Chronic Progressive External Ophthalmoplegia Is Associated with a Novel Mutation in the Mitochondrial tRNA(Asn) Gene

Chronic progressive external ophthalmoplegia (CPEO) is caused by a decreased oxidative phosphorylation (OXPHOS) activity due to large-scale deletions of the mitochondrial genome in 50 % of the patients. The deletions encompass structural OXPHOS genes as well as tRNA genes, required for their expression so that the pathogenesis could be due to the deleted OXPHOS subunits or to an impaired mitochondrial translation. We have analyzed the mitochondrial genome of a patient presenting with CPEO for single base substitutions and discovered a novel heteroplasmic mutation in the tRNAAsn gene at position 5692 that converts a highly conserved adenine into a guanine. This mutation is unique because it is located at the transition of the anticodon loop to the anticodon stem and it leads to an additional base pair, thus reducing the number of loop-forming nucleotides from seven to five. Our findings suggest that CPEO can be caused by a single base substition in a mitochondrial tRNA gene so that the mitochondrial protein synthesis becomes the rate limiting step in OXPHOS fidelity

A Probabilistic Model for LCF

Fatigue life of components or test specimens often exhibit a significant scatter. Furthermore, size effects have a non-negligible influence on fatigue life of parts with different geometries. We present a new probabilistic model for low-cycle fatigue (LCF) in the context of polycrystalline metal. The model takes size effects and inhomogeneous strain fields into account by means of the Poisson point process (PPP). This approach is based on the assumption of independently occurring LCF cracks and the Coffin-Manson-Basquin (CMB) equation. Within the probabilistic model, we give a new and more physical interpretation of the CMB parameters which are in the original approach no material parameters in a strict sense, as they depend on the specimen geometry. Calibration and validation of the proposed model is performed using results of strain controlled LCF tests of specimens with different surface areas. The test specimens are made of the nickel base superalloy RENE 80.Comment: 20 pages, 6 figure

Coronā Devī has entered the chat: South Asian goddesses associated with Covid-19, ritual practice, and online media discourse

Between June 2020 and September 2021, news reports from India detailing ritual practice devoted to goddesses associated with the novel coronavirus were published by both domestic and international media houses. This thesis analyzes discourses located within English-language media reports and online comments about these deities, associated practices, and devotees. It seeks to address the following questions: 1) How are questions of ‘authority’ and ‘authenticity’ vis-à-vis Hinduism discursively constructed? 2) How are discourses of ‘superstition’ differentially mobilized against groups and actors belonging to marginalized communities? 3) How do participants’ reported narratives and ritual practices reflect these concerns? Online criticism of ritual participants is found to be situated within two broad and antagonistic discourses: Hindu nationalist discourses concerned with defending ‘true’ Hinduism from outside critique and secular rationalist discourses. Meanwhile, participant narratives situate practices both within preexisting traditions of goddesses associated with disease and as responses to novel challenges presented by the Covid-19 pandemic. Additionally, themes of economic insecurity, relationships between religion and science, and expressions of collective concern are reflected by both critics and participants in various ways. Finally, the notable absence and structural exclusion of ritualists from online participatory discourse challenges naïve assumptions regarding democratic access to online religious expression

Metabolitenmuster im Blut und Genexpressionsmuster von Aryl-Hydrocarbon-Rezeptor-defizienten- und Wildtyp-Mäusen

