Cold collisions of OH and Rb. I: the free collision

We have calculated elastic and state-resolved inelastic cross sections for cold and ultracold collisions in the Rb($^1 S$) + OH($^2 \Pi_{3/2}$) system, including fine-structure and hyperfine effects. We have developed a new set of five potential energy surfaces for Rb-OH($^2 \Pi$) from high-level {\em ab initio} electronic structure calculations, which exhibit conical intersections between covalent and ion-pair states. The surfaces are transformed to a quasidiabatic representation. The collision problem is expanded in a set of channels suitable for handling the system in the presence of electric and/or magnetic fields, although we consider the zero-field limit in this work. Because of the large number of scattering channels involved, we propose and make use of suitable approximations. To account for the hyperfine structure of both collision partners in the short-range region we develop a frame-transformation procedure which includes most of the hyperfine Hamiltonian. Scattering cross sections on the order of $10^{-13}$ cm$^2$ are predicted for temperatures typical of Stark decelerators. We also conclude that spin orientation of the partners is completely disrupted during the collision. Implications for both sympathetic cooling of OH molecules in an environment of ultracold Rb atoms and experimental observability of the collisions are discussed.Comment: 20 pages, 16 figure

The Effect of Chronic Digitoxin Administration on the Contractile State of Normal and Nonfailing Hypertrophied Myocardium

A B S T R A C T To determine the effect of prolonged digitoxin administration on contractile function of nonfailing myocardium, right ventricular papillary muscle mechanics were examined after 6 or 24 wk of glycoside administration to control and pulmonary artery banded cats. Resting length-tension relations were not affected by digitoxin; however, isometrically developed force and the maximal rate of force development at the peak of the length-tension curve were increased in all treated groups. In untreated animals, banding resulted in a 28% incidence of deaths from heart failure. 6 wk after constriction, contractile function was depressed whereas normal function was observed 24 wk after banding. Digitoxin significantly reduced mortality from heart failure and enhanced the recovery of contractile function; contractile function in the 6 wk banded treated group approached that of untreated control and 24-wk banded groups. The long-term effects of digitoxin on contractile function were not importantly related to the temporal association between banding and institution of glycoside administration. Development of myocardial hypertrophy was comparable in treated and untreated banded groups. These results demonstrate that a significant positive inotropic effect persists in both normal and nonfailing hypertrophied myocardium during chronic digitoxin administration

Homologous and heterologous desensitization of guanylyl cyclase-B signaling in GH3 somatolactotropes

The guanylyl cyclases, GC-A and GC-B, are selective receptors for atrial and C-type natriuretic peptides (ANP and CNP, respectively). In the anterior pituitary, CNP and GC-B are major regulators of cGMP production in gonadotropes and yet mouse models of disrupted CNP and GC-B indicate a potential role in growth hormone secretion. In the current study, we investigate the molecular and pharmacological properties of the CNP/GC-B system in somatotrope lineage cells. Primary rat pituitary and GH3 somatolactotropes expressed functional GC-A and GC-B receptors that had similar EC50 properties in terms of cGMP production. Interestingly, GC-B signaling underwent rapid homologous desensitization in a protein phosphatase 2A (PP2A)-dependent manner. Chronic exposure to either CNP or ANP caused a significant down-regulation of both GC-A- and GC-B-dependent cGMP accumulation in a ligand-specific manner. However, this down-regulation was not accompanied by alterations in the sub-cellular localization of these receptors. Heterologous desensitization of GC-B signaling occurred in GH3 cells following exposure to either sphingosine-1-phosphate or thyrotrophin-releasing hormone (TRH). This heterologous desensitization was protein kinase C (PKC)-dependent, as pre-treatment with GF109203X prevented the effect of TRH on CNP/GC-B signaling. Collectively, these data indicate common and distinct properties of particulate guanylyl cyclase receptors in somatotropes and reveal that independent mechanisms of homologous and heterologous desensitization occur involving either PP2A or PKC. Guanylyl cyclase receptors thus represent potential novel therapeutic targets for treating growth-hormone-associated disorders

