Quantum skyrmions and the destruction of long-range antiferromagnetic order in the high-Tc superconductors La(2-x)Sr(x)CuO(4) and YBa(2)Cu(3)O(6+x)

We study the destruction of the antiferromagnetic order in the high-Tc superconductors La(2-x)Sr(x)CuO(4) and YBa(2)Cu(3)O(6+x) in the framework of the CP1-nonlinear sigma model formulation of the 2D quantum Heisenberg antiferromagnet. The dopants are introduced as independent fermions with appropriate dispersion relations determined by the shape of the Fermi surface. The energy of skyrmion topological defects, which are shown to be introduced by doping, is used as an order parameter for antiferromagnetic order. We obtain analytic expressions for this as a function of doping which allow us to plot the curves T_N(x_c)\times x_c and M(x)\times x, for both YBCO and LSCO, in good quantitative agreement with the experimental data.Comment: 4 pages, revtex, 5 embeeded figure

Predictors of Antibiotics Co-prescription with Antimalarials for Patients Presenting with Fever in Rural Tanzania.

Successful implementation of malaria treatment policy depends on the prescription practices for patients with malaria. This paper describes prescription patterns and assesses factors associated with co-prescription of antibiotics and artemether-lumefantrine (AL) for patients presenting with fever in rural Tanzania. From June 2009 to September 2011, a cohort event monitoring program was conducted among all patients treated at 8 selected health facilities in Ifakara and Rufiji Health and Demographic Surveillance System (HDSS).It included all patients presenting with fever and prescribed with AL. Logistic regression was used to model the predictors on the outcome variable which is co-prescription of AL and antibiotics on a single clinical visit. A cohort of 11,648 was recruited and followed up with 92% presenting with fever. Presumptive treatment was used in 56% of patients treated with AL. On average 2.4 (1 -- 7) drugs was prescribed per encounter, indicating co-prescription of AL with other drugs. Children under five had higher odds of AL and antibiotics co-prescription (OR = 0.63, 95% CI: 0.46 -- 0.85) than those aged more than five years. Patients testing negative had higher odds (OR = 2.22, 95%CI: 1.65 -- 2.97) of AL and antibiotics co-prescription. Patients receiving treatment from dispensaries had higher odds (OR = 1.45, 95% CI: 0.84 -- 2.30) of AL and antibiotics co-prescription than those from served in health centres even though the deference was not statistically significant. Regardless the fact that Malaria is declining but due to lack of laboratories and mRDT in most health facilities in the rural areas, clinicians are still treating malaria presumptively. This leads them to prescribe more drugs to treat all possibilities

Microbial ligand costimulation drives neutrophilic steroid-refractory asthma

Funding: The authors thank the Wellcome Trust (102705) and the Universities of Aberdeen and Cape Town for funding. This research was also supported, in part, by National Institutes of Health GM53522 and GM083016 to DLW. KF and BNL are funded by the Fonds Wetenschappelijk Onderzoek, BNL is the recipient of an European Research Commission consolidator grant and participates in the European Union FP7 programs EUBIOPRED and MedALL. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

The Endogenous Th17 Response in NO<inf>2</inf>-Promoted Allergic Airway Disease Is Dispensable for Airway Hyperresponsiveness and Distinct from Th17 Adoptive Transfer

Severe, glucocorticoid-resistant asthma comprises 5-7% of patients with asthma. IL-17 is a biomarker of severe asthma, and the adoptive transfer of Th17 cells in mice is sufficient to induce glucocorticoid-resistant allergic airway disease. Nitrogen dioxide (NO2) is an environmental toxin that correlates with asthma severity, exacerbation, and risk of adverse outcomes. Mice that are allergically sensitized to the antigen ovalbumin by exposure to NO2 exhibit a mixed Th2/Th17 adaptive immune response and eosinophil and neutrophil recruitment to the airway following antigen challenge, a phenotype reminiscent of severe clinical asthma. Because IL-1 receptor (IL-1R) signaling is critical in the generation of the Th17 response in vivo, we hypothesized that the IL-1R/Th17 axis contributes to pulmonary inflammation and airway hyperresponsiveness (AHR) in NO2-promoted allergic airway disease and manifests in glucocorticoid-resistant cytokine production. IL-17A neutralization at the time of antigen challenge or genetic deficiency in IL-1R resulted in decreased neutrophil recruitment to the airway following antigen challenge but did not protect against the development of AHR. Instead, IL-1R-/- mice developed exacerbated AHR compared to WT mice. Lung cells from NO2-allergically inflamed mice that were treated in vitro with dexamethasone (Dex) during antigen restimulation exhibited reduced Th17 cytokine production, whereas Th17 cytokine production by lung cells from recipient mice of in vitro Th17-polarized OTII T-cells was resistant to Dex. These results demonstrate that the IL-1R/Th17 axis does not contribute to AHR development in NO2-promoted allergic airway disease, that Th17 adoptive transfer does not necessarily reflect an endogenously-generated Th17 response, and that functions of Th17 responses are contingent on the experimental conditions in which they are generated. © 2013 Martin et al

