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The factors controlling the concentrations of HO radicals (= OH + peroxy) in the upper troposphere (8–12 km) are examined using concurrent aircraft observations of OH, HO, HO, CHOOH, and CHO made during the Subsonic Assessment Ozone and Nitrogen Oxide Experiment (SONEX) at northern midlatitudes in the fall. These observations, complemented by concurrent measurements of O, HO, NO, peroxyacetyl nitrate (PAN), HNO, CH, CO, acetone, hydrocarbons, actinic fluxes, and aerosols, allow a highly constrained mass balance analysis of HO and of the larger chemical family HO (= HO + 2 HO + 2 CHOOH + HNO + HNO). Observations of OH and HO are successfully simulated to within 40% by a diel steady state model constrained with observed HO and CHOOH. The model captures 85% of the observed HO variance, which is driven mainly by the concentrations of NO (= NO + NO) and by the strength of the HO primary sources. Exceptions to the good agreement between modeled and observed HO are at sunrise and sunset, where the model is too low by factors of 2–5, and inside cirrus clouds, where the model is too high by factors of 1.2–2. Heterogeneous conversion of NO to HONO on aerosols (γ = 10) during the night followed by photolysis of HONO could explain part of the discrepancy at sunrise. Heterogeneous loss of HO on ice crystals (γ = 0.025) could explain the discrepancy in cirrus. Primary sources of HO from O()+HO and acetone photolysis were of comparable magnitude during SONEX. The dominant sinks of HO were OH+HO (NO50 pptv). Observed HO concentrations are reproduced by model calculations to within 50% if one allows in the model for heterogeneous conversion of HO to HO on aerosols (γ = 0.2). Observed CHOOH concentrations are underestimated by a factor of 2 on average. Observed CHO concentrations were usually below the 50 pptv detection limit, consistent with model results; however, frequent occurrences of high values in the observations (up to 350 pptv) are not captured by the model. These high values are correlated with high CHOH and with cirrus clouds. Heterogeneous oxidation of CHOH to CHO on aerosols or ice crystals might provide an explanation (γ ∼ 0.01 would be needed)., Engineering and Applied Sciences

Round window membrane (RWM) application of ouabain is known to selectively destroy type I spiral ganglion cells (SGCs) in cochleas of several rodent species, while leaving hair cells intact. This protocol has been used in rats and Mongolian gerbils, but observations in the guinea pig are conflicting. This is why we reinvestigated the effect of ouabain on the guinea pig cochlea. Ouabain solutions of different concentrations were placed, in a piece of gelfoam, upon the RWM of the right cochleas. Auditory function was assessed using acoustically evoked auditory brainstem responses (aABR). Finally, cochleas were fixed and processed for histological examination. Due to variability within treatment groups, histological data was pooled and three categories based upon general histological observations were defined: cochleas without outer hair cell (OHC) and SGC loss (Category 1), cochleas with OHC loss only (Category 2), and cochleas with OHC and SGC loss (Category 3). Animals treated with 1 mM or 10 mM ouabain showed shifts in hearing thresholds, corresponding with varying histological changes in their cochleas. Most cochleas exhibited complete outer hair cell loss in the basal and middle turns, while some had no changes, together with either moderate or near-complete loss of SGCs. Neither loss of inner hair cells nor histological changes of the stria vascularis were observed in any of the animals. Cochleas in Category 1 had normal aABRs and morphology. On average, in Category 2 OHC loss was 46.0±5.7%, SGC loss was below threshold, ABR threshold shift was 44.9±2.7 dB, and ABR wave II amplitude was decreased by 17.1±3.8 dB. In Category 3 OHC loss was 68.3±6.9%, SGC loss was 49.4±4.3%, ABR threshold shift was 39.0±2.4 dB, and ABR amplitude was decreased by 15.8±1.6 dB. Our results show that ouabain does not solely destroy type I SGCs in the guinea pig cochlea. [ABSTRACT FROM AUTHOR]

Human hexokinase enzyme IV (EC 2.7.1.1) catalyzes the phosphorylation of glucose and regulates the level of glucose. This enzyme exhibits strong positive cooperativity due to an allosteric transition between an inactive form and a closed active form. This form can be stabilized by activators and, thus, can increase its turnover by a kinetic memory effect characterized by a slow decay to the inactive state. The structural details of this kinetic allostery are known. Several synthetic activators have been reported. We present a preliminary nuclear magnetic resonance (NMR) screening of a chemical library in search of molecules with some affinity for glucokinase (GK). The library, composed of eight molecules with known activity as well as molecules that display no interaction, has been tested using the FAXS (fluorine chemical shift anisotropy and exchange for screening) method, based on monitoring the R 2 relaxation of the 19 F spin. To ensure a valid interaction measurement, the enzyme was placed in the presence of glucose and magnesium. The binding signal of one known fluorinated ligand was measured by determining the displacement of the known ligand. This simple measure of the 19 F signal intensity after an 80-ms spin echo correlates nicely with the EC 50 , opening a route for NMR screening of GK activators. [ABSTRACT FROM AUTHOR]