Improvements in Raman Lidar Measurements Using New Interference Filter Technology

Narrow-band interference filters with improved transmission in the ultra-violet have been developed under NASA-funded research and used in the Raman Airborne Spectroscopic Lidar (RASL) in ground-based, upward-looking tests. Measurements were made of atmospheric water vapor, cirrus cloud optical properties and carbon dioxide that improve upon any previously demonstrated using Raman lidar. Daytime boundary and mixed layer profiling of water vapor mixing ratio up to an altitude of approximately 4 h is performed with less than 5% random error using temporal and spatial resolution of 2-minutes and 60 - 210, respectively. Daytime cirrus cloud optical depth and extinction-to-backscatter ratio measurements are made using 1 -minute average. Sufficient signal strength is demonstrated to permit the simultaneous profiling of carbon dioxide and water vapor mixing ratio into the free troposphere during the nighttime. A description of the filter technology developments is provided followed by examples of the improved Raman lidar measurements

Nerve Agent Hydrolysis Activity Designed into a Human Drug Metabolism Enzyme

Organophosphorus (OP) nerve agents are potent suicide inhibitors of the essential neurotransmitter-regulating enzyme acetylcholinesterase. Due to their acute toxicity, there is significant interest in developing effective countermeasures to OP poisoning. Here we impart nerve agent hydrolysis activity into the human drug metabolism enzyme carboxylesterase 1. Using crystal structures of the target enzyme in complex with nerve agent as a guide, a pair of histidine and glutamic acid residues were designed proximal to the enzyme's native catalytic triad. The resultant variant protein demonstrated significantly increased rates of reactivation following exposure to sarin, soman, and cyclosarin. Importantly, the addition of these residues did not alter the high affinity binding of nerve agents to this protein. Thus, using two amino acid substitutions, a novel enzyme was created that efficiently converted a group of hemisubstrates, compounds that can start but not complete a reaction cycle, into bona fide substrates. Such approaches may lead to novel countermeasures for nerve agent poisoning

Self-monitoring blood pressure in patients with hypertension: an internet-based survey of UK GPs.

BACKGROUND: Previous research suggests that most GPs in the UK use self-monitoring of blood pressure (SMBP) to monitor the control of hypertension rather than for diagnosis. This study sought to assess current practice in the use of self-monitoring and any changes in practice following more recent guideline recommendations. AIM: To survey the views and practice of UK GPs in 2015 with regard to SMBP and compare them with a previous survey carried out in 2011. DESIGN AND SETTING: Web-based survey of a regionally representative sample of 300 UK GPs. METHOD: GPs completed an online questionnaire concerning the use of SMBP in the management of hypertension. Analyses comprised descriptive statistics, tests for between-group differences (z, Wilcoxon signed-rank, and χ2 tests), and multivariate logistic regression. RESULTS: Results were available for 300 GPs (94% of those who started the survey). GPs reported using self-monitoring to diagnose hypertension (169/291; 58%; 95% confidence interval (CI) = 52 to 64) and to monitor control (245/291; 84%; 95% CI = 80 to 88), the former having significantly increased since 2011 (from 37%; 95% CI = 33 to 41; P<0.001) with no change in monitoring for control. More than half of GPs used higher systolic thresholds for diagnosis (118/169; 70%; 95% CI = 63 to 77) and treatment (168/225; 75%; 95% CI = 69 to 80) than recommended in guidelines, and under half (120/289; 42%; 95% CI = 36 to 47) adjusted the SMBP results to guide treatment decisions. CONCLUSION: Since new UK national guidance in 2011, GPs are more likely to use SMBP to diagnose hypertension. However, significant proportions of GPs continue to use non-standard diagnostic and monitoring thresholds. The use of out-of-office methods to improve the accuracy of diagnosis is unlikely to be beneficial if suboptimal thresholds are used.This study was funded by the British Hypertension Society and the NIHR. Ben Fletcher receives funding from the National Institute for Health Research (NIHR) School for Primary Care Research (SPCR) Doctoral Studentship. Richard McManus holds an NIHR Professorship (RP-02-12-015)) and receives funding from the NIHR Oxford CLAHRC. This article presents independent research funded by the NIHR. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.This is the author accepted manuscript. The final version is available from Royal College of General Practitioners via https://doi.org/10.3399/bjgp16X68703

