Quantum oscillations from Fermi arcs

When a metal is subjected to strong magnetic field B nearly all measurable quantities exhibit oscillations periodic in 1/B. Such quantum oscillations represent a canonical probe of the defining aspect of a metal, its Fermi surface (FS). In this study we establish a new mechanism for quantum oscillations which requires only finite segments of a FS to exist. Oscillations periodic in 1/B occur if the FS segments are terminated by a pairing gap. Our results reconcile the recent breakthrough experiments showing quantum oscillations in a cuprate superconductor YBCO, with a well-established result of many angle resolved photoemission (ARPES) studies which consistently indicate "Fermi arcs" -- truncated segments of a Fermi surface -- in the normal state of the cuprates.Comment: 8 pages, 5 figure

IL-6 and hsCRP in Somatic Symptom Disorders and related disorders.

Interleukin 6 (IL-6) and high-sensitivity C-reactive protein (hsCRP) are biomarkers of systemic low-grade inflammation (SLI) in depression and anxiety. The question if SLI in those conditions is related to comorbid chronic medical conditions has not been resolved. DSM-5 Somatic symptom disorders and related disorders (SSRD) are conditions with serious distress related to physical symptoms as main criterion. They can occur in patients with medically unexplained symptoms (MUS) and in patients with known comorbid chronic medical conditions. Often, comorbid depression and anxiety are present. SSRDs offer the opportunity to explore the role of SLI in relation to mental distress, including trauma, MUS, chronic medical conditions and comorbid mental disorder. AIM: We hypothesized that increased IL-6 and hsCRP may be directly linked to SLI in SSRD, and that comorbid chronic medical conditions, childhood trauma, current stress and comorbid depression and anxiety may be risk factors that account for some of the variance of SLI in SSRD. METHODS: We explored these relationships in a large sample of 241 consecutive outpatients with SSRD. RESULTS: Mean hsCRP level was 3.66 ​mg/l, and mean IL-6 level was 3.58 ​pg/ml. IL-6 and hsCRP levels were associated with each other: τ ​= ​0.249, p ​< ​.001; a medium size correlation. Comorbid chronic medical conditions, adverse childhood events other than sexual trauma, and current stress levels were not associated with IL-6 or hsCRP levels. CONCLUSION: IL-6 and hsCRP are elevated in SSRD, indicating SLI in SSRD independently of comorbid chronic medical conditions. In clinical research, elevated IL-6 and hsCRP can be used as biomarkers of SLI and can indicate risk for childhood sexual abuse in SSRD. Elevated hsCRP may be a biomarker indicating risk for comorbid depression or high pain levels in SSRD as well

Piperidinols that show anti-tubercular activity as inhibitors of arylamine N-acetyltransferase: an essential enzyme for mycobacterial survival inside macrophages

Latent M. tuberculosis infection presents one of the major obstacles in the global eradication of tuberculosis (TB). Cholesterol plays a critical role in the persistence of M. tuberculosis within the macrophage during latent infection. Catabolism of cholesterol contributes to the pool of propionyl-CoA, a precursor that is incorporated into cell-wall lipids. Arylamine N-acetyltransferase (NAT) is encoded within a gene cluster that is involved in the cholesterol sterol-ring degradation and is essential for intracellular survival. The ability of the NAT from M. tuberculosis (TBNAT) to utilise propionyl-CoA links it to the cholesterol-catabolism pathway. Deleting the nat gene or inhibiting the NAT enzyme prevents intracellular survival and results in depletion of cell-wall lipids. TBNAT has been investigated as a potential target for TB therapies. From a previous high-throughput screen, 3-benzoyl-4-phenyl-1-methylpiperidinol was identified as a selective inhibitor of prokaryotic NAT that exhibited antimycobacterial activity. The compound resulted in time-dependent irreversible inhibition of the NAT activity when tested against NAT from M. marinum (MMNAT). To further evaluate the antimycobacterial activity and the NAT inhibition of this compound, four piperidinol analogues were tested. All five compounds exert potent antimycobacterial activity against M. tuberculosis with MIC values of 2.3-16.9 µM. Treatment of the MMNAT enzyme with this set of inhibitors resulted in an irreversible time-dependent inhibition of NAT activity. Here we investigate the mechanism of NAT inhibition by studying protein-ligand interactions using mass spectrometry in combination with enzyme analysis and structure determination. We propose a covalent mechanism of NAT inhibition that involves the formation of a reactive intermediate and selective cysteine residue modification. These piperidinols present a unique class of antimycobacterial compounds that have a novel mode of action different from known anti-tubercular drugs