Polychlorierte Dibenzo-p-dioxine wie 2,3,7,8-Tetrachlordibenzo-p-dioxin (TCDD), die zur Stoffgruppe der polyhalogenierten Kohlenwasserstoffe gehören, sind lipophile und persistente Umweltkontaminanten. Sie entstehen als unerwünschte Verunreinigungen bzw. Begleitstoffe vor allem während Verbrennungsprozessen organischer Materialien wie Holz oder Müll, im Tabakrauch sowie als Nebenprodukt chlororganischer Synthesen. Aufgrund ihrer hohen Lipophile reichern sie sich in der Nahrungskette an. Dioxine wie TCDD verursachen eine Vielzahl von biochemischen und toxischen Effekten wie z.B. Enzym-Induktion, Lebertoxizität, dermale Toxizität, Immuntoxizität und Kanzerogenität. Im Tiermodell konnte eine Beeinträchtigung des Fortpflanzungssystems und des Hormonhaushaltes beobachtet werden. In der Literatur herrscht Einigkeit, dass die meisten wenn nicht sogar alle toxischen Wirkungen der Dioxine über den Aryl-Hydrocarbon-Rezeptor (AhR) vermittelt werden. Im letzten Jahrzehnt konnten jedoch in mehreren Studien AhR-unabhängige TCDD-Wirkungen beobachtet werden. Nur wenige Studien befassen sich mit der Niere als Zielorgan, wobei belegt werden konnte, dass der AhR auch für die Entwicklung der Niere eine wichtige Rolle zu spielen scheint. Im Rahmen dieser Doktorarbeit wurde eine Tierstudie mit Wildtyp- und AhR-defizienten-Mäusen durchgeführt und dabei auch die Niere als Zielorgan betrachtet. Zunächst wurden weibliche und männliche Wildtyp- und AhR-defiziente-Mäuse einmalig mit TCDD (25 µg/kg KG) oral behandelt. Anschließend wurden Genexpressionsmuster in den Nieren mittels Microarray analysiert. In den Nieren behandelter Wildtyp-Mäuse wiesen 172 Gene, und in den Nieren behandelter AhR-defizienter-Mäuse wiesen 325 Gene eine veränderte Expression auf. In den Nieren behandelter AhR-defizienter-Mäuse wurden Gene hochreguliert, die in Prozesse des blutbildenden Systems, der Blutgerinnung sowie der Biosynthese von Sterolen und des Katabolismus von organischen Säuren involviert sind. Herrunterreguliert wurden Gene, die in Prozesse des Lipidmetabolismus, der Biosynthese sowie des Metabolismus kleinerer Moleküle und des Metabolismus von Hormonen involviert sind. Mittels RT-PCR wurde die im Microarray beobachtete erhöhte Expression einiger ausgewählter Gene des blutbildenden Systems (z. B. Hba-a1, Hbb-b1 und Rps14) und der Blutgerinnung (z. B. Fgg und F10) sowie einiger hepatischer Gene wie Lpl, Anxa1, c-Myc, Igfbp1, Esm1 und Cdh1 (Microarray-Analyse der Lebern wurde in einer früheren Studie gemessen) bestätigt. Des Weiteren wurde eine leichte, teilweise signifikant erhöhte Expression einiger pro-bzw. antiinflammatorischer Zytokine (IL-1α, IL-1ß, Il-6, IL-10 und TNF-α) in den Lebern und Milzen behandelter AhR-defizienter-Mäuse beobachtet. Die Induktion fremdstoffemtabolisiernder Enzyme wie Cyp1a1, Cyp1a2 und Cyp1b1 in den Organen Leber, Niere, Lunge und Milz behandelter Wildtyp-Mäuse konnte mittels Western-Blot und RT-PCR bestätigt werden, jedoch mit einer Ausnahme. In den Milzen behandelter Wildtyp-Mäuse konnte keine Induktion dieser Enzyme auf mRNA-Ebene beobachtet werden. In den Lebern behandelter AhR-defizienter-Mäuse war die Cyp1b1-Expression signifikant erhöht sowie die AhR-Expression vermindert. Die Induktion der Vitmain D-Rezeptor (VDR)-regulierten Gene Cyp24a1, Cyp27b1 und VDR in den Nieren behandelter AhR-defizienter-Mäuse weist auf die Aktivierung des VDR hin. Des Weiteren stellt die verminderte Expression von c-Myc in den Nieren TCDD-behandelter Knockout-Mäuse ein Hinweis für die Aktivierung des VDR dar. Durch HPLC/MS-MS-gestützte Untersuchung des Vollblutes von AhR-Wildtyp- und AhR-Knockout-Mäusen konnten Unterschiede und Gemeinsamkeiten zwischen den Genotypen bestimmt werden. So war es möglich