Level of beta-adrenergic receptor kinase 1 inhibition determines degree of cardiac dysfunction after chronic pressure overload-induced heart failure.

BACKGROUND: Heart failure is characterized by abnormalities in beta-adrenergic receptor (betaAR) signaling, including increased level of myocardial betaAR kinase 1 (betaARK1). Our previous studies have shown that inhibition of betaARK1 with the use of the Gbetagamma sequestering peptide of betaARK1 (betaARKct) can prevent cardiac dysfunction in models of heart failure. Because inhibition of betaARK activity is pivotal for amelioration of cardiac dysfunction, we investigated whether the level of betaARK1 inhibition correlates with the degree of heart failure. METHODS AND RESULTS: Transgenic (TG) mice with varying degrees of cardiac-specific expression of betaARKct peptide underwent transverse aortic constriction (TAC) for 12 weeks. Cardiac function was assessed by serial echocardiography in conscious mice, and the level of myocardial betaARKct protein was quantified at termination of the study. TG mice showed a positive linear relationship between the level of betaARKct protein expression and fractional shortening at 12 weeks after TAC. TG mice with low betaARKct expression developed severe heart failure, whereas mice with high betaARKct expression showed significantly less cardiac deterioration than wild-type (WT) mice. Importantly, mice with a high level of betaARKct expression had preserved isoproterenol-stimulated adenylyl cyclase activity and normal betaAR densities in the cardiac membranes. In contrast, mice with low expression of the transgene had marked abnormalities in betaAR function, similar to the WT mice. CONCLUSIONS: These data show that the level of betaARK1 inhibition determines the degree to which cardiac function can be preserved in response to pressure overload and has important therapeutic implications when betaARK1 inhibition is considered as a molecular target.

Identification and assessment of potential wind energy project sites in the State of Maryland

Gemstone Team Renewables

The Role of mRNA Translation in the Regulation of Ribosome Trafficking to the Endoplasmic Reticulum

The goal of this research is to identify the trafficking patterns that direct ribosomes to the endoplasmic reticulum (ER). It is widely believed that the SRP pathway is the only mechanism that cells use to localize mRNA and ribosomes to the ER, but this has been found not to be a sufficient explanation for the patterns of RNA localization in cells, namely that non-signal sequence-containing mRNA are translated on the ER and that ribosomes retain their membrane association after translation termination. First, a summary of the history of the field is presented to provide context for the key, unanswered questions in the field. Then, experiments employing [32Pi] pulse-chase labeling of HeLa cells over a time course to follow nascent ribosome trafficking are presented. The purpose of the cell labeling was to track rRNA processing and assembly into nascent ribosomes, followed by their export into the cytoplasm and recruitment into active polysomes. A detergent-based cell fractionation procedure was also utilized to separate the cytosol and ER compartments in order to observe ribosomes on their path as they exit the nucleus and either localize to the ER or cytosolic cellular compartment. Through this method, it was seen that ribosomes appear in both compartments at the same time, suggesting a mechanism may be occurring in addition to SRP-dependent ribosome trafficking. This research provides an understanding toward a mechanism that is not currently known, but will one day more fully explain the patterns of ribosomal localization.

An evaluation of remifentanil-sevoflurane response surface models in patients emerging from anesthesia: model improvement using effect-site sevoflurane concentrations.

