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At least 19 recordsLinked to original sources

The conformational switch in 7-transmembrane receptors: the muscarinic receptor paradigm.

The rhodopsin-like superfamily of 7-transmembrane receptors is the largest class of signalling molecules in the mammalian genome. Recently, a combination of mutagenesis, biophysical and modelling studies have suggested a credible model for the alpha-carbon backbone in the transmembrane region of the 7-transmembrane receptors, and have started to reveal the structural basis of the conformational switch from the inactive to the active state. A key feature may be the replacement of a network of radial constraints, centred on transmembrane helix three, which stabilise the inactive ground state of the receptor by a new set of axial interactions which help to stabilise the activated state. Transmembrane helix three may act as a rotary switch in the activation mechanism.

Binding Sites↗

[A new method of establishing experimental model of chronic myocardial infarction by incision below xiphoid process in black goats].

OBJECTIVE: To establish an effective model of myocardial infarction in black goat so as to provide a safe, convenient and credible model of myocardial infarction for treatment and research. METHODS: Sixteen black goats were made chronic myocardial infarction by ligation of far end of left anterior descending coronary artery through incision below xiphoid process. Electrocardiogram (ECG) and serum myocardial enzymes were investigated before and after occlusion. Echocardiographic measurements were performed, and left coronary artery angiography was performed with digital subtraction angiography (DSA) before infarction and 6 weeks after infarction. The myocardial ultrastructure were observed. RESULTS: All goats survived more than 6 weeks. ECG showed ambulatory change, ST-segment elevated half an hour after occlusion and pathologic Q waves 6 weeks after infarction, CK-MB significantly increased. Echocardiographic indexes showed significant decrease of maximal peak A, percent wall thickening(WHT) and ejecting fraction (EF), increase of end-systolic volume (ESV), end-diastolic volume (EDV), and dilation of left ventricle. DSA showed block or decrease of perfusion of far end of left anterior descending coronary artery. CONCLUSION: It is safe, convenient and credible to establish model of myocardial infarction by ligation of far end of left anterior descending coronary artery through incision below xiphoid process in black goat.

Animals↗

Effect of tattoos on perceptions of credibility and attractiveness.

This study examined the effects of tattooing on perception of a male's and a female's credibility and attractiveness. 74 undergraduates viewed a photograph of a tattooed or nontattooed male or female model and then rated dimensions of the models' credibility and attractiveness. Analysis indicated that, although the models' attractiveness ratings were not affected by having a tattoo, their credibility ratings were generally lower when wearing a tattoo than when not wearing one.

Adult↗

A genetic algorithm approach to detecting lineage-specific variation in selection pressure.

The ratio of nonsynonymous (dN) to synonymous (dS) substitution rates, omega, provides a measure of selection at the protein level. Models have been developed that allow omega to vary among lineages. However, these models require the lineages in which differential selection has acted to be specified a priori. We propose a genetic algorithm approach to assign lineages in a phylogeny to a fixed number of different classes of omega, thus allowing variable selection pressure without a priori specification of particular lineages. This approach can identify models with a better fit than a single-ratio model, and with fits that are better than (in an information theoretic sense) a fully local model, in which all lineages are assumed to evolve under different values of omega, but with far fewer parameters. By averaging over models which explain the data reasonably well, we can assess the robustness of our conclusions to uncertainty in model estimation. Our approach can also be used to compare results from models in which branch classes are specified a priori with a wide range of credible models. We illustrate our methods on primate lysozyme sequences and compare them with previous methods applied to the same data sets.

Algorithms↗

Resolving neighborhood scale in air toxics modeling: a case study in Wilmington, CA.

Air quality modeling is useful for characterizing exposures to air pollutants. Whereas models typically provide results on regional scales, new concerns regarding the potential for differential exposures among racial/ethnic populations and income strata within communities are driving the need for increasingly refined modeling approaches. These approaches need to be capable of resolving concentrations on the scale of tens of meters, across modeling domains 10-100 km2 in size. One approach for refined air quality modeling is to combine Gaussian and regional photochemical grid models. In this paper, the authors demonstrate this approach on a case study of Wilmington, CA, focused on diesel exhaust particulate matter. Modeling results suggest that pollutant concentrations in the vicinity of emission sources are elevated, and, therefore, an understanding of local emission sources is necessary to generate credible modeling results. A probabilistic evaluation of the Gaussian model application indicated that spatial allocation, emission rates, and meteorological data are important contributors to input and parameter uncertainty in the model results. This uncertainty can be substantially reduced through the collection and integration of site-specific information about the location of emission sources and the activity and emission rates of key sources affecting model concentrations.

Air Pollutants↗

Mission aligned management and allocation: a successfully implemented model of mission-based budgeting.

