Skeletal Light-Scattering Accelerates Bleaching Response in Reef-Building Corals

Background At the forefront of ecosystems adversely affected by climate change, coral reefs are sensitive to anomalously high temperatures which disassociate (bleaching) photosynthetic symbionts (Symbiodinium) from coral hosts and cause increasingly frequent and severe mass mortality events. Susceptibility to bleaching and mortality is variable among corals, and is determined by unknown proportions of environmental history and the synergy of Symbiodinium- and coral-specific properties. Symbiodinium live within host tissues overlaying the coral skeleton, which increases light availability through multiple light-scattering, forming one of the most efficient biological collectors of solar radiation. Light-transport in the upper ~200 μm layer of corals skeletons (measured as ‘microscopic’ reduced-scattering coefficient, μ′S,m), has been identified as a determinant of excess light increase during bleaching and is therefore a potential determinant of the differential rate and severity of bleaching response among coral species. Results Here we experimentally demonstrate (in ten coral species) that, under thermal stress alone or combined thermal and light stress, low-μ′S,m corals bleach at higher rate and severity than high-μ′S,m corals and the Symbiodinium associated with low-μ′S,m corals experience twice the decrease in photochemical efficiency. We further modelled the light absorbed by Symbiodinium due to skeletal-scattering and show that the estimated skeleton-dependent light absorbed by Symbiodinium (per unit of photosynthetic pigment) and the temporal rate of increase in absorbed light during bleaching are several fold higher in low-μ′S,m corals. Conclusions While symbionts associated with low-μ′S,m corals receive less total light from the skeleton, they experience a higher rate of light increase once bleaching is initiated and absorbing bodies are lost; further precipitating the bleaching response. Because microscopic skeletal light-scattering is a robust predictor of light-dependent bleaching among the corals assessed here, this work establishes μ′S,m as one of the key determinants of differential bleaching response

Reconstructing the Deep Population History of Central and South America

We report genome-wide ancient DNA from 49 individuals forming four parallel time transects in Belize, Brazil, the Central Andes, and the Southern Cone, each dating to at least 9,000 years ago. The common ancestral population radiated rapidly from just one of the two early branches that contributed to Native Americans today. We document two previously unappreciated streams of gene flow between North and South America. One affected the Central Andes by 4,200 years ago, while the other explains an affinity between the oldest North American genome associated with the Clovis culture and the oldest Central and South Americans from Chile, Brazil, and Belize. However, this was not the primary source for later South Americans, as the other ancient individuals derive from lineages without specific affinity to the Clovis-associated genome, suggesting a population replacement that began at least 9,000 years ago and was followed by substantial population continuity in multiple regions

The contribution of X-linked coding variation to severe developmental disorders

Abstract: Over 130 X-linked genes have been robustly associated with developmental disorders, and X-linked causes have been hypothesised to underlie the higher developmental disorder rates in males. Here, we evaluate the burden of X-linked coding variation in 11,044 developmental disorder patients, and find a similar rate of X-linked causes in males and females (6.0% and 6.9%, respectively), indicating that such variants do not account for the 1.4-fold male bias. We develop an improved strategy to detect X-linked developmental disorders and identify 23 significant genes, all of which were previously known, consistent with our inference that the vast majority of the X-linked burden is in known developmental disorder-associated genes. Importantly, we estimate that, in male probands, only 13% of inherited rare missense variants in known developmental disorder-associated genes are likely to be pathogenic. Our results demonstrate that statistical analysis of large datasets can refine our understanding of modes of inheritance for individual X-linked disorders

Can a combined screening/treatment programme prevent premature failure of renal transplants due to chronic rejection in patients with HLA antibodies:study protocol for the multicentre randomised controlled OuTSMART trial

© 2014 Dorling et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

A Complete Mitochondrial Genome Sequence from a Mesolithic Wild Aurochs (Bos primigenius)