INTRODUCTION: We previously reported models that characterized the synergistic interaction between remifentanil and sevoflurane in blunting responses to verbal and painful stimuli. This preliminary study evaluated the ability of these models to predict a return of responsiveness during emergence from anesthesia and a response to tibial pressure when patients required analgesics in the recovery room. We hypothesized that model predictions would be consistent with observed responses. We also hypothesized that under non-steady-state conditions, accounting for the lag time between sevoflurane effect-site concentration (Ce) and end-tidal (ET) concentration would improve predictions. METHODS: Twenty patients received a sevoflurane, remifentanil, and fentanyl anesthetic. Two model predictions of responsiveness were recorded at emergence: an ET-based and a Ce-based prediction. Similarly, 2 predictions of a response to noxious stimuli were recorded when patients first required analgesics in the recovery room. Model predictions were compared with observations with graphical and temporal analyses. RESULTS: While patients were anesthetized, model predictions indicated a high likelihood that patients would be unresponsive (> or = 99%). However, after termination of the anesthetic, models exhibited a wide range of predictions at emergence (1%-97%). Although wide, the Ce-based predictions of responsiveness were better distributed over a percentage ranking of observations than the ET-based predictions. For the ET-based model, 45% of the patients awoke within 2 min of the 50% model predicted probability of unresponsiveness and 65% awoke within 4 min. For the Ce-based model, 45% of the patients awoke within 1 min of the 50% model predicted probability of unresponsiveness and 85% awoke within 3.2 min. Predictions of a response to a painful stimulus in the recovery room were similar for the Ce- and ET-based models. DISCUSSION: Results confirmed, in part, our study hypothesis; accounting for the lag time between Ce and ET sevoflurane concentrations improved model predictions of responsiveness but had no effect on predicting a response to a noxious stimulus in the recovery room. These models may be useful in predicting events of clinical interest but large-scale evaluations with numerous patients are needed to better characterize model performance.

Violence Exposure and Welfare over Time: Evidence from the Burundi Civil War

We investigate the relationship between exposure to conflict and poverty dynamics over time, using original three-waves panel data for Burundi which tracked individuals and reported local-level violence exposure from 1998 to 2012. Firstly, the data reveal that headcount poverty has not changed since 1998 while we observe multiple transitions into and out of poverty. Moreover, households exposed to the war exhibit a lower level of welfare than non-exposed households, with the difference between the two groups predicted to remain significant at least until 2017, i.e. twelve years after the conflict termination. The correlation between violence exposure and deprivation over time is confirmed in a household-level panel setting. Secondly, our empirical investigation shows how violence exposure over different time spans interacts with households' subsequent welfare. Our analysis of the determinants of households' likelihood to switch poverty status (i.e. to fall into poverty or escape poverty) combined with quantile regressions suggest that, (i) exposure during the first phase of the conflict has affected the entire distribution, and (ii) exposure during the second phase of the conflict has mostly affected the upper tail of the distribution: initially non-poor households have a higher propensity to fall into poverty while initially poor households see their propensity to pull through only slightly decrease with recent exposure to violence. Although not directly testable with the data at hand, these results are consistent with the changing nature of violence in the course of the Burundi civil war, from relatively more labour-destructive to relatively more capital-destructive.

Representing the influence of signage on evacuation behavior within an evacuation model

Occupant interaction with signage systems is being introduced into evacuation simulations through the newly developed concept of the Visibility Catchment Area or VCA. In this article, we describe the concept of VCA and how it has been extended to incorporate the presence of physical obstructions and termination distance. The VCA concept is then linked to a prototype behavior model intended to represent the occupant's interaction with the signage system. The functionality and performance of the newly developed model is then demonstrated through the simulation of various evacuation scenarios within a hypothetical supermarket layout

Ontological considerations of time, meta-predicates and temporal propositions

A natural approach to representing and reasoning about temporal propositions (i.e., statements with time-dependent truth-values) is to associate them with time elements. In the literature, there are three choices regarding the primitive for the ontology of time: (1) instantaneous points, (2) durative intervals and (3) both points and intervals. Problems may arise when one conflates different views of temporal structure and questions whether some certain types of temporal propositions can be validly and meaningfully associated with different time elements. In this paper, we shall summarize an ontological glossary with respect to time elements, and diversify a wider range of meta-predicates for ascribing temporal propositions to time elements. Based on these, we shall also devise a versatile categorization of temporal propositions, which can subsume those representative categories proposed in the literature, including that of Vendler, of McDermott, of Allen, of Shoham, of Galton and of Terenziani and Torasso. It is demonstrated that the new categorization of propositions, together with the proposed range of meta-predicates, provides the expressive power for modeling some typical temporal terms/phenomena, such as starting-instant, stopping-instant, dividing-instant, instigation, termination and intermingling etc.

