232 research outputs found
On the relationships between kinetic schemes and two-state single molecule trajectories
Trajectories of a signal that fluctuates between two states which originate
from single molecule activities have become ubiquitous. Common examples are
trajectories of ionic flux through individual membrane-channels, and of photon
counts collected from diffusion, activity, and conformational changes of
biopolymers. By analyzing the trajectory, one wishes to deduce the underlying
mechanism, which is usually described by a multi-substate kinetic scheme. In
previous works, we divided kinetic schemes that generate two-state trajectories
into two types: reducible schemes and irreducible schemes. We showed that all
the information in trajectories generated from reducible schemes is contained
in the waiting time probability density functions (PDFs) of the two states. It
follows that reducible schemes with the same waiting time PDFs are not
distinguishable. In this work, we further characterize the topologies of
kinetic schemes, now of irreducible schemes, and further study two-state
trajectories from the two types of scheme. We suggest various methods for
extracting information about the underlying kinetic scheme from the trajectory
(e. g., calculate the binned successive waiting times PDF and analyze the
ordered waiting times trajectory), and point out the advantages and
disadvantages of each. We show that the binned successive waiting times PDF is
not only more robust than other functions when analyzing finite trajectories,
but contains, in most cases, more information about the underlying kinetic
scheme than other functions in the limit of infinitely long trajectories. For
some cases however, analyzing the ordered waiting times trajectory may supply
unique information about the underlying kinetic scheme
iSchools and archival studies
Whispers and rumors about the iSchool movement lead some to fear that this represents yet another shift away from the valued traditions of library schools, threatening something far different than what library science pioneers ever envisioned. Predating the iSchool movement, however, were other programmatic shifts such as those that led to the formalization of graduate archival education. This essay argues that such evolution is essential to our future, as iSchools tackle the increasingly complex issues confronting a digital society. We consider the mission and history of iSchools and of archival studies, the basic elements and concepts of archival studies that are critical to iSchools, and the relationship between iSchools and the changing nature of personal and institutional archives. © 2009 Springer Science+Business Media B.V
The effects of neural synchronization and peripheral compression on the acoustic-reflex threshold
Long-Term Follow-Up After Gene Therapy for Canavan Disease
Canavan disease is a hereditary leukodystrophy caused by mutations in the aspartoacylase gene (ASPA), leading to loss of enzyme activity and increased concentrations of the substrate N-acetylaspartate (NAA) in the brain. Accumulation of NAA results in spongiform degeneration of white matter and severe impairment of psychomotor development. The goal of this prospective cohort study was to assess long-term safety and preliminary efficacy measures after gene therapy with an adeno-associated viral vector carrying the ASPA gene (AAV2-ASPA). Using noninvasive magnetic resonance imaging and standardized clinical rating scales, we observed Canavan disease in 28 patients, with a subset of 13 patients being treated with AAV2-ASPA. Each patient received 9 × 1011 vector genomes via intraparenchymal delivery at six brain infusion sites. Safety data collected over a minimum 5-year follow-up period showed a lack of long-term adverse events related to the AAV2 vector. Posttreatment effects were analyzed using a generalized linear mixed model, which showed changes in predefined surrogate markers of disease progression and clinical assessment subscores. AAV2-ASPA gene therapy resulted in a decrease in elevated NAA in the brain and slowed progression of brain atrophy, with some improvement in seizure frequency and with stabilization of overall clinical status
Evaluating a team-based approach to research capacity building using a matched-pairs study design
Background: There is a continuing need for research capacity building initiatives for primary health care professionals. Historically strategies have focused on interventions aimed at individuals but more recently theoretical frameworks have proposed team-based approaches. Few studies have evaluated these new approaches. This study aims to evaluate a team-based approach to research capacity building (RCB) in primary health using a validated quantitative measure of research capacity in individual, team and organisation domains
Surgimento e consolidação da Documentação: subsídios para compreensão da história da Ciência da Informação no Brasil
Assessment of thrombin-activatable fibrinolysis inhibitor (TAFI) activation in acquired hemostatic dysfunction: a diagnostic challenge
Structural Heterogeneity and Quantitative FRET Efficiency Distributions of Polyprolines through a Hybrid Atomistic Simulation and Monte Carlo Approach
