Docetaxel, cisplatin, and fluorouracil; docetaxel and cisplatin; and epirubicin, cisplatin, and fluorouracil as systemic treatment for advanced gastric carcinoma: a randomized phase II trial of the Swiss Group for Clinical Cancer Research

This randomized phase II trial evaluated two docetaxel-based regimens to see which would be most promising according to overall response rate (ORR) for comparison in a phase III trial with epirubicin-cisplatin-fluorouracil (ECF) as first-line advanced gastric cancer therapy.

TINF2, a component of the shelterin telomere protection complex, is mutated in dyskeratosis congenita

Patients with dyskeratosis congenita (DC), a heterogeneous inherited bone marrow failure syndrome, have abnormalities in telomere biology, including very short telomeres and germline mutations in DKC1, TERC, TERT, or NOP10, but approximately 60% of DC patients lack an identifiable mutation. With the very short telomere phenotype and a highly penetrant, rare disease model, a linkage scan was performed on a family with autosomal-dominant DC and no mutations in DKCI, TERC, or TERT. Evidence favoring linkage was found at 2p24 and 14q11.2, and this led to the identification of TINF2 (14q11.2) mutations, K280E, in the proband and her five affected relatives and TINF2 R282H in three additional unrelated DC probands, including one with Revesz syndrome; a fifth DC proband had a R282S mutation. TINF2 mutations were not present in unaffected relatives, DC probands with mutations in DKC1, TERC, or TERT or 298 control subjects. We demonstrate that a fifth gene, TINF2, is mutated in classical DC and, for the first time, in Revesz syndrome. This represents the first shelterin complex mutation linked to human disease and confirms the role of very short telomeres as a diagnostic test for DC.

Compliance of the L5-S1 spinal unit: a comparative study between an unconstrained and a partially constrained system

A comparison between an unconstrained and a partially constrained system for in vitro biomechanical testing of the L5-S1 spinal unit was conducted. The objective was to compare the compliance and the coupling of the L5-S1 unit measured with an unconstrained and a partially constrained test for the three major physiological motions of the human spine. Very few studies have compared unconstrained and partially constrained testing systems using the same cadaveric functional spinal units (FSUs). Seven human L5-S1 units were therefore tested on both a pneumatic, unconstrained, and a servohydraulic, partially constrained system. Each FSU was tested along three motions: flexion-extension (FE), lateral bending (LB) and axial rotation (AR). The obtained kinematics on both systems is not equivalent, except for the FE case, where both motions are similar. The directions of coupled motions were similar for both tests, but their magnitudes were smaller in the partially constrained configuration. The use of a partially constrained system to characterize LB and AR of the lumbosacral FSU decreased significantly the measured stiffness of the segment. The unconstrained system is today's "gold standard" for the characterization of FSUs. The selected partially constrained method seems also to be an appropriate way to characterize FSUs for specific applications. Care should be taken using the latter method when the coupled motions are important.

The role of ocean transport in the uptake of anthropogenic CO2

We compare modeled oceanic carbon uptake in response to pulse CO2 emissions using a suite of global ocean models and Earth system models. In response to a CO2 pulse emission of 590 Pg C (corresponding to an instantaneous doubling of atmospheric CO2 from 278 to 556 ppm), the fraction of CO2 emitted that is absorbed by the ocean is: 37±8%, 56±10%, and 81±4% (model mean ±2σ ) in year 30, 100, and 1000 after the emission pulse, respectively. Modeled oceanic uptake of pulse CO2 on timescales from decades to about a century is strongly correlated with simulated present-day uptake of chlorofluorocarbons (CFCs) and CO2 across all models, while the amount of pulse CO2 absorbed by the ocean from a century to a millennium is strongly correlated with modeled radiocarbon in the deep Southern and Pacific Ocean. However, restricting the analysis to models that are capable of reproducing observations within uncertainty, the correlation is generally much weaker. The rates of surface-to-deep ocean transport are determined for individual models from the instantaneous doubling CO2 simulations, and they are used to calculate oceanic CO2 uptake in response to pulse CO2 emissions of different sizes pulses of 1000 and 5000 Pg C. These results are compared with simulated oceanic uptake of CO2 by a number of models simulations with the coupling of climate-ocean carbon cycle and without it. This comparison demonstrates that the impact of different ocean transport rates across models on oceanic uptake of anthropogenic CO2 is of similar magnitude as that of climate-carbon cycle feedbacks in a single model, emphasizing the important role of ocean transport in the uptake of anthropogenic CO2.

