Approximating Nearest Neighbor Distances

Several researchers proposed using non-Euclidean metrics on point sets in Euclidean space for clustering noisy data. Almost always, a distance function is desired that recognizes the closeness of the points in the same cluster, even if the Euclidean cluster diameter is large. Therefore, it is preferred to assign smaller costs to the paths that stay close to the input points. In this paper, we consider the most natural metric with this property, which we call the nearest neighbor metric. Given a point set P and a path $\gamma$, our metric charges each point of $\gamma$ with its distance to P. The total charge along $\gamma$ determines its nearest neighbor length, which is formally defined as the integral of the distance to the input points along the curve. We describe a $(3+\varepsilon)$-approximation algorithm and a $(1+\varepsilon)$-approximation algorithm to compute the nearest neighbor metric. Both approximation algorithms work in near-linear time. The former uses shortest paths on a sparse graph using only the input points. The latter uses a sparse sample of the ambient space, to find good approximate geodesic paths.Comment: corrected author nam

Characterization of gene expression on genomic segment 7 of infectious salmon anaemia virus

BACKGROUND: Infectious salmon anaemia (ISA) virus (ISAV), an important pathogen of fish that causes disease accompanied by high mortality in marine-farmed Atlantic salmon, is the only species in the genus Isavirus, one of the five genera of the Orthomyxoviridae family. The Isavirus genome consists of eight single-stranded RNA species, and the virions have two surface glycoproteins; haemagglutinin-esterase (HE) protein encoded on segment 6 and fusion (F) protein encoded on segment 5. Based on the initial demonstration of two 5'-coterminal mRNA transcripts by RT-PCR, ISAV genomic segment 7 was suggested to share a similar coding strategy with segment 7 of influenza A virus, encoding two proteins. However, there appears to be confusion as to the protein sizes predicted from the two open reading frames (ORFs) of ISAV segment 7 which has in turn led to confusion of the predicted protein functions. The primary goal of the present work was to clone and express these two ORFs in order to assess whether the predicted protein sizes match those of the expressed proteins so as to clarify the coding assignments, and thereby identify any additional structural proteins of ISAV. RESULTS: In the present study we show that ISAV segment 7 encodes 3 proteins with estimated molecular masses of 32, 18, and 9.5 kDa. The 18-kDa and 9.5-kDa products are based on removal of an intron each from the primary transcript (7-ORF1) so that the translation continues in the +2 and +3 reading frames, respectively. The segment 7-ORF1/3 product is variably truncated in the sequence of ISAV isolates of the European genotype. All three proteins are recognized by rabbit antiserum against the 32-kDa product of the primary transcript, as they all share the N-terminal 22 amino acids. This antiserum detected a single 35-kDa protein in Western blots of purified virus, and immunoprecipitated a 32-kDa protein in ISAV-infected TO cells. Immunofluorescence staining of infected cells with the same antiserum revealed the protein(s) to be localized in the cytoplasm. Vaccination of farmed Atlantic salmon with the 32-kDa protein resulted in a higher survival rate than what was attainable with the HE protein, albeit a moderate protection against the low ISAV challenge. CONCLUSION: Collectively, our observations suggest that the product of ISAV segment 7 primary transcript (7-ORF1) is a structural protein. The 18-kDa (7-ORF1/2) protein is identified as the putative ISAV nuclear export protein based on the presence of nuclear export signals. The function of the 9.5-kDa (7-ORF1/3) protein is not presently known

Moduli Redefinitions and Moduli Stabilisation

Field redefinitions occur in string compactifications at the one loop level. We review arguments for why such redefinitions occur and study their effect on moduli stabilisation and supersymmetry breaking in the LARGE volume scenario. For small moduli, although the effect of such redefinitions can be larger than that of the $\alpha'$ corrections in both the K\"ahler and scalar potentials, they do not alter the structure of the scalar potential. For the less well motivated case of large moduli, the redefinitions can dominate all other terms in the scalar potential. We also study the effect of redefinitions on the structure of supersymmetry breaking and soft terms.Comment: 21 pages, 3 figures; v2. references adde

Deletion of parasite immune modulatory sequences combined with immune activating signals enhances vaccine mediated protection against filarial nematodes

