Elevated Levels of Interferon-γ Production by Memory T Cells Do Not Promote Transplant Tolerance Resistance in Aged Recipients

Immunosenescence predisposes the elderly to infectious and autoimmune diseases and impairs the response to vaccination. We recently demonstrated that ageing also impedes development of transplantation tolerance. Unlike their young counterparts (8-12 weeks of age) aged male recipients (greater than 12 months of age) transplanted with a full MHC-mismatched heart are resistant to tolerance mediated by anti-CD45RB antibody. Surprisingly, either chemical or surgical castration restored tolerance induction to levels observed using young recipients. Based on the strong impact of endocrine modulation on transplant tolerance, we explored the impact of ageing and castration on the immune system. Here we report a significant increase in the percentage of T cells that produce interferon-γ (IFN-γ) in aged male versus young male animals and that the overall increase in IFN-γ production was due to an expansion of IFN-γ-producing memory T cells in aged animals. In contrast to IFN-γ production, we did not observe differences in IL-10 expression in young versus old male mice. We hypothesized that endocrine modulation would diminish the elevated levels of IFN-γ production in aged recipients, however, we observed no significant reduction in the percentage of IFN-γ+ T cells upon castration. Furthermore, we neutralized interferon-γ by antibody and did not observe an effect on graft survival. We conclude that while elevated levels of interferon-γ serves as a marker of tolerance resistance in aged mice, other as yet to be identified factors are responsible for its cause. Defining these factors may be relevant to design of tolerogenic strategies for aged recipients

Mediated behavioural change in human-machine networks: exploring network characteristics, trust and motivation

Human-machine networks pervade much of contemporary life. Network change is the product of structural modifications along with differences in participant be-havior. If we assume that behavioural change in a human-machine network is the result of changing the attitudes of participants in the network, then the question arises whether network structure can affect participant attitude. Taking citizen par-ticipation as an example, engagement with relevant stakeholders reveals trust and motivation to be the major objectives for the network. Using a typology to de-scribe network state based on multiple characteristic or dimensions, we can pre-dict possible behavioural outcomes in the network. However, this has to be medi-ated via attitude change. Motivation for the citizen participation network can only increase in line with enhanced trust. The focus for changing network dynamics, therefore, shifts to the dimensional changes needed to encourage increased trust. It turns out that the coordinated manipulation of multiple dimensions is needed to bring about the desired shift in attitude.Comment: Paper submitted to SocInfo, organised by the Oxford Internet Institute, September 201

The XMM Cluster Survey: The interplay between the brightest cluster galaxy and the intra-cluster medium via AGN feedback

Using a sample of 123 X-ray clusters and groups drawn from the XMM-Cluster Survey first data release, we investigate the interplay between the brightest cluster galaxy (BCG), its black hole, and the intra-cluster/group medium (ICM). It appears that for groups and clusters with a BCG likely to host significant AGN feedback, gas cooling dominates in those with Tx > 2 keV while AGN feedback dominates below. This may be understood through the sub-unity exponent found in the scaling relation we derive between the BCG mass and cluster mass over the halo mass range 10^13 < M500 < 10^15Msol and the lack of correlation between radio luminosity and cluster mass, such that BCG AGN in groups can have relatively more energetic influence on the ICM. The Lx - Tx relation for systems with the most massive BCGs, or those with BCGs co-located with the peak of the ICM emission, is steeper than that for those with the least massive and most offset, which instead follows self-similarity. This is evidence that a combination of central gas cooling and powerful, well fuelled AGN causes the departure of the ICM from pure gravitational heating, with the steepened relation crossing self-similarity at Tx = 2 keV. Importantly, regardless of their black hole mass, BCGs are more likely to host radio-loud AGN if they are in a massive cluster (Tx > 2 keV) and again co-located with an effective fuel supply of dense, cooling gas. This demonstrates that the most massive black holes appear to know more about their host cluster than they do about their host galaxy. The results lead us to propose a physically motivated, empirical definition of 'cluster' and 'group', delineated at 2 keV.Comment: Accepted for publication in MNRAS - replaced to match corrected proo

Operationalizing local ecological knowledge in climate change research : challenges and opportunities of citizen science

Current research on the local impacts of climate change is based on contrasting results from the simulation of historical trends in climatic variables produced with global models against climate data from independent observations. To date, these observations have mostly consisted of weather data from standardized meteorological stations. Given that the spatial distribution of weather stations is patchy, climate scientists have called for the exploration of new data sources. Knowledge developed by Indigenous Peoples and local communities with a long history of interaction with their environment has been proposed as a data source with untapped potential to contribute to our understanding of the local impacts of climate change. In this chapter, we discuss an approach that aims to bring insights from local knowledge systems to climate change research. First, we present a number of theoretical arguments that give support to the idea that local knowledge systems can contribute in original ways to the endeavors of climate change research. Then, we explore the potential of using information and communication technologies to gather and share local knowledge of climate change impacts. We do so through the examination of a citizen science initiative aiming to collect local indicators of climate change impacts: the LICCI project (www.licci.eu). Our findings illustrate that citizen science can inspire new approaches to articulate the inclusion of local knowledge systems in climate change research. However, this requires outlining careful approaches, with high ethical standards, toward knowledge validation and recognizing that there are aspects of local ecological knowledge that are incommensurable with scientific knowledge

