Tiludronate and clodronate do not affect bone structure or remodeling kinetics over a 60 day randomized trial

Background Tiludronate and clodronate are FDA-approved bisphosphonate drug therapies for navicular disease in horses. Although clinical studies have determined their ability to reduce lameness associated with skeletal disorders in horses, data regarding the effect on bone structure and remodeling is lacking. Additionally, due to off-label use of these drugs in young performance horses, effects on bone in young horses need to be investigated. Therefore, the purpose of this randomized, experimental pilot study was to determine the effect of tiludronate and clodronate on normal bone cells, structure and remodeling after 60 days in clinically normal, young horses. Additionally, the effect of clodronate on bone healing 60 days after an induced defect was investigated. Results All horses tolerated surgery well, with no post-surgery lameness and all acquired biopsies being adequate for analyses. Overall, tiludronate and clodronate did not significantly alter any bone structure or remodeling parameters, as evaluated by microCT and dynamic histomorphometry. Tiludronate did not extensively impact bone formation or resorption parameters as evaluated by static histomorphometry. Similarly, clodronate did not affect bone formation or resorption after 60 days. Sixty days post-defect, healing was minimally affected by clodronate. Conclusions Tiludronate and clodronate do not appear to significantly impact bone tissue on a structural or cellular level using standard dose and administration schedules

The Sensitivity of the Proportionality between Temperature Change and Cumulative CO2 Emissions to Ocean Mixing

The ratio of global mean surface air temperature change to cumulative CO2 emissions, referred to as transient climate response to cumulative CO2 emissions (TCRE), has been shown to be approximately constant on centennial time scales. The mechanisms behind this constancy are not well understood, but previous studies suggest that compensating effects of ocean heat and carbon fluxes, which are governed by the same ocean mixing processes, could be one cause for this approximate constancy. This hypothesis is investigated by forcing different versions of the University of Victoria Earth System Climate Model, which differ in the ocean mixing parameterization, with an idealized scenario of 1% annually increasing atmospheric CO2 until quadrupling of the preindustrial CO2 concentration and constant concentration thereafter. The relationship between surface air warming and cumulative emissions remains close to linear, but the TCRE varies between model versions, spanning the range of 1.2°–2.1°C EgC−1 at the time of CO2 doubling. For all model versions, the TCRE is not constant over time while atmospheric CO2 concentrations increase. It is constant after atmospheric CO2 stabilizes at 1120 ppm, because of compensating changes in temperature sensitivity (temperature change per unit radiative forcing) and cumulative airborne fraction. The TCRE remains approximately constant over time even if temperature sensitivity, determined by ocean heat flux, and cumulative airborne fraction, determined by ocean carbon flux, are taken from different model versions with different ocean mixing settings. This can partially be explained with temperature sensitivity and cumulative airborne fraction following similar trajectories, which suggests ocean heat and carbon fluxes scale approximately linearly with changes in vertical mixing

The upper end of climate model temperature projections is inconsistent with past warming

Climate models predict a large range of possible future temperatures for a particular scenario of future emissions of greenhouse gases and other anthropogenic forcings of climate. Given that further warming in coming decades could threaten increasing risks of climatic disruption, it is important to determine whether model projections are consistent with temperature changes already observed. This can be achieved by quantifying the extent to which increases in well mixed greenhouse gases and changes in other anthropogenic and natural forcings have already altered temperature patterns around the globe. Here, for the first time, we combine multiple climate models into a single synthesized estimate of future warming rates consistent with past temperature changes. We show that the observed evolution of near-surface temperatures appears to indicate lower ranges (5–95%) for warming (0.35–0.82 K and 0.45–0.93 K by the 2020s (2020–9) relative to 1986–2005 under the RCP4.5 and 8.5 scenarios respectively) than the equivalent ranges projected by the CMIP5 climate models (0.48–1.00 K and 0.51–1.16 K respectively). Our results indicate that for each RCP the upper end of the range of CMIP5 climate model projections is inconsistent with past warming