<p>Background: Filarial nematodes are tissue-dwelling parasites that can be killed by Th2-driven immune effectors, but that have evolved to withstand immune attack and establish chronic infections by suppressing host immunity. As a consequence, the efficacy of a vaccine against filariasis may depend on its capacity to counter parasite-driven immunomodulation.</p> <p>Methodology and Principal Findings: We immunised mice with DNA plasmids expressing functionally-inactivated forms of two immunomodulatory molecules expressed by the filarial parasite Litomosoides sigmodontis: the abundant larval transcript-1 (LsALT) and cysteine protease inhibitor-2 (LsCPI). The mutant proteins enhanced antibody and cytokine responses to live parasite challenge, and led to more leukocyte recruitment to the site of infection than their native forms. The immune response was further enhanced when the antigens were targeted to dendritic cells using a single chain Fv-αDEC205 antibody and co-administered with plasmids that enhance T helper 2 immunity (IL-4) and antigen-presenting cell recruitment (Flt3L, MIP-1α). Mice immunised simultaneously against the mutated forms of LsALT and LsCPI eliminated adult parasites faster and consistently reduced peripheral microfilaraemia. A multifactorial analysis of the immune response revealed that protection was strongly correlated with the production of parasite-specific IgG1 and with the numbers of leukocytes present at the site of infection.</p> <p>Conclusions: We have developed a successful strategy for DNA vaccination against a nematode infection that specifically targets parasite-driven immunosuppression while simultaneously enhancing Th2 immune responses and parasite antigen presentation by dendritic cells.</p&gt

LXR Deficiency Confers Increased Protection against Visceral Leishmania Infection in Mice

Leishmania spp. are protozoan single-cell parasites that are transmitted to humans by the bite of an infected sand fly, and can cause a wide spectrum of disease, ranging from self-healing skin lesions to potentially fatal systemic infections. Certain species of Leishmania that cause visceral (systemic) disease are a source of significant mortality worldwide. Here, we use a mouse model of visceral Leishmania infection to investigate the effect of a host gene called LXR. The LXRs have demonstrated important functions in both cholesterol regulation and inflammation. These processes, in turn, are closely related to lipid metabolism and the development of atherosclerosis. LXRs have also previously been shown to be involved in protection against other intracellular pathogens that infect macrophages, including certain bacteria. We demonstrate here that LXR is involved in susceptibility to Leishmania, as animals deficient in the LXR gene are much more resistant to infection with the parasite. We also demonstrate that macrophages lacking LXR kill parasites more readily, and make higher levels of nitric oxide (an antimicrobial mediator) and IL-1β (an inflammatory cytokine) in response to Leishmania infection. These results could have important implications in designing therapeutics against this deadly pathogen, as well as other intracellular microbial pathogens

Internal construct validity of the Warwick-Edinburgh Mental Well-being Scale (WEMWBS): a Rasch analysis using data from the Scottish Health Education Population Survey

Background: The Warwick-Edinburgh Mental Well-Being Scale (WEMWBS) was developed to meet demand for instruments to measure mental well-being. It comprises 14 positively phrased Likert-style items and fulfils classic criteria for scale development. We report here the internal construct validity of WEMWBS from the perspective of the Rasch measurement model. Methods: The model was applied to data collected from 779 respondents in Wave 12 (Autumn 2006) of the Scottish Health Education Population Survey. Respondents were aged 16–74 (average 41.9) yrs. Results: Initial fit to model expectations was poor. The items 'I've been feeling good about myself', 'I've been interested in new things' and 'I've been feeling cheerful' all showed significant misfit to model expectations, and were deleted. This led to a marginal improvement in fit to the model. After further analysis, more items were deleted and a strict unidimensional seven item scale (the Short Warwick Edinburgh Mental Well-Being Scale (SWEMWBS)) was resolved. Many items deleted because of misfit with model expectations showed considerable bias for gender. Two retained items also demonstrated bias for gender but, at the scale level, cancelled out. One further retained item 'I've been feeling optimistic about the future' showed bias for age. The correlation between the 14 item and 7 item versions was 0.954. Given fit to the Rasch model, and strict unidimensionality, SWEMWBS provides an interval scale estimate of mental well-being. Conclusion: A short 7 item version of WEMWBS was found to satisfy the strict unidimensionality expectations of the Rasch model, and be largely free of bias. This scale, SWEMWBS, provides a raw score-interval scale transformation for use in parametric procedures. In terms of face validity, SWEMWBS presents a more restricted view of mental well-being than the 14 item WEMWBS, with most items representing aspects of psychological and eudemonic well-being, and few covering hedonic well-being or affect. However, robust measurement properties combined with brevity make SWEMWBS preferable to WEMWBS at present for monitoring mental well-being in populations. Where face validity is an issue there remain arguments for continuing to collect data on the full 14 item WEMWBS

