Integrated optics prototype beam combiner for long baseline interferometry in the L and M bands

In the last few years, integrated optics (IO) beam combiners have facilitated the emergence of 4-telescope interferometers such as PIONIER or GRAVITY, boosting the imaging capabilities of the VLTI. However, the spectral range beyond 2.2microns is not ideally covered by the conventional silica based IO. Here, we propose to consider new laser-written IO prototypes made of GLS glasses, a material that permits access to the mid-infrared spectral regime. Our goal is to conduct a full characterization of our mid-IR IO 2-telescope coupler in order to measure the performance levels directly relevant for long-baseline interferometry. We focus in particular on the exploitation of the L and M astronomical bands. We use a dedicated Michelson-interferometer setup to perform Fourier Transform spectroscopy on the coupler and measure its broadband interferometric performance. We also analyze the polarization properties of the coupler, the differential dispersion and phase degradation as well as the modal behavior and the total throughput. We measure broadband interferometric contrasts of 94.9% and 92.1% for unpolarized light in the L and M bands. Spectrally integrated splitting ratios are close to 50% but show chromatic dependence over the considered bandwidths. Additionally, the phase variation due to the combiner is measured and does not exceed 0.04rad and 0.07rad across the band L and M band, respectively. The total throughput of the coupler including Fresnel and injection losses from free-space is 25.4%. The laser-written IO GLS prototype combiners prove to be a reliable technological solution with promising performance for mid-infrared long-baseline interferometry. In the next steps, we will consider more advanced optical functions as well as a fiber-fed input and revise the optical design parameters in order the further enhance the total throughput and achromatic behavior

Fast protein folding is governed by memory-dependent friction

When described by a low-dimensional reaction coordinate, the folding rates of most proteins are determined by a subtle interplay between free-energy barriers, which separate folded and unfolded states, and friction. While it is commonplace to extract free-energy profiles from molecular trajectories, a direct evaluation of friction is far more elusive and typically relies on fits of measured reaction rates to memoryless reaction-rate theories. Here, using memory-kernel extraction methods founded on a generalized Langevin equation (GLE) formalism, we directly calculate the time-dependent friction acting on the fraction of native contacts reaction coordinate Q, evaluated for eight fast-folding proteins, taken from a published set of large-scale molecular dynamics protein simulations. Our results reveal that, across the diverse range of proteins represented in this dataset, friction is more influential than free-energy barriers in determining protein folding rates. We also show that proteins fold in a regime where the finite decay time of friction significantly reduces the folding times, in some instances by as much as a factor of 10, compared to predictions based on memoryless friction

Non-Markovian modeling of protein folding.

We extract the folding free energy landscape and the time-dependent friction function, the two ingredients of the generalized Langevin equation (GLE), from explicit-water molecular dynamics (MD) simulations of the α-helix forming polypeptide [Formula: see text] for a one-dimensional reaction coordinate based on the sum of the native H-bond distances. Folding and unfolding times from numerical integration of the GLE agree accurately with MD results, which demonstrate the robustness of our GLE-based non-Markovian model. In contrast, Markovian models do not accurately describe the peptide kinetics and in particular, cannot reproduce the folding and unfolding kinetics simultaneously, even if a spatially dependent friction profile is used. Analysis of the GLE demonstrates that memory effects in the friction significantly speed up peptide folding and unfolding kinetics, as predicted by the Grote-Hynes theory, and are the cause of anomalous diffusion in configuration space. Our methods are applicable to any reaction coordinate and in principle, also to experimental trajectories from single-molecule experiments. Our results demonstrate that a consistent description of protein-folding dynamics must account for memory friction effects

Motor learning outcomes of handrim wheelchair propulsion during active spinal cord injury rehabilitation in comparison with experienced wheelchair users