Unterschiede im Aminosäuremetabolismus sowie im Tryptophan-Metabolismus zu identifizieren. Außerdem konnte gezeigt werden, dass sowohl im unbehandelten wie auch im TCDD-behandelten Zustand, Unterschiede zwischen den Genotypen bestanden.Polychlorinated dibenzo-p-dioxins like 2,3,7,8-tetrachlordibenzo-p-dioxine (TCDD), which belong to the class of polyhalogenated aromatic hydrocarbons, are lipophilic and persistent environmental pollutants. They are generated as unwanted contaminants and by-products in chemical combustion processes for example waste and sewage sludge incinerations as well as in other chemical processes such as paper pulp bleaching or metal smelting. Due to their high persistence they accumulate in the feed and food chain. Dioxins evoke a broad spectrum of biochemical and toxicological effects like enzyme induction, hepatotoxicity, dermal toxicity, immunotoxicity and carcinogenicity. Adverse effects on reproduction, development, and the endocrine system have been demonstrated in numerous animal studies. Most, if not all, toxic effects of dioxins are mediated by the aryl-hydrocarbon-receptor (AhR). In the last decade AhR-independent TCDD-effects were observed in some studies. Only a few studies address the kidney as a target organ of TCDD, although the AhR seems to play an important role in kidney development. In the present work an animal study with AhR wild-type (AhR+/+) and AhR-deficient (AhR-/-) mice was performed. In this study female and male AhR+/+ and AhR-/- mice were treated with a single dose of TCDD (25 µg/kg bw) by gavage. A microarray analysis of renal gene expression patterns was performed aiming to characterize AhR-dependent and AhR-independent TCDD-mediated effects in AhR wild-type and AhR-Knockout mice. As a result of this study, 172 genes were regulated in the kidney of wild-type mice and 325 genes in the kidney of AhR-deficient mice. TCDD-treatment of AhR-/- mice resulted in upregualtion of genes involved in processes of hematopoietic system, blood coagulation, biosynthesis of sterols and catabolism of organic acids and downregulation of genes involved in processes of lipid metabolism, biosynthesis and metabolism of small molecules as well as hormone metabolism. Increased expression of a few selected renal genes of the hematopoietic system (e.g. Hba-a1, Hbb-b1 and Rps14), blood coagulation (e.g. Fgg and F10), as well as some hepatic genes such as Lpl, Anxa1, c-Myc, Igfbp1, Esm1 and Cdh1 (observed in earlier studies) were analyzed and confirmed by RT-PCR. In liver and spleen a slight and partly significant induction of some anti- and pro-inflammatory cytokines (IL-1α, IL-1ß, IL-6 and TNF-α) was determined. Furthermore the induction of the xenobiotic metabolizing enzymes Cyp1a1, Cyp1a2 and Cyp1b1 in liver, kidney, lung and spleen of TCDD-treated AhR wild-type mice were analyzed and confirmed by western blot and RT-PCR. With one exception, in spleen of treated wild-typ mice no induction was observed in RT-PCR. In livers of treated AhR-/- mice, the Cyp1b1-expression was significantly increased while gene expression of AhR was decreased. The induction of the vitamin d-receptor (VDR) regulated genes Cyp24a1, Cyp27b1 and VDR in kidneys of treated AhR-Knockout mice indicates an activation of VDR. Furthermore the additionally decreased c-Myc-expression in kidneys of treated AhR-deficient mice supports the proposed activation of VDR. Investigating the role of AhR in the metabolome, differences and similarities between AhR-deficient and wild-type mice were determined by HPLC/MS-MS analysis of mouse whole blood of each genotype with and without TCDD-treatment. Differences in amino acid and tryptophan metabolism between AhR+/+ and AhR-/- were observed

