Tonian-Cryogenian boundary sections of Argyll, Scotland

The Tonian-Cryogenian System boundary is to be defined at a GSSP (Global Boundary Stratigraphic Section and Point) beneath the first evidence of widespread glaciation. A candidate lies within the Dalradian Supergroup of Scotland and Ireland, which is least deformed and metamorphosed in Argyll, western Scotland. We present new stratigraphic profiles and interpretations from the Isle of Islay and the Garvellach Islands, update the chemostratigraphy of the Appin Group Tonian carbonates underlying the thick (ca. 1. km) glacigenic Port Askaig Formation (PAF) and demonstrate an environmental transition at the contact.The Appin Group forms a regionally extensive, > 4km-thick, succession of limestones, shales and sandstones deposited on a marine shelf. On Islay, the upper part of the lithostratigraphy has been clarified by measuring and correlating two sections containing distinctive stratigraphic levels including molar tooth structure, oolite, stromatolitic dolomite and intraclastic microbial mounds. Significantly deeper erosion at the unconformity at the base of the overlying PAF is demonstrated in the southern section. Carbonate facies show a gradual decline in δ 13 C VPDB from +5 to +2‰ upwards.In NE Garbh Eileach (Garvellach Islands), a continuously exposed section of Appin Group carbonates, 70m thick, here designated the Garbh Eileach Formation (GEF), lies conformably beneath the PAF. The GEF and the GEF-PAF boundary relationships are re-described with new sedimentological logs, petrological and stable isotope data. Interstratified limestone and dolomicrosparite with δ 13 C of -4 to -7‰ (a feature named the Garvellach anomaly, replacing the term Islay anomaly) are overlain by dolomite in which the isotope signature becomes weakly positive (up to +1‰) upwards. Shallow subtidal conditions become peritidal upwards, with evidence of wave and storm activity. Gypsum pseudomorphs and subaerial exposure surfaces are common near the top of the GEF. The basal diamictite (D1) of the PAF is rich in carbonate clasts similar to slightly deeper-water parts of the underlying succession. D1 is typically several metres thick with interstratified sandstone and conglomerate, but dies out laterally. Scattered siliciclastic coarse sandstone to pebble conglomerate with dropstones associated with soft-sediment deformation is interbedded with carbonate below and above D1. Dolomite beds with derived intraclasts and gypsum pseudomorphs are found above D1 (or equivalent position, where D1 is absent).Published and new Sr isotope studies, including successive leach data, demonstrate primary Tonian 87 Sr/ 86 Sr values of 0.7066-0.7069 on Islay, decreasing to 0.7064-0.7066 in the younger GEF limestones on the Garvellachs, with 1700-2700ppmSr. Other typically Tonian characteristics of the carbonates are the Sr-rich nature of limestones, molar tooth structure, and dolomitized peritidal facies with evidence of aridity. Seabed surveys suggesting uniformly-dipping strata and shallow borehole core material illustrate the potential for extending the Tonian record offshore of the Garvellachs.A candidate Tonian-Cryogenian GSSP is proposed on Garbh Eileach within the smooth δ 13 C profile at the cross-over to positive δ 13 C signatures, 4m below the first occurrence of ice-rafted sediment and 9m below the first diamictite. Although lacking radiometric constraints or stratigraphically significant biotas or biomarkers, the Scottish succession has a thick and relatively complete sedimentary record of glaciation, coherent carbon and strontium chemostratigraphy, lateral continuity of outcrops and 100% exposure at the proposed boundary interval

Individual differences in the use of the response scale determine valuations of hypothetical health states: an empirical study

Background. The effects of socio-demographic characteristics of the respondent, including age, on valuation scores of hypothetical health states remain inconclusive. Therefore, we analyzed data from a study designed to discriminate between the effects of respondents' age and time preference on valuations of health states to gain insight in the contribution of individual response patterns to the variance in valuation scores. Methods. A total of 212 respondents from three age g

