Mapping Geographic Areas of High and Low Drug Adherence in Patients Prescribed Continuing Treatment for Acute Coronary Syndrome After Discharge

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90283/1/phco.31.10.927.pd

Current measurement by real-time counting of single electrons

The fact that electrical current is carried by individual charges has been known for over 100 years, yet this discreteness has not been directly observed so far. Almost all current measurements involve measuring the voltage drop across a resistor, using Ohm's law, in which the discrete nature of charge does not come into play. However, by sending a direct current through a microelectronic circuit with a chain of islands connected by small tunnel junctions, the individual electrons can be observed one by one. The quantum mechanical tunnelling of single charges in this one-dimensional array is time correlated, and consequently the detected signal has the average frequency f=I/e, where I is the current and e is the electron charge. Here we report a direct observation of these time-correlated single-electron tunnelling oscillations, and show electron counting in the range 5 fA-1 pA. This represents a fundamentally new way to measure extremely small currents, without offset or drift. Moreover, our current measurement, which is based on electron counting, is self-calibrated, as the measured frequency is related to the current only by a natural constant.Comment: 9 pages, 4 figures; v2: minor revisions, 2 refs added, words added to title, typos correcte

A pilot study comparing the metabolic profiles of elite-level athletes from different sporting disciplines

Background: The outstanding performance of an elite athlete might be associated with changes in their blood metabolic profile. The aims of this study were to compare the blood metabolic profiles between moderate- and high-power and endurance elite athletes and to identify the potential metabolic pathways underlying these differences. Methods: Metabolic profiling of serum samples from 191 elite athletes from different sports disciplines (121 high- and 70 moderate-endurance athletes, including 44 high- and 144 moderate-power athletes), who participated in national or international sports events and tested negative for doping abuse at anti-doping laboratories, was performed using non-targeted metabolomics-based mass spectroscopy combined with ultrahigh-performance liquid chromatography. Multivariate analysis was conducted using orthogonal partial least squares discriminant analysis. Differences in metabolic levels between high- and moderate-power and endurance sports were assessed by univariate linear models. Results: Out of 743 analyzed metabolites, gamma-glutamyl amino acids were significantly reduced in both high-power and high-endurance athletes compared to moderate counterparts, indicating active glutathione cycle. High-endurance athletes exhibited significant increases in the levels of several sex hormone steroids involved in testosterone and progesterone synthesis, but decreases in diacylglycerols and ecosanoids. High-power athletes had increased levels of phospholipids and xanthine metabolites compared to moderate-power counterparts. Conclusions: This pilot data provides evidence that high-power and high-endurance athletes exhibit a distinct metabolic profile that reflects steroid biosynthesis, fatty acid metabolism, oxidative stress, and energy-related metabolites. Replication studies are warranted to confirm differences in the metabolic profiles associated with athletes’ elite performance in independent data sets, aiming ultimately for deeper understanding of the underlying biochemical processes that could be utilized as biomarkers with potential therapeutic implications

Optimality of mutation and selection in germinal centers

The population dynamics theory of B cells in a typical germinal center could play an important role in revealing how affinity maturation is achieved. However, the existing models encountered some conflicts with experiments. To resolve these conflicts, we present a coarse-grained model to calculate the B cell population development in affinity maturation, which allows a comprehensive analysis of its parameter space to look for optimal values of mutation rate, selection strength, and initial antibody-antigen binding level that maximize the affinity improvement. With these optimized parameters, the model is compatible with the experimental observations such as the ~100-fold affinity improvements, the number of mutations, the hypermutation rate, and the "all or none" phenomenon. Moreover, we study the reasons behind the optimal parameters. The optimal mutation rate, in agreement with the hypermutation rate in vivo, results from a tradeoff between accumulating enough beneficial mutations and avoiding too many deleterious or lethal mutations. The optimal selection strength evolves as a balance between the need for affinity improvement and the requirement to pass the population bottleneck. These findings point to the conclusion that germinal centers have been optimized by evolution to generate strong affinity antibodies effectively and rapidly. In addition, we study the enhancement of affinity improvement due to B cell migration between germinal centers. These results could enhance our understandings to the functions of germinal centers.Comment: 5 figures in main text, and 4 figures in Supplementary Informatio

