Calibrating the zenith of dinosaur diversity in the Campanian of the Western Interior Basin by CA-ID-TIMS U-Pb geochronology

The spectacular fossil fauna and flora preserved in the Upper Cretaceous terrestrial strata of North America’s Western Interior Basin record an exceptional peak in the diversification of fossil vertebrates in the Campanian, which has been termed the ‘zenith of dinosaur diversity’. The wide latitudinal distribution of rocks and fossils that represent this episode, spanning from northern Mexico to the northern slopes of Alaska, provides a unique opportunity to gain insights into dinosaur paleoecology and to address outstanding questions regarding faunal provinciality in connection to paleogeography and climate. Whereas reliable basin-wide correlations are fundamental to investigations of this sort, three decades of radioisotope geochronology of various vintages and limited compatibility has complicated correlation of distant fossil-bearing successions and given rise to contradictory paleobiogeographic and evolutionary hypotheses. Here we present new U–Pb geochronology by the CA-ID-TIMS method for 16 stratigraphically well constrained bentonite beds, ranging in age from 82.419 ± 0.074 Ma to 73.496 ± 0.039 Ma (2σ internal uncertainties), and the resulting Bayesian age models for six key fossil-bearing formations over a 1600 km latitudinal distance from northwest New Mexico, USA to southern Alberta, Canada. Our high-resolution chronostratigraphic framework for the upper Campanian of the Western Interior Basin reveals that despite their contrasting depositional settings and basin evolution histories, significant age overlap exists between the main fossil-bearing intervals of the Kaiparowits Formation (southern Utah), Judith River Formation (central Montana), Two Medicine Formation (western Montana) and Dinosaur Park Formation (southern Alberta). Pending more extensive paleontologic collecting that would allow more rigorous faunal analyses, our results support a first-order connection between paleoecologic and fossil diversities and help overcome the chronostratigraphic ambiguities that have impeded the testing of proposed models of latitudinal provinciality of dinosaur taxa during the Campanian

Examining the Impact of Imputation Errors on Fine-Mapping Using DNA Methylation QTL as a Model Trait

Genetic variants disrupting DNA methylation at CpG dinucleotides (CpG-SNP) provide a set of known causal variants to serve as models for testing fine-mapping methodology. We use 1716 CpG-SNPs to test three fine-mapping approaches (BIMBAM, BSLMM, and the J-test), assessing the impact of imputation errors and the choice of reference panel by using both whole-genome sequence (WGS), and genotype array data on the same individuals (n=1166). The choice of imputation reference panel had a strong effect on imputation accuracy, with the 1000 Genomes Phase 3 (1000G) reference panel (n=2504 from 26 populations) giving a mean non-reference discordance rate between imputed and sequenced genotypes of 3.2% compared to 1.6% when using the Haplotype Reference Consortium (HRC) reference panel (n=32470 Europeans). These imputation errors impacted on whether the CpG-SNP was included in the 95% credible set, with a difference of ∼ 23% and ∼ 7% between the WGS and the 1000G and HRC imputed datasets respectively. All of the fine-mapping methods failed to reach the expected 95% coverage of the CpG-SNP. This is attributed to secondary cis genetic effects that are unable to be statistically separated from the CpG-SNP, and through a masking mechanism where the effect of the methylation disrupting allele at the CpG-SNP is hidden by the effect of a nearby SNP that has strong LD with the CpG-SNP. The reduced accuracy in fine-mapping a known causal variant in a low level biological trait with imputed genetic data has implications for the study of higher order complex traits and disease

A Phase I study evaluating the safety and immunogenicity of MVA85A, a candidate TB vaccine, in HIV-infected adults