Purpose: To investigate changes in wheelchair propulsion technique and mechanical efficiency across first five weeks of active inpatient spinal cord injury rehabilitation and to compare the outcomes at discharge with experienced wheelchair users with spinal cord injury. Methods: Eight individuals with recent spinal cord injury performed six weekly submaximal exercise tests. The first and last measurement additionally contained a wheelchair circuit and peak graded exercise test. Fifteen experienced individuals performed all above-mentioned tests on one occasion. Results: Mechanical efficiency and propulsion technique did not change during the five weeks of inpatient rehabilitation. Peak power output during peak graded test and performance time on the wheelchair circuit improved between the first and the last week. No difference in propulsion technique, peak power output, and performance time was found between the persons with a recent injury and the experienced group. Mechanical efficiency was higher after the correction for the difference in relative power output in the experienced group. Conclusion: The group with a recent injury did not improve mechanical efficiency and propulsion technique over the period of active rehabilitation, despite significant improvements on the wheelchair circuit and in work capacity. The only significant difference between the groups was found in mechanical efficiency. Implications for rehabilitation The lack of time-dependent changes in mechanical efficiency and propulsion technique in the group with a recent spinal cord injury, combined with the lack of differences in technique, work capacity and on the wheelchair circuit between the groups, suggest that important adaptations of motor learning may happen even earlier in rehabilitation and emphasize that the group in active rehabilitation was relatively skilled. Standardized observational analyses of handrim wheelchair propulsion abilities during early spinal cord injury rehabilitation provide detailed understanding of wheelchair technique, skill as well as wheelchair propulsion capacity. Measurement of external power output is critical to interpretation of gross efficiency, propulsion technique, and capacity. Wheelchair quality and body weight - next to wheelchair fitness and skill - require careful consideration both in early rehabilitation as well as in the chronic phase of spinal cord injury

Longitudinal measures of lung function in infants with bronchopulmonary dysplasia

We previously demonstrated that infants with a history of bronchopulmonary dysplasia (BPD) exhibit airflow obstruction and air trapping. The purpose of this study was to assess longitudinal changes in pulmonary function in infants with a history of BPD over the first 3 years of life, and the relationship to somatic growth. Spirometry was measured using the raised volume rapid thoracoabdominal compression technique, and lung volumes measured by plethysmography. Eighteen infants (mean gestational age ± SD 27.3 ± 2.2 weeks, birthweight 971 ± 259 g) underwent two lung function studies. Average age at first test was 58.8 weeks. Spirometry demonstrated significant reductions in forced expiratory volume in 0.5 sec (FEV 0.5 , 76.0 ± 15.9% predicted, Z-score −2.13 ± 1.69), forced expiratory flow at 75% of expired forced vital capacity (FEF 75 , 54.8 ± 31.1%, −3.58 ± 2.73), and FEF 25–75 (67.8 ± 33.3%, −1.79 ± 1.76). Group mean total lung capacity (TLC) was in the low normal range (82.9 ± 13.5% predicted) and residual volume (RV)/TLC was mildly elevated (122.4 ± 38.2% predicted). Repeat testing was performed an average of 32.7 weeks after initial testing. At re-evaluation, group mean lung volumes and flows tracked at or near their previous values; thus, in general, there was a lack of catch-up growth. However, compared to infants with below average or average somatic growth (as represented by g/day), infants with above average growth showed significantly greater improvements in percent predicted FVC, FEV 0.5 , TLC, and RV/TLC (all P  < 0.05, ANOVA). We conclude that longitudinal measures of pulmonary function in infants and young children with BPD demonstrate significant airflow obstruction and modest restriction, which tends to persist with time. On the other hand, infants with above average somatic growth showed greater lung growth than their peers. Additional studies examining the effects of various nutritional regimens on lung function are warranted. Pediatr Pulmonol. 2011; 46:369–375. © 2010 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/83461/1/21378_ftp.pd

Impact of risk factors on the timing of first postpartum venous thromboembolism: a population-based cohort study from England

For women with preeclampsia, BMI &gt;30 kg/m2, infection, or those having cesarean delivery, VTE risk remained elevated for 6 weeks postpartum.For women with postpartum hemorrhage or preterm birth, the relative rate of VTE was only increased for the first 3 weeks postpartum.Impact on the timing of first postpartum venous thromboembolism (VTE) for women with specific risk factors is of crucial importance when planning the duration of thromboprophylaxis regimen. We observed this using a large linked primary and secondary care database containing 222 334 pregnancies resulting in live and stillbirth births between 1997 and 2010. We assessed the impact of risk factors on the timing of postpartum VTE in term of absolute rates (ARs) and incidence rate ratios (IRRs) using a Poisson regression model. Women with preeclampsia/eclampsia and postpartum acute systemic infection had the highest risk of VTE during the first 3 weeks postpartum (ARs ≥2263/100 000 person-years; IRR ≥2.5) and at 4-6 weeks postpartum (AR ≥1360; IRR ≥3.5). Women with body mass index (BMI) &gt;30 kg/m2 or those having cesarean delivery also had elevated rates up to 6 weeks (AR ≥1425 at 1-3 weeks and ≥722 at 4-6 weeks). Women with postpartum hemorrhage or preterm birth, had significantly increased VTE rates only in the first 3 weeks (AR ≥1736; IRR ≥2). Our findings suggest that the duration of the increased VTE risk after childbirth varies based on the type of risk factors and can extend up to the first 3 to 6 weeks postpartum

