Refinement of a 400-kb Critical Region Allows Genotypic Differentiation between Isolated Lissencephaly, Miller-Dieker Syndrome, and Other Phenotypes Secondary to Deletions of 17p13.3

Deletions of 17p13.3, including the LIS1 gene, result in the brain malformation lissencephaly, which is characterized by reduced gyration and cortical thickening; however, the phenotype can vary from isolated lissencephaly sequence (ILS) to Miller-Dieker syndrome (MDS). At the clinical level, these two phenotypes can be differentiated by the presence of significant dysmorphic facial features and a more severe grade of lissencephaly in MDS. Previous work has suggested that children with MDS have a larger deletion than those with ILS, but the precise boundaries of the MDS critical region and causative genes other than LIS1 have never been fully determined. We have completed a physical and transcriptional map of the 17p13.3 region from LIS1 to the telomere. Using fluorescence in situ hybridization, we have mapped the deletion size in 19 children with ILS, 11 children with MDS, and 4 children with 17p13.3 deletions not involving LIS1. We show that the critical region that differentiates ILS from MDS at the molecular level can be reduced to 400 kb. Using somatic cell hybrids from selected patients, we have identified eight genes that are consistently deleted in patients classified as having MDS. In addition, deletion of the genes CRK and 14-3-3ɛ delineates patients with the most severe lissencephaly grade. On the basis of recent functional data and the creation of a mouse model suggesting a role for 14-3-3ɛ in cortical development, we suggest that deletion of one or both of these genes in combination with deletion of LIS1 may contribute to the more severe form of lissencephaly seen only in patients with MDS

Modified bibenzimidazole ligands as spectator ligands in photoactive molecular functional Ru-polypyridine units? Implications from spectroscopy

The photophysical properties of Ruthenium-bipyridine complexes bearing a bibenzimidazole ligand were investigated. The nitrogens on the bibenzimidazole-ligand were protected, by adding either a phenylene group or a 1,2-ethandiyl group, to remove the photophysical dependence of the complex on the protonation state of the bibenzimidazole ligand. This protection results in the bibenzimidazole ligand contributing to the MLCT transition, which is experimentally evidenced by (resonance) Raman scattering in concert with DFT calculations for a detailed mode assignment in the (resonance) Raman spectra

Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability

Overgrowth disorders are a heterogeneous group of conditions characterized by increased growth parameters and other variable clinical features such as intellectual disability and facial dysmorphism. To identify new causes of human overgrowth, we performed exome sequencing in ten proband-parent trios and detected two de novo DNMT3A mutations. We identified 11 additional de novo mutations by sequencing DNMT3A in a further 142 individuals with overgrowth. The mutations alter residues in functional DNMT3A domains, and protein modeling suggests that they interfere with domain-domain interactions and histone binding. Similar mutations were not present in 1,000 UK population controls (13/152 cases versus 0/1,000 controls; P < 0.0001). Mutation carriers had a distinctive facial appearance, intellectual disability and greater height. DNMT3A encodes a DNA methyltransferase essential for establishing methylation during embryogenesis and is commonly somatically mutated in acute myeloid leukemia. Thus, DNMT3A joins an emerging group of epigenetic DNA- and histone-modifying genes associated with both developmental growth disorders and hematological malignancies

Carbene based photochemical molecular assemblies for solar driven hydrogen generation

Novel photocatalysts based on ruthenium complexes with NHC (N-heterocyclic carbene)-type bridging ligands have been prepared and structurally and photophysically characterised. The identity of the NHC-unit of the bridging ligand was established unambiguously by means of X-ray structural analysis of a heterodinuclear ruthenium–silver complex. The photophysical data indicate ultrafast intersystem crossing into an emissive and a non-emissive triplet excited state after excitation of the ruthenium centre. Exceptionally high luminescence quantum yields of up to 39% and long lifetimes of up to 2 μs are some of the triplet excited state characteristics. Preliminary studies into the visible light driven photocatalytic hydrogen formation show no induction phase and constant turnover frequencies that are independent on the concentration of the photocatalyst. In conclusion this supports the notion of a stable assembly under photocatalytic conditions

International consensus recommendations on the diagnostic work-up for malformations of cortical development

