Dysregulation of Endothelial Nitric Oxide Synthase Does Not Depend on Hemodynamic Alterations in Bicuspid Aortic Valve Aortopathy

Background Bicuspid aortic valves (BAVs) predispose to ascending aortic aneurysm. Turbulent blood flow and genetic factors have been proposed as underlying mechanisms. Endothelial nitric oxide synthase (eNOS) has been implicated in BAV aortopathy, and its expression is regulated by wall shear stress. We hypothesized that if turbulent flow induces aneurysm formation in patients with a BAV, regional differences in eNOS expression would be observed in BAVs. Methods and Results Ascending aortic specimens were harvested intraoperatively from 48 patients with tricuspid aortic valve (19 dilated, 29 nondilated) and 38 with BAV (28 dilated, 10 nondilated) undergoing cardiac surgery. eNOS mRNA and protein concentration were analyzed at the convex and concave aortic wall. In nondilated aortas, eNOS mRNA and protein concentration were decreased in BAV compared with tricuspid aortic valve (all P0.05). However, eNOS expression was increased at the concave wall (versus convexity) in tricuspid aortic valve dilated aortas (all P<0.05). Conclusions Dysregulated eNOS occurs independent of dilation in BAV aortas, suggesting a potential role for aberrantly regulated eNOS expression in the development of BAV-associated aneurysms. The absence of regional variations of eNOS expression suggests that eNOS dysregulation in BAV aortas is the result of underlying genetic factors associated with BAV disease, rather than changes stimulated by hemodynamic alterations. These findings provide insight into the underlying mechanisms of aortic dilation in patients with a BAV

Large-scale physical mapping within the region 22q12.3-13.1 in meningioma

The lack of physical mapping data strongly restricts the analysis of the meningioma chromosomal region that was assigned to the bands 22q12.3-qter. Recently, we reported a new marker D22S16 for chromosome 22 that was assigned to the region 22q13-qter by in situ hybridization. Utilizing somatic cell hybrids we now sublocalized the marker D22S16 within the band region 22q12-13.1, thus placing it in the vicinity of the gene for the platelet derived growth factor (PDGFB). A physical map was established for the regions surrounding the PDGFB gene and the D22S16 marker. By means of pulsed-field gel electrophoresis (PFGE) D22S16 and PDGFB were found to be physically linked within 900 kb. We also identified two CpG clusters bordering the PDGFB gene. For the enzyme NotI, a variation of the PDGFB restriction pattern was found between different individuals. PFGE analysis of the two loci (PDFGB and D22S16) failed to identify major rearrangements in meningioma.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29218/1/0000273.pd

Das Verbot der pränatalen Diagnostik spätmanifestierender Erkrankungen im deutschen Gendiagnostikgesetz - eine Diskussion medizinischer und rechtlicher Aspekte und deren Implikation für die medizinethische Diskussion

Zusammenfassung: Am 1. Februar 2010 ist das Gendiagnostikgesetz (GenDG) in Kraft getreten. Die Debatte um einige Regelungsbereiche, wie beispielsweise das Neugeborenenscreening, reißt nicht ab. Ein Aspekt des Gesetzes ist im Rahmen der Debatte um die Präimplantationsdiagnostik (PID) in Deutschland unter neuen Vorzeichen zu diskutieren: Das - international bislang einzigartige - Verbot der pränatalen Diagnostik so genannter spätmanifestierender Erkrankungen, die erst nach der Vollendung des 18. Lebensjahres ausbrechen. In diesem Beitrag möchten wir Hinweise zur differenzierten Diskussion dieser in §15(2) GenDG bestimmten Verbotsnorm liefern. Obgleich Argumente, insbesondere das Recht auf Nichtwissen des geborenen Kindes, für ein solches Verbot sprechen, kommen wir aufgrund der medizinischen Sachlage und nach einer Analyse der Pro- und Kontraargumente aus ethischer und rechtlicher Sicht zu dem Schluss, dass ein generelles Verbot der pränatalen Diagnostik spätmanifestierender Erkrankungen im Sinne der Zielsetzung womöglich insuffizient ist sowie in der Begründung Inkonsistenzen zum bereits bestehenden Regelwerk aufweist, und lenken daher den Blick auf unter Umständen bessere Alternativen

Comparative Structural Analysis of Human DEAD-Box RNA Helicases

DEAD-box RNA helicases play various, often critical, roles in all processes where RNAs are involved. Members of this family of proteins are linked to human disease, including cancer and viral infections. DEAD-box proteins contain two conserved domains that both contribute to RNA and ATP binding. Despite recent advances the molecular details of how these enzymes convert chemical energy into RNA remodeling is unknown. We present crystal structures of the isolated DEAD-domains of human DDX2A/eIF4A1, DDX2B/eIF4A2, DDX5, DDX10/DBP4, DDX18/myc-regulated DEAD-box protein, DDX20, DDX47, DDX52/ROK1, and DDX53/CAGE, and of the helicase domains of DDX25 and DDX41. Together with prior knowledge this enables a family-wide comparative structural analysis. We propose a general mechanism for opening of the RNA binding site. This analysis also provides insights into the diversity of DExD/H- proteins, with implications for understanding the functions of individual family members

