Nitrogen isotope evidence for expanded ocean suboxia in the early Cenozoic

The million-year variability of the marine nitrogen cycle is poorly understood. Before 57 million years (Ma) ago, the ^(15)N/^(14)N ratio (δ^(15)N) of foraminifera shell-bound organic matter from three sediment cores was high, indicating expanded water column suboxia and denitrification. Between 57 and 50 Ma ago, δ^(15)N declined by 13 to 16 per mil in the North Pacific and by 3 to 8 per mil in the Atlantic. The decline preceded global cooling and appears to have coincided with the early stages of the Asia-India collision. Warm, salty intermediate-depth water forming along the Tethys Sea margins may have caused the expanded suboxia, ending with the collision. From 50 to 35 Ma ago, δ^(15)N was lower than modern values, suggesting widespread sedimentary denitrification on broad continental shelves. Δ^(15)N rose at 35 Ma ago, as ice sheets grew, sea level fell, and continental shelves narrowed

Fast Evaluation of Feynman Diagrams

We develop a new representation for the integrals associated with Feynman diagrams. This leads directly to a novel method for the numerical evaluation of these integrals, which avoids the use of Monte Carlo techniques. Our approach is based on based on the theory of generalized sinc ($\sin(x)/x$) functions, from which we derive an approximation to the propagator that is expressed as an infinite sum. When the propagators in the Feynman integrals are replaced with the approximate form all integrals over internal momenta and vertices are converted into Gaussians, which can be evaluated analytically. Performing the Gaussians yields a multi-dimensional infinite sum which approximates the corresponding Feynman integral. The difference between the exact result and this approximation is set by an adjustable parameter, and can be made arbitrarily small. We discuss the extraction of regularization independent quantities and demonstrate, both in theory and practice, that these sums can be evaluated quickly, even for third or fourth order diagrams. Lastly, we survey strategies for numerically evaluating the multi-dimensional sums. We illustrate the method with specific examples, including the the second order sunset diagram from quartic scalar field theory, and several higher-order diagrams. In this initial paper we focus upon scalar field theories in Euclidean spacetime, but expect that this approach can be generalized to fields with spin.Comment: uses feynmp macros; v2 contains improved description of renormalization, plus other minor change

GRADE Guidelines: 18. How ROBINS-I and other tools to assess risk of bias in nonrandomized studies should be used to rate the certainty of a body of evidence

To provide guidance on how systematic review authors, guideline developers, and health technology assessment practitioners should approach the use of the risk of bias in non-randomized studies of interventions (ROBINS-I) tool as part of GRADE's certainty rating process. Iterative discussions, testing in systematic reviews, presentation at GRADE working group meetings with feedback from the GRADE Working Group. We describe where to start the initial assessment of a body of evidence with the use of ROBINS-I, and where one would anticipate the final rating would end up. GRADE accounted for issues that mitigate concerns about confounding and selection bias by introducing the upgrading domains: large effects, dose-effect relations, and when plausible residual confounders or other biases increase certainty. They will need to be considered in an assessment of a body of evidence when using ROBINS-I. The use of ROBINS-I in GRADE assessments may allow for a better comparison of evidence from RCTs and NRS because they are placed on a common metric for risk of bias. Challenges remain that include appropriate presentation of evidence from RCTs and NRS for decision-making and how to optimally integrate RCTs and NRS in an evidence assessment

Cadherin-11 Provides Specific Cellular Adhesion between Fibroblast-like Synoviocytes

Cadherins are integral membrane proteins expressed in tissue-restricted patterns that mediate homophilic intercellular adhesion. During development, they orchestrate tissue morphogenesis and, in the adult, they determine tissue integrity and architecture. The synovial lining is a condensation of fibroblast-like synoviocytes (FLS) and macrophages one to three cells thick. These cells are embedded within the extracellular matrix, but the structure is neither an epithelium nor an endothelium. Previously, the basis for organization of the synovium into a tissue was unknown. Here, we cloned cadherin-11 from human rheumatoid arthritis (RA)-derived FLS. We developed L cell transfectants expressing cadherin-11, cadherin-11 fusion proteins, and anti–cadherin-11 mAb. Cadherin-11 was found to be expressed mainly in the synovial lining by immunohistologic staining of human synovium. FLS adhered to cadherin-11–Fc, and transfection of cadherin-11 conferred the formation of tissue-like sheets and lining-like structures upon fibroblasts in vitro. These findings support a key role for cadherin-11 in the specific adhesion of FLS and in synovial tissue organization and behavior in health and RA

Nitrogen isotope evidence for expanded ocean suboxia in the early Cenozoic

The million-year variability of the marine nitrogen cycle is poorly understood. Before 57 million years (Ma) ago, the ^(15)N/^(14)N ratio (δ^(15)N) of foraminifera shell-bound organic matter from three sediment cores was high, indicating expanded water column suboxia and denitrification. Between 57 and 50 Ma ago, δ^(15)N declined by 13 to 16 per mil in the North Pacific and by 3 to 8 per mil in the Atlantic. The decline preceded global cooling and appears to have coincided with the early stages of the Asia-India collision. Warm, salty intermediate-depth water forming along the Tethys Sea margins may have caused the expanded suboxia, ending with the collision. From 50 to 35 Ma ago, δ^(15)N was lower than modern values, suggesting widespread sedimentary denitrification on broad continental shelves. Δ^(15)N rose at 35 Ma ago, as ice sheets grew, sea level fell, and continental shelves narrowed

