6,7,9,10-Tetra­hydro-16,22-ethano­oxyethano-5,8,11,19-tetra­oxa-16,22-diaza­dibenzo[h,q]cyclo­octa­decine-17,21-dione: a benzyl­annelated macrobicyclic diamide

The macrobicyclic title compound, C24H28N2O7, has two tertiary diamide bridgehead atoms and is composed of a 12-membered ring (N2O2 donor set) and two 18-membered rings (N2O4 donor sets). The solid-state structure shows that each of the amide groups is not coplanar with the adjacent benzene ring and NMR studies indicate that this conformational relationship persists in solution

Parasitism perturbs the mucosal microbiome of Atlantic Salmon

Interactions between parasite, host and host-associated microbiota are increasingly understood as important determinants of disease progression and morbidity. Salmon lice, including the parasitic copepod Lepeophtheirus salmonis and related species, are perhaps the most important problem facing Atlantic Salmon aquaculture after feed sustainability. Salmon lice parasitize the surface of the fish, feeding off mucus, scales and underlying tissue. Secondary bacterial infections are a major source of associated morbidity. In this study we tracked the diversity and composition of Salmo salar skin surface microbiota throughout a complete L. salmonis infection cycle among 800 post-smolts as compared to healthy controls. Among infected fish we observed a significant reduction in microbial richness (Chao1, P = 0.0136), raised diversity (Shannon, P < 7.86e-06) as well as highly significant destabilisation of microbial community composition (Pairwise Unifrac, beta-diversity, P < 1.86e-05; P = 0.0132) by comparison to controls. While undetectable on an individual level, network analysis of microbial taxa on infected fish revealed the association of multiple pathogenic genera (Vibrio, Flavobacterium, Tenacibaculum, Pseudomonas) with high louse burdens. We discuss our findings in the context of ecological theory and colonisation resistance, in addition to the role microbiota in driving primary and secondary pathology in the host

Neighborhood fast food restaurants and fast food consumption: A national study

<p>Abstract</p> <p>Background</p> <p>Recent studies suggest that neighborhood fast food restaurant availability is related to greater obesity, yet few studies have investigated whether neighborhood fast food restaurant availability promotes fast food consumption. Our aim was to estimate the effect of neighborhood fast food availability on frequency of fast food consumption in a national sample of young adults, a population at high risk for obesity.</p> <p>Methods</p> <p>We used national data from U.S. young adults enrolled in wave III (2001-02; ages 18-28) of the National Longitudinal Study of Adolescent Health (n = 13,150). Urbanicity-stratified multivariate negative binomial regression models were used to examine cross-sectional associations between neighborhood fast food availability and individual-level self-reported fast food consumption frequency, controlling for individual and neighborhood characteristics.</p> <p>Results</p> <p>In adjusted analysis, fast food availability was not associated with weekly frequency of fast food consumption in non-urban or low- or high-density urban areas.</p> <p>Conclusions</p> <p>Policies aiming to reduce neighborhood availability as a means to reduce fast food consumption among young adults may be unsuccessful. Consideration of fast food outlets near school or workplace locations, factors specific to more or less urban settings, and the role of individual lifestyle attitudes and preferences are needed in future research.</p

Observational Signatures and Non-Gaussianities of General Single Field Inflation

We perform a general study of primordial scalar non-Gaussianities in single field inflationary models in Einstein gravity. We consider models where the inflaton Lagrangian is an arbitrary function of the scalar field and its first derivative, and the sound speed is arbitrary. We find that under reasonable assumptions, the non-Gaussianity is completely determined by 5 parameters. In special limits of the parameter space, one finds distinctive ``shapes'' of the non-Gaussianity. In models with a small sound speed, several of these shapes would become potentially observable in the near future. Different limits of our formulae recover various previously known results.Comment: 53 pages, 5 figures; v3, minor revision, JCAP version; v4, numerical coefficients corrected in Appendix B, discussion on consistency condition revise

Observational Signatures and Non-Gaussianities of General Single Field Inflation

We perform a general study of primordial scalar non-Gaussianities in single field inflationary models in Einstein gravity. We consider models where the inflaton Lagrangian is an arbitrary function of the scalar field and its first derivative, and the sound speed is arbitrary. We find that under reasonable assumptions, the non-Gaussianity is completely determined by 5 parameters. In special limits of the parameter space, one finds distinctive ``shapes'' of the non-Gaussianity. In models with a small sound speed, several of these shapes would become potentially observable in the near future. Different limits of our formulae recover various previously known results.Comment: 53 pages, 5 figures; v3, minor revision, JCAP version; v4, numerical coefficients corrected in Appendix B, discussion on consistency condition revise

Phenotypic Anchoring of Acetaminophen-Induced Oxidative Stress with Gene Expression Profiles in Rat Liver