Since 15-deoxy-delta12,14-prostaglandin J2 (15dPGJ2) has been identified as an endogenous ligand of PPARγ thus inducing adipogenesis, it has been reported to play active parts in numerous cellular regulatory mechanisms. As 15dPGJ2 has been shown to covalently bind several peptides and proteins, we investigated whether it also covalently binds PPARγ. We first observed that after incubation of 15dPGJ2 with recombinant PPARγ, the quantity of free 15dPGJ2 measured was always lower than the initial amount. We then measured the ability of the labeled agonist rosiglitazone to displace the complex PPARγ2/15dPGJ2 obtained after pre-incubation. We observed that the binding of rosiglitazone was dependent on the initial concentration of 15dPGJ2. Finally using MALDI-TOF mass spectrometry analysis, after trypsinolysis of an incubate of the PPARγ2 ligand binding domain (GST-LBD) with 15dPGJ2, we found a fragment (m/z =1314.699) corresponding to the addition of 15dPGJ2 (m/z =316.203) to the GST-LBD peptide (m/z =998.481). All these observations demonstrate the existence of a covalent binding of 15dPGJ2 to PPARγ, which opens up new perspectives to study the molecular basis for selective activities of PPARs. [Copyright &y& Elsevier]

Background: The most common cause of preventable death after injury is haemorrhage. Resuscitative endovascular balloon occlusion of the aorta is intended to provide earlier, temporary haemorrhage control, to facilitate transfer to an operating theatre or interventional radiology suite for definitive haemostasis., Objective: To compare standard care plus resuscitative endovascular balloon occlusion of the aorta versus standard care in patients with exsanguinating haemorrhage in the emergency department., Design: Pragmatic, multicentre, Bayesian, group-sequential, registry-enabled, open-label, parallel-group randomised controlled trial to determine the clinical and cost-effectiveness of standard care plus resuscitative endovascular balloon occlusion of the aorta, compared to standard care alone., Setting: United Kingdom Major Trauma Centres., Participants: Trauma patients aged 16 years or older with confirmed or suspected life-threatening torso haemorrhage deemed amenable to adjunctive treatment with resuscitative endovascular balloon occlusion of the aorta., Interventions: Participants were randomly assigned 1 : 1 to: standard care, as expected in a major trauma centre standard care plus resuscitative endovascular balloon occlusion of the aorta., Main Outcome Measures: Primary: Mortality at 90 days. Secondary: Mortality at 6 months, while in hospital, and within 24, 6 and 3 hours; need for haemorrhage control procedures, time to commencement of haemorrhage procedure, complications, length of stay (hospital and intensive care unit-free days), blood product use. Health economic: Expected United Kingdom National Health Service perspective costs, life-years and quality-adjusted life-years, modelled over a lifetime horizon., Data Sources: Case report forms, Trauma Audit and Research Network registry, NHS Digital (Hospital Episode Statistics and Office of National Statistics data)., Results: Ninety patients were enrolled: 46 were randomised to standard care plus resuscitative endovascular balloon occlusion of the aorta and 44 to standard care. Mortality at 90 days was higher in the standard care plus resuscitative endovascular balloon occlusion of the aorta group (54%) compared to the standard care group (42%). The odds ratio was 1.58 (95% credible interval 0.72 to 3.52). The posterior probability of an odds ratio > 1 (indicating increased odds of death with resuscitative endovascular balloon occlusion of the aorta) was 86.9%. The overall effect did not change when an enthusiastic prior was used or when the estimate was adjusted for baseline characteristics. For the secondary outcomes (3, 6 and 24 hours mortality), the posterior probability that standard care plus resuscitative endovascular balloon occlusion of the aorta was harmful was higher than for the primary outcome. Additional analyses to account for intercurrent events did not change the direction of the estimate for mortality at any time point. Death due to haemorrhage was more common in the standard care plus resuscitative endovascular balloon occlusion of the aorta group than in the standard care group. There were no serious adverse device effects. Resuscitative endovascular balloon occlusion of the aorta is less costly (probability 99%), due to the competing mortality risk but also substantially less effective in terms of lifetime quality-adjusted life-years (probability 91%)., Limitations: The size of the study reflects the relative infrequency of exsanguinating traumatic haemorrhage in the United Kingdom. There were some baseline imbalances between groups, but adjusted analyses had little effect on the estimates., Conclusions: This is the first randomised trial of the addition of resuscitative endovascular balloon occlusion of the aorta to standard care in the management of exsanguinating haemorrhage. All the analyses suggest that a strategy of standard care plus resuscitative endovascular balloon occlusion of the aorta is potentially harmful., Future Work: The role (if any) of resuscitative endovascular balloon occlusion of the aorta in the pre-hospital setting remains unclear. Further research to clarify its potential (or not) may be required., Trial Registration: This trial is registered as ISRCTN16184981., Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 14/199/09) and is published in full in Health Technology Assessment ; Vol. 28, No. 54. See the NIHR Funding and Awards website for further award information.