Relating circulating thyroid hormone concentrations to serum interleukins-6 and -10 in association with non-thyroidal illnesses including chronic renal insufficiency

<p>Abstract</p> <p>Background</p> <p>Because of the possible role of cytokines including interleukins (IL) in systemic non-thyroidal illnesses' (NTI) pathogenesis and consequently the frequently associated alterations in thyroid hormone (TH) concentrations constituting the euthyroid sick syndrome (ESS), we aimed in this research to elucidate the possible relation between IL-6 & IL-10 and any documented ESS in a cohort of patients with NTI.</p> <p>Methods</p> <p>Sixty patients and twenty healthy volunteers were recruited. The patients were subdivided into three subgroups depending on their underlying NTI and included 20 patients with chronic renal insufficiency (CRI), congestive heart failure (CHF), and ICU patients with myocardial infarction (MI). Determination of the circulating serum levels of IL-6 and IL-10, thyroid stimulating hormone (TSH), as well as total T4 and T3 was carried out.</p> <p>Results</p> <p>In the whole group of patients, we detected a significantly lower T3 and T4 levels compared to control subjects (0.938 ± 0.477 vs 1.345 ± 0.44 nmol/L, p = 0.001 and 47.9 ± 28.41 vs 108 ± 19.49 nmol/L, p < 0.0001 respectively) while the TSH level was normal (1.08+0.518 μIU/L). Further, IL-6 was substantially higher above controls' levels (105.18 ± 72.01 vs 3.35 ± 1.18 ng/L, p < 0.00001) and correlated negatively with both T3 and T4 (r = -0.620, p < 0.0001 & -0.267, p < 0.001, respectively). Similarly was IL-10 level (74.13 ± 52.99 vs 2.64 ± 0.92 ng/ml, p < 0.00001) that correlated negatively with T3 (r = -0.512, p < 0.0001) but not T4. Interestingly, both interleukins correlated positively (r = 0.770, p = <0.001). Moreover, IL-6 (R²= 0.338, p = 0.001) and not IL-10 was a predictor of low T3 levels with only a borderline significance for T4 (R²= 0.082, p = 0.071).</p> <p>By subgroup analysis, the proportion of patients with subnormal T3, T4, and TSH levels was highest in the MI patients (70%, 70%, and 72%, respectively) who displayed the greatest IL-6 and IL-10 concentrations (192.5 ± 45.1 ng/L & 122.95 ± 46.1 ng/L, respectively) compared with CHF (82.95 ± 28.9 ng/L & 69.05 ± 44.0 ng/L, respectively) and CRI patients (40.05 ± 28.9 ng/L & 30.4 ± 10.6 ng/L, respectively). Surprisingly, CRI patients showed the least disturbance in IL-6 and IL-10 despite the lower levels of T3, T4, and TSH in a higher proportion of them compared to CHF patients (40%, 45%, & 26% vs 35%, 25%, & 18%, respectively).</p> <p>Conclusion</p> <p>the high prevalence of ESS we detected in NTI including CRI may be linked to IL-6 and IL-10 alterations. Further, perturbation of IL-6 and not IL-10 might be involved in ESS pathogenesis although it is not the only key player as suggested by our findings in CRI.</p

The Development of an Animal Welfare Impact Assessment (AWIA) Tool and Its Application to Bovine Tuberculosis and Badger Control in England