Anal HPV Infection in HIV-Positive Men Who Have Sex with Men from China

BACKGROUND: Anal HPV infection, which contributes to the development of anal warts and anal cancer, is well known to be common among men who have sex with men (MSM), especially among those HIV positives. However, HIV and anal HPV co-infection among MSM has not been addressed in China. METHODS: A cross-sectional study was conducted in Beijing and Tianjin, China. Study participants were recruited using multiple methods with the collaboration of local volunteer organizations. Blood and anal swabs were collected for HIV-1 serological test and HPV genotyping. RESULTS: A total of 602 MSM were recruited and laboratory data were available for 578 of them (96.0%). HIV and anal HPV prevalence were 8.5% and 62.1%, respectively. And 48 MSM (8.3%) were found to be co-infected. The HPV genotypes identified most frequently were HPV06 (19.6%), HPV16 (13.0%), HPV52 (8.5%) and HPV11 (7.6%). Different modes of HPV genotypes distribution were observed with respect to HIV status. A strong dose-response relationship was found between HIV seropositivity and multiplicity of HPV genotypes (p<0.001), which is consistent with the observation that anal HPV infection was an independent predictor for HIV infection. CONCLUSIONS: A high prevalence of HIV and anal HPV co-infection was observed in the MSM community in Beijing and Tianjin, China. Anal HPV infection was found to be independently associated with increased HIV seropositivity, which suggests the application of HPV vaccine might be a potential strategy to reduce the acquisition of HIV infection though controlling the prevalence of HPV

Aqueous Cinnamon Extract (ACE-c) from the bark of Cinnamomum cassia causes apoptosis in human cervical cancer cell line (SiHa) through loss of mitochondrial membrane potential

<p>Abstract</p> <p>Background</p> <p>Chemoprevention, which includes the use of synthetic or natural agents (alone or in combination) to block the development of cancer in human beings, is an extremely promising strategy for cancer prevention. Cinnamon is one of the most widely used herbal medicines with diverse biological activities including anti-tumor activity. In the present study, we have reported the anti-neoplastic activity of cinnamon in cervical cancer cell line, SiHa.</p> <p>Methods</p> <p>The aqueous cinnamon extract (ACE-<it>c</it>) was analyzed for its cinnamaldehyde content by HPTLC analysis. The polyphenol content of ACE-<it>c </it>was measured by Folin-Ciocalteau method. Cytotoxicity analysis was performed by MTT assay. We studied the effect of cinnamon on growth kinetics by performing growth curve, colony formation and soft agar assays. The cells treated with ACE-<it>c </it>were analyzed for wound healing assay as well as for matrix metalloproteinase-2 (MMP-2) expression at mRNA and protein level by RT-PCR and zymography, respectively. Her-2 protein expression was analyzed in the control and ACE-<it>c </it>treated samples by immunoblotting as well as confocal microscopy. Apoptosis studies and calcium signaling assays were analyzed by FACS. Loss of mitochondrial membrane potential (Δψ_m) in cinnamon treated cells was studied by JC-1 staining and analyzed by confocal microscopy as well as FACS.</p> <p>Results</p> <p>Cinnamon alters the growth kinetics of SiHa cells in a dose-dependent manner. Cells treated with ACE-<it>c </it>exhibited reduced number of colonies compared to the control cells. The treated cells exhibited reduced migration potential that could be explained due to downregulation of MMP-2 expression. Interestingly, the expression of Her-2 oncoprotein was significantly reduced in the presence of ACE-<it>c</it>. Cinnamon extract induced apoptosis in the cervical cancer cells through increase in intracellular calcium signaling as well as loss of mitochondrial membrane potential.</p> <p>Conclusion</p> <p>Cinnamon could be used as a potent chemopreventive drug in cervical cancer.</p

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015

SummaryBackground The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors—the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6–58·8) of global deaths and 41·2% (39·8–42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding Bill & Melinda Gates Foundation

Cataloging Coding Sequence Variations in Human Genome Databases

BACKGROUND: With the recent growth of information on sequence variations in the human genome, predictions regarding the functional effects and relevance to disease phenotypes of coding sequence variations are becoming increasingly important. The aims of this study were to catalog protein-coding sequence variations (CVs) occurring in genetic variation databases and to use bioinformatic programs to analyze CVs. In addition, we aim to provide insight into the functionality of the reference databases. METHODOLOGY AND FINDINGS: To catalog CVs on a genome-wide scale with regard to protein function and disease, we investigated three representative databases; the Human Gene Mutation Database (HGMD), the Single Nucleotide Polymorphisms database (dbSNP), and the Haplotype Map (HapMap). Using these three databases, we analyzed CVs at the protein function level with bioinformatic programs. We proposed a combinatorial approach using the Support Vector Machine (SVM) to increase the performance of the prediction programs. By cataloging the coding sequence variations using these databases, we found that 4.36% of CVs from HGMD are concurrently registered in dbSNP (8.11% of CVs from dbSNP are concurrent in HGMD). The pattern of substitutions and functional consequences predicted by three bioinformatic programs was significantly different among concurrent CVs, and CVs occurring solely in HGMD or in dbSNP. The experimental results showed that the proposed SVM combination noticeably outperformed the individual prediction programs. CONCLUSIONS: This is the first study to compare human sequence variations in HGMD, dbSNP and HapMap at the genome-wide level. We found that a significant proportion of CVs in HGMD and dbSNP overlap, and we emphasize the need to use caution when interpreting the phenotypic relevance of these concurrent CVs. Combining bioinformatic programs can be helpful in predicting the functional consequences of CVs because it improved the performance of functional predictions