Malformations of cortical development (MCDs) are neurodevelopmental disorders that result from abnormal development of the cerebral cortex in utero. MCDs place a substantial burden on affected individuals, their families and societies worldwide, as these individuals can experience lifelong drug-resistant epilepsy, cerebral palsy, feeding difficulties, intellectual disability and other neurological and behavioural anomalies. The diagnostic pathway for MCDs is complex owing to wide variations in presentation and aetiology, thereby hampering timely and adequate management. In this article, the international MCD network Neuro-MIG provides consensus recommendations to aid both expert and non-expert clinicians in the diagnostic work-up of MCDs with the aim of improving patient management worldwide. We reviewed the literature on clinical presentation, aetiology and diagnostic approaches for the main MCD subtypes and collected data on current practices and recommendations from clinicians and diagnostic laboratories within Neuro-MIG. We reached consensus by 42 professionals from 20 countries, using expert discussions and a Delphi consensus process. We present a diagnostic workflow that can be applied to any individual with MCD and a comprehensive list of MCD-related genes with their associated phenotypes. The workflow is designed to maximize the diagnostic yield and increase the number of patients receiving personalized care and counselling on prognosis and recurrence risk

Exploring Barriers and Opportunities in Adopting Crowdsourcing Based New Product Development in Manufacturing SMEs

Crowdsourcing is an innovative business practice of obtaining needed services, ideas, or content or even funds by soliciting contributions from a large group of people (the ‘Crowd’). The potential benefits of utilizing crowdsourcing in product design are well-documented, but little research exists on what are the barriers and opportunities in adopting crowdsourcing in new product development (NPD) of manufacturing SMEs. In order to answer the above questions, a Proof of Market study is carried out on crowdsourcing-based product design under an Innovate UK funded Smart project, which aims at identifying the needs, challenges and future development opportunities associated with adopting crowdsourcing strategies for NPD. The research findings from this study are reported here and can be used to guide future development of crowdsourcing-based collaborative design methods and tools and provide some practical references for industry to adopt this new and emerging collaborative design method in their business

De novo CCND2 mutations leading to stabilization of cyclin D2 cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome

Activating mutations in genes encoding phosphatidylinositol 3-kinase (PI3K)-AKT pathway components cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH, OMIM 603387). Here we report that individuals with MPPH lacking upstream PI3K-AKT pathway mutations carry de novo mutations in CCND2 (encoding cyclin D2) that are clustered around a residue that can be phosphorylated by glycogen synthase kinase 3β (GSK-3β). Mutant CCND2 was resistant to proteasomal degradation in vitro compared to wild-type CCND2. The PI3K-AKT pathway modulates GSK-3β activity, and cells from individuals with PIK3CA, PIK3R2 or AKT3 mutations showed similar CCND2 accumulation. CCND2 was expressed at higher levels in brains of mouse embryos expressing activated AKT3. In utero electroporation of mutant CCND2 into embryonic mouse brains produced more proliferating transfected progenitors and a smaller fraction of progenitors exiting the cell cycle compared to cells electroporated with wild-type CCND2. These observations suggest that cyclin D2 stabilization, caused by CCND2 mutation or PI3K-AKT activation, is a unifying mechanism in PI3K-AKT–related megalencephaly syndromes

EFSA Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids (CEF); Scientific Opinion on Flavouring Group Evaluation 96 (FGE.96): Consideration of 88 flavouring substances considered by EFSA for which EU production volumes / anticipated production volumes have been submitted on request by DG SANCO. Addendum to FGE. 51, 52, 53, 54, 56, 58, 61, 62, 63, 64, 68, 69, 70, 71, 73, 76, 77, 79, 80, 83, 84, 85 and 87

Overgrowth disorders are a heterogeneous group of conditions characterized by increased growth parameters and other variable clinical features such as intellectual disability and facial dysmorphism1. To identify new causes of human overgrowth, we performed exome sequencing in ten proband-parent trios and detected two de novo DNMT3A mutations. We identified 11 additional de novo mutations by sequencing DNMT3A in a further 142 individuals with overgrowth. The mutations alter residues in functional DNMT3A domains, and protein modeling suggests that they interfere with domain-domain interactions and histone binding. Similar mutations were not present in 1,000 UK population controls (13/152 cases versus 0/1,000 controls; P &lt; 0.0001). Mutation carriers had a distinctive facial appearance, intellectual disability and greater height. DNMT3A encodes a DNA methyltransferase essential for establishing methylation during embryogenesis and is commonly somatically mutated in acute myeloid leukemia2, 3, 4. Thus, DNMT3A joins an emerging group of epigenetic DNA- and histone-modifying genes associated with both developmental growth disorders and hematological malignancie