Extensive transmission of isoniazid resistant M. tuberculosis and its association with increased multidrug-resistant TB in two rural counties of eastern China: A molecular epidemiological study

<p>Abstract</p> <p>Background</p> <p>The aim of this study was to investigate the molecular characteristics of isoniazid resistant <it>Mycobacterium tuberculosis </it>(MTB), as well as its contribution to the dissemination of multi-drug resistant TB (MDR-TB) in rural areas of eastern China.</p> <p>Methods</p> <p>A population-based epidemiological study was conducted in two rural counties of eastern China from 2004 to 2005. In total, 131 isoniazid resistant MTB isolates were molecularly characterized by DNA sequencing and genotyped by IS<it>6110 </it>restriction fragment length polymorphism (RFLP) and spoligotyping.</p> <p>Results</p> <p>The <it>katG</it>315Thr mutation was observed in 74 of 131 isoniazid resistant isolates and more likely to be MDR-TB (48.6%) and have mutations in <it>rpoB </it>gene (47.3%). Spoligotyping identified 80.2% of isoniazid resistant MTB isolates as belonging to the Beijing family. Cluster analysis by genotyping based on IS<it>6110 </it>RFLP, showed that 48.1% isoniazid resistant isolates were grouped into 26 clusters and <it>katG</it>315Thr mutants had a significantly higher clustering proportion compared to those with <it>katG </it>wild type (73%.vs.18%; OR, 12.70; 95%CI, 6.357-14.80). Thirty-one of the 53 MDR-TB isolates were observed in 19 clusters. Of these clusters, isoniazid resistance in MDR-TB isolates was all due to the <it>katG</it>315Thr mutation; 18 clusters also contained mono-isoniazid resistant and other isoniazid resistant isolates.</p> <p>Conclusions</p> <p>These results highlighted that isoniazid resistant MTB especially with <it>katG</it>315Thr is likely to be clustered in a community, develop extra resistance to rifampicin and become MDR-TB in Chinese rural settings.</p

Transmission Pattern of Drug-Resistant Tuberculosis and Its Implication for Tuberculosis Control in Eastern Rural China

OBJECTIVE: Transmission patterns of drug-resistant Mycobacterium tuberculosis (MTB) may be influenced by differences in socio-demographics, local tuberculosis (TB) endemicity and efficaciousness of TB control programs. This study aimed to investigate the impact of DOTS on the transmission of drug-resistant TB in eastern rural China. METHODS: We conducted a cross-sectional study of all patients diagnosed with drug-resistant TB over a one-year period in two rural Chinese counties with varying lengths of DOTS implementation. Counties included Deqing, with over 11 years' DOTS implementation and Guanyun, where DOTS was introduced 1 year prior to start of this study. We combined demographic, clinical and epidemiologic information with IS6110-based restricted fragment length polymorphism (RFLP) and Spoligotyping analysis of MTB isolates. In addition, we conducted DNA sequencing of resistance determining regions to first-line anti-tuberculosis agents. RESULTS: Of the 223 drug-resistant isolates, 73(32.7%) isolates were identified with clustered IS6110RFLP patterns. The clustering proportion among total drug-resistant TB was higher in Guanyun than Deqing (26/101.vs.47/122; p,0.04), but not significantly different among the 53 multidrug-resistant isolates (10/18.vs.24/35; p,0.35). Patients with cavitary had increased risk of clustering in both counties. In Guanyun, patients with positive smear test or previous treatment history had a higher clustering proportion. Beijing genotype and isolates resistant to isoniazid and/or rifampicin were more likely to be clustered. Of the 73 patients with clustered drug-resistant isolates, 71.2% lived in the same or neighboring villages. Epidemiological link (household and social contact) was confirmed in 12.3% of the clustered isolates. CONCLUSION: Transmission of drug-resistant TB in eastern rural China is characterized by small clusters and limited geographic spread. Our observations highlight the need for supplementing DOTS with additional strategies, including active case finding at the village level, effective treatment for patients with cavities and drug susceptibility testing for patients at increased risk for drug-resistance

