The general gaugings of maximal d=9 supergravity

We use the embedding tensor method to construct the most general maximal gauged/massive supergravity in d=9 dimensions and to determine its extended field content. Only the 8 independent deformation parameters (embedding tensor components, mass parameters etc.) identified by Bergshoeff \textit{et al.} (an SL(2,R) triplet, two doublets and a singlet can be consistently introduced in the theory, but their simultaneous use is subject to a number of quadratic constraints. These constraints have to be kept and enforced because they cannot be used to solve some deformation parameters in terms of the rest. The deformation parameters are associated to the possible 8-forms of the theory, and the constraints are associated to the 9-forms, all of them transforming in the conjugate representations. We also give the field strengths and the gauge and supersymmetry transformations for the electric fields in the most general case. We compare these results with the predictions of the E11 approach, finding that the latter predicts one additional doublet of 9-forms, analogously to what happens in N=2, d=4,5,6 theories.Comment: Latex file, 43 pages, reference adde

Digital PCR methods improve detection sensitivity and measurement precision of low abundance mtDNA deletions

Mitochondrial DNA (mtDNA) mutations are a common cause of primary mitochondrial disorders, and have also been implicated in a broad collection of conditions, including aging, neurodegeneration, and cancer. Prevalent among these pathogenic variants are mtDNA deletions, which show a strong bias for the loss of sequence in the major arc between, but not including, the heavy and light strand origins of replication. Because individual mtDNA deletions can accumulate focally, occur with multiple mixed breakpoints, and in the presence of normal mtDNA sequences, methods that detect broad-spectrum mutations with enhanced sensitivity and limited costs have both research and clinical applications. In this study, we evaluated semi-quantitative and digital PCR-based methods of mtDNA deletion detection using double-stranded reference templates or biological samples. Our aim was to describe key experimental assay parameters that will enable the analysis of low levels or small differences in mtDNA deletion load during disease progression, with limited false-positive detection. We determined that the digital PCR method significantly improved mtDNA deletion detection sensitivity through absolute quantitation, improved precision and reduced assay standard error

Charting the landscape of N=4 flux compactifications

We analyse the vacuum structure of isotropic Z_2 x Z_2 flux compactifications, allowing for a single set of sources. Combining algebraic geometry with supergravity techniques, we are able to classify all vacua for both type IIA and IIB backgrounds with arbitrary gauge and geometric fluxes. Surprisingly, geometric IIA compactifications lead to a unique theory with four different vacua. In this case we also perform the general analysis allowing for sources compatible with minimal supersymmetry. Moreover, some relevant examples of type IIB non-geometric compactifications are studied. The computation of the full N=4 mass spectrum reveals the presence of a number of non-supersymmetric and nevertheless stable AdS_4 vacua. In addition we find a novel dS_4 solution based on a non-semisimple gauging.Comment: Minor corrections and references added. Version published in JHE

The mitochondrial DNA 4,977-bp deletion and its implication in copy number alteration in colorectal cancer

<p>Abstract</p> <p>Background</p> <p>Qualitative and quantitative changes in human mitochondrial DNA (mtDNA) have been implicated in various cancer types. A 4,977 bp deletion in the major arch of the mitochondrial genome is one of the most common mutations associated with a variety of human diseases and aging.</p> <p>Methods</p> <p>We conducted a comprehensive study on clinical features and mtDNA of 104 colorectal cancer patients in the Wenzhou area of China. In particular, using a quantitative real time PCR method, we analyzed the 4,977 bp deletion and mtDNA content in tumor tissues and paired non-tumor areas from these patients.</p> <p>Results</p> <p>We found that the 4,977 bp deletion was more likely to be present in patients of younger age (≤65 years, p = 0.027). In patients with the 4,977 bp deletion, the deletion level decreased as the cancer stage advanced (p = 0.031). Moreover, mtDNA copy number in tumor tissues of patients with this deletion increased, both compared with that in adjacent non-tumor tissues and with in tumors of patients without the deletion. Such mtDNA content increase correlated with the levels of the 4,977 bp deletion and with cancer stage (p < 0.001).</p> <p>Conclusions</p> <p>Our study indicates that the mtDNA 4,977 bp deletion may play a role in the early stage of colorectal cancer, and it is also implicated in alteration of mtDNA content in cancer cells.</p

Resistance to First-Line Anti-TB Drugs Is Associated with Reduced Nitric Oxide Susceptibility in Mycobacterium tuberculosis

Background and objective: The relative contribution of nitric oxide (NO) to the killing of Mycobacterium tuberculosis in human tuberculosis (TB) is controversial, although this has been firmly established in rodents. Studies have demonstrated that clinical strains of M. tuberculosis differ in susceptibility to NO, but how this correlates to drug resistance and clinical outcome is not known. Methods: In this study, 50 sputum smear- and culture-positive patients with pulmonary TB in Gondar, Ethiopia were included. Clinical parameters were recorded and drug susceptibility profile and spoligotyping patterns were investigated. NO susceptibility was studied by exposing the strains to the NO donor DETA/NO. Results: Clinical isolates of M. tuberculosis showed a dose- and time-dependent response when exposed to NO. The most frequent spoligotypes found were CAS1-Delhi and T3_ETH in a total of nine known spoligotypes and four orphan patterns. There was a significant association between reduced susceptibility to NO (&gt;10% survival after exposure to 1mM DETA/NO) and resistance against first-line anti-TB drugs, in particular isoniazid (INH). Patients infected with strains of M. tuberculosis with reduced susceptibility to NO showed no difference in cure rate or other clinical parameters, but a tendency towards lower rate of weight gain after two months of treatment. Conclusion: There is a correlation between resistance to first-line anti-TB drugs and reduced NO susceptibility in clinical strains of M. tuberculosis. Further studies including the mechanisms of reduced NO susceptibility are warranted and could identify targets for new therapeutic interventions

