Hypermoduli Stabilization, Flux Attractors, and Generating Functions

We study stabilization of hypermoduli with emphasis on the effects of generalized fluxes. We find a class of no-scale vacua described by ISD conditions even in the presence of geometric flux. The associated flux attractor equations can be integrated by a generating function with the property that the hypermoduli are determined by a simple extremization principle. We work out several orbifold examples where all vector moduli and many hypermoduli are stabilized, with VEVs given explicitly in terms of fluxes.Comment: 45 pages, no figures; Version submitted to JHE

Assessment of cardiovascular risk factors prior to NHS Health Checks in an urban setting: cross-sectional study

OBJECTIVES: To assess the completeness of cardiovascular disease (CVD) risk factor recording and levels of risk factors in patients eligible for the NHS Health Check. DESIGN: Cross-sectional study. SETTING: Twenty-eight general practices located in Hammersmith and Fulham, London, UK. PARTICIPANTS: 42,306 patients aged 40 to 74 years without existing cardiovascular disease or diabetes. MAIN OUTCOME MEASURES: MEASUREMENT AND LEVEL OF CVD RISK FACTORS: blood pressure, cholesterol, body mass index (BMI), blood glucose and smoking status. RESULTS: There was a high recording of smoking status (86.1%) and blood pressure (82.5%); whilst BMI, cholesterol and glucose recording was lower. There was large variation in BMI, cholesterol, glucose recording between practices (29.7-91.5% for BMI). Women had significantly better risk factor recording than men (AOR = 1.70 [1.61-1.80] for blood pressure). All risk factors were better recorded in the least deprived patient group (AOR = 0.79 [0.73-0.85] for blood pressure) and patients with diagnosed hypertension (AOR = 7.24 [6.67-7.86] for cholesterol). Risk factor recording varied considerably between practices but was more strongly associated with patient than practice level characteristics. Age-adjusted levels of cholesterol and BMI were not significantly different between men and women. More men had raised blood glucose, blood pressure and BMI than women (29.7% [29.1-30.4] compared to 19.8% [19.3-20.3] for blood pressure). CONCLUSIONS: Before the NHS Health Check, CVD risk factor recording varied considerably by practice and patient characteristics. We identified significant elevated levels of raised CVD risk factors in the population eligible for a Health Check, which will require considerable work to manage

Low pH immobilizes and kills human leukocytes and prevents transmission of cell-associated HIV in a mouse model

BACKGROUND: Both cell-associated and cell-free HIV virions are present in semen and cervical secretions of HIV-infected individuals. Thus, topical microbicides may need to inactivate both cell-associated and cell-free HIV to prevent sexual transmission of HIV/AIDS. To determine if the mild acidity of the healthy vagina and acid buffering microbicides would prevent transmission by HIV-infected leukocytes, we measured the effect of pH on leukocyte motility, viability and intracellular pH and tested the ability of an acidic buffering microbicide (BufferGel(®)) to prevent the transmission of cell-associated HIV in a HuPBL-SCID mouse model. METHODS: Human lymphocyte, monocyte, and macrophage motilities were measured as a function of time and pH using various acidifying agents. Lymphocyte and macrophage motilities were measured using video microscopy. Monocyte motility was measured using video microscopy and chemotactic chambers. Peripheral blood mononuclear cell (PBMC) viability and intracellular pH were determined as a function of time and pH using fluorescent dyes. HuPBL-SCID mice were pretreated with BufferGel, saline, or a control gel and challenged with HIV-1-infected human PBMCs. RESULTS: Progressive motility was completely abolished in all cell types between pH 5.5 and 6.0. Concomitantly, at and below pH 5.5, the intracellular pH of PBMCs dropped precipitously to match the extracellular medium and did not recover. After acidification with hydrochloric acid to pH 4.5 for 60 min, although completely immotile, 58% of PBMCs excluded ethidium homodimer-1 (dead-cell dye). In contrast, when acidified to this pH with BufferGel, a microbicide designed to maintain vaginal acidity in the presence of semen, only 4% excluded dye at 10 min and none excluded dye after 30 min. BufferGel significantly reduced transmission of HIV-1 in HuPBL-SCID mice (1 of 12 infected) compared to saline (12 of 12 infected) and a control gel (5 of 7 infected). CONCLUSION: These results suggest that physiologic or microbicide-induced acid immobilization and killing of infected white blood cells may be effective in preventing sexual transmission of cell-associated HIV

Subcellular distribution of nuclear import-defective isoforms of the promyelocytic leukemia protein

