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alpha,beta-Unsaturated d-lactones are accessible via a sequential ring-closing metathesis (RCM) double-bond migration reaction starting from butenoates of allyl alcohols. This approach proceeds efficiently with lower catalyst loadings and higher initial substrate concentrations compared to the alternative RCM of acrylates derived from homoallylic alcohols.
microRNAs (miRNAs) have been identified as high-value drug targets. A widely applied strategy in miRNA inhibition is the use of antisense agents. However, it has been shown that oligonucleotides are poorly cell permeable because of their complex chemical structure and due to their negatively charged backbone. Consequently, the general application of oligonucleotides in therapy is limited. Since miRNAs’ functions are executed exclusively by the Argonaute 2 protein, we therefore describe a protocol for the design of a novel miRNA inhibitor class: antagonists of the miRNA-Argonaute 2 protein complex, so-called anti-miR-AGOs, that not only block the crucial binding site of the target miRNA but also bind to the protein’s active site. Due to their lower molecular weight and, thus, more drug-like chemical structure, the novel inhibitor class may show better pharmacokinetic properties than reported oligonucleotide inhibitors, enabling them for potential therapeutic use.
Starting from the conveniently available ex-chiral pool building block (R,R)-hexa-1,5-diene-3,4-diol, the ten-membered ring lactones stagonolide E and curvulide A were synthesized using a bidirectional olefin-metathesis functionalization of the terminal double bonds. Key steps are (i) a site-selective cross metathesis, (ii) a highly diastereoselective extended tethered RCM to furnish a (Z,E)-configured dienyl carboxylic acid and (iii) a Ru-lipase-catalyzed dynamic kinetic resolution to establish the desired configuration at C9. Ring closure was accomplished by macrolactonization. Curvulide A was synthesized from stagonolide E through Sharpless epoxidation.
To identify genetic variants associated with head circumference in infancy, we performed a meta-analysis of seven genome-wide association studies (GWAS) (N = 10,768 individuals of European ancestry enrolled in pregnancy and/or birth cohorts) and followed up three lead signals in six replication studies (combined N = 19,089). rs7980687 on chromosome 12q24 (P = 8.1 x 10(-9)) and rs1042725 on chromosome 12q15 (P = 2.8 x 10(-10)) were robustly associated with head circumference in infancy. Although these loci have previously been associated with adult height(1), their effects on infant head circumference were largely independent of height (P = 3.8 x 10(-7) for rs7980687 and P = 1.3 x 10(-7) for rs1042725 after adjustment for infant height). A third signal, rs11655470 on chromosome 17q21, showed suggestive evidence of association with head circumference (P = 3.9 x 10(-6)). SNPs correlated to the 17q21 signal have shown genome-wide association with adult intracranial volume(2), Parkinson's disease and other neurodegenerative diseases(3-5), indicating that a common genetic variant in this region might link early brain growth with neurological disease in later life.
During aging, intracranial volume remains unchanged and represents maximally attained brain size, while various interacting biological phenomena lead to brain volume loss. Consequently, intracranial volume and brain volume in late life reflect different genetic influences. Our genome-wide association study (GWAS) in 8,175 community-dwelling elderly persons did not reveal any associations at genome-wide significance (P < 5 x 10(-8)) for brain volume. In contrast, intracranial volume was significantly associated with two loci: rs4273712 (P = 3.4 x 10(-11)), a known height-associated locus on chromosome 6q22, and rs9915547 (P = 1.5 x 10(-12)), localized to the inversion on chromosome 17q21. We replicated the associations of these loci with intracranial volume in a separate sample of 1,752 elderly persons (P = 1.1 x 10(-3) for 6q22 and 1.2 x 10(-3) for 17q21). Furthermore, we also found suggestive associations of the 17q21 locus with head circumference in 10,768 children (mean age of 14.5 months). Our data identify two loci associated with head size, with the inversion at 17q21 also likely to be involved in attaining maximal brain size.
A nova is a cataclysmic event on the surface of a white dwarf in a binary system that increases the overall brightness by several orders of magnitude. Although binary systems with a white dwarf are expected to be overabundant in globular clusters compared with in the Galaxy, only two novae from Galactic globular clusters have been observed. We present the discovery of an emission nebula in the Galactic globular cluster M 22 (NGC 6656) in observations made with the integral-field spectrograph MUSE. We extracted the spectrum of the nebula and used the radial velocity determined from the emission lines to confirm that the nebula is part of NGC 6656. Emission-line ratios were used to determine the electron temperature and density. It is estimated to have a mass of 1-17 x 10(-5) M-circle dot. This mass and the emission-line ratios indicate that the nebula is a nova remnant. Its position coincides with the reported location of a "guest star", an ancient Chinese term for transients, observed in May 48 BCE. With this discovery, this nova may be one of the oldest confirmed extra-solar events recorded in human history.