Increased Virulence of an Epidemic Strain of Mycobacterium massiliense in Mice

Chronic pulmonary disease and skin/soft tissue infections due to non-tuberculous mycobacteria (NTM) of the Mycobacterium chelonae-abscessus-massiliense group is an emerging health problem worldwide. Moreover, the cure rate for the infections this group causes is low despite aggressive treatment. Post-surgical outbreaks that reached epidemic proportions in Brazil recently were caused by M. massiliense isolates resistant to high-level disinfection with glutaraldehyde (GTA). Understanding the differences in the virulence and host immune responses induced by NTM differing in their sensitivity to disinfectants, and therefore their relative threat of causing outbreaks in hospitals, is an important issue.We compared the replication and survival inside macrophages of a GTA-susceptible reference Mycobacterium massiliense clinical isolate CIP 108297 and an epidemic strain from Brazil, CRM-0019, and characterized the immune responses of IFNγ knockout mice exposed to a high dose aerosol with these two isolates. CRM-0019 replicated more efficiently than CIP 108297 inside mouse bone marrow macrophages. Moreover, the animals infected with CRM-0019 showed a progressive lung infection characterized by a delayed influx of CD4+ and CD8+ T cells, culminating in extensive lung consolidation and demonstrated increased numbers of pulmonary CD4+ Foxp3+ regulatory T cells compared to those infected with the reference strain. Immunosuppressive activity of regulatory T cells may contribute to the progression and worsening of NTM disease by preventing the induction of specific protective immune responses.These results provide the first direct evidence of the increased virulence in macrophages and mice and pathogenicity in vivo of the Brazilian epidemic isolate and the first observation that NTM infections can be associated with variable levels of regulatory T cells which may impact on their virulence and ability to persist in the host

Pathogenic Roles of CD14, Galectin-3, and OX40 during Experimental Cerebral Malaria in Mice

An in-depth knowledge of the host molecules and biological pathways that contribute towards the pathogenesis of cerebral malaria would help guide the development of novel prognostics and therapeutics. Genome-wide transcriptional profiling of the brain tissue during experimental cerebral malaria (ECM ) caused by Plasmodium berghei ANKA parasites in mice, a well established surrogate of human cerebral malaria, has been useful in predicting the functional classes of genes involved and pathways altered during the course of disease. To further understand the contribution of individual genes to the pathogenesis of ECM, we examined the biological relevance of three molecules – CD14, galectin-3, and OX40 that were previously shown to be overexpressed during ECM. We find that CD14 plays a predominant role in the induction of ECM and regulation of parasite density; deletion of the CD14 gene not only prevented the onset of disease in a majority of susceptible mice (only 21% of CD14-deficient compared to 80% of wildtype mice developed ECM, p<0.0004) but also had an ameliorating effect on parasitemia (a 2 fold reduction during the cerebral phase). Furthermore, deletion of the galectin-3 gene in susceptible C57BL/6 mice resulted in partial protection from ECM (47% of galectin-3-deficient versus 93% of wildtype mice developed ECM, p<0.0073). Subsequent adherence assays suggest that galectin-3 induced pathogenesis of ECM is not mediated by the recognition and binding of galectin-3 to P. berghei ANKA parasites. A previous study of ECM has demonstrated that brain infiltrating T cells are strongly activated and are CD44+CD62L− differentiated memory T cells [1]. We find that OX40, a marker of both T cell activation and memory, is selectively upregulated in the brain during ECM and its distribution among CD4+ and CD8+ T cells accumulated in the brain vasculature is approximately equal

Gene promoter hypermethylation in ductal lavage fluid from healthy BRCA gene mutation carriers and mutation-negative controls

INTRODUCTION: Female germline BRCA gene mutation carriers are at increased risk for developing breast cancer. The purpose of our study was to establish whether healthy BRCA mutation carriers demonstrate an increased frequency of aberrant gene promoter hypermethylation in ductal lavage (DL) fluid, compared with predictive genetic test negative controls, that might serve as a surrogate marker of BRCA1/2 mutation status and/or breast cancer risk. METHODS: The pattern of CpG island hypermethylation within the promoter region of a panel of four genes (RAR-β, HIN-1, Twist and Cyclin D2) was assessed by methylation-specific polymerase chain reaction using free DNA extracted from DL fluid. RESULTS: Fifty-one DL samples from 24 healthy women of known BRCA mutation status (7 BRCA1 mutation carriers, 12 BRCA2 mutation carriers and 5 controls) were available for methylation analysis. Eight of 19 (42.1%) BRCA mutation carriers were found to have at least one hypermethylated gene in the four-gene panel. Two BRCA mutation carriers, in whom aberrant methylation was found, also had duct epithelial cell atypia identified. No hypermethylation was found in DL samples from 5 negative controls(p = 0.13). CONCLUSION: We found substantial levels of aberrant methylation, with the use of a four-gene panel, in the fluid from the breasts of healthy BRCA mutation carriers compared with controls. Methylation analysis of free DNA in DL fluid may offer a useful surrogate marker for BRCA1/2 mutation status and/or breast cancer risk. Further studies are required for the evaluation of the specificity and predictive value of aberrant methylation in DL fluid for future breast cancer development in BRCA1/2 mutation carriers