The Wasteland of Random Supergravities

We show that in a general \cal{N} = 1 supergravity with N \gg 1 scalar fields, an exponentially small fraction of the de Sitter critical points are metastable vacua. Taking the superpotential and Kahler potential to be random functions, we construct a random matrix model for the Hessian matrix, which is well-approximated by the sum of a Wigner matrix and two Wishart matrices. We compute the eigenvalue spectrum analytically from the free convolution of the constituent spectra and find that in typical configurations, a significant fraction of the eigenvalues are negative. Building on the Tracy-Widom law governing fluctuations of extreme eigenvalues, we determine the probability P of a large fluctuation in which all the eigenvalues become positive. Strong eigenvalue repulsion makes this extremely unlikely: we find P \propto exp(-c N^p), with c, p being constants. For generic critical points we find p \approx 1.5, while for approximately-supersymmetric critical points, p \approx 1.3. Our results have significant implications for the counting of de Sitter vacua in string theory, but the number of vacua remains vast.Comment: 39 pages, 9 figures; v2: fixed typos, added refs and clarification

A Temporal Threshold for Formaldehyde Crosslinking and Fixation

Formaldehyde crosslinking is in widespread use as a biological fixative for microscopy and molecular biology. An assumption behind its use is that most biologically meaningful interactions are preserved by crosslinking, but the minimum length of time required for an interaction to become fixed has not been determined.Using a unique series of mutations in the DNA binding protein MeCP2, we show that in vivo interactions lasting less than 5 seconds are invisible in the microscope after formaldehyde fixation, though they are obvious in live cells. The stark contrast between live cell and fixed cell images illustrates hitherto unsuspected limitations to the fixation process. We show that chromatin immunoprecipitation, a technique in widespread use that depends on formaldehyde crosslinking, also fails to capture these transient interactions.Our findings for the first time establish a minimum temporal limitation to crosslink chemistry that has implications for many fields of research

Evidence and rationale for the World Health Organization recommended standards for Japanese encephalitis surveillance

<p>Abstract</p> <p>Background</p> <p>Japanese encephalitis (JE) is the most important form of viral encephalitis in Asia. Surveillance for the disease in many countries has been limited. To improve collection of accurate surveillance data in order to increase understanding of the full impact of JE and monitor control programs, World Health Organization (WHO) Recommended Standards for JE Surveillance have been developed. To aid acceptance of the Standards, we describe the process of development, provide the supporting evidence, and explain the rationale for the recommendations made in the document.</p> <p>Methods</p> <p>A JE Core Working Group was formed in 2002 and worked on development of JE surveillance standards. A series of questions on specific topics was initially developed. A literature review was undertaken and the findings were discussed and documented. The group then prepared a draft document, with emphasis placed on the feasibility of implementation in Asian countries. A field test version of the Standards was published by WHO in January 2006. Feedback was then sought from countries that piloted the Standards and from public health professionals in forums and individual meetings to modify the Standards accordingly.</p> <p>Results</p> <p>After revisions, a final version of the JE surveillance standards was published in August 2008. The supporting information is presented here together with explanations of the rationale and levels of evidence for specific recommendations.</p> <p>Conclusion</p> <p>Provision of the supporting evidence and rationale should help to facilitate successful implementation of the JE surveillance standards in JE-endemic countries which will in turn enable better understanding of disease burden and the impact of control programs.</p

Two-sample mendelian randomization analysis of associations between periodontal disease and risk of cancer.

Background: Observational studies indicate that periodontal disease may increase the risk of colorectal, lung, and pancreatic cancers. Using a 2-sample Mendelian randomization (MR) analysis, we assessed whether a genetic predisposition index for periodontal disease was associated with colorectal, lung, or pancreatic cancer risks. Methods: Our primary instrument included single nucleotide polymorphisms with strong genome-wide association study evidence for associations with chronic, aggressive, and/or severe periodontal disease (rs729876, rs1537415, rs2738058, rs12461706, rs16870060, rs2521634, rs3826782, and rs7762544). We used summary-level genetic data for colorectal cancer (n = 58 131 cases; Genetics and Epidemiology of Colorectal Cancer Consortium, Colon Cancer Family Registry, and Colorectal Transdisciplinary Study), lung cancer (n = 18 082 cases; International Lung Cancer Consortium), and pancreatic cancer (n = 9254 cases; Pancreatic Cancer Consortia). Four MR approaches were employed for this analysis: random-effects inverse-variance weighted (primary analyses), Mendelian Randomization-Pleiotropy RESidual Sum and Outlier, simple median, and weighted median. We conducted secondary analyses to determine if associations varied by cancer subtype (colorectal cancer location, lung cancer histology), sex (colorectal and pancreatic cancers), or smoking history (lung and pancreatic cancer). All statistical tests were 2-sided. Results: The genetic predisposition index for chronic or aggressive periodontitis was statistically significantly associated with a 3% increased risk of colorectal cancer (per unit increase in genetic index of periodontal disease; P = .03), 3% increased risk of colon cancer (P = .02), 4% increased risk of proximal colon cancer (P = .01), and 3% increased risk of colorectal cancer among females (P = .04); however, it was not statistically significantly associated with the risk of lung cancer or pancreatic cancer, overall or within most subgroups. Conclusions: Genetic predisposition to periodontitis may be associated with colorectal cancer risk. Further research should determine whether increased periodontitis prevention and increased cancer surveillance of patients with periodontitis is warranted