<p>Abstract</p> <p>Background</p> <p>The promyelocytic leukemia (PML) protein participates in a number of cellular processes, including transcription regulation, apoptosis, differentiation, virus defense and genome maintenance. This protein is structurally organized into a tripartite motif (TRIM) at its N-terminus, a nuclear localization signal (NLS) at its central region and a C-terminus that varies between alternatively spliced isoforms. Most PML splice variants target the nucleus where they define sub-nuclear compartments termed PML nuclear bodies (PML NBs). However, PML variants that lack the NLS are also expressed, suggesting the existence of PML isoforms with cytoplasmic functions. In the present study we expressed PML isoforms with a mutated NLS in U2OS cells to identify potential cytoplasmic compartments targeted by this protein.</p> <p>Results</p> <p>Expression of NLS mutated PML isoforms in U2OS cells revealed that PML I targets early endosomes, PML II targets the inner nuclear membrane (partially due to an extra NLS at its C-terminus), and PML III, IV and V target late endosomes/lysosomes. Clustering of PML at all of these subcellular locations depended on a functional TRIM domain.</p> <p>Conclusions</p> <p>This study demonstrates the capacity of PML to form macromolecular protein assemblies at several different subcellular sites. Further, it emphasizes a role of the variable C-terminus in subcellular target selection and a general role of the N-terminal TRIM domain in promoting protein clustering.</p

Detection of myxoma viruses encoding a defective M135R gene from clinical cases of myxomatosis; possible implications for the role of the M135R protein as a virulence factor

<p>Abstract</p> <p>Background</p> <p>Myxoma virus is a member of the <it>Poxviridae </it>and causes disease in European rabbits. Laboratory confirmation of the clinical disease, which occurs in the autumn of most years in Denmark, has been achieved previously using antigen ELISA and electron microscopy.</p> <p>Results</p> <p>An unusually large number of clinically suspected cases of myxomatosis were observed in Denmark during 2007. Myxoma virus DNA was detected, using a new real time PCR assay which targets the M029L gene, in over 70% of the clinical samples submitted for laboratory confirmation. Unexpectedly, further analysis revealed that a high proportion of these viral DNA preparations contained a frame-shift mutation within the M135R gene that has previously been identified as a virulence factor. This frame-shift mutation results in expression of a greatly truncated product. The same frame-shift mutation has also been found recently within an avirulent strain of myxoma virus (6918). However, three other frame-shift mutations found in this strain (in the genes M009L, M036L and M148R) were not shared with the Danish viruses but a single nucleotide deletion in the M138R/M139R intergenic region was a common feature.</p> <p>Conclusions</p> <p>It appears that expression of the full-length myxoma virus M135R protein is not required for virulence in rabbits. Hence, the frame-shift mutation in the M135R gene in the nonpathogenic 6918 virus strain is not sufficient to explain the attenuation of this myxoma virus but one/some of the other frame-shift mutations alone or in conjunction with one/some of the thirty two amino acid substitutions must also contribute. The real time PCR assay for myxoma virus is a useful diagnostic tool for laboratory confirmation of suspected cases of myxomatosis.</p

Influence of arthritis and non-arthritis related factors on areal bone mineral density (BMDa) in women with longstanding inflammatory polyarthritis: a primary care based inception cohort

<p>Abstract</p> <p>Background</p> <p>The aim of this analysis was to determine the relative influence of disease and non-disease factors on areal bone mineral density (BMD_a) in a primary care based cohort of women with inflammatory polyarthritis.</p> <p>Methods</p> <p>Women aged 16 years and over with recent onset inflammatory polyarthritis were recruited to the Norfolk Arthritis Register (NOAR) between 1990 and 1993. Subjects were examined at both baseline and follow up for the presence of tender, swollen and deformed joints. At the 10^thanniversary visit, a sub-sample of women were invited to complete a bone health questionnaire and attend for BMD_a(Hologic, QDR 4000). Linear regression was used to examine the association between BMD_awith both (i) arthritis-related factors assessed at baseline and the 10^thanniversary visit and (ii) standard risk factors for osteoporosis. Adjustments were made for age.</p> <p>Results</p> <p>108 women, mean age 58.0 years were studied. Older age, decreasing weight and BMI at follow up were all associated with lower BMD_aat both the spine and femoral neck. None of the lifestyle factors were linked. Indices of joint damage including 10^thanniversary deformed joint count and erosive joint count were the arthritis-related variables linked with a reduction in BMD_aat the femoral neck. By contrast, disease activity as determined by the number of tender and or swollen joints assessed both at baseline and follow up was not linked with BMD_aat either site.</p> <p>Conclusion</p> <p>Cumulative disease damage was the strongest predictor of reduced femoral bone density. Other disease and lifestyle factors have only a modest influence.</p

