Novel homozygous RARS2 mutation in two siblings without pontocerebellar hypoplasia - further expansion of the phenotypic spectrum.

BACKGROUND: Pontocerebellar hypoplasia type 6 (PCH6) is a mitochondrial disease caused by mutations in the RARS2 gene. RARS2 encodes mitochondrial arginyl transfer RNA synthetase, an enzyme involved in mitochondrial protein translation. A total of 27 patients from 14 families have been reported so far. Characteristic clinical features comprise neonatal lactic acidosis, severe encephalopathy, intractable seizures, feeding problems and profound developmental delay. Most patients show typical neuroradiologic abnormalities including cerebellar hypoplasia and progressive pontocerebellar atrophy. METHODS: We describe the clinical, biochemical and molecular features of 2 siblings with a novel homozygous mutation in RARS2. Both patients presented neonatally with lactic acidosis. While the older sibling had severe neurological symptoms with microcephaly, seizures and developmental delay, the younger patient was still neurologically asymptomatic at the age of 2 months. RESULTS: MRI studies in both children lacked pontocerebellar involvement. The expression of the OXPHOS complex proteins was decreased in both patients, whereas oxygen consumption was increased. CONCLUSIONS: Characteristic neuroradiological abnormalities of PCH6 such as vermis and cerebellar hypoplasia and progressive pontocerebellar atrophy may be missing in patients with RARS2 mutations. RARS2 testing should therefore also be performed in patients without pontocerebellar hypoplasia but otherwise typical clinical symptoms

Handlungsmöglichkeiten für Kommunikation und Beteiligung beim Stromnetzausbau. Ein Praxishandbuch für Abgeordnete. Abschlussbericht zum TA-Projekt »Interessenausgleich bei Infrastrukturprojekten: Handlungsoptionen für die Kommunikation und Organisation vor Ort«

Aktuell sind in Deutschland ein weitreichender Umbau und eine Erweiterung des Stromnetzes im Gang. Hierbei treten immer wieder Konflikte vor Ort auf. Bürger lehnen neue Leitungen ab, gründen Bürgerinitiativen, organisieren Protest. Die Diskussionen werden sehr engagiert und emotional geführt. Bundestagsabgeordnete nehmen als Vermittler zwischen bundespolitischen Entscheidungen und den lokalen Ansprüchen eine Schlüsselrolle ein. Einerseits erwarten die Bürger von ihnen eine klare Positionierung und eine aktive Rolle als Sachwalter ihrer Interessen. Auf der anderen Seite gehen die Betreiber der Übertragungsnetze davon aus, dass die Politik die gefassten Beschlüsse rechtfertigt und dafür einsteht, dass sie möglichst reibungslos umgesetzt werden können. Das vorliegende TAB-Hintergrundpapier stellt wissenschaftliche Erkenntnisse und Praxiserfahrungen zu Kommunikation und Beteiligung beim Netzausbau zusammenfassend dar und gibt daraus folgernd Hinweise auf Handlungsmöglichkeiten für Kommunikationsstrategien und Beteiligungsverfahren. Mitglieder des Deutschen Bundestages, in deren Wahlkreisen Netzausbauvorhaben geplant sind, sollen auf diese Weise beim Umgang mit den daraus entstehenden Interessenkollisionen und Konflikten vor Ort unterstützt werden. INHALT ZUSAMMENFASSUNG 7 I. EINLEITUNG 9 II. KOMMUNIKATION UND BETEILIGUNG BEIM INFRASTRUKTURAUSBAU VOR ORT 11 1. Kommunikation und Beteiligung – was ist das und was können sie leisten? 11 2. Die Rolle der Mitglieder des Bundestages 13 3. Bürgerfragen zum Netzausbau 15 4. Erkenntnisse zu Information und Beteiligung aus der Forschung 17 4.1 Bürgerbeteiligung und Demokratie – Konzepte und Definitionen 18 4.2 Erkenntnisse aus der Partizipationsforschung 23 4.3 Ausgewählte Methoden der Beteiligung 28 5. Erkenntnisse aus Praxisbeispielen 31 5.1 Dialog zur Westküstenleitung in Schleswig-Holstein 31 5.2 Dialog zur Leitung Dörpen/West–Niederrhein in Niedersachsen 36 5.3 Dialoge im Rahmen des BESTGRID-Projekts 39 5.4 Mediationsverfahren Umspannwerk Hagen-Garenfeld 41 5.5 Tunneldialog Schwäbisch Gmünd 42 5.6 Dialog zur Bahnstrecke Hanau–Fulda 43 5.7 Aktuelle MdB-Veranstaltungen zum Netzausbau 43 6. Fazit aus den Praxiserfahrungen mit Kommunikation und Beteiligung 51 III. HANDLUNGSMÖGLICHKEITEN FÜR MDB FÜR EINE ERFOLGREICHE KOMMUNIKATION UND BÜRGERBETEILIGUNG 55 1. Ziele und Zielgruppe 55 2. Der richtige Zeitpunkt 55 3. Vertrauen als wichtigster »weicher Faktor« 56 4. Eigene Veranstaltungen – welches Format ist geeignet? 57 5. Praktische Komponenten einer erfolgreichen Veranstaltung 60 IV. HINTERGRUNDWISSEN ZUM NETZAUSBAU 67 1. Rechtlicher Rahmen – das Planungsverfahren 67 2. Akteure und ihre Rollen 72 3. Hintergründe zu den häufigsten Fragen der Bürger 74 3.1 Gesundheitsschutz 74 3.2 Wohnumfeldschutz – Abstandsregelungen 75 3.3 Wertverlust von Grundstücken 76 3.4 Landschafts-/Ortsbild – Möglichkeiten der Verkabelung 77 3.5 Einschränkung der Bewirtschaftung 78 3.6 Bündelung/Überbündelung 78 3.7 Mitnahme/Rückbau 79 3.8 Vogelschutz 79 4. Kleiner Exkurs zur Technik des Netzausbaus 80 LITERATUR 82 1. In Auftrag gegebene Gutachten 82 2. Weitere Literatur 82 ANHANG 86 1. Tabellenverzeichnis 86 2. Abbildungsverzeichnis 8