Japanese Encephalitis—A Pathological and Clinical Perspective

Japanese encephalitis (JE) is the leading form of viral encephalitis in Asia. It is caused by the JE virus (JEV), which belongs to the family Flaviviridae. JEV is endemic to many parts of Asia, where periodic outbreaks take hundreds of lives. Despite the catastrophes it causes, JE has remained a tropical disease uncommon in the West. With rapid globalization and climatic shift, JEV has started to emerge in areas where the threat was previously unknown. Scientific evidence predicts that JEV will soon become a global pathogen and cause of worldwide pandemics. Although some research documents JEV pathogenesis and drug discovery, worldwide awareness of the need for extensive research to deal with JE is still lacking. This review focuses on the exigency of developing a worldwide effort to acknowledge the prime importance of performing an extensive study of this thus far neglected tropical viral disease. This review also outlines the pathogenesis, the scientific efforts channeled into develop a therapy, and the outlook for a possible future breakthrough addressing this killer disease

Specific fatty acid intake and the risk of pancreatic cancer in Canada

The possible association of specific fatty acid (FA) intake and pancreatic cancer risk was investigated in a population-based case–control study of 462 histologically confirmed cases and 4721 frequency-matched controls in eight Canadian provinces between 1994 and 1997. Dietary intake was assessed by means of a self-administered food frequency questionnaire. Unconditional logistic regression was used to assess associations between dietary FAs and pancreatic cancer risk. After adjustment for age, province, body mass index, smoking, educational attainment, fat and total energy intake, statistically significant inverse associations were observed between pancreatic cancer risk and palmitate (odds ratios (ORs)=0.73; 95% confidence intervals (CIs) 0.56–0.96; P-trend=0.02), stearate (OR=0.70; 95% CI 0.51–0.94; P-trend=0.04), oleate (OR=0.75; 95% CI 0.55–1.02; P-trend=0.04), saturated FAs (OR=0.67; 95% CI 0.50–0.91; P-trend=0.01), and monounsaturated FAs (OR=0.72; 95% CI 0.53–0.98; P-trend=0.02), when comparing the highest quartile of intake to the lowest. Significant interactions were detected between body mass index and both saturated and monounsaturated FAs, with a markedly reduced risk associated with intake of stearate (OR=0.36; 95% CI 0.18–0.70; P-trend=0.001), oleate (OR=0.36; 95% CI 0.19–0.72; P-trend=0.002), saturated FAs (OR=0.35; 95% CI 0.18–0.67; P-trend=0.002), and monounsaturated FAs (OR=0.32; 95% CI 0.16–0.63; P-trend<0.0001) among subjects who are obese. The results suggest that substituting polyunsaturated FAs with saturated or monounsaturated FAs may reduce pancreatic cancer risk, independently of total energy intake, particularly among obese subjects

A preliminary randomized double blind placebo-controlled trial of intravenous immunoglobulin for Japanese encephalitis in Nepal

BACKGROUND: Japanese encephalitis (JE) virus (JEV) is a mosquito-borne flavivirus found across Asia that is closely related to West Nile virus. There is no known antiviral treatment for any flavivirus. Results from in vitro studies and animal models suggest intravenous immunoglobulin (IVIG) containing virus-specific neutralizing antibody may be effective in improving outcome in viral encephalitis. IVIG's anti-inflammatory properties may also be beneficial. METHODOLOGY/PRINCIPAL FINDINGS: We performed a pilot feasibility randomized double-blind placebo-controlled trial of IVIG containing anti-JEV neutralizing antibody (ImmunoRel, 400mg/kg/day for 5 days) in children with suspected JE at two sites in Nepal; we also examined the effect on serum neutralizing antibody titre and cytokine profiles. 22 children were recruited, 13 of whom had confirmed JE; 11 received IVIG and 11 placebo, with no protocol violations. One child (IVIG group) died during treatment and two (placebo) subsequently following hospital discharge. Overall, there was no difference in outcome between treatment groups at discharge or follow up. Passive transfer of anti-JEV antibody was seen in JEV negative children. JEV positive children treated with IVIG had JEV-specific neutralizing antibody titres approximately 16 times higher than those treated with placebo (p=0.2), which was more than could be explained by passive transfer alone. IL-4 and IL-6 were higher in the IVIG group. CONCLUSIONS/SIGNIFICANCE: A trial of IVIG for JE in Nepal is feasible. IVIG may augment the development of neutralizing antibodies in JEV positive patients. IVIG appears an appealing option for JE treatment that warrants further study. TRIAL REGISTRATION: ClinicalTrials.gov NCT01856205

Sweets, sweetened beverages, and risk of pancreatic cancer in a large population-based case–control study

We examined the associations between sweets, sweetened and unsweetened beverages, and sugars and pancreatic cancer risk. We conducted a population-based case–control study (532 cases, 1,701 controls) and used multivariate logistic regression models to calculate odds ratios (OR) and 95% confidence intervals (CI). Because associations were often different by sex, we present results for men and women combined and separately. Among men, greater intakes of total and specific sweets were associated with pancreatic cancer risk (total sweets: OR = 1.9, 95% CI: 1.0, 3.6; sweet condiments: OR = 1.9, 95% CI: 1.2, 3.1; chocolate candy: OR = 2.4, 95% CI: 1.1, 5.0; other mixed candy bars: OR = 3.3, 95% CI: 1.5, 7.3 for 1 + servings/day versus none/rarely). Sweets were not consistently associated with risk among women. Sweetened beverages were not associated with increased pancreatic cancer risk. In contrast, low-calorie soft drinks were associated with increased risk among men only; while other low-/non-caloric beverages (e.g., coffee, tea, and water) were unassociated with risk. Of the three sugars assessed (lactose, fructose, and sucrose), only the milk sugar lactose was associated with pancreatic cancer risk (OR = 2.0, 95% CI: 1.5, 2.7 comparing extreme quartiles). These results provide limited support for the hypothesis that sweets or sugars increase pancreatic cancer risk