Preclinical correction of human Fanconi anemia complementation group A bone marrow cells using a safety-modified lentiviral vector.

One of the major hurdles for the development of gene therapy for Fanconi anemia (FA) is the increased sensitivity of FA stem cells to free radical-induced DNA damage during ex vivo culture and manipulation. To minimize this damage, we have developed a brief transduction procedure for lentivirus vector-mediated transduction of hematopoietic progenitor cells from patients with Fanconi anemia complementation group A (FANCA). The lentiviral vector FancA-sW contains the phosphoglycerate kinase promoter, the FANCA cDNA, and a synthetic, safety-modified woodchuck post transcriptional regulatory element (sW). Bone marrow mononuclear cells or purified CD34(+) cells from patients with FANCA were transduced in an overnight culture on recombinant fibronectin peptide CH-296, in low (5%) oxygen, with the reducing agent, N-acetyl-L-cysteine (NAC), and a combination of growth factors, granulocyte colony-stimulating factor (G-CSF), Flt3 ligand, stem cell factor, and thrombopoietin. Transduced cells plated in methylcellulose in hypoxia with NAC showed increased colony formation compared with 21% oxygen without NAC (P<0.03), showed increased resistance to mitomycin C compared with green fluorescent protein (GFP) vector-transduced controls (P<0.007), and increased survival. Thus, combining short transduction and reducing oxidative stress may enhance the viability and engraftment of gene-corrected cells in patients with FANCA

6D supergravity without tensor multiplets

We systematically investigate the finite set of possible gauge groups and matter content for N = 1 supergravity theories in six dimensions with no tensor multiplets, focusing on nonabelian gauge groups which are a product of SU(N) factors. We identify a number of models which obey all known low-energy consistency conditions, but which have no known string theory realization. Many of these models contain novel matter representations, suggesting possible new string theory constructions. Many of the most exotic matter structures arise in models which precisely saturate the gravitational anomaly bound on the number of hypermultiplets. Such models have a rigid symmetry structure, in the sense that there are no moduli which leave the full gauge group unbroken.Comment: 31 pages, latex; v2, v3: minor corrections, references adde

Access to interpreting services in England: secondary analysis of national data

Background: Overcoming language barriers to health care is a global challenge. There is great linguistic diversity in the major cities in the UK with more than 300 languages, excluding dialects, spoken by children in London alone. However, there is dearth of data on the number of non-English speakers for planning effective interpreting services. The aim was to estimate the number of people requiring language support amongst the minority ethnic communities in England. Methods: Secondary analysis of national representative sample of subjects recruited to the Health Surveys for England 1999 and 2004. Results: 298,432 individuals from the four main minority ethnic communities (Indian, Pakistani, Bangladeshi and Chinese) who may be unable to communicate effectively with a health professional. This represents 2,520,885 general practice consultations per year where interpreting services might be required. Conclusion: Effective interpreting services are required to improve access and health outcomes of non-English speakers and thereby facilitate a reduction in health inequalities

Evolutionary relationships between Rhynchosporium lolii sp. nov. and other Rhynchosporium species on grass.

Copyright: 2013 King et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are creditedThe fungal genus Rhynchosporium (causative agent of leaf blotch) contains several host-specialised species, including R. commune (colonising barley and brome-grass), R. agropyri (couch-grass), R. secalis (rye and triticale) and the more distantly related R. orthosporum (cocksfoot). This study used molecular fingerprinting, multilocus DNA sequence data, conidial morphology, host range tests and scanning electron microscopy to investigate the relationship between Rhynchosporium species on ryegrasses, both economically important forage grasses and common wild grasses in many cereal growing areas, and other plant species. Two different types of Rhynchosporium were found on ryegrasses in the UK. Firstly, there were isolates of R. commune that were pathogenic to both barley and Italian ryegrass. Secondly, there were isolates of a new species, here named R. lolii, that were pathogenic only to ryegrass species. R. lolii was most closely related to R. orthosporum, but exhibited clear molecular, morphological and host range differences. The species was estimated to have diverged from R. orthosporum ca. 5735 years before the present. The colonisation strategy of all of the different Rhynchosporium species involved extensive hyphal growth in the sub-cuticular regions of the leaves. Finally, new species-specific PCR diagnostic tests were developed that could distinguish between these five closely related Rhynchosporium species.Peer reviewedFinal Published versio

Action for the eleven dimensional multiple M-wave system

We present the covariant supersymmetric and kappa-symmetric action for a system of N nearly coincident M-waves (multiple M0-brane system) in flat eleven dimensional superspace.Comment: 4+ pages, RevTeX4, no figures. V2: misprints corrected, discussion extended, references added, LaTeX, 10 pages. V3: misprints corrected. V4, extended version, 1+13 pages, to appear in JHE