In response to declining funding support and increasing competition, medical schools have developed financial management models to assure that resource allocation supports core mission-related activities. The authors describe the development and implementation of such a model at the University of Wisconsin Medical School. The development occurred in three phases and included consensus building on the need for mission-based budgeting, extensive faculty involvement to create a credible model, and decisions about basic principles for the model. While each school may encounter different constraints and opportunities, the authors outline a series of generic issues that any medical school is likely to face when implementing a mission-based budgeting model. These issues include decisions about the amounts and sources of funds to be used in the budgeting process, whether funds should be allocated at the department or individual faculty level, the specific metrics for measuring academic activities, the relative amounts for research and teaching activities, and how to use the budget process to support new initiatives and strategic priorities. The University of Wisconsin Medical School's Mission Aligned Management and Allocation (MAMA) model was implemented in 1999. The authors discuss implementation issues, including timetable, formulas used to cap budget changes among departments during phase-in, outcome measures used to monitor the effect of the new budget model, and a process for school-wide budget oversight. Finally, they discuss outcomes tracked during two years of full implementation to assess the success of the new MAMA budget process.

Budgets↗

How do Zimbabweans value health states?

BACKGROUND: Quality of life weights based on valuations of health states are often used in cost utility analysis and population health measures. This paper reports on an attempt to develop quality of life weights within the Zimbabwe context. METHODS: 2,384 residents in randomly selected small residential plots of land in a high-density suburb of Harare valued descriptors of 38 health states based on different combinations of the five domains of the EQ-5D (mobility, self-care, usual activities, pain or discomfort and anxiety or depression). The English version of the EQ-5D was used. The time trade-off method was used to determine the values, and 19,020 individual preferences for health states were analysed. A residual maximum likelihood linear mixed model was used to estimate a function for predicting the values of all possible combinations of levels on the five domains. The model was fit to a random subset of two-thirds of the observations, with the remaining observations reserved for analysis of predictive validity. The results were compared to a similar study undertaken in the United Kingdom. RESULTS: A credible model was developed to predict the values of states that were not valued directly. In the subset of observations reserved for validation, the mean absolute difference between predicted and observed values was 0.045. All domains of the EQ-5D were found to contribute significantly to the model, both at the moderate and severe levels. Severe pain was found to have the largest negative coefficient, followed by the inability to wash and dress oneself. CONCLUSION: Despite a generally lower education level than their European counterparts, urban Zimbabweans appear to value health states in a consistent manner, and the determination of a global method of establishing quality of life weights may be feasible and valid. However, as the relative weightings of the different domains, although correlated, differed from the standard set of weights recommended by the EuroQol Group, the locally determined coefficients should be used within the Zimbabwean context.

Journal Article↗

Predicting spring phenology and frost damage risk of Betula spp. under climatic warming: a comparison of two models.

Timing of bud burst and frost damage risk for leaves of Betula spp. in response to climatic warming in Finland was examined with two models. In the first model, ontogenetic development in spring was triggered by an accumulation of chilling temperatures. The second model assumed an additional signal from the light climate. The two models gave radically different estimates of frost damage risk in response to climate warming. The chilling-triggered model forecast a significant and increasing risk with increased warming, whereas the light-climate-triggered model predicted little or no risk. The chilling-triggered model is widely applied in phenological research; however, there is increasing experimental evidence that light conditions play a role in the timing of spring phenology. Although it is not clear if the light response mechanisms are appropriately represented in our model, the results imply that reliance on a light signal for spring development would afford a degree of protection against possible frost damage under climate warming that would not be present if chilling were the sole determinant. Further experimental tests are required to ascertain the light-related mechanisms controlling phenological timing, so that credible model extrapolations can be undertaken.

Journal Article↗

Developing a quality measure for clinical inertia in diabetes care.

OBJECTIVE: To develop a valid quality measure that captures clinical inertia, the failure to initiate or intensify therapy in response to medical need, in diabetes care and to link this process measure with outcomes of glycemic control. DATA SOURCES: Existing databases from 13 Department of Veterans Affairs hospitals between 1997 and 1999. STUDY DESIGN: Laboratory results, medications, and diagnoses were collected on 23,291 patients with diabetes. We modeled the decision to increase antiglycemic medications at individual visits. We then aggregated all visits for individual patients and calculated a treatment intensity score by comparing the observed number of increases to that expected based on our model. The association between treatment intensity and two measures of glycemic control, change in HbA1c during the observation period, and whether the outcome glycosylated hemoglobin (HbA1c) was greater than 8 percent, was then examined. PRINCIPAL FINDINGS: Increases in antiglycemic medications occurred at only 9.8 percent of visits despite 39 percent of patients having an initial HbA1c level greater than 8 percent. A clinically credible model predicting increase in therapy was developed with the principal predictor being a recent HbA1c greater than 8 percent. There were considerable differences in the intensity of therapy received by patients. Those patients receiving more intensive therapy had greater improvements in control (p < .001). CONCLUSIONS: Clinical inertia can be measured in diabetes care and this process measure is linked to patient outcomes of glycemic control. This measure may be useful in efforts to improve clinicians management of patients with diabetes.