ATG24 represses autophagy and differentiation and is essential for homeostasy of the flagellar pocket in trypanosoma brucei

We have previously identified homologs for nearly half of the approximately 30 known yeast Atg's in the genome database of the human sleeping sickness parasite Trypanosoma brucei. So far, only a few of these homologs have their role in autophagy experimentally confirmed. Among the candidates was the ortholog of Atg24 that is involved in pexophagy in yeast. In T. brucei, the peroxisome-like organelles named glycosomes harbor core metabolic processes, especially glycolysis. In the autotrophic yeast, autophagy is essential for adaptation to different nutritional environments by participating in the renewal of the peroxisome population. We hypothesized that autophagic turnover of the parasite's glycosomes plays a role in differentiation during its life cycle, which demands adaptation to different host environments and associated dramatic changes in nutritional conditions. We therefore characterized T. brucei ATG24, the T. brucei ortholog of yeast Atg24 and mammalian SNX4, and found it to have a regulatory role in autophagy and differentiation as well as endocytic trafficking. ATG24 partially localized on endocytic membranes where it was recruited via PI3-kinase III/VPS34. ATG24 silencing severely impaired receptor-mediated endocytosis of transferrin, but not adsorptive uptake of a lectin, and caused a major enlargement of the flagellar pocket. ATG24 silencing approximately doubled the number of autophagosomes, suggesting a role in repressing autophagy, and strongly accelerated differentiation, in accordance with a role of autophagy in parasite differentiation. Overexpression of the two isoforms of T. brucei ATG8 fused to GFP slowed down differentiation, possibly by a dominant-negative effect. This was overcome by ATG24 depletion, further supporting its regulatory role

A Large Gene Network in Immature Erythroid Cells Is Controlled by the Myeloid and B Cell Transcriptional Regulator PU.1

PU.1 is a hematopoietic transcription factor that is required for the development of myeloid and B cells. PU.1 is also expressed in erythroid progenitors, where it blocks erythroid differentiation by binding to and inhibiting the main erythroid promoting factor, GATA-1. However, other mechanisms by which PU.1 affects the fate of erythroid progenitors have not been thoroughly explored. Here, we used ChIP-Seq analysis for PU.1 and gene expression profiling in erythroid cells to show that PU.1 regulates an extensive network of genes that constitute major pathways for controlling growth and survival of immature erythroid cells. By analyzing fetal liver erythroid progenitors from mice with low PU.1 expression, we also show that the earliest erythroid committed cells are dramatically reduced in vivo. Furthermore, we find that PU.1 also regulates many of the same genes and pathways in other blood cells, leading us to propose that PU.1 is a multifaceted factor with overlapping, as well as distinct, functions in several hematopoietic lineages

Prion Uptake in the Gut: Identification of the First Uptake and Replication Sites

After oral exposure, prions are thought to enter Peyer's patches via M cells and accumulate first upon follicular dendritic cells (FDCs) before spreading to the nervous system. How prions are actually initially acquired from the gut lumen is not known. Using high-resolution immunofluorescence and cryo-immunogold electron microscopy, we report the trafficking of the prion protein (PrP) toward Peyer's patches of wild-type and PrP-deficient mice. PrP was transiently detectable at 1 day post feeding (dpf) within large multivesicular LAMP1-positive endosomes of enterocytes in the follicle-associated epithelium (FAE) and at much lower levels within M cells. Subsequently, PrP was detected on vesicles in the late endosomal compartments of macrophages in the subepithelial dome. At 7–21 dpf, increased PrP labelling was observed on the plasma membranes of FDCs in germinal centres of Peyer's patches from wild-type mice only, identifying FDCs as the first sites of PrP conversion and replication. Detection of PrP on extracellular vesicles displaying FAE enterocyte-derived A33 protein implied transport towards FDCs in association with FAE-derived vesicles. By 21 dpf, PrP was observed on the plasma membranes of neurons within neighbouring myenteric plexi. Together, these data identify a novel potential M cell-independent mechanism for prion transport, mediated by FAE enterocytes, which acts to initiate conversion and replication upon FDCs and subsequent infection of enteric nerves