Objectives Control of the tuberculosis (TB) epidemic is a global health priority and one that is likely to be achieved only through vaccination. The critical overlap with the HIV epidemic requires any effective TB vaccine regimen to be safe in individuals who are infected with HIV. The objectives of this clinical trial were to evaluate the safety and immunogenicity of a leading candidate TB vaccine, MVA85A, in healthy, HIV-infected adults. Design This was an open-label Phase I trial, performed in 20 healthy HIV-infected, antiretroviral-naïve subjects. Two different doses of MVA85A were each evaluated as a single immunisation in 10 subjects, with 24 weeks of follow-up. The safety of MVA85A was assessed by clinical and laboratory markers, including regular CD4 counts and HIV RNA load measurements. Vaccine immunogenicity was assessed by ex vivo interferon γ (IFN-γ) ELISpot assays and flow-cytometric analysis. Results MVA85A was safe in subjects with HIV infection, with an adverse-event profile comparable with historical data from previous trials in HIV-uninfected subjects. There were no clinically significant vaccine-related changes in CD4 count or HIV RNA load in any subjects, and no evidence from qPCR analyses to indicate that MVA85A vaccination leads to widespread preferential infection of vaccine-induced CD4 T cell populations. Both doses of MVA85A induced an antigen-specific IFN-γ response that was durable for 24 weeks, although of a lesser magnitude compared with historical data from HIV-uninfected subjects. The functional quality of the vaccine-induced T cell response in HIV-infected subjects was remarkably comparable with that observed in healthy HIV-uninfected controls, but less durable. Conclusion MVA85A is safe and immunogenic in healthy adults infected with HIV. Further safety and efficacy evaluation of this candidate vaccine in TB- and HIV-endemic areas is merited

Involvement of Noradrenergic Neurotransmission in the Stress- but not Cocaine-Induced Reinstatement of Extinguished Cocaine-Induced Conditioned Place Preference in Mice: Role for β-2 Adrenergic Receptors

The responsiveness of central noradrenergic systems to stressors and cocaine poses norepinephrine as a potential common mechanism through which drug re-exposure and stressful stimuli promote relapse. This study investigated the role of noradrenergic systems in the reinstatement of extinguished cocaine-induced conditioned place preference by cocaine and stress in male C57BL/6 mice. Cocaine- (15 mg/kg, i.p.) induced conditioned place preference was extinguished by repeated exposure to the apparatus in the absence of drug and reestablished by a cocaine challenge (15 mg/kg), exposure to a stressor (6-min forced swim (FS); 20–25°C water), or administration of the α-2 adrenergic receptor (AR) antagonists yohimbine (2 mg/kg, i.p.) or BRL44408 (5, 10 mg/kg, i.p.). To investigate the role of ARs, mice were administered the nonselective β-AR antagonist, propranolol (5, 10 mg/kg, i.p.), the α-1 AR antagonist, prazosin (1, 2 mg/kg, i.p.), or the α-2 AR agonist, clonidine (0.03, 0.3 mg/kg, i.p.) before reinstatement testing. Clonidine, prazosin, and propranolol failed to block cocaine-induced reinstatement. The low (0.03 mg/kg) but not high (0.3 mg/kg) clonidine dose fully blocked FS-induced reinstatement but not reinstatement by yohimbine. Propranolol, but not prazosin, blocked reinstatement by both yohimbine and FS, suggesting the involvement of β-ARs. The β-2 AR antagonist ICI-118551 (1 mg/kg, i.p.), but not the β-1 AR antagonist betaxolol (10 mg/kg, i.p.), also blocked FS-induced reinstatement. These findings suggest that stress-induced reinstatement requires noradrenergic signaling through β-2 ARs and that cocaine-induced reinstatement does not require AR activation, even though stimulation of central noradrenergic neurotransmission is sufficient to reinstate

Passing the Panda Standard: A TAD Off the Mark?