Aged↗

Catalytic mechanism of F1-ATPase.

The structure of the core catalytic unit of ATP synthase, alpha 3 beta 3 gamma, has been determined by X-ray crystallography, revealing a roughly symmetrical arrangement of alternating alpha and beta subunits around a central cavity in which helical portions of gamma are found. A low-resolution structural model of F0, based on electron spectroscopic imaging, locates subunit a and the two copies of subunit b outside of a subunit c oligomer. The structures of individual subunits epsilon and c (largely) have been solved by NMR spectroscopy, but the oligomeric structure of c is still unknown. The structures of subunits a and delta remain undefined, that of b has not yet been defined but biochemical evidence indicates a credible model. Subunits gamma, epsilon, b, and delta are at the interface between F1 and F0; gamma epsilon complex forms one element of the stalk, interacting with c at the base and alpha and beta at the top. The locations of b and delta are less clear. Elucidation of the structure F0, of the stalk, and of the entire F1F0 remains a challenging goal.

Adenosine Diphosphate↗

The structure of poly(dA):poly(dT) in a condensed state and in solution.

New X-ray and energetically optimal models of poly(dA):poly(dT) with the hydration spine in the minor groove have been compared with the NMR data in solution (Behling, R.W. and Kearns, D.R. (1986) Biochemistry 25, 3335-3346). These models have been refined to achieve a better fit with the NMR data. The obtained results suggest that the poly(dA):poly(dT) structure in a condensed state is similar to that in solution. The proposed conformations of poly(dA):poly(dT), unlike the classic B form, satisfy virtually all geometrical requirements which follow from the NMR data. Thus, the X-ray and energetically optimal poly(dA):poly(dT) structures (or those with slight modifications) can be considered as credible models of the poly(dA):poly(dT) double helix in solution. One of the features distinguishing these models from the classic B form is a narrowed minor groove.

DNA↗

Estimation and projection of population lung cancer trends (United Kingdom).

OBJECTIVE: Reduction of overall cancer mortality in the UK will require a marked decrease in lung cancer incidence and mortality. A method was sought to predict future lung cancer trends at regional and subregional levels to improve planning, aid the monitoring of health promotion strategies, and to assess health gains that might be achieved. METHODS: Data on 55,000 lung cancer patients were used in an age-cohort model of lung cancer incidence (1981-95) and a parametric model of survival (1981-91). Indicators of deprivation were included in the models. Prevalence was estimated from the product of incidence and survival. Lung cancer trends were predicted to 2015, both at steady state and with an incidence perturbation. RESULTS: Female lung cancer is predicted to increase, until by 2015 the numbers will almost equal those in men. Cohort coefficients reveal an increasing risk of lung cancer in females born after 1941. Changing these female cohort coefficients to equate to a declining risk after 1941 suggests that, by 2015, around 200 cases per year might be prevented. This would necessitate a marked change in smoking behavior. Survival from lung cancer was significantly associated with social deprivation and health authority of residence. CONCLUSIONS: A credible model has been derived which can be used for health service and outcome monitoring. The model results have highlighted a priority area for smoking intervention which currently seems to attract little attention.

Adult↗

[Risk factors, life habits and personal beliefs of nurses and nurse-students about cardiovascular prevention].

BACKGROUND: The contribution of conventional factors (hypertension, dyslipidemia, diabetes mellitus and smoke) to the risk of development of atherosclerotic cardiovascular disease is known. Nurses have a strong role in helping patients improve their risk profile, and change their lifestyle. Behaviors and beliefs of the nurses (and physicians as well) are relevant to their "reliability" as models and educators. METHODS: A questionnaire was administered to a cohort of 98 students attending the last course-year in a school of nursing, and to a cohort of 84 nurses working in a cardiovascular department, to investigate their awareness of their own risk factors, their lifestyle, and their attitudes as to the primary prevention of cardiovascular disease. RESULTS: Among heritable risk factors, hypertension ranked first in the awareness of both students and nurses, but the risk inherent in a family history of sudden death and early myocardial infarction was recognized only by 36% of subjects. Smokers were more frequent among students than among nurses (40 vs 25%); in both cohorts the misconception was common among smokers, that "light" cigarettes or smoking "no more than 5-10 cigarettes per day" is not harmful (15 and 30% of responders, respectively). The knowledge of upper normal limits for blood pressure, plasma cholesterol and triglycerides was often poor in both cohorts. CONCLUSIONS: The knowledge and awareness of risk factors and harmful life habits should be improved by stressing their importance to the nurse students with a high priority during the school, and to the practicing nurses during postgraduate courses. This may be especially important for smoking. On the whole, however, our data suggest that the majority of the interviewed subjects, especially among the nurses, have a lifestyle that is a credible model for our patients.

