Inboard and outboard radial electric field wells in the H- and I-mode pedestal of Alcator C-Mod and poloidal variations of impurity temperature

We present inboard (HFS) and outboard (LFS) radial electric field (E[subscript r]) and impurity temperature (T[subscript z]) measurements in the I-mode and H-mode pedestal of Alcator C-Mod. These measurements reveal strong Er wells at the HFS and the LFS midplane in both regimes and clear pedestals in T[subscript z], which are of similar shape and height for the HFS and LFS. While the H-mode E[subscript r] well has a radially symmetric structure, the E[subscript r] well in I-mode is asymmetric, with a stronger ExB shear layer at the outer edge of the E[subscript r] well, near the separatrix. Comparison of HFS and LFS profiles indicates that impurity temperature and plasma potential are not simultaneously flux functions. Uncertainties in radial alignment after mapping HFS measurements along flux surfaces to the LFS do not, however, allow direct determination as to which quantity varies poloidally and to what extent. Radially aligning HFS and LFS measurements based on the T[subscript z] profiles would result in substantial inboard-outboard variations of plasma potential and electron density. Aligning HFS and LFS E[subscript r] wells instead also approximately aligns the impurity poloidal flow profiles, while resulting in a LFS impurity temperature exceeding the HFS values in the region of steepest gradients by up to 70%. Considerations based on a simplified form of total parallel momentum balance and estimates of parallel and perpendicular heat transport time scales seem to favor an approximate alignment of the E[subscript r] wells and a substantial poloidal asymmetry in impurity temperature.United States. Dept. of Energy (Cooperative Agreement DE-FC02-99ER54512)Swiss National Science Foundatio

Use cases, best practice and reporting standards for metabolomics in regulatory toxicology

Metabolomics is a widely used technology in academic research, yet its application to regulatory science has been limited. The most commonly cited barrier to its translation is lack of performance and reporting standards. The MEtabolomics standaRds Initiative in Toxicology (MERIT) project brings together international experts from multiple sectors to address this need. Here, we identify the most relevant applications for metabolomics in regulatory toxicology and develop best practice guidelines, performance and reporting standards for acquiring and analysing untargeted metabolomics and targeted metabolite data. We recommend that these guidelines are evaluated and implemented for several regulatory use cases

Helminth burden and ecological factors associated with alterations in wild host gastrointestinal microbiota

Infection by gastrointestinal helminths of humans, livestock and wild animals is common, but the impact of such endoparasites on wild hosts and their gut microbiota represents an important overlooked component of population dynamics. Wild host gut microbiota and endoparasites occupy the same physical niche spaces with both affecting host nutrition and health. However, associations between the two are poorly understood. Here we used the commonly parasitized European shag (Phalacrocorax aristotelis) as a model wild host. Forty live adults from the same colony were sampled. Endoscopy was employed to quantify helminth infection in situ. Microbiota from the significantly distinct proventriculus (site of infection), cloacal and faecal gastrointestinal tract microbiomes were characterised using 16S rRNA gene-targeted high-throughput sequencing. We found increasingly strong associations between helminth infection and microbiota composition progressing away from the site of infection, observing a pronounced dysbiosis in microbiota when samples were partitioned into high- and low-burden groups. We posit this dysbiosis is predominately explained by helminths inducing an anti-inflammatory environment in the proventriculus, diverting host immune responses away from themselves. This study, within live wild animals, provides a vital foundation to better understand the mechanisms that underpin the three-way relationship between helminths, microbiota and hosts

Guidelines for diagnosis and management of the cobalamin-related remethylation disorders cblC, cblD, cblE, cblF, cblG, cblJ and MTHFR deficiency