Operator non-availability periods

In the scheduling literature, the notion of machine non availability periods is well known, for instance for maintenance. In our case of planning chemical experiments, we have special periods (the week-ends, holidays, vacations) where the chemists are not available. However, human intervention by the chemists is required to handle the starting and termination of the experiments. This gives rise to a new type of scheduling problems, namely problems of finding schedules that respect the operator non availability periods. These problems are analyzed on a single machine with the makespan as criterion. Properties are described and performance ratios are given for list scheduling and other polynomial-time algorithms.

Long-Term Oceanographic and Ecological Research in the Western English Channel

Long-term research in the western English Channel, undertaken by the marine laboratories in Plymouth, is described and details of survey methods, sites, and time series given in this chapter. Major findings are summarized and their limitations outlined. Current research, with recent reestablishment and expansion of many sampling programmes, is presented, and possible future approaches are indicated. These unique long-term data sets provide an environmental baseline for predicting complex ecological responses to local, regional, and global environmental change. Between 1888 and the present, investigations have been carried out into the physical, chemical, and biological components (ranging from plankton and fish to benthic and intertidal assemblages) of the western English Channel ecosystem. The Marine Biological Association of the United Kingdom has performed the main body of these observations. More recent contributions come from the Continuous Plankton Recorder Survey, now the Sir Alister Hardy Foundation for Ocean Science, dating from 1957; the Institute for Marine Environmental Research, from 1974 to 1987; and the Plymouth Marine Laboratory, which was formed by amalgamation of the Institute for Marine Environmental Research and part of the Marine Biological Association, from 1988. Together, these contributions constitute a unique data series; one of the longest and most comprehensive samplings of environmental and marine biological variables in the world. Since the termination of many of these time series in 1987-1988 during a reorganisation of UK marine research, there has been a resurgence of interest in long-term environmental change. Many programmes have been restarted and expanded with support from several agencies. The observations span significant periods of warming (1921-1961; 1985-present) and cooling (1962-1980). During these periods of change, the abundance of key species underwent dramatic shifts. The first period of warming saw changes in zooplankton, pelagic fish, and larval fish, including the collapse of an important herring fishery. During later periods of change, shifts in species abundances have been reflected in other assemblages, such as the intertidal zone and the benthic fauna. Many of these changes appear to be related to climate, manifested as temperature changes, acting directly or indirectly. The hypothesis that climate is a forcing factor is widely supported today and has been reinforced by recent studies that show responses of marine organisms to climatic attributes such as the strength of the North Atlantic Oscillation. The long-term data also yield important insights into the effects of anthropogenic disturbances such as fisheries exploitation and pollution. Comparison of demersal fish hauls over time highlights fisheries effects not only on commercially important species but also on the entire demersal community. The effects of acute ("Torrey Canyon" oil spill) and chronic (tributyltin [TBT] antifoulants) pollution are clearly seen in the intertidal records. Significant advances in diverse scientific disciplines have been generated from research undertaken alongside the long-term data series.

Phytoplankton phenology indices in coral reef ecosystems: Application to ocean-color observations in the Red Sea