Bovine tuberculosis (bovine TB) is a controversial animal health policy issue in England, which impacts farmers, the public, cattle and badgers. Badgers (Meles meles) act as a wildlife reservoir of disease. Policy options for badger control include (1) do nothing, (2) badger culling, and (3) badger vaccination. This paper argues for mandatory Animal Welfare Impact Assessment (AWIA) for all policy that significantly affects sentient animals. AWIA includes (1) species description, and (2) AWIA analysis stages. In this paper, AWIA is applied to impacts of bovine TB policy options on cattle and badgers. Over 4 years, 85,000 badgers will be culled to prevent the slaughter of ~17,750 cattle over 9 years. Hence, about five badgers are culled for every cow which avoids slaughter. The AWIA analyses the impact of badger vaccination on cows and badgers based on a set of stated assumptions. The AWIA estimates badger vaccination to reduce the number of cows slaughtered by 11,600, i.e. a 12.5% reduction. Additional to the harm of killing, culling has greater welfare impacts on badgers compared to non-culling options. Actors in animal health and welfare policy were interviewed about the concept of AWIA. Policy actors supported the idea of AWIA to provide objective data to feed into policy making. The paper concludes with the proposal that AWIA is a necessary stage of just policy making where sentient animals are impacted by government policy

Homo-PROTACs:bivalent small-molecule dimerizers of the VHL E3 ubiquitin ligase to induce self-degradation

E3 ubiquitin ligases are key enzymes within the ubiquitin proteasome system which catalyze the ubiquitination of proteins, targeting them for proteasomal degradation. E3 ligases are gaining importance as targets to small molecules, both for direct inhibition and to be hijacked to induce the degradation of non-native neo-substrates using bivalent compounds known as PROTACs (for 'proteolysis-targeting chimeras'). We describe Homo-PROTACs as an approach to dimerize an E3 ligase to trigger its suicide-type chemical knockdown inside cells. We provide proof-of-concept of Homo-PROTACs using diverse molecules composed of two instances of a ligand for the von Hippel-Lindau (VHL) E3 ligase. The most active compound, CM11, dimerizes VHL with high avidity in vitro and induces potent, rapid and proteasome-dependent self-degradation of VHL in different cell lines, in a highly isoform-selective fashion and without triggering a hypoxic response. This approach offers a novel chemical probe for selective VHL knockdown, and demonstrates the potential for a new modality of chemical intervention on E3 ligases.Targeting the ubiquitin proteasome system to modulate protein homeostasis using small molecules has promising therapeutic potential. Here the authors describe Homo-PROTACS: small molecules that can induce the homo-dimerization of E3 ubiquitin ligases and cause their proteasome-dependent degradation

Genome-wide fine-scale recombination rate variation in Drosophila melanogaster

Estimating fine-scale recombination maps of Drosophila from population genomic data is a challenging problem, in particular because of the high background recombination rate. In this paper, a new computational method is developed to address this challenge. Through an extensive simulation study, it is demonstrated that the method allows more accurate inference, and exhibits greater robustness to the effects of natural selection and noise, compared to a well-used previous method developed for studying fine-scale recombination rate variation in the human genome. As an application, a genome-wide analysis of genetic variation data is performed for two Drosophila melanogaster populations, one from North America (Raleigh, USA) and the other from Africa (Gikongoro, Rwanda). It is shown that fine-scale recombination rate variation is widespread throughout the D. melanogaster genome, across all chromosomes and in both populations. At the fine-scale, a conservative, systematic search for evidence of recombination hotspots suggests the existence of a handful of putative hotspots each with at least a tenfold increase in intensity over the background rate. A wavelet analysis is carried out to compare the estimated recombination maps in the two populations and to quantify the extent to which recombination rates are conserved. In general, similarity is observed at very broad scales, but substantial differences are seen at fine scales. The average recombination rate of the X chromosome appears to be higher than that of the autosomes in both populations, and this pattern is much more pronounced in the African population than the North American population. The correlation between various genomic features—including recombination rates, diversity, divergence, GC content, gene content, and sequence quality—is examined using the wavelet analysis, and it is shown that the most notable difference between D. melanogaster and humans is in the correlation between recombination and diversity

Duffy blood group gene polymorphisms among malaria vivax patients in four areas of the Brazilian Amazon region