Genetic diversity in the modern horse illustrated from genome-wide SNP data.

Horses were domesticated from the Eurasian steppes 5,000-6,000 years ago. Since then, the use of horses for transportation, warfare, and agriculture, as well as selection for desired traits and fitness, has resulted in diverse populations distributed across the world, many of which have become or are in the process of becoming formally organized into closed, breeding populations (breeds). This report describes the use of a genome-wide set of autosomal SNPs and 814 horses from 36 breeds to provide the first detailed description of equine breed diversity. F(ST) calculations, parsimony, and distance analysis demonstrated relationships among the breeds that largely reflect geographic origins and known breed histories. Low levels of population divergence were observed between breeds that are relatively early on in the process of breed development, and between those with high levels of within-breed diversity, whether due to large population size, ongoing outcrossing, or large within-breed phenotypic diversity. Populations with low within-breed diversity included those which have experienced population bottlenecks, have been under intense selective pressure, or are closed populations with long breed histories. These results provide new insights into the relationships among and the diversity within breeds of horses. In addition these results will facilitate future genome-wide association studies and investigations into genomic targets of selection.

Genome-wide analysis reveals selection for important traits in domestic horse breeds.

Intense selective pressures applied over short evolutionary time have resulted in homogeneity within, but substantial variation among, horse breeds. Utilizing this population structure, 744 individuals from 33 breeds, and a 54,000 SNP genotyping array, breed-specific targets of selection were identified using an F(ST)-based statistic calculated in 500-kb windows across the genome. A 5.5-Mb region of ECA18, in which the myostatin (MSTN) gene was centered, contained the highest signature of selection in both the Paint and Quarter Horse. Gene sequencing and histological analysis of gluteal muscle biopsies showed a promoter variant and intronic SNP of MSTN were each significantly associated with higher Type 2B and lower Type 1 muscle fiber proportions in the Quarter Horse, demonstrating a functional consequence of selection at this locus. Signatures of selection on ECA23 in all gaited breeds in the sample led to the identification of a shared, 186-kb haplotype including two doublesex related mab transcription factor genes (DMRT2 and 3). The recent identification of a DMRT3 mutation within this haplotype, which appears necessary for the ability to perform alternative gaits, provides further evidence for selection at this locus. Finally, putative loci for the determination of size were identified in the draft breeds and the Miniature horse on ECA11, as well as when signatures of selection surrounding candidate genes at other loci were examined. This work provides further evidence of the importance of MSTN in racing breeds, provides strong evidence for selection upon gait and size, and illustrates the potential for population-based techniques to find genomic regions driving important phenotypes in the modern horse.

Oxygen and indicators of stress for marine life in multi-model global warming projections

Decadal-to-century scale trends for a range of marine environmental variables in the upper mesopelagic layer (UML, 100–600 m) are investigated using results from seven Earth System Models forced by a high greenhouse gas emission scenario. The models as a class represent the observation-based distribution of oxygen (O2) and carbon dioxide (CO2), albeit major mismatches between observation-based and simulated values remain for individual models. By year 2100 all models project an increase in SST between 2 °C and 3 °C, and a decrease in the pH and in the saturation state of water with respect to calcium carbonate minerals in the UML. A decrease in the total ocean inventory of dissolved oxygen by 2% to 4% is projected by the range of models. Projected O2 changes in the UML show a complex pattern with both increasing and decreasing trends reflecting the subtle balance of different competing factors such as circulation, production, remineralization, and temperature changes. Projected changes in the total volume of hypoxic and suboxic waters remain relatively small in all models. A widespread increase of CO2 in the UML is projected. The median of the CO2 distribution between 100 and 600m shifts from 0.1–0.2 mol m−3 in year 1990 to 0.2–0.4 mol m−3 in year 2100, primarily as a result of the invasion of anthropogenic carbon from the atmosphere. The co-occurrence of changes in a range of environmental variables indicates the need to further investigate their synergistic impacts on marine ecosystems and Earth System feedbacks.