Phytoplankton, at the base of the marine food web, represent a fundamental food source in coral reef ecosystems. The timing (phenology) and magnitude of the phytoplankton biomass are major determinants of trophic interactions. The Red Sea is one of the warmest and most saline basins in the world, characterized by an arid tropical climate regulated by the monsoon. These extreme conditions are particularly challenging for marine life. Phytoplankton phenological indices provide objective and quantitative metrics to characterize phytoplank- ton seasonality. The indices i.e. timings of initiation, peak, termination and duration are estimated here using 15 years (1997–2012) of remote sensing ocean-color data from the European Space Agency (ESA) Climate Change Initiative project (OC-CCI) in the entire Red Sea basin. The OC-CCI product, comprising merged and bias-corrected observations from three independent ocean-color sensors (SeaWiFS, MODIS and MERIS), and processed using the POLYMER algorithm (MERIS period), shows a significant increase in chlorophyll data cover- age, especially in the southern Red Sea during the months of summer NW monsoon. In open and reef-bound coastal waters, the performance of OC-CCI chlorophyll data is shown to be comparable with the performance of other standard chlorophyll products for the global oceans. These features have permitted us to investigate phytoplankton phenology in the entire Red Sea basin, and during both winter SE monsoon and summer NW monsoon periods. The phenological indices are estimated in the four open water provinces of the basin, and further examined at six coral reef complexes of particular socio-economic importance in the Red Sea, including Siyal Islands, Sharm El Sheikh, Al Wajh bank, Thuwal reefs, Al Lith reefs and Farasan Islands. Most of the open and deeper waters of the basin show an apparent higher chlorophyll concentration and longer duration of phyto- plankton growth during the winter period (relative to the summer phytoplankton growth period). In contrast, most of the reef-bound coastal waters display equal or higher peak chlorophyll concentrations and equal or lon- ger duration of phytoplankton growth during the summer period (relative to the winter phytoplankton growth period). The ecological and biological significance of the phytoplankton seasonal characteristics are discussed in context of ecosystem state assessment, and particularly to support further understanding of the structure and functioning of coral reef ecosystems in the Red Sea.

Is big best? Queen size, usurpation and nest closure in a primitively eusocial sweat bee (Lasioglossum malachurum).

For primitively eusocial insects in which a single foundress establishes a nest at the start of the colony cycle, the solitary provisioning phase before first worker emergence represents a risky period when other, nestless foundresses may attempt to usurp the nest. In the primitively eusocial sweat bee Lasioglossum malachurum (Hymenoptera, Halictidae), spring foundresses compete for nests which are dug into hard soil. Nest-searching foundresses (‘floaters’) frequently inspected nests during this solitary phase and thereby exerted a usurpation pressure on resident queens. Usurpation has been hypothesised to increase across the solitary provisioning phase and favour closure of nests at an aggregation, marking the termination of the solitary provisioning phase by foundresses, before worker emergence. However, our experimental and observational data suggest that usurpation pressure may remain constant or even decrease across the solitary provisioning phase and therefore cannot explain nest closure before first worker emergence. Levels of aggression during encounters between residents and floaters were surprisingly low (9% of encounters across 2 years), and the outcome of confrontations was in favour of residents (resident maintains residency in 94% of encounters across 2 years). Residents were significantly larger than floaters. However, the relationship between queen size and offspring production, though positive, was not statistically significant. Size therefore seems to confer a considerable advantage to a queen during the solitary provisioning phase in terms of nest residency, but its importance in terms of worker production appears marginal. Factors other than intraspecific usurpation need to be invoked to explain the break in provisioning activity of a foundress before first worker emergence.

Analysis of DNA processing reactions in bacterial conjugation by using suicide oligonucleotides

Protein TrwC is the conjugative relaxase responsible for DNA processing in plasmid R388 bacterial conjugation. TrwC has two catalytic tyrosines, Y18 and Y26, both able to carry out cleavage reactions using unmodified oligonucleotide substrates. Suicide substrates containing a 30-Sphosphorothiolate linkage at the cleavage site displaced TrwC reaction towards covalent adducts and thereby enabled intermediate steps in relaxase reactions to be investigated. Two distinct covalent TrwC–oligonucleotide complexes could be separated from noncovalently bound protein by SDS–PAGE. As observed by mass spectrometry, one complex contained a single, cleaved oligonucleotide bound to Y18, whereas the other contained two cleaved oligonucleotides, bound to Y18 and Y26. Analysis of the cleavage reaction using suicide substrates and Y18F or Y26F mutants showed that efficient Y26 cleavage only occurs after Y18 cleavage. Strand-transfer reactions carried out with the isolated Y18–DNA complex allowed the assignment of specific roles to each tyrosine. Thus, only Y18 was used for initiation. Y26 was specifically used in the second transesterification that leads to strand transfer, thus catalyzing the termination reaction that occurs in the recipient cell.