Toxicogenomics provides the ability to examine in greater detail the underlying molecular events that precede and accompany toxicity, thus allowing prediction of adverse events at much earlier times compared to classical toxicological endpoints. Acetaminophen (APAP) is a pharmaceutical that has similar metabolic and toxic responses in rodents and humans. Recent gene expression profiling studies with APAP found an oxidative stress signature at a sub-toxic dose that we hypothesized can be phenotypically anchored to conventional biomarkers of oxidative stress. Liver tissue was obtained from experimental animals used to generate microarray data where male rats were given APAP at sub-toxic (150 mg/kg), or overtly toxic (1500 and 2000 mg/kg) doses and sacrificed at 6, 24, or 48 hrs. Oxidative stress in liver was evaluated by a diverse panel of markers that included assessing expression of base excision repair (BER) genes, quantifying oxidative lesions in genomic DNA, and evaluating protein and lipid oxidation. A sub-toxic dose of APAP produced significant accumulation of nitrotyrosine protein adducts, while both sub-toxic and toxic doses caused a significant increase in 8-hydroxy-deoxyguanosine. Only toxic doses of APAP significantly induced expression levels of BER genes. None of the doses examined resulted in a significant increase in the number of abasic sites, or in the amount of lipid peroxidation. The accumulation of nitrotyrosine and 8-hydroxy-deoxyguanosine adducts phenotypically anchors the oxidative stress gene expression signature observed with a sub-toxic dose of APAP, lending support to the validity of gene expression studies as a sensitive and biologically-meaningful endpoint in toxicology

Mucosal immune profiles associated with diarrheal disease severity in shigella - and enteropathogenic escherichia coli-infected children enrolled in the global enteric multicenter study

Enteropathogenic Escherichia coli (EPEC) and Shigella are etiologic agents of diarrhea in children <5 years old living in resource-poor countries. Repeated bouts of infection lead to lifelong morbidity and even death. The goal of this study was to characterize local mucosal immune responses in Shigella- and EPEC-infected children <5 years of age with moderate to severe diarrhea (MSD) enrolled in the Global Enteric Multicenter Study (GEMS). We hypothesized that infection with each of these pathogens would induce distinct gut mucosal immune profiles indicative of disease etiology and severity. To test this hypothesis, innate and adaptive immune markers were measured in stools from children with diarrhea due to EPEC, Shigella, or other organisms and in children who had no diarrhea. Shigella-positive diarrhea evoked robust proinflammatory and TH1/TH2 cytokine responses compared to diarrhea caused by EPEC or other organisms, with the exception of interleukin 5 (IL-5), which was associated with EPEC infection. The presence of IL-1β, IL-4, IL-16, and tumor necrosis factor beta (TNF-β) was associated with the absence of dysentery. EPEC-positive diarrhea evoked high levels of IL-1β, vascular endothelial growth factor (VEGF), and IL-10. Granulocyte-macrophage colony-stimulating factor (GM-CSF) had opposing roles in disease severity, being associated with absence of diarrhea in EPEC-infected children and with dysenteric Shigella infection. High levels of antigen-specific antibodies were detected in the controls and children with Shigella without dysentery, which suggests a protective role against severe disease. In summary, this study identified distinct local immune responses associated with two clinically relevant diarrheagenic pathogens, Shigella and EPEC, in children and identified protective immune phenotypes that can inform the development of preventive measures

Adsorption of hydroxamate siderophores and EDTA on goethite in the presence of the surfactant sodium dodecyl sulfate

Siderophore-promoted iron acquisition by microorganisms usually occurs in the presence of other organic molecules, including biosurfactants. We have investigated the influence of the anionic surfactant sodium dodecyl sulfate (SDS) on the adsorption of the siderophores DFOB (cationic) and DFOD (neutral) and the ligand EDTA (anionic) onto goethite (α-FeOOH) at pH 6. We also studied the adsorption of the corresponding 1:1 Fe(III)-ligand complexes, which are products of the dissolution process. Adsorption of the two free siderophores increased in a similar fashion with increasing SDS concentration, despite their difference in molecule charge. In contrast, SDS had little effect on the adsorption of EDTA. Adsorption of the Fe-DFOB and Fe-DFOD complexes also increased with increasing SDS concentrations, while adsorption of Fe-EDTA decreased. Our results suggest that hydrophobic interactions between adsorbed surfactants and siderophores are more important than electrostatic interactions. However, for strongly hydrophilic molecules, such as EDTA and its iron complex, the influence of SDS on their adsorption seems to depend on their tendency to form inner-sphere or outer-sphere surface complexes. Our results demonstrate that surfactants have a strong influence on the adsorption of siderophores to Fe oxides, which has important implications for siderophore-promoted dissolution of iron oxides and biological iron acquisition

Genetic improvement of tomato by targeted control of fruit softening

Controlling the rate of softening to extend shelf life was a key target for researchers engineering genetically modified (GM) tomatoes in the 1990s, but only modest improvements were achieved. Hybrids grown nowadays contain 'non-ripening mutations' that slow ripening and improve shelf life, but adversely affect flavor and color. We report substantial, targeted control of tomato softening, without affecting other aspects of ripening, by silencing a gene encoding a pectate lyase