Lack of association between polymorphisms of MASP2 and susceptibility to SARS coronavirus infection

<p>Abstract</p> <p>Background</p> <p>The pathogenesis of severe acute respiratory disease syndrome (SARS) is not fully understood. One case-control study has reported an association between susceptibility to SARS and <it>mannan-binding lectin </it>(<it>MBL</it>) in China. As the downstream protein of <it>MBL</it>, variants of the <it>MBL</it>-associated serine protease-2 (<it>MASP2</it>) gene may be associated with SARS coronavirus (SARS-CoV) infection in the same population.</p> <p>Methods</p> <p>Thirty individuals with SARS were chosen for analysis of <it>MASP2 </it>polymorphisms by means of PCR direct sequencing. Tag single nucleotide polymorphisms (tagSNPs) were chosen using pairwise tagging algorithms. The frequencies of four tag SNPs (rs12711521, rs2261695, rs2273346 and rs7548659) were ascertained in 376 SARS patients and 523 control subjects, using the Beckman SNPstream Ultra High Throughput genotyping platform.</p> <p>Results</p> <p>There is no significant association between alleles or genotypes of the <it>MASP2 </it>tagSNP and susceptibility to SARS-CoV in both Beijing and Guangzhou populations. Diplotype (rs2273346 and rs12711521)were analyzed for association with susceptibility to SARS, no statistically significant evidence of association was observed. The Beijing and Guangzhou sample groups were homogeneous regarding demographic and genetic parameters, a joined analysis also showed no statistically significant evidence of association.</p> <p>Conclusion</p> <p>Our data do not suggest a role for <it>MASP2 </it>polymorphisms in SARS susceptibility in northern and southern China.</p

Topcolor assisted technicolor models and muon anomalous magnetic moment

We discuss and estimate the contributions of the new particles predicted by topcolor assisted technicolor(TC2) models to the muon anomalous magnetic moment $a_{\mu}$. Our results show that the contributions of Pseudo Goldstone bosons are very small which can be safely ignored. The main contributions come from the ETC gauge boson $x_{\mu}$ and topcolor gauge boson $Z^{\prime}$. If we demand that the mass of $Z^{\prime}$ is consistent with other experimental constrains, its contributions are smaller than that of $x_{\mu}$. With reasonable values of the parameters in TC2 models, the observed BNL results for $a_{\mu}$ could be explained.Comment: latex file, 11 pages, several figures and references adde

TraceDiag: Adaptive, Interpretable, and Efficient Root Cause Analysis on Large-Scale Microservice Systems

Root Cause Analysis (RCA) is becoming increasingly crucial for ensuring the reliability of microservice systems. However, performing RCA on modern microservice systems can be challenging due to their large scale, as they usually comprise hundreds of components, leading significant human effort. This paper proposes TraceDiag, an end-to-end RCA framework that addresses the challenges for large-scale microservice systems. It leverages reinforcement learning to learn a pruning policy for the service dependency graph to automatically eliminates redundant components, thereby significantly improving the RCA efficiency. The learned pruning policy is interpretable and fully adaptive to new RCA instances. With the pruned graph, a causal-based method can be executed with high accuracy and efficiency. The proposed TraceDiag framework is evaluated on real data traces collected from the Microsoft Exchange system, and demonstrates superior performance compared to state-of-the-art RCA approaches. Notably, TraceDiag has been integrated as a critical component in the Microsoft M365 Exchange, resulting in a significant improvement in the system's reliability and a considerable reduction in the human effort required for RCA

Self-reported data: a major tool to assess compliance with anti-malarial combination therapy among children in Senegal

Background: Although there are many methods available for measuring compliance, there is no formal gold standard. Different techniques used to measure compliance were compared among children treated by the anti-malarial amodiaquine/sulphadoxine-pyrimethamine (AQ/SP) combination therapy, in use in Senegal between 2004 and 2006. Methods: The study was carried out in 2004, in five health centres located in the Thies region (Senegal). Children who had AQ/SP prescribed for three and one day respectively at the health centre were recruited. The day following the theoretical last intake of AQ, venous blood, and urine samples were collected for anti-malarial drugs dosage. Caregivers and children above five years were interviewed concerning children's drug intake. Results: Among the children, 64.7% adhered to 80% of the prescribed dose and only 37.7% were strict full adherent to the prescription. There was 72.7% agreement between self-reported data and blood drug dosage for amodiaquine treatment. Concerning SP, results found that blood dosages were 91.4% concordant with urine tests and 90% with self-reported data based on questionnaires. Conclusion: Self-reported data could provide useful quantitative information on drug intake and administration. Under strict methodological conditions this method, easy to implement, can be used to describe patients' behaviors and their use of new anti-malarial treatment. Self-reported data is a major tool for assessing compliance in resource poor countries. Blood and urine drug dosages provide qualitative results that confirm any drug intake. Urine assays for SP could be useful to obtain public health data, for example on chemoprophylaxis among pregnant women

Adherence of community caretakers of children to pre-packaged antimalarial medicines (HOMAPAK(®)) among internally displaced people in Gulu district, Uganda

