Exceptional Flux Compactifications

We consider type II (non-)geometric flux backgrounds in the absence of brane sources, and construct their explicit embedding into maximal gauged D=4 supergravity. This enables one to investigate the critical points, mass spectra and gauge groups of such backgrounds. We focus on a class of type IIA geometric vacua and find a novel, non-supersymmetric and stable AdS vacuum in maximal supergravity with a non-semisimple gauge group. Our construction relies on a non-trivial mapping between SL(2) x SO(6,6) fluxes, SU(8) mass spectra and gaugings of E7(7) subgroups.Comment: 51 pages, 2 figures and 4 tables. v3: change of SO(6,6) spinorial conventions, published versio

Gauged Double Field Theory

We find necessary and sufficient conditions for gauge invariance of the action of Double Field Theory (DFT) as well as closure of the algebra of gauge symmetries. The so-called weak and strong constraints are sufficient to satisfy them, but not necessary. We then analyze compactifications of DFT on twisted double tori satisfying the consistency conditions. The effective theory is a Gauged DFT where the gaugings come from the duality twists. The action, bracket, global symmetries, gauge symmetries and their closure are computed by twisting their analogs in the higher dimensional DFT. The non-Abelian heterotic string and lower dimensional gauged supergravities are particular examples of Gauged DFT.Comment: Minor changes, references adde

Cytokine and Protein Markers of Leprosy Reactions in Skin and Nerves: Baseline Results for the North Indian INFIR Cohort

Leprosy affects skin and peripheral nerves. Although we have effective antibiotics to treat the mycobacterial infection, a key part of the disease process is the accompanying inflammation. This can worsen after starting antibacterial treatment with episodes of immune mediated inflammation, so called ‘reactions’. These reactions are associated with worsening of the nerve damage. We recruited a cohort of 303 newly diagnosed leprosy patients in North India with the aim of understanding and defining the pathological processes better. We took skin and nerve biopsies from patients and examined them to define which molecules and mediators of inflammation were present. We found high levels of the cytokines Tumour Necrosis Factor alpha, Transforming Growth Factor beta and inducible Nitric Oxide Synthase in biopsies from patients with reactions. We also found high levels of bacteria and inflammation in the nerves. These experiments tell us that we need to determine which other molecules are present and to explore ways of switching off the production of these pro-inflammatory molecules

Use of whole genome sequencing to determine genetic basis of suspected mitochondrial disorders: cohort study.

OBJECTIVE: To determine whether whole genome sequencing can be used to define the molecular basis of suspected mitochondrial disease. DESIGN: Cohort study. SETTING: National Health Service, England, including secondary and tertiary care. PARTICIPANTS: 345 patients with suspected mitochondrial disorders recruited to the 100 000 Genomes Project in England between 2015 and 2018. INTERVENTION: Short read whole genome sequencing was performed. Nuclear variants were prioritised on the basis of gene panels chosen according to phenotypes, ClinVar pathogenic/likely pathogenic variants, and the top 10 prioritised variants from Exomiser. Mitochondrial DNA variants were called using an in-house pipeline and compared with a list of pathogenic variants. Copy number variants and short tandem repeats for 13 neurological disorders were also analysed. American College of Medical Genetics guidelines were followed for classification of variants. MAIN OUTCOME MEASURE: Definite or probable genetic diagnosis. RESULTS: A definite or probable genetic diagnosis was identified in 98/319 (31%) families, with an additional 6 (2%) possible diagnoses. Fourteen of the diagnoses (4% of the 319 families) explained only part of the clinical features. A total of 95 different genes were implicated. Of 104 families given a diagnosis, 39 (38%) had a mitochondrial diagnosis and 65 (63%) had a non-mitochondrial diagnosis. CONCLUSION: Whole genome sequencing is a useful diagnostic test in patients with suspected mitochondrial disorders, yielding a diagnosis in a further 31% after exclusion of common causes. Most diagnoses were non-mitochondrial disorders and included developmental disorders with intellectual disability, epileptic encephalopathies, other metabolic disorders, cardiomyopathies, and leukodystrophies. These would have been missed if a targeted approach was taken, and some have specific treatments

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

Defoliation and Soil Compaction Jointly Drive Large-Herbivore Grazing Effects on Plants and Soil Arthropods on Clay Soil

In addition to the well-studied impacts of defecation and defoliation, large herbivores also affect plant and arthropod communities through trampling, and the associated soil compaction. Soil compaction can be expected to be particularly important on wet, fine-textured soils. Therefore, we established a full factorial experiment of defoliation (monthly mowing) and soil compaction (using a rammer, annually) on a clay-rich salt marsh at the Dutch coast, aiming to disentangle the importance of these two factors. Additionally, we compared the effects on soil physical properties, plants, and arthropods to those at a nearby cattle-grazed marsh under dry and under waterlogged conditions. Soil physical conditions of the compacted plots were similar to the conditions at cattle-grazed plots, showing decreased soil aeration and increased waterlogging. Soil salinity was doubled by defoliation and quadrupled by combined defoliation and compaction. Cover of the dominant tall grass Elytrigia atherica was decreased by 80% in the defoliated plots, but cover of halophytes only increased under combined defoliation and compaction. Effects on soil micro-arthropods were most severe under waterlogging, showing a fourfold decrease in abundance and a smaller mean body size under compaction. Although the combined treatment of defoliation and trampling indeed proved most similar to the grazed marsh, large discrepancies remained for both plant and soil fauna communities, presumably because of colonization time lags. We conclude that soil compaction and defoliation differently affect plant and arthropod communities in grazed ecosystems, and that the magnitude of their effects depends on herbivore density, productivity, and soil physical properties

Neuromuscular disease genetics in under-represented populations: increasing data diversity

Neuromuscular diseases (NMDs) affect ∼15 million people globally. In high income settings DNA-based diagnosis has transformed care pathways and led to gene-specific therapies. However, most affected families are in low-to-middle income countries (LMICs) with limited access to DNA-based diagnosis. Most (86%) published genetic data is derived from European ancestry. This marked genetic data inequality hampers understanding of genetic diversity and hinders accurate genetic diagnosis in all income settings. We developed a cloud-based transcontinental partnership to build diverse, deeply-phenotyped and genetically characterized cohorts to improve genetic architecture knowledge, and potentially advance diagnosis and clinical management. We connected 18 centres in Brazil, India, South Africa, Turkey, Zambia, Netherlands and the UK. We co-developed a cloud-based data solution and trained 17 international neurology fellows in clinical genomic data interpretation. Single gene and whole exome data were analysed via a bespoke bioinformatics pipeline and reviewed alongside clinical and phenotypic data in global webinars to inform genetic outcome decisions. We recruited 6001 participants in the first 43 months. Initial genetic analyses ‘solved’ or ‘possibly solved’ ∼56% probands overall. In-depth genetic data review of the four commonest clinical categories (limb girdle muscular dystrophy, inherited peripheral neuropathies, congenital myopathy/muscular dystrophies and Duchenne/Becker muscular dystrophy) delivered a ∼59% ‘solved’ and ∼13% ‘possibly solved’ outcome. Almost 29% of disease causing variants were novel, increasing diverse pathogenic variant knowledge. Unsolved participants represent a new discovery cohort. The dataset provides a large resource from under-represented populations for genetic and translational research. In conclusion, we established a remote transcontinental partnership to assess genetic architecture of NMDs across diverse populations. It supported DNA-based diagnosis, potentially enabling genetic counselling, care pathways and eligibility for gene-specific trials. Similar virtual partnerships could be adopted by other areas of global genomic neurological practice to reduce genetic data inequality and benefit patients globally