Background The derivation of domestic cattle from the extinct wild aurochs (Bos primigenius) has been well-documented by archaeological and genetic studies. Genetic studies point towards the Neolithic Near East as the centre of origin for Bos taurus, with some lines of evidence suggesting possible, albeit rare, genetic contributions from locally domesticated wild aurochsen across Eurasia. Inferences from these investigations have been based largely on the analysis of partial mitochondrial DNA sequences generated from modern animals, with limited sequence data from ancient aurochsen samples. Recent developments in DNA sequencing technologies, however, are affording new opportunities for the examination of genetic material retrieved from extinct species, providing new insight into their evolutionary history. Here we present DNA sequence analysis of the first complete mitochondrial genome (16,338 base pairs) from an archaeologically-verified and exceptionally-well preserved aurochs bone sample. Methodology DNA extracts were generated from an aurochs humerus bone sample recovered from a cave site located in Derbyshire, England and radiocarbon-dated to 6,738±68 calibrated years before present. These extracts were prepared for both Sanger and next generation DNA sequencing technologies (Illumina Genome Analyzer). In total, 289.9 megabases (22.48%) of the post-filtered DNA sequences generated using the Illumina Genome Analyzer from this sample mapped with confidence to the bovine genome. A consensus B. primigenius mitochondrial genome sequence was constructed and was analysed alongside all available complete bovine mitochondrial genome sequences. Conclusions For all nucleotide positions where both Sanger and Illumina Genome Analyzer sequencing methods gave high-confidence calls, no discrepancies were observed. Sequence analysis reveals evidence of heteroplasmy in this sample and places this mitochondrial genome sequence securely within a previously identified aurochsen haplogroup (haplogroup P), thus providing novel insights into pre-domestic patterns of variation. The high proportion of authentic, endogenous aurochs DNA preserved in this sample bodes well for future efforts to determine the complete genome sequence of a wild ancestor of domestic cattle

Helicobacter pylori "test and treat" or endoscopy for managing dyspepsia: An individual patient data meta-analysis

Background & Aims: Helicobacter pylori "test and treat" has been recommended for the management of young dyspeptic patients without alarm symptoms, and trials have suggested that it is as effective as endoscopy. However, none of these trials have had sufficient sample size to confirm that "test and treat" costs less or to detect small differences in effect. A collaborative group has prospectively registered trials comparing prompt endoscopy with a "test and treat" approach, with the aim of performing an individual patient data meta-analysis of both effect and resource utilization data. Methods: Researchers provided data for meta-analysis, pooling effects of interventions on individual dyspepsia symptoms. Standardized unit costs were applied to resource utilization, and net benefit was calculated at patient level. Effects, costs, and net benefit were then pooled at study level. Results: Five trials were identified, containing 1924 patients (946 endoscopy [mean age, 40 years], 978 "test and treat" [mean age, 41 years]). The relative risk (RR) of remaining symptomatic after 1 year was reduced with endoscopy compared with "test and treat" (RR = 0.95; 95% confidence interval [CI]: 0.92-0.99). "Test and treat" cost $389 less per patient (95$275-$502). Using the net benefit approach, at no realistic level of willingness to pay per patient symptom-free did prompt endoscopy become cost-effective. Conclusions: Prompt endoscopy confers a small benefit in terms of cure of dyspepsia but costs more than "test and treat" and is not a cost-effective strategy for the initial management of dyspepsia

Discovery of N-trisubstituted Pyrimidine Derivatives as Type-I RET and RET Gatekeeper Mutant Inhibitors with a Novel Kinase Binding Pose

Rearranged during transfection (RET) kinase is an attractive therapeutic target in cancers in which RET gene fusions and point mutations in the kinase domain are reported. Mutation of V804, the RET gatekeeper residue, leads to resistance to several FDA approved inhibitors. In this study, we discovered a series of N-trisubstituted pyrimidine derivatives as potent inhibitors for both wt-RET and RETV804M. Enzyme kinetics indicate that these inhibitors are ATP-competitive. The X-ray structure of a representative inhibitor in complex with RET reveals that the compound binds a unique pose that bifurcates beneath the P-loop; this is the first time that such a binding pose for a kinase inhibitor is described. Moreover, this binding pose explained the ability of N-trisubstituted pyrimidine compounds of targeting RETV804M. A structure activity relationship (SAR) was performed and compound 20 was identified as a lead one, displaying potent inhibition of RET and RETV804M with IC50 of 6.20nM and 18.68nM, respectively. Additionally, compound 20 showed potent anti-proliferative activity in CCDC6-RET driven LC-2/ad lung carcinoma cells. A wound healing assay indicated that compound 20 inhibits migration of RET mutant tumor cells. Analysis of apoptosis and RET phosphorylation indicated that such biological activities were mediated by RET inhibition. Collectively, N-trisubstituted pyrimidine derivatives could serve as scaffolds for the discovery and development of potent type-I RET and its gatekeeper mutant inhibitors for the treatment of RET driven cancers