Molecular and Clinical Analyses of Greig Cephalopolysyndactyly and Pallister-Hall Syndromes: Robust Phenotype Prediction from the Type and Position of GLI3 Mutations

Mutations in the GLI3 zinc-finger transcription factor gene cause Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS), which are variable but distinct clinical entities. We hypothesized that GLI3 mutations that predict a truncated functional repressor protein cause PHS and that functional haploinsufficiency of GLI3 causes GCPS. To test these hypotheses, we screened patients with PHS and GCPS for GLI3 mutations. The patient group consisted of 135 individuals: 89 patients with GCPS and 46 patients with PHS. We detected 47 pathological mutations (among 60 probands); when these were combined with previously published mutations, two genotype-phenotype correlations were evident. First, GCPS was caused by many types of alterations, including translocations, large deletions, exonic deletions and duplications, small in-frame deletions, and missense, frameshift/nonsense, and splicing mutations. In contrast, PHS was caused only by frameshift/nonsense and splicing mutations. Second, among the frameshift/nonsense mutations, there was a clear genotype-phenotype correlation. Mutations in the first third of the gene (from open reading frame [ORF] nucleotides [nt] 1–1997) caused GCPS, and mutations in the second third of the gene (from ORF nt 1998–3481) caused primarily PHS. Surprisingly, there were 12 mutations in patients with GCPS in the 3′ third of the gene (after ORF nt 3481), and no patients with PHS had mutations in this region. These results demonstrate a robust correlation of genotype and phenotype for GLI3 mutations and strongly support the hypothesis that these two allelic disorders have distinct modes of pathogenesis

The recovery of European freshwater biodiversity has come to a halt

Owing to a long history of anthropogenic pressures, freshwater ecosystems are among the most vulnerable to biodiversity loss1. Mitigation measures, including wastewater treatment and hydromorphological restoration, have aimed to improve environmental quality and foster the recovery of freshwater biodiversity2. Here, using 1,816 time series of freshwater invertebrate communities collected across 22 European countries between 1968 and 2020, we quantified temporal trends in taxonomic and functional diversity and their responses to environmental pressures and gradients. We observed overall increases in taxon richness (0.73% per year), functional richness (2.4% per year) and abundance (1.17% per year). However, these increases primarily occurred before the 2010s, and have since plateaued. Freshwater communities downstream of dams, urban areas and cropland were less likely to experience recovery. Communities at sites with faster rates of warming had fewer gains in taxon richness, functional richness and abundance. Although biodiversity gains in the 1990s and 2000s probably reflect the effectiveness of water-quality improvements and restoration projects, the decelerating trajectory in the 2010s suggests that the current measures offer diminishing returns. Given new and persistent pressures on freshwater ecosystems, including emerging pollutants, climate change and the spread of invasive species, we call for additional mitigation to revive the recovery of freshwater biodiversity.N. Kaffenberger helped with initial data compilation. Funding for authors and data collection and processing was provided by the EU Horizon 2020 project eLTER PLUS (grant agreement no. 871128); the German Federal Ministry of Education and Research (BMBF; 033W034A); the German Research Foundation (DFG FZT 118, 202548816); Czech Republic project no. P505-20-17305S; the Leibniz Competition (J45/2018, P74/2018); the Spanish Ministerio de Economía, Industria y Competitividad—Agencia Estatal de Investigación and the European Regional Development Fund (MECODISPER project CTM 2017-89295-P); Ramón y Cajal contracts and the project funded by the Spanish Ministry of Science and Innovation (RYC2019-027446-I, RYC2020-029829-I, PID2020-115830GB-100); the Danish Environment Agency; the Norwegian Environment Agency; SOMINCOR—Lundin mining & FCT—Fundação para a Ciência e Tecnologia, Portugal; the Swedish University of Agricultural Sciences; the Swiss National Science Foundation (grant PP00P3_179089); the EU LIFE programme (DIVAQUA project, LIFE18 NAT/ES/000121); the UK Natural Environment Research Council (GLiTRS project NE/V006886/1 and NE/R016429/1 as part of the UK-SCAPE programme); the Autonomous Province of Bolzano (Italy); and the Estonian Research Council (grant no. PRG1266), Estonian National Program ‘Humanitarian and natural science collections’. The Environment Agency of England, the Scottish Environmental Protection Agency and Natural Resources Wales provided publicly available data. We acknowledge the members of the Flanders Environment Agency for providing data. This article is a contribution of the Alliance for Freshwater Life (www.allianceforfreshwaterlife.org).Peer reviewe