Red cell ABO incompatibility and production of tumour necrosis factor-alpha

Tumour necrosis factor-alpha (TNF) is a major mediator of diverse pathophysiological events similar to those of haemolytic transfusion reactions (HTR), such as fever, intravascular coagulation and organ failure. However, the possible role of TNF in HTR has not been investigated. We have constructed an in vitro whole blood model of HTR to examine whether TNF may be produced in red cell ABO incompatibility. TNF was observed in plasma, in a dose dependent manner, when ABO incompatible red cells were added, but not with compatible (group O) cells. Plasma TNF levels were maximal at 2 h, and declined to control levels by 24 h. Haemolysis of incompatible red cells was accompanied by TNF production. Immune haemolysis induced TNF gene expression by buffy coat leucocytes, as determined by Northern blot analysis. Heat inactivation of plasma abolished TNF production, whereas prior treatment with interferongamma augmented the response. These results demonstrate that a major cytokine is produced in response to red cell incompatibility, and suggest that TNF may play a role in the pathogenesis of haemolytic transfusion reactions.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75627/1/j.1365-2141.1991.tb04485.x.pd

Weather, disease, and wheat breeding effects on Kansas wheat varietal yields, 1985 to 2011.

Wheat (Triticum aestivum L.) yields in Kansas have increased due to wheat breeding and improved agronomic practices, but are subject to climate and disease challenges. The objective of this research is to quantify the impact of weather, disease, and genetic improvement on wheat yields of varieties grown in 11 locations in Kansas from 1985 to 2011. Wheat variety yield data from Kansas performance tests were matched with comprehensive location-specific disease and weather data, including seasonal precipitation, monthly air temperature, air temperature and solar radiation around anthesis, and vapor pressure deficit (VPD). The results show that wheat breeding programs increased yield by 34 kg ha⁻¹ yr⁻¹. From 1985 through 2011, wheat breeding increased average wheat yields by 917 kg ha⁻¹, or 27% of total yield. Weather was found to have a large impact on wheat yields. Simulations demonstrated that a 1°C increase in projected mean temperature was associated with a decrease in wheat yields of 715 kg ha⁻¹, or 21%. Weather, diseases, and genetics all had significant impacts on wheat yields in 11 locations in Kansas during 1985 to 2011

Extent and Causes of Chesapeake Bay Warming

Coastal environments such as the Chesapeake Bay have long been impacted by eutrophication stressors resulting from human activities, and these impacts are now being compounded by global warming trends. However, there are few studies documenting long-term estuarine temperature change and the relative contributions of rivers, the atmosphere, and the ocean. In this study, Chesapeake Bay warming, since 1985, is quantified using a combination of cruise observations and model outputs, and the relative contributions to that warming are estimated via numerical sensitivity experiments with a watershed–estuarine modeling system. Throughout the Bay’s main stem, similar warming rates are found at the surface and bottom between the late 1980s and late 2010s (0.02 +/- 0.02C/year, mean +/- 1 standard error), with elevated summer rates (0.04 +/- 0.01C/year) and lower rates of winter warming (0.01 +/- 0.01C/year). Most (~85%) of this estuarine warming is driven by atmospheric effects. The secondary influence of ocean warming increases with proximity to the Bay mouth, where it accounts for more than half of summer warming in bottom waters. Sea level rise has slightly reduced summer warming, and the influence of riverine warming has been limited to the heads of tidal tributaries. Future rates of warming in Chesapeake Bay will depend not only on global atmospheric trends, but also on regional circulation patterns in mid-Atlantic waters, which are currently warming faster than the atmosphere. Supporting model data available at: https://doi.org/10.25773/c774-a36

Comprehensive characterization of the Published Kinase Inhibitor Set

Despite the success of protein kinase inhibitors as approved therapeutics, drug discovery has focused on a small subset of kinase targets. Here we provide a thorough characterization of the Published Kinase Inhibitor Set (PKIS), a set of 367 small-molecule ATP-competitive kinase inhibitors that was recently made freely available with the aim of expanding research in this field and as an experiment in open-source target validation. We screen the set in activity assays with 224 recombinant kinases and 24 G protein-coupled receptors and in cellular assays of cancer cell proliferation and angiogenesis. We identify chemical starting points for designing new chemical probes of orphan kinases and illustrate the utility of these leads by developing a selective inhibitor for the previously untargeted kinases LOK and SLK. Our cellular screens reveal compounds that modulate cancer cell growth and angiogenesis in vitro. These reagents and associated data illustrate an efficient way forward to increasing understanding of the historically untargeted kinome

DNA mismatch repair gene MSH6 implicated in determining age at natural menopause

notes: PMCID: PMC3976329This is a freely-available open access publication. Please cite the published version which is available via the DOI link in this record.The length of female reproductive lifespan is associated with multiple adverse outcomes, including breast cancer, cardiovascular disease and infertility. The biological processes that govern the timing of the beginning and end of reproductive life are not well understood. Genetic variants are known to contribute to ∼50% of the variation in both age at menarche and menopause, but to date the known genes explain <15% of the genetic component. We have used genome-wide association in a bivariate meta-analysis of both traits to identify genes involved in determining reproductive lifespan. We observed significant genetic correlation between the two traits using genome-wide complex trait analysis. However, we found no robust statistical evidence for individual variants with an effect on both traits. A novel association with age at menopause was detected for a variant rs1800932 in the mismatch repair gene MSH6 (P = 1.9 × 10(-9)), which was also associated with altered expression levels of MSH6 mRNA in multiple tissues. This study contributes to the growing evidence that DNA repair processes play a key role in ovarian ageing and could be an important therapeutic target for infertility.UK Medical Research CouncilWellcome Trus