Bulk de novo mitogenome assembly from pooled total DNA elucidates the phylogeny of weevils (Coleoptera: Curculionoidea)

Complete mitochondrial genomes have been shown to be reliable markers for phylogeny reconstruction among diverse animal groups. However, the relative difficulty and high cost associated with obtaining de novo full mitogenomes have frequently led to conspicuously low taxon sampling in ensuing studies. Here, we report the successful use of an economical and accessible method for assembling complete or near-complete mitogenomes through shot-gun next-generation sequencing of a single library made from pooled total DNA extracts of numerous target species. To avoid the use of separate indexed libraries for each specimen, and an associated increase in cost, we incorporate standard polymerase chain reaction-based “bait” sequences to identify the assembled mitogenomes. The method was applied to study the higher level phylogenetic relationships in the weevils (Coleoptera: Curculionoidea), producing 92 newly assembled mitogenomes obtained in a single Illumina MiSeq run. The analysis supported a separate origin of wood-boring behavior by the subfamilies Scolytinae, Platypodinae, and Cossoninae. This finding contradicts morphological hypotheses proposing a close relationship between the first two of these but is congruent with previous molecular studies, reinforcing the utility of mitogenomes in phylogeny reconstruction. Our methodology provides a technically simple procedure for generating densely sampled trees from whole mitogenomes and is widely applicable to groups of animals for which bait sequences are the only required prior genome knowledge

Superconductivity up to 29 K in SrFe2As2 and BaFe2As2 at high pressures

We report the discovery of superconductivity at high pressure in SrFe2As2 and BaFe2As2. The superconducting transition temperatures are up to 27 K in SrFe2As2 and 29 K in BaFe2As2, making these the highest pressure-induced superconducting materials discovered thus far.Comment: Accepted in Journal of Physics: Condensed Matte

The presence of Y674/Y675 phosphorylated NTRK1 via TP53 repression of PTPN6 expression as a potential prognostic marker in neuroblastoma

The tumor suppressor TP53 promotes nerve growth factor receptor (NTRK1) -Y674/Y675 phosphorylation (NTRK1-pY674/pY675) via repression of the NTRK1 phosphatase PTPN6 in a ligand-independent manner, resulting in suppression of breast cancer cell proliferation. Moreover, NTRK1-pY674/pY675 together with low levels of PTPN6 and TP53 expression is associated with favorable disease-free survival of breast cancer patients. We determined whether in neuroblastoma this protein expression pattern impacts relapse-free survival (RFS). NTRK1-pY674/pY675, PTPN6, and TP53 expression was assessed in 98 neuroblastoma samples by immunohistochemistry. Association between expression levels and RFS was investigated by multivariate and Kaplan-Meier analysis. Mutant or wild-type TP53 was identified by sequencing tumor DNA. Tumors expressing NTRK1-pY674/pY675 and low or undetectable levels of PTPN6 and TP53 were significantly associated with 5-year RFS (P = .014) when the dataset was stratified by MYCN amplification, segmental chromosomal abnormalities and histology. Similar results were observed with tumors expressing wild-type TP53, NTRK1-pY674/pY675 and low or undetectable levels of PTPN6. Kaplan-Meier analysis demonstrated a significant correlation (P = .004), with a 50% probability of RFS (median survival 4.73 years) when present compared with 19.51% (median survival 11.63 months) when absent. Similar results were seen with non-amplified MYCN or unfavorable/undifferentiating samples and tumors from patients aged 18 months or less. Importantly, NTRK1-pY674/pY675 is an independent predictor of improved RFS. These results strongly suggest that NTRK1-pY674/pY675 together with wild-type TP53 and undetectable or low levels of PTPN6 expression is a potential biomarker of improved RFS of neuroblastoma patients. The predictive value of NTRK1-pY674/pY675 together with wild-type TP53 and low PTPN6 expression could contribute to neuroblastoma patient prognosis