<p>Abstract</p> <p>Background</p> <p>Duffy blood group polymorphisms are important in areas where <it>Plasmodium vivax </it>predominates, because this molecule acts as a receptor for this protozoan. In the present study, Duffy blood group genotyping in <it>P. vivax </it>malaria patients from four different Brazilian endemic areas is reported, exploring significant associations between blood group variants and susceptibility or resistance to malaria.</p> <p>Methods</p> <p>The <it>P. vivax </it>identification was determined by non-genotypic and genotypic screening tests. The Duffy blood group was genotyped by PCR/RFLP in 330 blood donors and 312 malaria patients from four Brazilian Amazon areas. In order to assess the variables significance and to obtain independence among the proportions, the Fisher's exact test was used.</p> <p>Results</p> <p>The data show a high frequency of the <it>FYA/FYB </it>genotype, followed by <it>FYB/FYB, FYA/FYA</it>, <it>FYA/FYB-33 </it>and <it>FYB/FYB-33</it>. Low frequencies were detected for the <it>FYA/FY</it>^<it>X</it>, <it>FYB/FY</it>^<it>X</it>, <it>FYX/FY</it>^{<it>X </it>}and <it>FYB-33/FYB-33 </it>genotypes. Negative Duffy genotype (<it>FYB-33/FYB-33</it>) was found in both groups: individuals infected and non-infected (blood donors). No individual carried the <it>FY</it>^<it>X</it><it>/FYB-33 </it>genotype. Some of the Duffy genotypes frequencies showed significant differences between donors and malaria patients.</p> <p>Conclusion</p> <p>The obtained data suggest that individuals with the <it>FYA/FYB </it>genotype have higher susceptibility to malaria. The presence of the <it>FYB-33 </it>allele may be a selective advantage in the population, reducing the rate of infection by <it>P. vivax </it>in this region. Additional efforts may contribute to better elucidate the physiopathologic differences in this parasite/host relationship in regions endemic for <it>P. vivax </it>malaria, in particular the Brazilian Amazon region.</p

The MHV68 M2 Protein Drives IL-10 Dependent B Cell Proliferation and Differentiation

Murine gammaherpesvirus 68 (MHV68) establishes long-term latency in memory B cells similar to the human gammaherpesvirus Epstein Barr Virus (EBV). EBV encodes an interleukin-10 (IL-10) homolog and modulates cellular IL-10 expression; however, the role of IL-10 in the establishment and/or maintenance of chronic EBV infection remains unclear. Notably, MHV68 does not encode an IL-10 homolog, but virus infection has been shown to result in elevated serum IL-10 levels in wild-type mice, and IL-10 deficiency results in decreased establishment of virus latency. Here we show that a unique MHV68 latency-associated gene product, the M2 protein, is required for the elevated serum IL-10 levels observed at 2 weeks post-infection. Furthermore, M2 protein expression in primary murine B cells drives high level IL-10 expression along with increased secretion of IL-2, IL-6, and MIP-1α. M2 expression was also shown to significantly augment LPS driven survival and proliferation of primary murine B cells. The latter was dependent on IL-10 expression as demonstrated by the failure of IL10−/− B cells to proliferate in response to M2 protein expression and rescue of M2-associated proliferation by addition of recombinant murine IL-10. M2 protein expression in primary B cells also led to upregulated surface expression of the high affinity IL-2 receptor (CD25) and the activation marker GL7, along with down-regulated surface expression of B220, MHC II, and sIgD. The cells retained CD19 and sIgG expression, suggesting differentiation to a pre-plasma memory B cell phenotype. These observations are consistent with previous analyses of M2-null MHV68 mutants that have suggested a role for the M2 protein in expansion and differentiation of MHV68 latently infected B cells—perhaps facilitating the establishment of virus latency in memory B cells. Thus, while the M2 protein is unique to MHV68, analysis of M2 function has revealed an important role for IL-10 in MHV68 pathogenesis—identifying a strategy that appears to be conserved between at least EBV and MHV68