Activation of Human Stearoyl-Coenzyme A Desaturase 1 Contributes to the Lipogenic Effect of PXR in HepG2 Cells

The pregnane X receptor (PXR) was previously known as a xenobiotic receptor. Several recent studies suggested that PXR also played an important role in lipid homeostasis but the underlying mechanism remains to be clearly defined. In this study, we found that rifampicin, an agonist of human PXR, induced lipid accumulation in HepG2 cells. Lipid analysis showed the total cholesterol level increased. However, the free cholesterol and triglyceride levels were not changed. Treatment of HepG2 cells with rifampicin induced the expression of the free fatty acid transporter CD36 and ABCG1, as well as several lipogenic enzymes, including stearoyl-CoA desaturase-1 (SCD1), long chain free fatty acid elongase (FAE), and lecithin-cholesterol acyltransferase (LCAT), while the expression of acyl:cholesterol acetyltransferase(ACAT1) was not affected. Moreover, in PXR over-expressing HepG2 cells (HepG2-PXR), the SCD1 expression was significantly higher than in HepG2-Vector cells, even in the absence of rifampicin. Down-regulation of PXR by shRNA abolished the rifampicin-induced SCD1 gene expression in HepG2 cells. Promoter analysis showed that the human SCD1 gene promoter is activated by PXR and a novel DR-7 type PXR response element (PXRE) response element was located at -338 bp of the SCD1 gene promoter. Taken together, these results indicated that PXR activation promoted lipid synthesis in HepG2 cells and SCD1 is a novel PXR target gene. © 2013 Zhang et al

Adherence to self-administered tuberculosis treatment in a high HIV-prevalence setting: a cross-sectional survey in Homa Bay, Kenya.

Good adherence to treatment is crucial to control tuberculosis (TB). Efficiency and feasibility of directly observed therapy (DOT) under routine program conditions have been questioned. As an alternative, Médecins sans Frontières introduced self-administered therapy (SAT) in several TB programs. We aimed to measure adherence to TB treatment among patients receiving TB chemotherapy with fixed dose combination (FDC) under SAT at the Homa Bay district hospital (Kenya). A second objective was to compare the adherence agreement between different assessment tools

Fully automated screening of veterinary drugs in milk by turbulent flow chromatography and tandem mass spectrometry

There is an increasing interest in screening methods for quick and sensitive analysis of various classes of veterinary drugs with limited sample pre-treatment. Turbulent flow chromatography in combination with tandem mass spectrometry has been applied for the first time as an efficient screening method in routine analysis of milk samples. Eight veterinary drugs, belonging to seven different classes were selected for this study. After developing and optimising the method, parameters such as linearity, repeatability, matrix effects and carry-over were studied. The screening method was then tested in the routine analysis of 12 raw milk samples. Even without internal standards, the linearity of the method was found to be good in the concentration range of 50 to 500 µg/L. Regarding repeatability, RSDs below 12% were obtained for all analytes, with only a few exceptions. The limits of detection were between 0.1 and 5.2 µg/L, far below the maximum residue levels for milk set by the EU regulations. While matrix effects—ion suppression or enhancement—are obtained for all the analytes the method has proved to be useful for screening purposes because of its sensitivity, linearity and repeatability. Furthermore, when performing the routine analysis of the raw milk samples, no false positive or negative results were obtained

Superpotential de-sequestering in string models

Non-perturbative superpotential cross-couplings between visible sector matter and K\"ahler moduli can lead to significant flavour-changing neutral currents in compactifications of type IIB string theory. Here, we compute corrections to Yukawa couplings in orbifold models with chiral matter localised on D3-branes and non-perturbative effects on distant D7-branes. By evaluating a threshold correction to the D7-brane gauge coupling, we determine conditions under which the non-perturbative corrections to the Yukawa couplings appear. The flavour structure of the induced Yukawa coupling generically fails to be aligned with the tree-flavour structure. We check our results by also evaluating a correlation function of two D7-brane gauginos and a D3-brane Yukawa coupling. Finally, by calculating a string amplitude between n hidden scalars and visible matter we show how non-vanishing vacuum expectation values of distant D7-brane scalars, if present, may correct visible Yukawa couplings with a flavour structure that differs from the tree-level flavour structure.Comment: 37 pages + appendices, 8 figure