Adult↗

The role of meta-analysis in monitoring clinical trials.

The randomized clinical trial is the gold standard methodology for evaluating treatment interventions. The randomized trial is a prospective experimental study, the embodiment of the scientific method applied to the clinic. Both organizational and ethical considerations encourage the use of formal criteria for termination. Such criteria, typically based on an overall 5 per cent significance test, are frequently portrayed as guidelines, but none the less usually succeed in focusing the debate on termination decisions and thus facilitate decision making. The use of the 5 per cent criterion is entirely arbitrary and is not based in any way on optimality considerations. No credible model for optimizing the decision to terminate trials has been developed. Meta-analysis is an evolving technique for evaluating the totality of the evidence on general treatment strategies. It has enjoyed considerable success in influencing medical opinion and treatment practice in selected areas. Its role is in establishing proof of concept of general treatment strategies, and is thus a consensus builder, making use of data from trials which may be heterogeneous in the details of treatment administration and patient selection, but similar in conceptual intent. The level of evidence required for consensus is not well understood and cannot be defined precisely. The retrospective nature of meta-analysis and the risks of biased data acquisition mandate a conservative approach to data analysis and interpretation. Randomized trials and meta-analyses have distinct but complementary goals. Meta-analysis can be used productively in planning new clinical trials, and in supplying updated information to study monitors in the course of a trial. However, it is not advisable to employ meta-analysis in formal statistical procedures for terminating clinical trials.

Bias↗

Climate of the earth: an overview.

Climate has varied over a large range in the recent history of the Earth, with extremes represented by equable environments of the Cretaceous and Eocene and the comparatively frigid conditions of the ice ages that punctuated the past few million years. It is suggested that major shifts in climate are controlled largely by variations in CO(2) with related fluctuations in modes of ocean circulation. Changes in climate can proceed rapidly, on time scales as short as centuries or even decades, as indicated by data for the Younger Dryas (a period of globally cold conditions interrupting recovery of the Earth from the last ice age) and the Little Ice Age (a cold snap extending from about 1250 to about 1850 ad). Rapid fluctuations in climate appear to be linked to changes in production of deep water in the North Atlantic, possibly also to variations in circulation of intermediate waters in the Pacific. Mechanisms are discussed whereby changes in ocean circulation can result in shifts of climate on a global scale. A 10 000 year record of climate from Norway is used to provide context for a discussion of possible changes in climate today arising as a result of the build-up of industrially related greenhouse gases. Brief, somewhat pessimistic, comments are offered concerning the prospects for meaningful near-term predictions of the response of climate to increased concentrations of greenhouse gases. Studies of past climates, by drawing attention to important processes and feedbacks, can play a valuable role in the development of credible models for the future.

Journal Article↗

Levels of selection in positive-strand virus dynamics.

Conflicting selection pressures occurring over the life cycle of an organism constitute serious challenges to the robustness of replication. Viruses present a credible model system for analysing problems that arise through evolutionary conflicts of interest. We present a multi-level selection model for the life cycle of positive-strand RNA viruses. The model combines within-cell replication kinetics and protein synthesis, and between-cell population dynamics of virion production and transmission. We show how these two levels of within-host selection interact to produce tradeoffs in the life history strategy of a virus without consideration of host mortality. We find that viruses evolve towards intermediate rather than maximum encapsidation rates. This can be interpreted as selection for intermediate virulence through cellular persistence. We characterize a theoretical persistence threshold arising from the trade-off between genome replication and genetic translation within the cell. We present counter-intuitive relationships whereby increasing genome decay rates and rates of encapsidation lead to increases in the abundance of virus-encoded proteins. Data from poliovirus suggest that viruses might be unable to resolve the vertical conflicts of interests among different levels of selection.

Biological Evolution↗

Direct calculation of light-induced structural change and diffusive motion in glassy As2Se3

Photostructural change of glassy As2Se3 was simulated on an experimentally credible model with excited electronic dynamics within first-principles molecular dynamics. Bond breaking and bond switching reactions account for local changes around defect sites at the short time phase of illumination. For long-time relaxation, defect pairs associated with band tail states become involved in a rearrangement in the network, giving rise to a low energy, nonlocal "polaronlike" collective oscillation. Diffusive motion is observed for short times, which we tentatively interpret as the initial phase of athermal photomelting.

Journal Article↗