BACKGROUND: Remethylation defects are rare inherited disorders in which impaired remethylation of homocysteine to methionine leads to accumulation of homocysteine and perturbation of numerous methylation reactions. OBJECTIVE: To summarise clinical and biochemical characteristics of these severe disorders and to provide guidelines on diagnosis and management. DATA SOURCES: Review, evaluation and discussion of the medical literature (Medline, Cochrane databases) by a panel of experts on these rare diseases following the GRADE approach. KEY RECOMMENDATIONS: We strongly recommend measuring plasma total homocysteine in any patient presenting with the combination of neurological and/or visual and/or haematological symptoms, subacute spinal cord degeneration, atypical haemolytic uraemic syndrome or unexplained vascular thrombosis. We strongly recommend to initiate treatment with parenteral hydroxocobalamin without delay in any suspected remethylation disorder; it significantly improves survival and incidence of severe complications. We strongly recommend betaine treatment in individuals with MTHFR deficiency; it improves the outcome and prevents disease when given early

T-cell activation is enhanced by targeting IL-10 cytokine production in toll-like receptor- stimulated macrophages

Ryan M Walk,1,2 Steven T Elliott,2 Felix C Blanco,2 Jason A Snyder,2 Ashley M Jacobi,3 Scott D Rose,3 Mark A Behlke,3 Aliasger K Salem,4 Stanislav Vukmanovic,2 Anthony D Sandler21Department of Surgery, Walter Reed Army Medical Center, Washington, DC, USA; 2Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's National Medical Center, Washington, DC, USA; 3Integrated DNA Technologies, Coralville, IA, USA; 4Division of Pharmaceutics, University of Iowa, Iowa City, IA, USAAbstract: Toll-like receptor (TLR) agonists represent potentially useful cancer vaccine adjuvants in their ability to stimulate antigen-presenting cells (APCs) and subsequently amplify the cytotoxic T-cell response. The purpose of this study was to characterize APC responses to TLR activation and to determine the subsequent effect on lymphocyte activation. We exposed murine primary bone marrow-derived macrophages to increasing concentrations of agonists to TLRs 2, 3, 4, and 9. This resulted in a dose-dependent increase in production of not only tumor necrosis factor–alpha (TNF-α), a surrogate marker of the proinflammatory response, but also interleukin 10 (IL-10), a well-described inhibitory cytokine. Importantly, IL-10 secretion was not induced by low concentrations of TLR agonists that readily produced TNF-α. We subsequently stimulated lymphocytes with anti-CD3 antibody in the presence of media from macrophages activated with higher doses of TLR agonists and observed suppression of interferon gamma release. Use of both IL-10 knockout macrophages and IL-10 small-interfering RNA (siRNA) ablated this suppressive effect. Finally, IL-10 siRNA was successfully used to suppress CpG-induced IL-10 production in vivo. We conclude that TLR-mediated APC stimulation can induce a paradoxical inhibitory effect on T-cell activation mediated by IL-10.Keywords: toll-like receptors, innate immunity, IL-1

Inboard and outboard radial electric field wells in the H- and I-mode pedestal of Alcator C-Mod and poloidal variations of impurity temperature

We present inboard (HFS) and outboard (LFS) radial electric field (E r) and impurity temperature (Tz) measurements in the I-mode and H-mode pedestal of Alcator C-Mod. These measurements reveal strong Er wells at the HFS and the LFS midplane in both regimes and clear pedestals in Tz, which are of similar shape and height for the HFS and LFS. While the H-mode Er well has a radially symmetric structure, the Er well in I-mode is asymmetric, with a stronger ExB shear layer at the outer edge of the Er well, near the separatrix. Comparison of HFS and LFS profiles indicates that impurity temperature and plasma potential are not simultaneously flux functions. Uncertainties in radial alignment after mapping HFS measurements along flux surfaces to the LFS do not, however, allow direct determination as to which quantity varies poloidally and to what extent. Radially aligning HFS and LFS measurements based on the Tz profiles would result in substantial inboard-outboard variations of plasma potential and electron density. Aligning HFS and LFS Er wells instead also approximately aligns the impurity poloidal flow profiles, while resulting in a LFS impurity temperature exceeding the HFS values in the region of steepest gradients by up to 70%. Considerations based on a simplified form of total parallel momentum balance and estimates of parallel and perpendicular heat transport time scales seem to favor an approximate alignment of the E r wells and a substantial poloidal asymmetry in impurity temperature. © 2014 IAEA, Vienna