Sex differences in mathematics and reading achievement are inversely related: within- and across-nation assessment of 10 years of PISA data

We analyzed one decade of data collected by the Programme for International Student Assessment (PISA), including the mathematics and reading performance of nearly 1.5 million 15 year olds in 75 countries. Across nations, boys scored higher than girls in mathematics, but lower than girls in reading. The sex difference in reading was three times as large as in mathematics. There was considerable variation in the extent of the sex differences between nations. There are countries without a sex difference in mathematics performance, and in some countries girls scored higher than boys. Boys scored lower in reading in all nations in all four PISA assessments (2000, 2003, 2006, 2009). Contrary to several previous studies, we found no evidence that the sex differences were related to nations’ gender equality indicators. Further, paradoxically, sex differences in mathematics were consistently and strongly inversely correlated with sex differences in reading: Countries with a smaller sex difference in mathematics had a larger sex difference in reading and vice versa. We demonstrate that this was not merely a between-nation, but also a within-nation effect. This effect is related to relative changes in these sex differences across the performance continuum: We did not find a sex difference in mathematics among the lowest performing students, but this is where the sex difference in reading was largest. In contrast, the sex difference in mathematics was largest among the higher performing students, and this is where the sex difference in reading was smallest. The implication is that if policy makers decide that changes in these sex differences are desired, different approaches will be needed to achieve this for reading and mathematics. Interventions that focus on high-achieving girls in mathematics and on low achieving boys in reading are likely to yield the strongest educational benefits

Shot noise in mesoscopic systems

This is a review of shot noise, the time-dependent fluctuations in the electrical current due to the discreteness of the electron charge, in small conductors. The shot-noise power can be smaller than that of a Poisson process as a result of correlations in the electron transmission imposed by the Pauli principle. This suppression takes on simple universal values in a symmetric double-barrier junction (suppression factor 1/2), a disordered metal (factor 1/3), and a chaotic cavity (factor 1/4). Loss of phase coherence has no effect on this shot-noise suppression, while thermalization of the electrons due to electron-electron scattering increases the shot noise slightly. Sub-Poissonian shot noise has been observed experimentally. So far unobserved phenomena involve the interplay of shot noise with the Aharonov-Bohm effect, Andreev reflection, and the fractional quantum Hall effect.Comment: 37 pages, Latex, 10 figures (eps). To be published in "Mesoscopic Electron Transport," edited by L. P. Kouwenhoven, G. Schoen, and L. L. Sohn, NATO ASI Series E (Kluwer Academic Publishing, Dordrecht

Roy-Steiner equations for pion-nucleon scattering

Starting from hyperbolic dispersion relations, we derive a closed system of Roy-Steiner equations for pion-nucleon scattering that respects analyticity, unitarity, and crossing symmetry. We work out analytically all kernel functions and unitarity relations required for the lowest partial waves. In order to suppress the dependence on the high-energy regime we also consider once- and twice-subtracted versions of the equations, where we identify the subtraction constants with subthreshold parameters. Assuming Mandelstam analyticity we determine the maximal range of validity of these equations. As a first step towards the solution of the full system we cast the equations for the $\pi\pi\to\bar NN$ partial waves into the form of a Muskhelishvili-Omn\`es problem with finite matching point, which we solve numerically in the single-channel approximation. We investigate in detail the role of individual contributions to our solutions and discuss some consequences for the spectral functions of the nucleon electromagnetic form factors.Comment: 106 pages, 18 figures; version published in JHE

CRISPR transcriptional repression devices and layered circuits in mammalian cells

A key obstacle to creating sophisticated genetic circuits has been the lack of scalable device libraries. Here we present a modular transcriptional repression architecture based on clustered regularly interspaced palindromic repeats (CRISPR) system and examine approaches for regulated expression of guide RNAs in human cells. Subsequently we demonstrate that CRISPR regulatory devices can be layered to create functional cascaded circuits, which provide a valuable toolbox for engineering purposes.National Institutes of Health (U.S.) (Grant 5R01CA155320-04)National Institutes of Health (U.S.) (Grant P50 GM098792)Korea (South). Ministry of Science, Information and Communication Technolgy. Intelligent Synthetic Biology Center of Global Frontier Project (2013M3A6A8073557