Tilapia, a tropical freshwater fish native to Africa, is an increasingly important global food commodity. The World Wide Fund for Nature (WWF), a major environmental nongovernmental organization, has established stakeholder dialogues to formulate farm certification standards that promote ‘‘responsible’’ culture practices. As a preface to its ‘‘tilapia aquaculture dialogue,’’ the WWF for Nature commissioned a review of potential certification issues, later published as a peer-reviewed article. This article contends that both the review and the draft certification standards subsequently developed fail to adequately integrate critical factors governing the relative sustainability of tilapia production and thereby miss more significant issues related to resource-use efficiency and the appropriation of ecosystem space and services. This raises a distinct possibility that subsequent certification will promote intensive systems of tilapia production that are far less ecologically benign than existing widely practiced semiintensive alternatives. Given the likely future significance of this emergent standard, it is contended that a more holistic approach to certification is essential

Seafood in Food Security: a call for bridging the terrestrial-aquatic divide

The contribution of seafood to global food security is being increasingly highlighted in policy. However, the extent to which such claims are supported in the current food security literature is unclear. This review assesses the extent to which seafood is represented in the recent food security literature, both individually and from a food systems perspective, in combination with terrestrially-based production systems. The results demonstrate that seafood remains under-researched compared to the role of terrestrial animal and plant production in food security. Furthermore, seafood and terrestrial production remain siloed, with very few papers addressing the combined contribution or relations between terrestrial and aquatic systems. We conclude that far more attention is needed to the specific and relative role of seafood in global food security and call for the integration of seafood in a wider interdisciplinary approach to global food system research

Seafood in Food Security: A Call for Bridging the Terrestrial-Aquatic Divide

The contribution of seafood to global food security is being increasingly highlighted in policy. However, the extent to which such claims are supported in the current food security literature is unclear. This review assesses the extent to which seafood is represented in the recent food security literature, both individually and from a food systems perspective, in combination with terrestrially-based production systems. The results demonstrate that seafood remains under-researched compared to the role of terrestrial animal and plant production in food security. Furthermore, seafood and terrestrial production remain siloed, with very few papers addressing the combined contribution or relations between terrestrial and aquatic systems. We conclude that far more attention is needed to the specific and relative role of seafood in global food security and call for the integration of seafood in a wider interdisciplinary approach to global food system research

Enumeration of Functional T-Cell Subsets by Fluorescence-Immunospot Defines Signatures of Pathogen Burden in Tuberculosis

IFN-γ and IL-2 cytokine-profiles define three functional T-cell subsets which may correlate with pathogen load in chronic intracellular infections. We therefore investigated the feasibility of the immunospot platform to rapidly enumerate T-cell subsets by single-cell IFN-γ/IL-2 cytokine-profiling and establish whether immunospot-based T-cell signatures distinguish different clinical stages of human tuberculosis infection.We used fluorophore-labelled anti-IFN-γ and anti-IL-2 antibodies with digital overlay of spatially-mapped colour-filtered images to enumerate dual and single cytokine-secreting M. tuberculosis antigen-specific T-cells in tuberculosis patients and in latent tuberculosis infection (LTBI). We validated results against established measures of cytokine-secreting T-cells.Fluorescence-immunospot correlated closely with single-cytokine enzyme-linked-immunospot for IFN-γ-secreting T-cells and IL-2-secreting T-cells and flow-cytometry-based detection of dual IFN-γ/IL-2-secreting T-cells. The untreated tuberculosis signature was dominated by IFN-γ-only-secreting T-cells which shifted consistently in longitudinally-followed patients during treatment to a signature dominated by dual IFN-γ/IL-2-secreting T-cells in treated patients. The LTBI signature differed from active tuberculosis, with higher proportions of IL-2-only and IFN-γ/IL-2-secreting T-cells and lower proportions of IFN-γ-only-secreting T-cells.Fluorescence-immunospot is a quantitative, accurate measure of functional T-cell subsets; identification of cytokine-signatures of pathogen burden, distinct clinical stages of M. tuberculosis infection and long-term immune containment suggests application for treatment monitoring and vaccine evaluation