Projected pH reductions by 2100 might put deep North Atlantic biodiversity at risk

This study aims to evaluate the potential for impacts of ocean acidification on North Atlantic deep-sea ecosystems in response to IPCC AR5 Representative Concentration Pathways (RCPs). Deep-sea biota is likely highly vulnerable to changes in seawater chemistry and sensitive to moderate excursions in pH. Here we show, from seven fully coupled Earth system models, that for three out of four RCPs over 17% of the seafloor area below 500 m depth in the North Atlantic sector will experience pH reductions exceeding −0.2 units by 2100. Increased stratification in response to climate change partially alleviates the impact of ocean acidification on deep benthic environments. We report on major pH reductions over the deep North Atlantic seafloor (depth >500 m) and at important deep-sea features, such as seamounts and canyons. By 2100, and under the high CO2 scenario RCP8.5, pH reductions exceeding −0.2 (−0.3) units are projected in close to 23% (~15%) of North Atlantic deep-sea canyons and ~8% (3%) of seamounts – including seamounts proposed as sites of marine protected areas. The spatial pattern of impacts reflects the depth of the pH perturbation and does not scale linearly with atmospheric CO2 concentration. Impacts may cause negative changes of the same magnitude or exceeding the current target of 10% of preservation of marine biomes set by the convention on biological diversity, implying that ocean acidification may offset benefits from conservation/management strategies relying on the regulation of resource exploitation.

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.

Probing the Electrocatalytic Oxygen Reduction Reaction Reactivity of Immobilized Multicopper Oxidase CueO

The bioelectrocatalytic (oxygen reduction reaction, ORR) properties of the multicopper oxidase CueO immobilized on gold electrodes were investigated. Macroscopic electrochemical techniques were combined with in situ scanning tunneling microscopy (STM) and surface-enhanced Raman spectroscopy at the ensemble and at the single-molecule level. Self-assembled monolayer of mercaptopropionic acid, cysteamine, and p-aminothiophenol were chosen as redox mediators. The highest ORR activity was observed for the protein attached to amino-terminated adlayers. In situ STM experiments revealed that the presence of oxygen causes distinct structure and electronic changes in the metallic centers of the enzyme, which determine the rate of intramolecular electron transfer and, consequently, affect the rate of electron tunneling through the protein. Complementary Raman spectroscopy experiments provided access for monitoring structural changes in the redox state of the type 1 copper center of the immobilized enzyme during the CueO-catalyzed oxygen reduction cycle. These results unequivocally demonstrate the existence of a direct electronic communication between the electrode substrate and the type 1 copper center.

Bevacizumab, Pemetrexed, and Cisplatin, or Bevacizumab and Erlotinib for Patients With Advanced Non-Small-Cell Lung Cancer Stratified by Epidermal Growth Factor Receptor Mutation: Phase II Trial SAKK19/09

Treatment allocation by epidermal growth factor receptor mutation status is a new standard in patients with metastatic nonesmall-cell lung cancer. Yet, relatively few modern chemotherapy trials were conducted in patients characterized by epidermal growth factor receptor wild type. We describe the results of a multicenter phase II trial, testing in parallel 2 novel combination therapies, predefined molecular markers, and tumor rebiopsy at progression. Objective: The goal was to demonstrate that tailored therapy, according to tumor histology and epidermal growth factor receptor (EGFR) mutation status, and the introduction of novel drug combinations in the treatment of advanced nonesmall-cell lung cancer are promising for further investigation. Methods: We conducted a multicenter phase II trial with mandatory EGFR testing and 2 strata. Patients with EGFR wild type received 4 cycles of bevacizumab, pemetrexed, and cisplatin, followed by maintenance with bevacizumab and pemetrexed until progression. Patients with EGFR mutations received bevacizumab and erlotinib until progression. Patients had computed tomography scans every 6 weeks and repeat biopsy at progression. The primary end point was progression-free survival (PFS) ≥ 35% at 6 months in stratum EGFR wild type; 77 patients were required to reach a power of 90% with an alpha of 5%. Secondary end points were median PFS, overall survival, best overall response rate (ORR), and tolerability. Further biomarkers and biopsy at progression were also evaluated. Results: A total of 77 evaluable patients with EGFR wild type received an average of 9 cycles (range, 1-25). PFS at 6 months was 45.5%, median PFS was 6.9 months, overall survival was 12.1 months, and ORR was 62%. Kirsten rat sarcoma oncogene mutations and circulating vascular endothelial growth factor negatively correlated with survival, but thymidylate synthase expression did not. A total of 20 patients with EGFR mutations received an average of 16.