The Interaction of Hypotaurine and Other Sulfinates with Reactive Oxygen and Nitrogen Species:A Survey of Reaction Mechanisms

Considerable strides have been made in understanding the oxidative mechanisms involved in the final steps of the cysteine pathway leading to taurine. The oxidation of sulfinates, hypotaurine and cysteine sulfinic acid, to the respective sulfonates, taurine and cysteic acid, has never been associated with any specific enzyme. Conversely, there is strong evidence that in vivo formation of taurine and cysteic acid is the result of sulfinate interaction with a variety of biologically relevant oxidants. In the last decade, many experiments have been performed to understand whether peroxynitrite, nitrogen dioxide and carbonate radical anion could be included in the biologically relevant reactive species capable of oxidizing sulfinates. Thanks to this work, it has been possible to highlight two possible reaction mechanisms (direct and indirect reaction) of sulfinates with reactive oxygen and nitrogen species.The sulfinates oxidation, mediated by peroxynitrite, is an example of both reaction mechanisms: through a two-electron-direct-reaction with peroxynitrite or through a one-electron-indirect-transfer reaction. In the indirect mechanism, the peroxynitrite homolysis releases hydroxyl and nitrogen dioxide radical and in addition the degradation of short-lived adduct formed by peroxynitrite and CO2 can generate carbonate radical anion. The reaction of hypotaurine and cysteine sulfinic acid with peroxynitrite-derived radicals is accompanied by extensive oxygen uptake with the generation of transient intermediates, which can begin a reaction by an oxygen-dependent mechanism with the sulfonates, taurine, and cysteic acid as final products. Due to pulse radiolysis studies, it has been shown that transient sulfonyl radicals (RSO2(•)) have been produced during the oxidation of both sulfinates by one-electron transfer reaction.The purpose is to analyze all the aspects of the reactive mechanism in the sulfinic group oxidation of hypotaurine and cysteine sulfinic acid through the results obtained from our laboratory in recent years

Inequities in energy-balance related behaviours and family environmental determinants in European children : baseline results of the prospective EPHE evaluation study

Background: Tackling inequalities in overweight, obesity and related determinants has become a top priority for the European research and policy agendas. Although it has been established that such inequalities accumulate from early childhood onward, they have not been studied extensively in children. The current article discusses the results of an explorative analysis for the identification of inequalities in behaviours and their determinants between groups with high and low socio-economic status. Methods: This study is part of the Epode for the Promotion of Health Equity (EPHE) evaluation study, the overall aim of which is to assess the impact and sustainability of EPODE methodology to diminish inequalities in childhood obesity and overweight. Seven community-based programmes from different European countries (Belgium, Bulgaria, France, Greece, Portugal, Romania, The Netherlands) participate in the EPHE study. In each of the communities, children aged 6-8 years participated, resulting in a total sample of 1266 children and their families. A parental self-administrated questionnaire was disseminated in order to assess the socio-economic status of the household, selected energy balance-related behaviours (1. fruit and vegetable consumption; 2. soft drink/fruit juices and water consumption; 3. screen time and 4. sleep duration) of the children and associated family environmental determinants. The Mann-Whitney U test and Pearson's chi-square test were used to test differences between the low and high education groups. The country-specific median was chosen as the cut-off point to determine the educational level, given the different average educational level in every country. Results: Children with mothers of relatively high educational level consumed fruits and vegetables more frequently than their peers of low socio-economic status. The latter group of children had a higher intake of fruit juices and/or soft drinks and had higher screen time. Parental rules and home availability were consistently different between the two socio-economic groups in our study in all countries. However we did not find a common pattern for all behaviours and the variability across the countries was large. Conclusions: Our findings are indicative of socio-economic inequalities in our samples, although the variability across the countries was large. The effectiveness of interventions aimed at chancing parental rules and behaviour on health inequalities should be studied