Drug-gene interactions of antihypertensive medications and risk of incident cardiovascular disease: A pharmacogenomics study from the CHARGE consortium

Background Hypertension is a major risk factor for a spectrum of cardiovascular diseases (CVD), including myocardial infarction, sudden death, and stroke. In the US, over 65 million people have high blood pressure and a large proportion of these individuals are prescribed antihypertensive medications. Although large long-term clinical trials conducted in the last several decades have identified a number of effective antihypertensive treatments that reduce the risk of future clinical complications, responses to therapy and protection from cardiovascular events vary among individuals. Methods Using a genome-wide association study among 21,267 participants with pharmaceutically treated hypertension, we explored the hypothesis that genetic variants might influence or modify the effectiveness of common antihypertensive therapies on the risk ofmajor cardiovascular outcomes. The classes of drug treatments included angiotensin-converting enzyme inhibitors, beta-blockers, calcium channel blockers, and diuretics. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, each study performed array-based genome-wide genotyping, imputed to HapMap Phase II reference panels, and used additive genetic models in proportional hazards or logistic regressionmodels to evaluate drug-gene interactions for each of four therapeutic drug classes. We used meta-analysis to combine study-specific interaction estimates for approximately 2 million single nucleotide polymorphisms (SNPs) in a discovery analysis among 15,375 European Ancestry participants (3,527 CVD cases) with targeted follow-up in a case-only study of 1,751 European Ancestry GenHAT participants as well as among 4,141 African-Americans (1,267 CVD cases). Results Although drug-SNP interactions were biologically plausible, exposures and outcomes were well measured, and power was sufficient to detect modest interactions, we did not identify any statistically significant interactions from the four antihypertensive therapy meta-analyses (Pinteraction > 5.0×10-8). Similarly, findings were null for meta-analyses restricted to 66 SNPs with significant main effects on coronary artery disease or blood pressure from large published genom

Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications.

To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases

Carbon inputs from Miscanthus displace older soil organic carbon without inducing priming

The carbon (C) dynamics of a bioenergy system are key to correctly defining its viability as a sustainable alternative to conventional fossil fuel energy sources. Recent studies have quantified the greenhouse gas mitigation potential of these bioenergy crops, often concluding that C sequestration in soils plays a primary role in offsetting emissions through energy generation. Miscanthus is a particularly promising bioenergy crop and research has shown that soil C stocks can increase by more than 2 t C ha−1 yr−1. In this study, we use a stable isotope (13C) technique to trace the inputs and outputs from soils below a commercial Miscanthus plantation in Lincolnshire, UK, over the first 7 years of growth after conversion from a conventional arable crop. Results suggest that an unchanging total topsoil (0–30 cm) C stock is caused by Miscanthus additions displacing older soil organic matter. Further, using a comparison between bare soil plots (no new Miscanthus inputs) and undisturbed Miscanthus controls, soil respiration was seen to be unaffected through priming by fresh inputs or rhizosphere. The temperature sensitivity of old soil C was also seen to be very similar with and without the presence of live root biomass. Total soil respiration from control plots was dominated by Miscanthus-derived emissions with autotrophic respiration alone accounting for ∼50 % of CO2. Although total soil C stocks did not change significantly over time, the Miscanthus-derived soil C accumulated at a rate of 860 kg C ha−1 yr−1 over the top 30 cm. Ultimately, the results from this study indicate that soil C stocks below Miscanthus plantations do not necessarily increase during the first 7 years

Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications

To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases

Genome-wide association study of 23,500 individuals identifies 7 loci associated with brain ventricular volume

The volume of the lateral ventricles (LV) increases with age and their abnormal enlargement is a key feature of several neurological and psychiatric diseases. Although lateral ventricular volume is heritable, a comprehensive investigation of its genetic determinants is lacking. In this meta-analysis of genome-wide association studies of 23,533 healthy middle-aged to elderly individuals from 26 population-based cohorts, we identify 7 genetic loci associated with LV volume. These loci map to chromosomes 3q28, 7p22.3, 10p12.31, 11q23.1, 12q23.3, 16q24.2, and 22q13.1 and implicate pathways related to tau pathology, S1P signaling, and cytoskeleton organization. We also report a significant genetic overlap between the thalamus and LV volumes (ρgenetic = -0.59, p-value = 3.14 × 10-6), suggesting that these brain structures may share a common biology. These genetic associations of LV volume provide insights into brain morphology

Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications

To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases.</p