A Search for Variations of Fundamental Constants using Atomic Fountain Clocks

Over five years we have compared the hyperfine frequencies of 133Cs and 87Rb atoms in their electronic ground state using several laser cooled 133Cs and 87Rb atomic fountains with an accuracy of ~10^{-15}. These measurements set a stringent upper bound to a possible fractional time variation of the ratio between the two frequencies : (d/dt)ln(nu_Rb/nu_Cs)=(0.2 +/- 7.0)*10^{-16} yr^{-1} (1 sigma uncertainty). The same limit applies to a possible variation of the quantity (mu_Rb/mu_Cs)*alpha^{-0.44}, which involves the ratio of nuclear magnetic moments and the fine structure constant.Comment: 4 pages, 3 figures, 1 table submitted to Phys. Rev. Let

Cytoplasmic PML promotes TGF-β-associated epithelial–mesenchymal transition and invasion in prostate cancer

Epithelial–mesenchymal transition (EMT) is a key event that is involved in the invasion and dissemination of cancer cells. Although typically considered as having tumour-suppressive properties, transforming growth factor (TGF)-β signalling is altered during cancer and has been associated with the invasion of cancer cells and metastasis. In this study, we report a previously unknown role for the cytoplasmic promyelocytic leukaemia (cPML) tumour suppressor in TGF-β signalling-induced regulation of prostate cancer-associated EMT and invasion. We demonstrate that cPML promotes a mesenchymal phenotype and increases the invasiveness of prostate cancer cells. This event is associated with activation of TGF-β canonical signalling pathway through the induction of Sma and Mad related family 2 and 3 (SMAD2 and SMAD3) phosphorylation. Furthermore, the cytoplasmic localization of promyelocytic leukaemia (PML) is mediated by its nuclear export in a chromosomal maintenance 1 (CRM1)-dependent manner. This was clinically tested in prostate cancer tissue and shown that cytoplasmic PML and CRM1 co-expression correlates with reduced disease-specific survival. In summary, we provide evidence of dysfunctional TGF-β signalling occurring at an early stage in prostate cancer. We show that this disease pathway is mediated by cPML and CRM1 and results in a more aggressive cancer cell phenotype. We propose that the targeting of this pathway could be therapeutically exploited for clinical benefit

Cold atom Clocks and Applications

This paper describes advances in microwave frequency standards using laser-cooled atoms at BNM-SYRTE. First, recent improvements of the $^{133}$Cs and $^{87}$Rb atomic fountains are described. Thanks to the routine use of a cryogenic sapphire oscillator as an ultra-stable local frequency reference, a fountain frequency instability of $1.6\times 10^{-14}\tau^{-1/2}$ where $\tau$ is the measurement time in seconds is measured. The second advance is a powerful method to control the frequency shift due to cold collisions. These two advances lead to a frequency stability of $2\times 10^{-16}$ at $50,000s for the first time for primary standards. In addition, these clocks realize the SI second with an accuracy of$7\times 10^{-16}$, one order of magnitude below that of uncooled devices. In a second part, we describe tests of possible variations of fundamental constants using$^{87}$Rb and$^{133}$Cs fountains. Finally we give an update on the cold atom space clock PHARAO developed in collaboration with CNES. This clock is one of the main instruments of the ACES/ESA mission which is scheduled to fly on board the International Space Station in 2008, enabling a new generation of relativity tests.Comment: 30 pages, 11 figure