Abrogated Inflammatory Response Promotes Neurogenesis in a Murine Model of Japanese Encephalitis

Japanese encephalitis virus (JEV) induces neuroinflammation with typical features of viral encephalitis, including inflammatory cell infiltration, activation of microglia, and neuronal degeneration. The detrimental effects of inflammation on neurogenesis have been reported in various models of acute and chronic inflammation. We investigated whether JEV-induced inflammation has similar adverse effects on neurogenesis and whether those effects can be reversed using an anti-inflammatory compound minocycline.Here, using in vitro studies and mouse models, we observed that an acute inflammatory milieu is created in the subventricular neurogenic niche following Japanese encephalitis (JE) and a resultant impairment in neurogenesis occurs, which can be reversed with minocycline treatment. Immunohistological studies showed that proliferating cells were replenished and the population of migrating neuroblasts was restored in the niche following minocycline treatment. In vitro, we checked for the efficacy of minocycline as an anti-inflammatory compound and cytokine bead array showed that production of cyto/chemokines decreased in JEV-activated BV2 cells. Furthermore, mouse neurospheres grown in the conditioned media from JEV-activated microglia exhibit arrest in both proliferation and differentiation of the spheres compared to conditioned media from control microglia. These effects were completely reversed when conditioned media from JEV-activated and minocycline treated microglia was used.This study provides conclusive evidence that JEV-activated microglia and the resultant inflammatory molecules are anti-proliferative and anti-neurogenic for NSPCs growth and development, and therefore contribute to the viral neuropathogenesis. The role of minocycline in restoring neurogenesis may implicate enhanced neuronal repair and attenuation of the neuropsychiatric sequelae in JE survivors

Lost opportunities in HIV prevention: programmes miss places where exposures are highest

Background: Efforts at HIV prevention that focus on high risk places might be more effective and less stigmatizing than those targeting high risk groups. The objective of the present study was to assess risk behaviour patterns, signs of current preventive interventions and apparent gaps in places where the risk of HIV transmission is high and in communities with high HIV prevalence. Methods: The PLACE method was used to collect data. Inhabitants of selected communities in Lusaka and Livingstone were interviewed about where people met new sexual partners. Signs of HIV preventive activities in these places were recorded. At selected venues, people were interviewed about their sexual behaviour. Peer educators and staff of NGOs were also interviewed. Results: The places identified were mostly bars, restaurants or sherbeens, and fewer than 20% reported any HIV preventive activity such as meetings, pamphlets or posters. In 43% of places in Livingstone and 26% in Lusaka, condoms were never available. There were few active peer educators. Among the 432 persons in Lusaka and 676 in Livingstone who were invited for interview about sexual behaviour, consistent condom use was relatively high in Lusaka (77%) but low in Livingstone (44% of men and 34% of women). Having no condom available was the most common reason for not using one. Condom use in Livingstone was higher among individuals socializing in places where condoms always were available. Conclusion: In the places studied we found a high prevalence of behaviours with a high potential for HIV transmission but few signs of HIV preventive interventions. Covering the gaps in prevention in these high exposure places should be given the highest priority

Enhanced Discrimination of Malignant from Benign Pancreatic Disease by Measuring the CA 19-9 Antigen on Specific Protein Carriers

The CA 19-9 assay detects a carbohydrate antigen on multiple protein carriers, some of which may be preferential carriers of the antigen in cancer. We tested the hypothesis that the measurement of the CA 19-9 antigen on individual proteins could improve performance over the standard CA 19-9 assay. We used antibody arrays to measure the levels of the CA 19-9 antigen on multiple proteins in serum or plasma samples from patients with pancreatic adenocarcinoma or pancreatitis. Sample sets from three different institutions were examined, comprising 531 individual samples. The measurement of the CA 19-9 antigen on any individual protein did not improve upon the performance of the standard CA 19-9 assay (82% sensitivity at 75% specificity for early-stage cancer), owing to diversity among patients in their CA 19-9 protein carriers. However, a subset of cancer patients with no elevation in the standard CA 19-9 assay showed elevations of the CA 19-9 antigen specifically on the proteins MUC5AC or MUC16 in all sample sets. By combining measurements of the standard CA 19-9 assay with detection of CA 19-9 on MUC5AC and MUC16, the sensitivity of cancer detection was improved relative to CA 19-9 alone in each sample set, achieving 67–80% sensitivity at 98% specificity. This finding demonstrates the value of measuring glycans on specific proteins for improving biomarker performance. Diagnostic tests with improved sensitivity for detecting pancreatic cancer could have important applications for improving the treatment and management of patients suffering from this disease