Pathways to Care: Duration of Untreated Psychosis from Karachi, Pakistan

Background: Substantial amount of time is lost before initiation of treatment in Schizophrenia. The delay in treatment is labelled as Duration of Untreated Psychosis (DUP). Most of these estimates come from western countries, where health systems are relatively better developed. There is dearth of information on pathway to care from developing countries. Methods And Results: Patients with ICD-10 based diagnosis of Schizophrenia were enrolled by convenient method of sampling. The pathway to care was explored through a semi-structured questionnaire. Onset, course and symptoms of psychosis were assessed using Interview for the Retrospective Assessment of the Onset of Schizophrenia (IRAOS). Ethical approval of the project was taken from The Aga Khan University, Ethics Review Committee. Of the enrolled 93 subjects, 55 (59%) were males and 38 (41%) were females. In our sample, 1.56 mean (median, 2) attempts were made prior to successful help seeking. The duration of untreated psychosis was 14.8 months (St. Deviation, 29.4). DUP was 16.8 months (St. Deviation, 34.9) for males and 11.8 months (St. Deviation, 18.9) for females. In the pathway to care, psychiatrists featured prominently as initial care providers. In the first attempt at help-seeking, 43% Patients were initially taken to psychiatrists. After the initial consultation, 45% were prescribed psychotropic medication while 7% were hospitalized. Only 9% subjects were given the diagnosis of schizophrenia initially. When participants were inquired about the reasons for delay, 29% reported financial difficulties as the barrier to care. Positive symptoms of psychosis were present in 57% subjects while negative symptoms were present in 30% subjects. There was a statistically significant difference (Chi-square, 7.928, df: 1, Sig 0.005) between DUP and the positive and negative symptoms category. Conclusion: In the absence of well developed primary care health system in Pakistan, majority of Patients present to psychiatrists as a first contact. DUP, as a measurement of help seeking behaviour, tends to be shorter with positive symptoms of Schizophrenia. Substantial amount of time is lost due to non recognition of disease and subsequently, inadequate treatment. Secondary prevention strategies should focus on families, which play an important role in the treatment-seeking process of psychotic Patients

Ultrasound-Mediated DNA Transformation in Thermophilic Gram-Positive Anaerobes

Thermophilic, Gram-positive, anaerobic bacteria (TGPAs) are generally recalcitrant to chemical and electrotransformation due to their special cell-wall structure and the low intrinsic permeability of plasma membranes. transformants/µg of methylated DNA. Delivery into X514 cells was confirmed via detecting the kanamycin-resistance gene for pIKM2, while confirmation of pHL015 was detected by visualization of fluorescence signals of secondary host-cells following a plasmid-rescue experiment. Furthermore, the foreign β-1,4-glucanase gene was functionally expressed in X514, converting the host into a prototypic thermophilic consolidated bioprocessing organism that is not only ethanologenic but cellulolytic.In this study, we developed an ultrasound-based sonoporation method in TGPAs. This new DNA-delivery method could significantly improve the throughput in developing genetic systems for TGPAs, many of which are of industrial interest yet remain difficult to manipulate genetically

Interpopulation differences in expression of candidate genes for salinity tolerance in winter migrating anadromous brown trout (Salmo trutta L.)

<p>Abstract</p> <p>Background</p> <p>Winter migration of immature brown trout (<it>Salmo trutta</it>) into freshwater rivers has been hypothesized to result from physiologically stressful combinations of high salinity and low temperature in the sea.</p> <p>Results</p> <p>We sampled brown trout from two Danish populations entering different saline conditions and quantified expression of the <it>hsp70 </it>and <it>Na/K-ATPases α 1b </it>genes following acclimation to freshwater and full-strength seawater at 2°C and 10°C. An interaction effect of low temperature and high salinity on expression of both <it>hsp70 </it>and <it>Na/K-ATPase α 1b </it>was found in trout from the river entering high saline conditions, while a temperature independent up-regulation of both genes in full-strength seawater was found for trout entering marine conditions with lower salinities.</p> <p>Conclusion</p> <p>Overall our results support the hypothesis that physiologically stressful conditions in the sea drive sea-run brown trout into freshwater rivers in winter. However, our results also demonstrate intra-specific differences in expression of important stress and osmoregulative genes most likely reflecting adaptive differences between trout populations on a regional scale, thus strongly suggesting local adaptations driven by the local marine environment.</p