Requirement of Podocalyxin in TGF-Beta Induced Epithelial Mesenchymal Transition

Epithelial mesenchymal transition (EMT) is characterized by the development of mesenchymal properties such as a fibroblast-like morphology with altered cytoskeletal organization and enhanced migratory potential. We report that the expression of podocalyxin (PODXL), a member of the CD34 family, is markedly increased during TGF-β induced EMT. PODXL is enriched on the leading edges of migrating A549 cells. Silencing of podocalyxin expression reduced cell ruffle formation, spreading, migration and affected the expression patterns of several proteins that normally change during EMT (e.g., vimentin, E-cadherin). Cytoskeletion assembly in EMT was also found to be dependent on the production of podocalyin. Compositional analysis of podocalyxin containing immunoprecipitates revealed that collagen type 1 was consistently associated with these isolates. Collagen type 1 was also found to co-localize with podocalyxin on the leading edges of migrating cells. The interactions with collagen may be a critical aspect of podocalyxin function. Podocalyxin is an important regulator of the EMT like process as it regulates the loss of epithelial features and the acquisition of a motile phenotype

Nanofocusing of hard X-ray free electron laser pulses using diamond based Fresnel zone plates

Peer reviewe

Consensus recommendations for the diagnosis, treatment and follow-up of inherited methylation disorders

Inherited methylation disorders are a group of rarely reported, probably largely underdiagnosed disorders affecting transmethylation processes in the metabolic pathway between methionine and homocysteine. These are methionine adenosyltransferase I/III, glycine N-methyltransferase, S-adenosylhomocysteine hydrolase and adenosine kinase deficiencies. This paper provides the first consensus recommendations for the diagnosis and management of methylation disorders. Following search of the literature and evaluation according to the SIGN-methodology of all reported patients with methylation defects, graded recommendations are provided in a structured way comprising diagnosis (clinical presentation, biochemical abnormalities, differential diagnosis, newborn screening, prenatal diagnosis), therapy and follow-up. Methylation disorders predominantly affect the liver, central nervous system and muscles, but clinical presentation can vary considerably between and within disorders. Although isolated hypermethioninemia is the biochemical hallmark of this group of disorders, it is not always present, especially in early infancy. Plasma S-adenosylmethionine and S-adenosylhomocysteine are key metabolites for the biochemical clarification of isolated hypermethioninemia. Mild hyperhomocysteinemia can be present in all methylation disorders. Methylation disorders do not qualify as primary targets of newborn screening. A low-methionine diet can be beneficial in patients with methionine adenosyltransferase I/III deficiency if plasma methionine concentrations exceed 800 μmol/L. There is some evidence that this diet may also be beneficial in patients with S-adenosylhomocysteine hydrolase and adenosine kinase deficiencies. S-adenosylmethionine supplementation may be useful in patients with methionine adenosyltransferase I/III deficiency. Recommendations given in this article are based on general principles and in practice should be adjusted individually according to patient's age, severity of the disease, clinical and laboratory findings

Characterization and Whole Genome Analysis of Human Papillomavirus Type 16 E1-1374^63nt Variants

Background. The variation of the most common Human papillomavirus (HPV) type found in cervical cancer, the HPV16, has been extensively investigated in almost all viral genes. The E1 gene variation, however, has been rarely studied. The main objective of the present investigation was to analyze the variability of the E6 and E1 genes, focusing on the recently identified E1-1374^63nt variant. Methodology/Principal Findings. Variation within the E6 of 786 HPV16 positive cervical samples was analyzed using high-resolution melting, while the E1-1374^63nt duplication was assayed by PCR. Both techniques were supplemented with sequencing. The E1-1374^63nt duplication was linked with the E-G350 and the E-C109/G350 variants. In comparison to the referent HPV16, the E1-1374^63nt E-G350 variant was significantly associated with lower grade cervical lesions (p=0.029), while the E1-1374^63nt E-C109/G350 variant was equally distributed between high and low grade lesions. The E1-1374^63nt variants were phylogenetically closest to E-G350 variant lineage (A2 sub-lineage based on full genome classification). The major differences between E1-1374^63nt variants were within the LCR and the E6 region. On the other hand, changes within the E1 region were the major differences from the A2 sub-lineage, which has been historically but inconclusively associated with high grade cervical disease. Thus, the shared variations cannot explain the particular association of the E1-1374^63nt variant with lower grade cervical lesions. Conclusions/Significance. The E1 region has been thus far considered to be well conserved among all HPVs and therefore uninteresting for variability studies. However, this study shows that the variations within the E1 region could possibly affect cervical disease, since the E1-1374^63nt E-G350 variant is significantly associated with lower grade cervical lesions, in comparison to the A1 and A2 sub-lineage variants. Furthermore, it appears that the silent variation 109T>C of the E-C109/G350 variant might have a significant role in the viral life cycle and warrants further study