Strategies to overcome physician shortages in northern Ontario: A study of policy implementation over 35 years

<p>Abstract</p> <p>Background</p> <p>Shortages and maldistibution of physicians in northern Ontario, Canada, have been a long-standing issue. This study seeks to document, in a chronological manner, the introduction of programmes intended to help solve the problem by the provincial government over a 35-year period and to examine several aspects of policy implementation, using these programmes as a case study.</p> <p>Methods</p> <p>A programme analysis approach was adopted to examine each of a broad range of programmes to determine its year of introduction, strategic category, complexity, time frame, and expected outcome. A chronology of programme initiation was constructed, on the basis of which an analysis was done to examine changes in strategies used by the provincial government from 1969 to 2004.</p> <p>Results</p> <p>Many programmes were introduced during the study period, which could be grouped into nine strategic categories. The range of policy instruments used became broader in later years. But conspicuous by their absence were programmes of a directive nature. Programmes introduced in more recent years tended to be more complex and were more likely to have a longer time perspective and pay more attention to physician retention. The study also discusses the choice of policy instruments and use of multiple strategies.</p> <p>Conclusion</p> <p>The findings suggest that an examination of a policy is incomplete if implementation has not been taken into consideration. The study has revealed a process of trial-and-error experimentation and an accumulation of past experience. The study sheds light on the intricate relationships between policy, policy implementation and use of policy instruments and programmes.</p

Creative destruction in science

Drawing on the concept of a gale of creative destruction in a capitalistic economy, we argue that initiatives to assess the robustness of findings in the organizational literature should aim to simultaneously test competing ideas operating in the same theoretical space. In other words, replication efforts should seek not just to support or question the original findings, but also to replace them with revised, stronger theories with greater explanatory power. Achieving this will typically require adding new measures, conditions, and subject populations to research designs, in order to carry out conceptual tests of multiple theories in addition to directly replicating the original findings. To illustrate the value of the creative destruction approach for theory pruning in organizational scholarship, we describe recent replication initiatives re-examining culture and work morality, working parents\u2019 reasoning about day care options, and gender discrimination in hiring decisions. Significance statement It is becoming increasingly clear that many, if not most, published research findings across scientific fields are not readily replicable when the same method is repeated. Although extremely valuable, failed replications risk leaving a theoretical void\u2014 reducing confidence the original theoretical prediction is true, but not replacing it with positive evidence in favor of an alternative theory. We introduce the creative destruction approach to replication, which combines theory pruning methods from the field of management with emerging best practices from the open science movement, with the aim of making replications as generative as possible. In effect, we advocate for a Replication 2.0 movement in which the goal shifts from checking on the reliability of past findings to actively engaging in competitive theory testing and theory building. Scientific transparency statement The materials, code, and data for this article are posted publicly on the Open Science Framework, with links provided in the article

Tau filament self-assembly and structure: tau as a therapeutic target

Tau plays an important pathological role in a group of neurodegenerative diseases called tauopathies, including Alzheimer's disease, Pick's disease, chronic traumatic encephalopathy and corticobasal degeneration. In each disease, tau self-assembles abnormally to form filaments that deposit in the brain. Tau is a natively unfolded protein that can adopt distinct structures in different pathological disorders. Cryo-electron microscopy has recently provided a series of structures for the core of the filaments purified from brain tissue from patients with different tauopathies and revealed that they share a common core region, while differing in their specific conformation. This structurally resolvable part of the core is contained within a proteolytically stable core region from the repeat domain initially isolated from AD tau filaments. Tau has recently become an important target for therapy. Recent work has suggested that the prevention of tau self-assembly may be effective in slowing the progression of Alzheimer's disease and other tauopathies. Here we review the work that explores the importance of tau filament structures and tau self-assembly mechanisms, as well as examining model systems that permit the exploration of the mode of action of potential inhibitors