Historisch wie aktuell werden durch gewalttätige soziale Auseinandersetzungen bestehende gesellschaftliche Ordnungen infrage gestellt. In der Geschichtswissenschaft wie in der Soziologie waren Tumulte, Aufstände oder soziale Erhebungen immer wieder Gegenstand von Untersuchungen. Während der historische Zugriff auf diese Phänomene gewöhnlich durch detaillierte Beschreibungen historische Abläufe genau zu rekonstruieren versucht hat, um diese verstehen zu können, geht es soziologischen Arbeiten zumeist um einen viel stärker generalisierenden und erklärenden Zugriff. Zwar gab es immer wieder Anläufe, diese scheinbar unüberbrückbare Differenz zwischen den Disziplinen zu überwinden, doch alle die Versuche müssen als mehr oder weniger gescheitert angesehen werden. Nach wie vor gilt deshalb, dass mit der ausschließlichen Konzentration auf die je eigene disziplinäre Herangehensweise viel Erkenntnispotenzial verschenkt wird. Aus diesem Grund unterbreitet die vorliegende Studie einen neuen Vorschlag, Geschichtswissenschaft und Soziologie zusammenzubringen. Der Verfasser unternimmt hier den Versuch, die beiden vermeintlich so gegensätzlichen Auffassungen von Wissenschaftlichkeit über eine gemeinsame methodologische Perspektive zusammenzuführen und auf dieser Grundlage einen vereinten, erklärenden Zugriff von Geschichtswissenschaft und Soziologie zu skizzieren, der nach dem „Wie“ eines Ereignisses fragt, zugleich aber auch erklären will, „warum“ es dazu gekommen ist. Das vorliegende Buch untersucht auf dieser methodologischen Grundlage und mittels eines historisch-soziologischen Zugangs sozialen Protest im Vormärz, es schließt an Arbeiten der historischen Soziologie und Sozialgeschichte an und entwickelt dazu einen stringenten historisch-soziologischen Erklärungsansatz.
Heterosis-associated cellular and molecular processes were analyzed in seeds and seedlings of Arabidopsis thaliana accessions Col-0 and C24 and their heterotic hybrids. Microscopic examination revealed no advantages in terms of hybrid mature embryo organ sizes or cell numbers. Increased cotyledon sizes were detectable 4 days after sowing. Growth heterosis results from elevated cell sizes and numbers, and is well established at 10 days after sowing. The relative growth rates of hybrid seedlings were most enhanced between 3 and 4 days after sowing. Global metabolite profiling and targeted fatty acid analysis revealed maternal inheritance patterns for a large proportion of metabolites in the very early stages. During developmental progression, the distribution shifts to dominant, intermediate and heterotic patterns, with most changes occurring between 4 and 6 days after sowing. The highest incidence of heterotic patterns coincides with establishment of size differences at 4 days after sowing. In contrast, overall transcript patterns at 4, 6 and 10 days after sowing are characterized by intermediate to dominant patterns, with parental transcript levels showing the largest differences. Overall, the results suggest that, during early developmental stages, intermediate gene expression and higher metabolic activity in the hybrids compared to the parents lead to better resource efficiency, and therefore enhanced performance in the hybrids.
In a comparison of three human service organisations in which the human body plays a key role, we examine how organisations regulate religious body practices. We concentrate on Muslim norms of dressing and undressing as a potential focal point of cultural and religious diversity. Inspired by Ray’s (2019) idea of racialized organizations, we assume that state-run organizations in Germany are characterized by a strong commitment to religious tolerance and non-discrimination but also marked by anti- Muslim sentiment prevalent among the German population. Our study looks for mechanism that explain how Human Service Organizations accommodate Muslim body practices. It draws on qualitative empirical data collected in state-run hospitals, schools and swimming pools in Germany. Our analyses show that the organizations draw on formal and informal rules at the organizational level to accommodate Islam. We identify five general organizational mechanisms that may hinder Muslim accommodation in human service organizations. In particular, we see a risk of decoupling between the expectation of religious tolerance and processes that lead to informal discrimination, driven mainly by the difficulty of controlling group dynamics among users.