced analysis. An extreme case was also examined to determine when the number of pedestrians became critical. The load function is derived from a Swedish standard, and the load has been reduced according to that standard. Checks with manual calculations were performed to confirm the program's accuracy.The results obtained from this study were presented in terms of maximum accelerations and Root Mean Square (r.m.s.) values, as these evaluation methods were the most recommended. The accelerations were then compared with the requirements from the standard ISO 10137. During the analysis, it was found that the load cases with the highest pedestrian frequencies also exhibited the highest acceleration values. The study also revealed that the lightest floor slab was most affected from a structural dynamic perspective. The simulations also showed that vibrations from a realistic pedestrian scenario posed no risk of disturbance. This is explained by the fact that the required number of pedestrians to generate a risk on the floor slab exceeds the number that can fit on a single floor slab. The number of elements in the width was found to have a negligible impact on the accelerations, provided that the number of pedestrians per slab remained constant

Selective C-Arylation of 2,5-Dibromo-3-hexylthiophene via Suzuki Cross Coupling Reaction and Their Pharmacological Aspects

The present study reports the synthesis of various new derivatives based on 5-aryl-2-bromo-3-hexylthiophene with moderate-to-good yields via a palladium-catalyzed Suzuki cross-coupling reaction. This coupling method involved the reaction of 2,5-dibromo-3-hexylthiophene with several arylboronic acids in order to synthesize corresponding thiophene derivatives under controlled and optimal reaction conditions. The different substituents (CH3, OCH3, Cl, F etc.) present on arylboronic acids are found to have significant electronic effects on the overall properties of new products. The synthesized thiophene molecules were studied for their haemolytic, biofilm inhibition and anti-thrombolytic activities, and almost all products showed potentially good properties. The compound 2-bromo-5-(3-chloro-4-fluorophenyl)-3-hexylthiophenein particular exhibited the highest values for haemolytic and bio-film inhibition activities among all newly synthesized derivatives. In addition, the compound 2-bromo-3-hexyl-5-(4-iodophenyl)thiophene also showed high anti-thrombolytic activity, suggesting the potential medicinal applications of these newly synthesized compounds

Efficient double Suzuki cross-coupling reactions of 2,5-dibromo-3-hexylthiophene: anti-tumor, haemolytic, anti-thrombolytic and biofilm inhibition studies

The present study describes several novel 2,5-biaryl-3-hexylthiophene derivatives (3a-i) synthesized via a Pd(0)-catalyzed Suzuki cross-coupling reaction in moderate to good yields. The novel compounds were also analyzed for their anti-thrombolytic, haemolytic, and biofilm inhibition activities. In addition, the anti-tumor activity was also evaluated in vitro for newly-synthesized compounds, where 3-hexyl-2,5-bis(4-(methylthio)phenyl)thiophene exhibited the best anti-tumor activity against 4T1 cells with IC50 value of 16 μM. Moreover, 2,5-bis(4-methylphenyl)-3-hexylthiophene showed the highest activity against MCF-7 cells with an IC50 value of 26.2 μM. On the other hand, the compound 2,5-bis(4-chloropheny)-3-hexylthiophene exhibited excellent biofilm inhibition activity. Furthermore, the compound 2,5-bis(3-chloro-4-fluorophenyl)-3-hexylthiophene also exhibited better anti-thrombolytic and hemolytic activity results as compared to the other newly-synthesized compounds