Integrated life cycle assessment and thermodynamic simulation of a public building's envelope renovation : Conventional vs. Passivhaus proposal

Unidad de excelencia María de Maeztu MdM-2015-0552The need to improve the energy efficiency of buildings has introduced the concept of nearly zero-energy buildings into European energy policies. Moreover, a percentage of the building stock will have to be renovated annually to attain high energy performance. Conventional passive interventions in buildings are focused on increasing the insulation of the building envelope to increase its energy efficiency during the operating phase. Often, however, intervention practices imply the incorporation of embodied energy into the building materials and increase the associated environmental impacts.This paper presents and evaluates a comparison of two different proposals for a real-world building renovation. The first proposal was a conventional project for energy renovation, while the second was a low-energy building proposal (following the Passivhaus standard). This study analysed the proposals using an integrated life cycle and thermal dynamic simulation assessment to identify the adequacy of each renovation alternative regarding the post-renovation energy performance of the building, including an evaluation of the introduction of a renewable insulation material into the low-energy building proposal, specifically a specific cork solution. The most significant conclusion was the convenience of the renovation, achieving energy savings of 60% and 80% for the conventional and Passivhaus renovations (ENERPHIT), respectively. The former supposed less embodied energy and environmental impacts but also generated less energy savings. The latter increased the embodied impacts in the building, mainly for the large amount of insulation material. The environmental implications of both proposals can be compensated for within a reasonable period of time, over 2 years in the majority of alternatives and impact categories. However, the ENERPHIT project was 30% better than the conventional proposal when the total lifespan of the building was considered. The introduction of cork did not fit the requirements for competing with the common non-renewable insulation materials because it did not imply better environmental performance in buildings, but cork insulation solutions currently present ample room for improvement

NSD1 mutations generate a genome-wide DNA methylation signature

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A revised nomenclature for the lemur family of protein kinases

The lemur family of protein kinases has gained much interest in recent years as they are involved in a variety of cellular processes including regulation of axonal transport and endosomal trafficking, modulation of synaptic functions, memory and learning, and they are centrally placed in several intracellular signalling pathways. Numerous studies have also implicated role of the lemur kinases in the development and progression of a wide range of cancers, cystic fibrosis, and neurodegenerative diseases. However, parallel discoveries and inaccurate prediction of their kinase activity have resulted in a confusing and misleading nomenclature of these proteins. Herein, a group of international scientists with expertise in lemur family of protein kinases set forth a novel nomenclature to rectify this problem and ultimately help the scientific community by providing consistent information about these molecules

The phenotype of Floating-Harbor syndrome: Clinical characterization of 52 individuals with mutations in exon 34 of SRCAP

Background: Floating-Harbor syndrome (FHS) is a rare condition characterized by short stature, delays in expressive language, and a distinctive facial appearance. Recently, heterozygous truncating mutations in SRCAP were determined to be disease-causing. With the availability of a DNA based confirmatory test, we set forth to define the clinical features of this syndrome. Methods and results. Clinical information on fifty-two individuals with SRCAP mutations was collected using standardized questionnaires. Twenty-four males and twenty-eight females were studied with ages ranging from

A founder MLH1 mutation in families from the districts of Modena and Reggio-Emilia in northern Italy with hereditary non-polyposis colorectal cancer associated with protein elongation and instability.

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EHMT1 pathogenic variants and 9q34.3 microdeletions share altered DNA methylation patterns in patients with Kleefstra syndrome