Synchronous visual analysis and editing of RNA sequence and secondary structure alignments using 4SALE

<p>Abstract</p> <p>Background</p> <p>The function of a noncoding RNA sequence is mainly determined by its secondary structure and therefore a family of noncoding RNA sequences is much more conserved on the structural level than on the sequence level. Understanding the function of noncoding RNA sequence families requires two things: a hand-crafted or hand-improved alignment and detailed analyses of the secondary structures. There are several tools available that help performing these tasks, but all of them are specialized and focus on only one aspect, editing the alignment or plotting the secondary structure. The problem is both these tasks need to be performed simultaneously.</p> <p>Findings</p> <p>4SALE is designed to handle sequence and secondary structure information of RNAs synchronously. By including a complete new method of simultaneous visualization and editing RNA sequences and secondary structure information, 4SALE enables to improve and understand RNA sequence and secondary structure evolution much more easily.</p> <p>Conclusion</p> <p>4SALE is a step further for simultaneously handling RNA sequence and secondary structure information. It provides a complete new way of visual monitoring different structural aspects, while editing the alignment. The software is freely available and distributed from its website at <url>http://4sale.bioapps.biozentrum.uni-wuerzburg.de/</url></p

4SALE – A tool for synchronous RNA sequence and secondary structure alignment and editing

BACKGROUND: In sequence analysis the multiple alignment builds the fundament of all proceeding analyses. Errors in an alignment could strongly influence all succeeding analyses and therefore could lead to wrong predictions. Hand-crafted and hand-improved alignments are necessary and meanwhile good common practice. For RNA sequences often the primary sequence as well as a secondary structure consensus is well known, e.g., the cloverleaf structure of the t-RNA. Recently, some alignment editors are proposed that are able to include and model both kinds of information. However, with the advent of a large amount of reliable RNA sequences together with their solved secondary structures (available from e.g. the ITS2 Database), we are faced with the problem to handle sequences and their associated secondary structures synchronously. RESULTS: 4SALE fills this gap. The application allows a fast sequence and synchronous secondary structure alignment for large data sets and for the first time synchronous manual editing of aligned sequences and their secondary structures. This study describes an algorithm for the synchronous alignment of sequences and their associated secondary structures as well as the main features of 4SALE used for further analyses and editing. 4SALE builds an optimal and unique starting point for every RNA sequence and structure analysis. CONCLUSION: 4SALE, which provides an user-friendly and intuitive interface, is a comprehensive toolbox for RNA analysis based on sequence and secondary structure information. The program connects sequence and structure databases like the ITS2 Database to phylogeny programs as for example the CBCAnalyzer. 4SALE is written in JAVA and therefore platform independent. The software is freely available and distributed from the website a

Berichtsmodul 'Landwirtschaft und Umwelt' in den Umweltökonomischen Gesamtrechnungen: Konzept und beispielhafte Darstellung erster Ergebnisse

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Temperature compensation of aerobic capacity and performance in the Antarctic pteropod, \u3cem\u3eClione antarctica\u3c/em\u3e, compared with its northern congener, \u3cem\u3eC. limacina\u3c/em\u3e

In ectotherms living in cold waters, locomotory performance is constrained by a slower generation of the ATP that is needed to fuel muscle contraction. Both polar and temperate pteropods of the genus Clione, however, are able to swim continuously by flapping their parapodia (wings) at comparable frequencies at their respective habitat temperatures. Therefore, we expected polar species to have increased aerobic capacities in their wing muscles when measured at common temperatures. We investigated muscle and mitochondrial ultrastructure of Clione antarctica from the Southern Ocean (−1.8°C) and populations of a sister species, Clione limacina, from the Arctic (−0.5 to 3°C) and from the North Atlantic (10°C). We also measured oxygen consumption and the activity of the mitochondrial enzyme citrate synthase (CS) in isolated wings of the two species. The Antarctic species showed a substantial up-regulation of the density of oxidative muscle fibers, but at the expense of fast-twitch muscle fibers. Mitochondrial capacity was also substantially increased in the Antarctic species, with the cristae surface density (58.2±1.3μm2μm−3) more than twice that found in temperate species (34.3±0.8μm2μm−3). Arctic C. limacina was intermediate between these two populations (43.7±0.5μm2μm−3). The values for cold-adapted populations are on par with those found in high-performance vertebrates. As a result of oxidative muscle proliferation, CS activity was 4-fold greater in C. antarctica wings than in temperate C. limacina when measured at a common temperature (20°C). Oxygen consumption of isolated wing preparations was comparable in the two species when measured at their respective habitat temperatures. These findings indicate complete compensation of ATP generation in wing muscles across a 10°C temperature range, which supports similar wing-beat frequencies during locomotion at each species\u27 respective temperature. The elevated capacity in the wing muscles is reflected in the partial compensation of whole-animal oxygen consumption and feeding rates