Knowledge ‘Translation’ as Social Learning: Negotiating the Uptake of Research-Based Knowledge in Practice

BACKGROUND: Knowledge translation and evidence-based practice have relied on research derived from clinical trials, which are considered to be methodologically rigorous. The result is practice recommendations based on a narrow view of evidence. We discuss how, within a practice environment, in fact individuals adopt and apply new evidence derived from multiple sources through ongoing, iterative learning cycles. DISCUSSION: The discussion is presented in four sections. After elaborating on the multiple forms of evidence used in practice, in section 2 we argue that the practitioner derives contextualized knowledge through reflective practice. Then, in section 3, the focus shifts from the individual to the team with consideration of social learning and theories of practice. In section 4 we discuss the implications of integrative and negotiated knowledge exchange and generation within the practice environment. Namely, how can we promote the use of research within a team-based, contextualized knowledge environment? We suggest support for: 1) collaborative learning environments for active learning and reflection, 2) engaged scholarship approaches so that practice can inform research in a collaborative manner and 3) leveraging authoritative opinion leaders for their clinical expertise during the shared negotiation of knowledge and research. Our approach also points to implications for studying evidence-informed practice: the identification of practice change (as an outcome) ought to be supplemented with understandings of how and when social negotiation processes occur to achieve integrated knowledge. SUMMARY: This article discusses practice knowledge as dependent on the practice context and on social learning processes, and suggests how research knowledge uptake might be supported from this vantage point

Gene Expression in a Drosophila Model of Mitochondrial Disease

Background A point mutation in the Drosophila gene technical knockout (tko), encoding mitoribosomal protein S12, was previously shown to cause a phenotype of respiratory chain deficiency, developmental delay, and neurological abnormalities similar to those presented in many human mitochondrial disorders, as well as defective courtship behavior. Methodology/Principal Findings Here, we describe a transcriptome-wide analysis of gene expression in tko25t mutant flies that revealed systematic and compensatory changes in the expression of genes connected with metabolism, including up-regulation of lactate dehydrogenase and of many genes involved in the catabolism of fats and proteins, and various anaplerotic pathways. Gut-specific enzymes involved in the primary mobilization of dietary fats and proteins, as well as a number of transport functions, were also strongly up-regulated, consistent with the idea that oxidative phosphorylation OXPHOS dysfunction is perceived physiologically as a starvation for particular biomolecules. In addition, many stress-response genes were induced. Other changes may reflect a signature of developmental delay, notably a down-regulation of genes connected with reproduction, including gametogenesis, as well as courtship behavior in males; logically this represents a programmed response to a mitochondrially generated starvation signal. The underlying signalling pathway, if conserved, could influence many physiological processes in response to nutritional stress, although any such pathway involved remains unidentified. Conclusions/Significance These studies indicate that general and organ-specific metabolism is transformed in response to mitochondrial dysfunction, including digestive and absorptive functions, and give important clues as to how novel therapeutic strategies for mitochondrial disorders might be developed.Public Library of Scienc

Independent impacts of aging on mitochondrial DNA quantity and quality in humans

Background The accumulation of mitochondrial DNA (mtDNA) mutations, and the reduction of mtDNA copy number, both disrupt mitochondrial energetics, and may contribute to aging and age-associated phenotypes. However, there are few genetic and epidemiological studies on the spectra of blood mtDNA heteroplasmies, and the distribution of mtDNA copy numbers in different age groups and their impact on age-related phenotypes. In this work, we used whole-genome sequencing data of isolated peripheral blood mononuclear cells (PBMCs) from the UK10K project to investigate in parallel mtDNA heteroplasmy and copy number in 1511 women, between 17 and 85 years old, recruited in the TwinsUK cohorts. Results We report a high prevalence of pathogenic mtDNA heteroplasmies in this population. We also find an increase in mtDNA heteroplasmies with age (β = 0.011, P = 5.77e-6), and showed that, on average, individuals aged 70-years or older had 58.5% more mtDNA heteroplasmies than those under 40-years old. Conversely, mtDNA copy number decreased by an average of 0.4 copies per year (β = −0.395, P = 0.0097). Multiple regression analyses also showed that age had independent effects on mtDNA copy number decrease and heteroplasmy accumulation. Finally, mtDNA copy number was positively associated with serum bicarbonate level (P = 4.46e-5), and inversely correlated with white blood cell count (P = 0.0006). Moreover, the aggregated heteroplasmy load was associated with blood apolipoprotein B level (P = 1.33e-5), linking the accumulation of mtDNA mutations to age-related physiological markers. Conclusions Our population-based study indicates that both mtDNA quality and quantity are influenced by age. An open question for the future is whether interventions that would contribute to maintain optimal mtDNA copy number and prevent the expansion of heteroplasmy could promote healthy aging