Modification of smooth muscle Ca2+-sparks by tetracaine: evidence for sequential RyR activation.

Spontaneous Ca(2+)-sparks were imaged using confocal line scans of fluo-4 loaded myocytes in retinal arterioles. Tetracaine produced concentration-dependent decreases in spark frequency, and modified the spatiotemporal characteristics of residual sparks. Tetracaine (10 microM) reduced the rate of rise but prolonged the average rise time so that average spark amplitude was unaltered. The mean half-time of spark decay was also unaffected, suggesting that spark termination, although delayed, remained well synchronized. Sparks spread transversely across the myocytes in these vessels, and the speed of spread within individual sparks was slowed by approximately 60% in 10 microM tetracaine, as expected if the spark was propagated across the cell but the average P(o) for RyRs was reduced. Staining of isolated vessels with BODIPY-ryanodine and di-4-ANEPPS showed that RyRs were located both peripherally, adjacent to the plasma membrane, and in transverse extensions of the SR from one side of the cell to the other. Immuno-labelling of retinal flat mounts demonstrated the presence RyR(2) in arteriole smooth muscle but not RyR(1). We conclude that Ca(2+)-sparks in smooth muscle can result from sequential activation of RyRs distributed over an area of several microm(2), rather than from tightly clustered channels as in striated muscle.

2.4 GHz Class-E power amplifier with transmissionline harmonic terminations

The design procedure, fabrication and measurement of a Class-E power amplifier with excellent second- and third-harmonic suppression levels are presented. A simplified design technique offering compact physical layout is proposed. With a 1.2 mm gate-width GaAs MESFET as a switching device, the amplifier is capable of delivering 19.2 dBm output power at 2.41 GHz, achieves peak PAE of 60% and drain efficiency of 69%, and exhibits 9 dB power gain when operated from a 3 V DC supply voltage. When compared to the classical Class-E two-harmonic termination amplifier, the Class-E amplifier employing three-harmonic terminations has more than 10% higher drain efficiency and 23 dB better third-harmonic suppression level. Experimental results are presented and good agreement with simulation is obtained. Further, to verify the practical implementation in communication systems, the Bluetooth-standard GFSK modulated signal is applied to both two- and three-harmonic amplifiers. The measured RMS FSK deviation error and RMS magnitude error were, for the three-harmonic case, 1.01 kHz and 0.122%, respectively, and, for the two-harmonic case, 1.09 kHz and 0.133%. © 2007 The Institution of Engineering and Technology.

Exploring the perspective of midwives involved in offering serum screening for Down's syndrome in Northern Ireland

Aims. To explore the perspective of midwives offering serum screening for Down’s syndrome.

Background. Previous literature has indicated that the offer and discussion of prenatal serum screening tests with women is complex, and health professionals may influence women’s decisions to accept or decline screening. Midwives are usually the key professional to offer serum screening for Down’s syndrome in the UK but their perspective is relatively neglected in the literature.

Design. An explorative qualitative interview study with 15 midwives employed in a maternity unit in Northern Ireland involved in offering prenatal screening to pregnant women. Data were collected from 1 July 2005–31 October 2005.

Methods. A focused ethnographic approach was used to explore the perspective of midwives.

Results. Midwives reported difficulty in explaining the test to women and felt unable to provide the necessary information to adequately inform women within their appointment time. The test offered (the triple test) and potential pathway of subsequent care, were identified as sources of professional and personal conflict by midwives. The expectation that midwives would provide a universal offer of Down’s syndrome serum screening but be unable to support women regarding termination of pregnancy also created dissonance.

Conclusions. The feasibility of proceeding with a universal serum screening programme for Down’s syndrome is questionable in countries which legally or culturally oppose termination of pregnancy. Professionals practising within environments such as this experience conflict in their role, which affects communication with women when discussing screening tests.

Relevance to clinical practice. As midwives are often, the primary health professional providing information to women, it is important that midwives are key participants in ongoing planning and discussions about screening policy to ensure programmes are implemented successfully.