Canine rabies in Australia: a review of preparedness and research needs

Australia is unique as a populated continent in that canine rabies is exotic, with only one likely incursion in 1867. This is despite the presence of a widespread free-ranging dog population, which includes the naturalized dingo, feral domestic dogs and dingo-dog cross-breeds. To Australia's immediate north, rabies has recently spread within the Indonesian archipelago, with outbreaks occurring in historically free islands to the east including Bali, Flores, Ambon and the Tanimbar Islands. Australia depends on strict quarantine protocols to prevent importation of a rabid animal, but the risk of illegal animal movements by fishing and recreational vessels circumventing quarantine remains. Predicting where rabies will enter Australia is important, but understanding dog population dynamics and interactions, including contact rates in and around human populations, is essential for rabies preparedness. The interactions among and between Australia's large populations of wild, free-roaming and restrained domestic dogs require quantification for rabies incursions to be detected and controlled. The imminent risk of rabies breaching Australian borders makes the development of disease spread models that will assist in the deployment of cost-effective surveillance, improve preventive strategies and guide disease management protocols vitally important. Here, we critically review Australia's preparedness for rabies, discuss prevailing assumptions and models, identify knowledge deficits in free-roaming dog ecology relating to rabies maintenance and speculate on the likely consequences of endemic rabies for Australia.

The colloidal tool-box approach for fuel cell catalysts: Systematic study of perfluorosulfonate-ionomer impregnation and Pt loading

In this study, the correlation between the impregnation of proton exchange membrane fuel cell catalysts with perfluorosulfonate-ionomer (PFSI) and its electrochemical and electrocatalytic properties is investigated for different Pt loadings and carbon supports using a rotating-disk electrode (RDE) setup. We concentrate on its influence on the electrochemical surface area (ECSA) and the oxygen reduction reaction (ORR) activity. For this purpose, platinum (Pt) nanoparticles are prepared via a colloidal based preparation route and supported on three different carbon supports. Based on RDE experiments, we show that the ionomer has an influence both on the Pt utilization and the apparent kinetic current density of ORR. The experimental data reveal a strong interaction in the microstructure between the electrochemical properties and the surface properties of the carbon supports, metal loading and ionomer content. This study demonstrates that the colloidal synthesis approach offers interesting potential for systematic studies for the optimization of fuel cell catalysts.

Oxygen Reduction Reaction on Pt Overlayers Deposited onto a Gold Film: Ligand, Strain, and Ensemble Effect

We study the oxygen reduction reaction (ORR), the catalytic process occurring at the cathode in fuel cells, on Pt layers prepared by electrodeposition onto an Au substrate. Using a nominal Pt layer by layer deposition method previously proposed, imperfect layers of Pt on Au are obtained. The ORR on deposited Pt layers decreases with increasing Pt thickness. In the submonolayer region, however, the ORR activity is superior to that of bulk Pt. Using density functional theory (DFT) calculations, we correlate the observed activity trend to strain, ligand, and ensemble effects. At submonolayer coverage certain atom configurations weaken the binding energies of reaction intermediates due to a ligand and ensemble effect, thus effectively increasing the ORR activity. At higher Pt coverage the activity is governed by a strain effect, which lowers the activity by decreasing the oxidation potential of water. This study is a nice example of how the influence of strain, ligand, and ensemble effects on the ORR can be deconvoluted.