BACKGROUND: In 2002, home-based management of fever (HBMF) was introduced in Uganda, to improve access to prompt, effective antimalarial treatment of all fevers in children under 5 years. Implementation is through community drug distributors (CDDs) who distribute pre-packaged chloroquine plus sulfadoxine-pyrimethamine (HOMAPAK(®)) free of charge to caretakers of febrile children. Adherence of caretakers to this regimen has not been studied. METHODS: A questionnaire-based survey combined with inspection of blister packaging was conducted to investigate caretakers' adherence to HOMAPAK(®). The population surveyed consisted of internally displaced people (IDPs) from eight camps. RESULTS: A total of 241 caretakers were interviewed. 95.0% (CI: 93.3% – 98.4%) of their children had received the correct dose for their age and 52.3% of caretakers had retained the blister pack. Assuming correct self-reporting, the overall adherence was 96.3% (CI: 93.9% – 98.7%). The nine caretakers who had not adhered had done so because the child had improved, had vomited, did not like the taste of the tablets, or because they forgot to administer the treatment. For 85.5% of cases treatment had been sought within 24 hours. Blister packaging was considered useful by virtually all respondents, mainly because it kept the drugs clean and dry. Information provided on, and inside, the package was of limited use, because most respondents were illiterate. However, CDDs had often told caretakers how to administer the treatment. For 39.4% of respondents consultation with the CDD was their reported first action when their child has fever and 52.7% stated that they consult her/him if the child does not get better. CONCLUSION: In IDP camps, the HBMF strategy forms an important component of medical care for young children. In case of febrile illness, most caretakers obtain prompt and adequate antimalarial treatment, and adhere to it. A large proportion of malaria episodes are thus likely to be treated before complications can arise. Implementation in the IDP camps now needs to focus on improving monitoring, supervision and general support to CDDs, as well as on targeting them and caretakers with educational messages. The national treatment policy for uncomplicated malaria has recently been changed to artemether-lumefantrine. Discussions on a suitable replacement combination for HBMF are well advanced, and have raised new questions about adherence

The gap in injury mortality rates between urban and rural residents of Hubei province, China

<p>Abstract</p> <p>Background</p> <p>Injury is a growing public health concern in China. Injury death rates are often higher in rural areas than in urban areas in general. The objective of this study is to compare the injury mortality rates in urban and rural residents in Hubei Province in central China by age, sex and mechanism of injury.</p> <p>Methods</p> <p>Using data from the Disease Surveillance Points (DSP) system maintained by the Hubei Province Centers for Disease Control and Prevention (CDC) from 2006 to 2008, injury deaths were classified according to the International Classification of Disease-10^thRevision (ICD-10). Crude and age-adjusted annual mortality rates were calculated for rural and urban residents of Hubei Province.</p> <p>Results</p> <p>The crude and age-adjusted injury death rates were significantly higher for rural residents than for urban residents (crude rate ratio 1.9, 95% confidence interval 1.8-2.0; adjusted rate ratio 2.4, 95% confidence interval 2.3-2.4). The age-adjusted injury death rate for males was 81.6/100,000 in rural areas compared with 37.0/100 000 in urban areas; for females, the respective rates were 57.9/100,000 and 22.4/100 000. Death rates for suicide (32.4 per 100 000 vs 3.9 per 100 000), traffic-related injuries (15.8 per 100 000 vs 9.5 per 100 000), drowning (6.9 per 100 000 vs 2.3 per 100 000) and crushing injuries (2.0 per 100 000 vs 0.7 per 100 000) were significantly higher in rural areas. Overall injury death rates were much higher in persons over 65 years, with significantly higher rates in rural residents compared with urban residents for suicide (279.8 per 100 000 vs 10.7 per 100 000), traffic-related injuries, and drownings in this age group. Death rates for falls, poisoning, and suffocation were similar in the two geographic groups.</p> <p>Conclusions</p> <p>Rates of suicide, traffic-related injury deaths and drownings are demonstrably higher in rural compared with urban locations and should be targeted for injury prevention activity. There is a need for injury prevention policies targeted at elderly residents, especially with regard to suicide prevention in rural areas in Central China.</p

Genetic Variation of the Human α-2-Heremans-Schmid Glycoprotein (AHSG) Gene Associated with the Risk of SARS-CoV Infection