A novel method to derive a human safety limit for PFOA by gene expression profiling and modelling

Perfluorooctanoic acid (PFOA) is a persistent environmental contaminant that can accumulate in the human body due to its long half-life. This substance has been associated with liver, pancreatic, testicular and breast cancers, liver steatosis and endocrine disruption. PFOA is a member of a large group of substances also known as “forever chemicals” and the vast majority of substances of this group lack toxicological data that would enable their effective risk assessment in terms of human health hazards. This study aimed to derive a health-based guidance value for PFOA intake (ng/kg BW/day) from in vitro transcriptomics data. To this end, we developed an in silico workflow comprising five components: (i) sourcing in vitro hepatic transcriptomics concentration-response data; (ii) deriving molecular points of departure using BMDExpress3 and performing pathway analysis using gene set enrichment analysis (GSEA) to identify the most sensitive molecular pathways to PFOA exposure; (iii) estimating freely-dissolved PFOA concentrations in vitro using a mass balance model; (iv) estimating in vivo doses by reverse dosimetry using a PBK model for PFOA as part of a quantitative in vitro to in vivo extrapolation (QIVIVE) algorithm; and (v) calculating a tolerable daily intake (TDI) for PFOA. Fourteen percent of interrogated genes exhibited in vitro concentration-response relationships. GSEA pathway enrichment analysis revealed that “fatty acid metabolism” was the most sensitive pathway to PFOA exposure. In vitro free PFOA concentrations were calculated to be 2.9% of the nominal applied concentrations, and these free concentrations were input into the QIVIVE workflow. Exposure doses for a virtual population of 3,000 individuals were estimated, from which a TDI of 0.15 ng/kg BW/day for PFOA was calculated using the benchmark dose modelling software, PROAST. This TDI is comparable to previously published values of 1.16, 0.69, and 0.86 ng/kg BW/day by the European Food Safety Authority. In conclusion, this study demonstrates the combined utility of an “omics”-derived molecular point of departure and in silico QIVIVE workflow for setting health-based guidance values in anticipation of the acceptance of in vitro concentration-response molecular measurements in chemical risk assessment

Impaired fas-fas ligand interactions result in greater recurrent herpetic stromal keratitis in mice

Herpes simplex virus-1 (HSV-1) infection of the cornea leads to a potentially blinding condition termed herpetic stromal keratitis (HSK). Clinical studies have indicated that disease is primarily associated with recurrent HSK following reactivation of a latent viral infection of the trigeminal ganglia. One of the key factors that limit inflammation of the cornea is the expression of Fas ligand (FasL). We demonstrate that infection of the cornea with HSV-1 results in increased functional expression of FasL and that mice expressing mutations in Fas (lpr) and FasL (gld) display increased recurrent HSK following reactivation compared to wild-type mice. Furthermore, both gld and lpr mice took longer to clear their corneas of infectious virus and the reactivation rate for these strains was significantly greater than that seen with wild-type mice. Collectively, these findings indicate that the interaction of Fas with FasL in the cornea restricts the development of recurrent HSK

Formalising the Continuous/Discrete Modeling Step

Formally capturing the transition from a continuous model to a discrete model is investigated using model based refinement techniques. A very simple model for stopping (eg. of a train) is developed in both the continuous and discrete domains. The difference between the two is quantified using generic results from ODE theory, and these estimates can be compared with the exact solutions. Such results do not fit well into a conventional model based refinement framework; however they can be accommodated into a model based retrenchment. The retrenchment is described, and the way it can interface to refinement development on both the continuous and discrete sides is outlined. The approach is compared to what can be achieved using hybrid systems techniques.Comment: In Proceedings Refine 2011, arXiv:1106.348