Dynamic SU(2) Structure from Seven-branes

We obtain a family of supersymmetric solutions of type IIB supergravity with dynamic SU(2) structure, which describe the local geometry near a stack of four D7-branes and one O7-plane wrapping a rigid four-cycle. The deformation to a generalized complex geometry is interpreted as a consequence of nonperturbative effects in the seven-brane gauge theory. We formulate the problem for seven-branes wrapping the base of an appropriate del Pezzo cone, and in the near-stack limit in which the four-cycle is flat, we obtain an exact solution in closed form. Our solutions serve to characterize the local geometry of nonperturbatively-stabilized flux compactifications.Comment: 49 pages, 2 figures; v2: minor corrections, references adde

Non-abelian Action for Multiple Five-Branes with Self-Dual Tensors

We construct an action for non-abelian 2-form in 6-dimensions. Our action consists of a non-abelian generalization of the abelian action of Perry and Schwarz for a single five-brane. It admits a self-duality equation on the field strength as the equation of motion. It has a modified 6d Lorentz symmetry. On dimensional reduction on a circle, our action gives the standard 5d Yang-Mills action plus higher order corrections. Based on these properties, we propose that our theory describes the gauge sector of multiple M5-branes in flat space.Comment: LaTeX, 26 pages. v2: improved discussion of Lorentz symmetry. ref added. v3: add comments in the discussion section on the inclusion of scalar fields and supersymmetry; title changed to a more suitable one; version published in JHE

Characterisation of the pathogenic effects of the in vivo expression of an ALS-linked mutation in D-amino acid oxidase: Phenotype and loss of spinal cord motor neurons

Amyotrophic lateral sclerosis (ALS) is the most common adult-onset neuromuscular disorder characterised by selective loss of motor neurons leading to fatal paralysis. Current therapeutic approaches are limited in their effectiveness. Substantial advances in understanding ALS disease mechanisms has come from the identification of pathogenic mutations in dominantly inherited familial ALS (FALS). We previously reported a coding mutation in D-amino acid oxidase (DAOR199W) associated with FALS. DAO metabolises D-serine, an essential co-agonist at the N-Methyl-D-aspartic acid glutamate receptor subtype (NMDAR). Using primary motor neuron cultures or motor neuron cell lines we demonstrated that expression of DAOR199W, promoted the formation of ubiquitinated protein aggregates, activated autophagy and increased apoptosis. The aim of this study was to characterise the effects of DAOR199W in vivo, using transgenic mice overexpressing DAOR199W. Marked abnormal motor features, e.g. kyphosis, were evident in mice expressing DAOR199W, which were associated with a significant loss (19%) of lumbar spinal cord motor neurons, analysed at 14 months. When separated by gender, this effect was greater in females (26%; p< 0.0132). In addition, we crossed the DAOR199W transgenic mouse line with the SOD1G93A mouse model of ALS to determine whether the effects of SOD1G93A were potentiated in the double transgenic line (DAOR199W/SOD1G93A). Although overall survival was not affected, onset of neurological signs was significantly earlier in female double transgenic animals than their female SOD1G93A littermates (125 days vs 131 days, P = 0.0239). In summary, some significant in vivo effects of DAOR199W on motor neuron function (i.e. kyphosis and loss of motor neurons) were detected which were most marked in females and could contribute to the earlier onset of neurological signs in double transgenic females compared to SOD1G93A littermates, highlighting the importance of recognizing gender effects present in animal models of ALS

Dp-branes, NS5-branes and U-duality from nonabelian (2,0) theory with Lie 3-algebra

We derive the super Yang-Mills action of Dp-branes on a torus T^{p-4} from the nonabelian (2,0) theory with Lie 3-algebra. Our realization is based on Lie 3-algebra with pairs of Lorentzian metric generators. The resultant theory then has negative norm modes, but it results in a unitary theory by setting VEV's of these modes. This procedure corresponds to the torus compactification, therefore by taking a transformation which is equivalent to T-duality, the Dp-brane action is obtained. We also study type IIA/IIB NS5-brane and Kaluza-Klein monopole systems by taking other VEV assignments. Such various compactifications can be realized in the nonabelian (2,0) theory, since both longitudinal and transverse directions can be compactified, which is different from the BLG theory. We finally discuss U-duality among these branes, and show that most of the moduli parameters in U-duality group are recovered. Especially in D5-brane case, the whole U-duality relation is properly reproduced.Comment: 1+26 page

Field evidence for the upwind velocity shift at the crest of low dunes

Wind topographically forced by hills and sand dunes accelerates on the upwind (stoss) slopes and reduces on the downwind (lee) slopes. This secondary wind regime, however, possesses a subtle effect, reported here for the first time from field measurements of near-surface wind velocity over a low dune: the wind velocity close to the surface reaches its maximum upwind of the crest. Our field-measured data show that this upwind phase shift of velocity with respect to topography is found to be in quantitative agreement with the prediction of hydrodynamical linear analysis for turbulent flows with first order closures. This effect, together with sand transport spatial relaxation, is at the origin of the mechanisms of dune initiation, instability and growth.Comment: 13 pages, 6 figures. Version accepted for publication in Boundary-Layer Meteorolog