Förster Resonance Energy Transfer (FRET) experiments probe molecular distances via distance dependent energy transfer from an excited donor dye to an acceptor dye. Single molecule experiments not only probe average distances, but also distance distributions or even fluctuations, and thus provide a powerful tool to study biomolecular structure and dynamics. However, the measured energy transfer efficiency depends not only on the distance between the dyes, but also on their mutual orientation, which is typically inaccessible to experiments. Thus, assumptions on the orientation distributions and averages are usually made, limiting the accuracy of the distance distributions extracted from FRET experiments. Here, we demonstrate that by combining single molecule FRET experiments with the mutual dye orientation statistics obtained from Molecular Dynamics (MD) simulations, improved estimates of distances and distributions are obtained. From the simulated time-dependent mutual orientations, FRET efficiencies are calculated and the full statistics of individual photon absorption, energy transfer, and photon emission events is obtained from subsequent Monte Carlo (MC) simulations of the FRET kinetics. All recorded emission events are collected to bursts from which efficiency distributions are calculated in close resemblance to the actual FRET experiment, taking shot noise fully into account. Using polyproline chains with attached Alexa 488 and Alexa 594 dyes as a test system, we demonstrate the feasibility of this approach by direct comparison to experimental data. We identified cis-isomers and different static local environments as sources of the experimentally observed heterogeneity. Reconstructions of distance distributions from experimental data at different levels of theory demonstrate how the respective underlying assumptions and approximations affect the obtained accuracy. Our results show that dye fluctuations obtained from MD simulations, combined with MC single photon kinetics, provide a versatile tool to improve the accuracy of distance distributions that can be extracted from measured single molecule FRET efficiencies
Cardiovascular disease, chronic kidney disease, and diabetes mortality burden of cardiometabolic risk factors from 1980 to 2010: a comparative risk assessment
Background High blood pressure, blood glucose, serum cholesterol, and BMI are risk factors for cardiovascular
diseases and some of these factors also increase the risk of chronic kidney disease and diabetes. We estimated mortality from cardiovascular diseases, chronic kidney disease, and diabetes that was attributable to these four
cardiometabolic risk factors for all countries and regions from 1980 to 2010.
Methods We used data for exposure to risk factors by country, age group, and sex from pooled analyses of populationbased health surveys. We obtained relative risks for the eff ects of risk factors on cause-specifi c mortality from metaanalyses
of large prospective studies. We calculated the population attributable fractions for- each risk factor alone,
and for the combination of all risk factors, accounting for multicausality and for mediation of the eff ects of BMI by the other three risks. We calculated attributable deaths by multiplying the cause-specifi c population attributable fractions by the number of disease-specifi c deaths. We obtained cause-specifi c mortality from the Global Burden of Diseases, Injuries, and Risk Factors 2010 Study. We propagated the uncertainties of all the inputs to the fi nal estimates.
Findings In 2010, high blood pressure was the leading risk factor for deaths due to cardiovascular diseases, chronic kidney disease, and diabetes in every region, causing more than 40% of worldwide deaths from these diseases; high BMI and glucose were each responsible for about 15% of deaths, and high cholesterol for more than 10%. After
accounting for multicausality, 63% (10\ub78 million deaths, 95% CI 10\ub71\u201311\ub75) of deaths from these diseases in 2010 were attributable to the combined eff ect of these four metabolic risk factors, compared with 67% (7\ub71 million deaths,
6\ub76\u20137\ub76) in 1980. The mortality burden of high BMI and glucose nearly doubled from 1980 to 2010. At the country
level, age-standardised death rates from these diseases attributable to the combined eff ects of these four risk factors
surpassed 925 deaths per 100 000 for men in Belarus, Kazakhstan, and Mongolia, but were less than 130 deaths per 100 000 for women and less than 200 for men in some high-income countries including Australia, Canada, France,
Japan, the Netherlands, Singapore, South Korea, and Spain.
Interpretation The salient features of the cardiometabolic disease and risk factor epidemic at the beginning of
the 21st century are high blood pressure and an increasing eff ect of obesity and diabetes. The mortality burden
of cardiometabolic risk factors has shifted from high-income to low-income and middle-income countries. Lowering
cardiometabolic risks through dietary, behavioural, and pharmacological interventions should be a part of the globalresponse to non-communicable diseases
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