Aim: Kleefstra syndrome (KS) is a rare neurodevelopmental disorder caused by haploinsufficiency of the euchromatic histone lysine methyltransferase 1 gene, EHMT1, due to either a submicroscopic 9q34.3 deletion or a pathogenic EHMT1 variant. KS is characterized by intellectual disability, autistic-like features, heart defects, hypotonia and distinctive facial features. Here, we aimed to (1) identify a unique DNA methylation signature in patients with KS, and (2) demonstrate the efficacy of DNA methylation in predicting the pathogenicity of copy number and sequence variants. Methods: We assayed genome-wide DNA methylation at > 850,000 CpG sites in the blood of KS patients (n = 10) carrying pathogenic variants in EHMT1 or 9q34.3 deletions, as compared to neurotypical controls (n = 42). Differentially methylated sites were validated using additional KS patients (n = 10) and controls (n = 29) to assess specificity and sensitivity of these patterns. Results: The DNA methylation signature of KS demonstrated high sensitivity and specificity; controls and KS patients with a confirmed molecular diagnosis were classified correctly. In additional individuals with EHMT1 alterations, including frameshift or missense variants and partial gene duplications, DNA methylation classifications were consistent with clinical presentation. Furthermore, genes containing differentially methylated CpG sites were enriched for functions related to KS features, including heart formation and synaptic activity. Conclusion: The KS DNA methylation signature did not differ in patients with deletions and variants, supporting haploinsufficiency of EHMT1 as the likely causative mechanism. Beyond this finding, it provides new insights into epigenetic dysregulation associated with KS and can be used to classify individuals with uncertain genomic findings or ambiguous clinical presentations.published_or_final_versio

Mutations in the latent TGF-beta binding protein 3 (LTBP3) gene cause brachyolmia with amelogenesis imperfecta

Inherited dental malformations constitute a clinically and genetically heterogeneous group of disorders. Here, we report on four families, three of them consanguineous, with an identical phenotype, characterized by significant short stature with brachyolmia and hypoplastic amelogenesis imperfecta (AI) with almost absent enamel. This phenotype was first described in 1996 by Verloes et al. as an autosomal recessive form of brachyolmia associated with AI. Whole-exome sequencing resulted in the identification of recessive hypomorphic mutations including deletion, nonsense and splice mutations, in the LTBP3 gene, which is involved in the TGF-beta signaling pathway. We further investigated gene expression during mouse development and tooth formation. Differentiated ameloblasts synthesizing enamel matrix proteins and odontoblasts expressed the gene. Study of an available knockout mouse model showed that the mutant mice displayed very thin to absent enamel in both incisors and molars, hereby recapitulating the AI phenotype in the human disorder

DNA Methylation Signature for EZH2 Functionally Classifies Sequence Variants in Three PRC2 Complex Genes.

Weaver syndrome (WS), an overgrowth/intellectual disability syndrome (OGID), is caused by pathogenic variants in the histone methyltransferase EZH2, which encodes a core component of the Polycomb repressive complex-2 (PRC2). Using genome-wide DNA methylation (DNAm) data for 187 individuals with OGID and 969 control subjects, we show that pathogenic variants in EZH2 generate a highly specific and sensitive DNAm signature reflecting the phenotype of WS. This signature can be used to distinguish loss-of-function from gain-of-function missense variants and to detect somatic mosaicism. We also show that the signature can accurately classify sequence variants in EED and SUZ12, which encode two other core components of PRC2, and predict the presence of pathogenic variants in undiagnosed individuals with OGID. The discovery of a functionally relevant signature with utility for diagnostic classification of sequence variants in EZH2, EED, and SUZ12 supports the emerging paradigm shift for implementation of DNAm signatures into diagnostics and translational research

hMSH2 is the most commonly mutated MMR gene in a cohort of Greek HNPCC patients

Germline mutations in genes encoding proteins involved in DNA mismatch repair are responsible for the autosomal dominantly inherited cancer predisposition syndrome hereditary nonpolyposis colorectal cancer (HNPCC). We describe here analysis of hMLH1 and hMSH2 in nine Greek families referred to our centre for HNPCC. A unique disease-causing mutation has been identified in seven out of nine (78%) families. The types of mutations identified are nonsense (five out of seven) (hMLH1: E557X, R226X; hMSH2: Q158X, R359X and R711X), a 2 bp deletion (hMSH2 1704_1705delAG) and a 2.2 kb Alu-mediated deletion encompassing exon 3 of the hMSH2 gene. The majority of mutations identified in this cohort are found in hMSH2 (77.7%). Furthermore, four of the mutations identified are novel. Finally, a number of novel benign variations were observed in both genes. This is the first report of HNPCC analysis in the Greek population, further underscoring the differences observed in the various geographic populations