Genetic background may play an important role in the process of SARS-CoV infection and SARS development. We found several proteins that could interact with the nucleocapsid protein of the SARS coronavirus (SARS-CoV). α-2-Heremans-Schmid Glycoprotein (AHSG), which is required for macrophage deactivation by endogenous cations, is associated with inflammatory regulation. Cytochrome P450 Family 3A (CYP4F3A) is an ω-oxidase that inactivates Leukotriene B4 (LTB4) in human neutrophils and the liver. We investigated the association between the polymorphisms of these two inflammation-associated genes and SARS development. The linkage disequilibrium (LD) maps of these two genes were built with Haploview using data on CHB+JPT (version 2) from the HapMap. A total of ten tag SNPs were selected and genotyped. In the Guangzhou cohort study, after adjusting for age and sex, two AHSG SNPs and one CYP4F3 SNP were found to be associated with SARS susceptibility: rs2248690 (adjusted odds ratio [AOR] 2.42; 95% confidence interval [CI] 1.30-4.51); rs4917 (AOR 1.84; 95% CI 1.02-3.34); and rs3794987 (AOR 2.01; 95% CI 1.10–3.68). To further validate the association, the ten tag SNPs were genotyped in the Beijing cohort. After adjusting for age and sex, only rs2248690 (AOR, 1.63; 95% CI, 1.30–2.04) was found to be associated with SARS susceptibility. The combined analysis of the two studies confirmed tag SNP rs2248690 in AHSG as a susceptibility variant (AOR 1.70; 95% CI 1.37–2.09). The statistical analysis of the rs2248690 genotype data among the patients and healthy controls in the HCW cohort, who were all similarly exposed to the SARS virus, also supported the findings. Further, the SNP rs2248690 affected the transcriptional activity of the AHSG promoter and thus regulated the AHSG serum level. Therefore, our study has demonstrated that the AA genotype of rs2268690, which leads to a higher AHSG serum concentration, was significantly associated with protection against SARS development

Phage Display against Corneal Epithelial Cells Produced Bioactive Peptides That Inhibit Aspergillus Adhesion to the Corneas

Dissection of host-pathogen interactions is important for both understanding the pathogenesis of infectious diseases and developing therapeutics for the infectious diseases like various infectious keratitis. To enhance the knowledge about pathogenesis infectious keratitis, a random 12-mer peptide phage display library was screened against cultured human corneal epithelial cells (HCEC). Fourteen sequences were obtained and BLASTp analysis showed that most of their homologue counterparts in GenBank were for defined or putative proteins in various pathogens. Based on known or predicted functions of the homologue proteins, ten synthetic peptides (Pc-A to Pc-J) were measured for their affinity to bind cells and their potential efficacy to interfere with pathogen adhesion to the cells. Besides binding to HCEC, most of them also bound to human corneal stromal cells and umbilical endothelial cells to different extents. When added to HCEC culture, the peptides induced expression of MyD88 and IL-17 in HCEC, and the stimulated cell culture medium showed fungicidal potency to various extents. While peptides Pc-C and Pc-E inhibited Aspergillus fumigatus (A.f) adhesion to HCEC in a dose-dependent manner, the similar inhibition ability of peptides Pc-A and Pc-B required presence of their homologue ligand Alb1p on A.f. When utilized in an eyeball organ culture model and an in vivo A.f keratitis model established in mouse, Pc-C and Pc-E inhibited fungal adhesion to corneas, hence decreased corneal disruption caused by inflammatory infiltration. Affinity pull-down of HCEC membrane proteins with peptide Pc-C revealed several molecules as potential receptors for this peptide. In conclusion, besides proving that phage display-selected peptides could be utilized to interfere with adhesion of pathogens to host cells, hence could be exploited for managing infectious diseases including infectious keratitis, we also proposed that the phage display technique and the resultant peptides could be used to explore host-pathogen interactions at molecular levels

Lysine-Specific Demethylase 1 (LSD1) Is Required for the Transcriptional Repression of the Telomerase Reverse Transcriptase (hTERT) Gene

BACKGROUND: Lysine-specific demethylase 1 (LSD1), catalysing demethylation of mono- and di-methylated histone H3-K4 or K9, exhibits diverse transcriptional activities by mediating chromatin reconfiguration. The telomerase reverse transcriptase (hTERT) gene, encoding an essential component for telomerase activity that is involved in cellular immortalization and transformation, is silent in most normal human cells while activated in up to 90% of human cancers. It remains to be defined how exactly the transcriptional activation of the hTERT gene occurs during the oncogenic process. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, we determined the effect of LSD1 on hTERT transcription. In normal human fibroblasts with a tight hTERT repression, a pharmacological inhibition of LSD1 led to a weak hTERT expression, and a robust induction of hTERT mRNA was observed when LSD1 and histone deacetylases (HDACs) were both inhibited. Small interference RNA-mediated depletion of both LSD1 and CoREST, a co-repressor in HDAC-containing complexes, synergistically activated hTERT transcription. In cancer cells, inhibition of LSD1 activity or knocking-down of its expression led to significant increases in levels of hTERT mRNA and telomerase activity. Chromatin immunoprecipitation assay showed that LSD1 occupied the hTERT proximal promoter, and its depletion resulted in elevated di-methylation of histone H3-K4 accompanied by increased H3 acetylation locally in cancer cells. Moreover, during the differentiation of leukemic HL60 cells, the decreased hTERT expression was accompanied by the LSD1 recruitment to the hTERT promoter. CONCLUSIONS/SIGNIFICANCE: LSD1 represses hTERT transcription via demethylating H3-K4 in normal and cancerous cells, and together with HDACs, participates in the establishment of a stable repression state of the hTERT gene in normal or differentiated malignant cells. The findings contribute to better understandings of hTERT/telomerase regulation, which may be implicated in the development of therapeutic strategies for telomerase dysregulation-associated human diseases including cancers