Analysis of exome data for 4293 trios suggests GPI-anchor biogenesis defects are a rare cause of developmental disorders.

Over 150 different proteins attach to the plasma membrane using glycosylphosphatidylinositol (GPI) anchors. Mutations in 18 genes that encode components of GPI-anchor biogenesis result in a phenotypic spectrum that includes learning disability, epilepsy, microcephaly, congenital malformations and mild dysmorphic features. To determine the incidence of GPI-anchor defects, we analysed the exome data from 4293 parent-child trios recruited to the Deciphering Developmental Disorders (DDD) study. All probands recruited had a neurodevelopmental disorder. We searched for variants in 31 genes linked to GPI-anchor biogenesis and detected rare biallelic variants in PGAP3, PIGN, PIGT (n=2), PIGO and PIGL, providing a likely diagnosis for six families. In five families, the variants were in a compound heterozygous configuration while in a consanguineous Afghani kindred, a homozygous c.709G>C; p.(E237Q) variant in PIGT was identified within 10-12 Mb of autozygosity. Validation and segregation analysis was performed using Sanger sequencing. Across the six families, five siblings were available for testing and in all cases variants co-segregated consistent with them being causative. In four families, abnormal alkaline phosphatase results were observed in the direction expected. FACS analysis of knockout HEK293 cells that had been transfected with wild-type or mutant cDNA constructs demonstrated that the variants in PIGN, PIGT and PIGO all led to reduced activity. Splicing assays, performed using leucocyte RNA, showed that a c.336-2A>G variant in PIGL resulted in exon skipping and p.D113fs*2. Our results strengthen recently reported disease associations, suggest that defective GPI-anchor biogenesis may explain ~0.15% of individuals with developmental disorders and highlight the benefits of data sharing

X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes

X-linked intellectual disability (XLID) is a clinically and genetically heterogeneous disorder. During the past two decades in excess of 100 X-chromosome ID genes have been identified. Yet, a large number of families mapping to the X-chromosome remained unresolved suggesting that more XLID genes or loci are yet to be identified. Here, we have investigated 405 unresolved families with XLID. We employed massively parallel sequencing of all X-chromosome exons in the index males. The majority of these males were previously tested negative for copy number variations and for mutations in a subset of known XLID genes by Sanger sequencing. In total, 745 X-chromosomal genes were screened. After stringent filtering, a total of 1297 non-recurrent exonic variants remained for prioritization. Co-segregation analysis of potential clinically relevant changes revealed that 80 families (20%) carried pathogenic variants in established XLID genes. In 19 families, we detected likely causative protein truncating and missense variants in 7 novel and validated XLID genes (CLCN4, CNKSR2, FRMPD4, KLHL15, LAS1L, RLIM and USP27X) and potentially deleterious variants in 2 novel candidate XLID genes (CDK16 and TAF1). We show that the CLCN4 and CNKSR2 variants impair protein functions as indicated by electrophysiological studies and altered differentiation of cultured primary neurons from Clcn4−/− mice or after mRNA knock-down. The newly identified and candidate XLID proteins belong to pathways and networks with established roles in cognitive function and intellectual disability in particular. We suggest that systematic sequencing of all X-chromosomal genes in a cohort of patients with genetic evidence for X-chromosome locus involvement may resolve up to 58% of Fragile X-negative cases

Sol-gel Syntheses of Photocatalysts for the Removal of Pharmaceutical Products in Water

A screening study on seven photocatalysts was performed to identify the best candidate for pharmaceutical products degradation in water. Photocatalysts were deposited as thin films through a sol-gel process and subsequent dip-coating on glass slides. The efficiency of each photocatalyst was assessed through the degradation of methylene blue first, and then, through the degradation of 15 different pharmaceutical products. Two main types of synthesis methods were considered: aqueous syntheses, where the reaction takes place in water, and organic syntheses, where reactions take place in an organic solvent and only a stoichiometric amount of water is added to the reaction medium. Photocatalysts synthesized via aqueous sol-gel routes showed relatively lower degradation efficiencies; however, the organic route required a calcination step at high temperature to form the photoactive crystalline phase, while the aqueous route did not. The best performances for the degradation of pharmaceuticals arose when Evonik P25 and silver nanoparticles were added to TiO₂, which was synthesized using an organic solvent. In the case of methylene blue degradation, TiO₂ modified with Evonik P25 and TiO₂ doped with MnO₂ nanoparticles were the two best candidates.status: publishe

Clot-based radiomics features predict first pass effect in acute ischemic stroke

Purpos

Nanocomposites of Titanium Dioxide and Peripherally Substituted Phthalocyanines for the Photocatalytic Degradation of Sulfamethoxazole.

peer reviewedPhthalocyanines (Pcs) are often used in photosensitization of titanium(IV) oxide, a commonly employed photocatalyst, as such an approach holds the promise of obtaining highly stable and efficient visible light-harvesting materials. Herein, we report on the preparation, characterization and photoactivity of a series of composites based on TiO2 and peripherally modified metallophthalocyanines: either tetrasulfonated or 4,4′,4′′,4′′′-tetraazaphthalocyanines, with either copper(II), nickel(II) or zinc(II) as the central metal ion. Physicochemical characterization was performed using UV-Vis diffuse reflectance spectroscopy, hydrodynamic particle-size analysis, surface-area analysis using N2 adsorption-desorption measurements and thermogravimetry combined with differential scanning calorimetry. The band-gap energy values were lower for the composites with peripherally modified phthalocyanines than for the commercial TiO2 P25 or the unsubstituted zinc(II) phthalocyanine-grafted TiO2. TG–DSC results confirmed that the chemical deposition, used for the preparation of Pc/TiO2 composites, is a simple and efficient method for TiO2 surface modification, as all the Pc load was successfully grafted on TiO2. The photocatalytic potential of the Pc/TiO2 materials was assessed in the photocatalytic removal of sulfamethoxazole—a commonly used antibacterial drug of emerging ecological concern. To compare the activity of the materials in different conditions, photodegradation tests were conducted both in water and in an organic medium

Influencing public health policy with data-informed mathematical models of infectious diseases: Recent developments and new challenges

Modern data and computational resources, coupled with algorithmic and theoretical advances to exploit these, allow disease dynamic models to be parameterised with increasing detail and accuracy. While this enhances models' usefulness in prediction and policy, major challenges remain. In particular, lack of identifiability of a model's parameters may limit the usefulness of the model. While lack of parameter identifiability may be resolved through incorporation into an inference procedure of prior knowledge, formulating such knowledge is often difficult. Furthermore, there are practical challenges associated with acquiring data of sufficient quantity and quality. Here, we discuss recent progress on these issues