Understanding co-polymerization in amyloid formation by direct observation of mixed oligomers

Although amyloid assembly in vitro is commonly investigated using single protein sequences, fibril formation in vivo can be more heterogeneous, involving co-assembly of proteins of different length, sequence and/or post-translational modifications. Emerging evidence suggests that co-polymerization can alter the rate and/or mechanism of aggregation and can contribute to pathogenicity. Electrospray ionization-ion mobility spectrometry-mass spectrometry (ESI-IMS-MS) is uniquely suited to the study of these heterogeneous ensembles. Here, ESI-IMS-MS combined with analysis of fibrillation rates using thioflavin T (ThT) fluorescence, is used to track the course of aggregation of variants of islet-amyloid polypeptide (IAPP) in isolation and in pairwise mixtures. We identify a sub-population of extended monomers as the key precursors of amyloid assembly, and reveal that the fastest aggregating sequence in peptide mixtures determines the lag time of fibrillation, despite being unable to cross-seed polymerization. The results demonstrate that co-polymerization of IAPP sequences radically alters the rate of amyloid assembly by altering the conformational properties of the mixed oligomers that form

Designing an automated clinical decision support system to match clinical practice guidelines for opioid therapy for chronic pain

Abstract Background Opioid prescribing for chronic pain is common and controversial, but recommended clinical practices are followed inconsistently in many clinical settings. Strategies for increasing adherence to clinical practice guideline recommendations are needed to increase effectiveness and reduce negative consequences of opioid prescribing in chronic pain patients. Methods Here we describe the process and outcomes of a project to operationalize the 2003 VA/DOD Clinical Practice Guideline for Opioid Therapy for Chronic Non-Cancer Pain into a computerized decision support system (DSS) to encourage good opioid prescribing practices during primary care visits. We based the DSS on the existing ATHENA-DSS. We used an iterative process of design, testing, and revision of the DSS by a diverse team including guideline authors, medical informatics experts, clinical content experts, and end-users to convert the written clinical practice guideline into a computable algorithm to generate patient-specific recommendations for care based upon existing information in the electronic medical record (EMR), and a set of clinical tools. Results The iterative revision process identified numerous and varied problems with the initially designed system despite diverse expert participation in the design process. The process of operationalizing the guideline identified areas in which the guideline was vague, left decisions to clinical judgment, or required clarification of detail to insure safe clinical implementation. The revisions led to workable solutions to problems, defined the limits of the DSS and its utility in clinical practice, improved integration into clinical workflow, and improved the clarity and accuracy of system recommendations and tools. Conclusions Use of this iterative process led to development of a multifunctional DSS that met the approval of the clinical practice guideline authors, content experts, and clinicians involved in testing. The process and experiences described provide a model for development of other DSSs that translate written guidelines into actionable, real-time clinical recommendations.http://deepblue.lib.umich.edu/bitstream/2027.42/78267/1/1748-5908-5-26.xmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/78267/2/1748-5908-5-26.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/78267/3/1748-5908-5-26-S3.TIFFhttp://deepblue.lib.umich.edu/bitstream/2027.42/78267/4/1748-5908-5-26-S2.TIFFhttp://deepblue.lib.umich.edu/bitstream/2027.42/78267/5/1748-5908-5-26-S1.TIFFPeer Reviewe

Regulation of the dystrophin-associated glycoprotein complex composition by the metabolic properties of muscle fibres

The dystrophin-glycoprotein complex (DGC) links the muscle cytoskeleton to the extracellular matrix and is responsible for force transduction and protects the muscle fibres from contraction induced damage. Mutations in components of the DGC are responsible for muscular dystrophies and congenital myopathies. Expression of DGC components have been shown to be altered in many myopathies. In contrast we have very little evidence of whether adaptive changes in muscle impact on DGC expression. In this study we investigated connection between muscle fibre phenotype and the DGC. Our study reveals that the levels of DGC proteins at the sarcolemma differ in highly glycolytic muscle compared to wild-type and that these changes can be normalised by the super-imposition of an oxidative metabolic programme. Importantly we show that the metabolic properties of the muscle do not impact on the total amount of DGC components at the protein level. Our work shows that the metabolic property of a muscle fibre is a key factor in regulating the expression of DGC proteins at the sarcolemma

Formation of Super-Earths

Super-Earths are the most abundant planets known to date and are characterized by having sizes between that of Earth and Neptune, typical orbital periods of less than 100 days and gaseous envelopes that are often massive enough to significantly contribute to the planet's overall radius. Furthermore, super-Earths regularly appear in tightly-packed multiple-planet systems, but resonant configurations in such systems are rare. This chapters summarizes current super-Earth formation theories. It starts from the formation of rocky cores and subsequent accretion of gaseous envelopes. We follow the thermal evolution of newly formed super-Earths and discuss their atmospheric mass loss due to disk dispersal, photoevaporation, core-cooling and collisions. We conclude with a comparison of observations and theoretical predictions, highlighting that even super-Earths that appear as barren rocky cores today likely formed with primordial hydrogen and helium envelopes and discuss some paths forward for the future.Comment: Invited review accepted for publication in the 'Handbook of Exoplanets,' Planet Formation section, Springer Reference Works, Juan Antonio Belmonte and Hans Deeg, Ed

The validity of using ICD-9 codes and pharmacy records to identify patients with chronic obstructive pulmonary disease

Background: Administrative data is often used to identify patients with chronic obstructive pulmonary disease (COPD), yet the validity of this approach is unclear. We sought to develop a predictive model utilizing administrative data to accurately identify patients with COPD. Methods: Sequential logistic regression models were constructed using 9573 patients with postbronchodilator spirometry at two Veterans Affairs medical centers (2003-2007). COPD was defined as: 1) FEV1/FVC <0.70, and 2) FEV1/FVC < lower limits of normal. Model inputs included age, outpatient or inpatient COPD-related ICD-9 codes, and the number of metered does inhalers (MDI) prescribed over the one year prior to and one year post spirometry. Model performance was assessed using standard criteria. Results: 4564 of 9573 patients (47.7%) had an FEV1/FVC < 0.70. The presence of ≥1 outpatient COPD visit had a sensitivity of 76% and specificity of 67%; the AUC was 0.75 (95% CI 0.74-0.76). Adding the use of albuterol MDI increased the AUC of this model to 0.76 (95% CI 0.75-0.77) while the addition of ipratropium bromide MDI increased the AUC to 0.77 (95% CI 0.76-0.78). The best performing model included: ≥6 albuterol MDI, ≥3 ipratropium MDI, ≥1 outpatient ICD-9 code, ≥1 inpatient ICD-9 code, and age, achieving an AUC of 0.79 (95% CI 0.78-0.80). Conclusion: Commonly used definitions of COPD in observational studies misclassify the majority of patients as having COPD. Using multiple diagnostic codes in combination with pharmacy data improves the ability to accurately identify patients with COPD.Department of Veterans Affairs, Health Services Research and Development (DHA), American Lung Association (CI- 51755-N) awarded to DHA, the American Thoracic Society Fellow Career Development AwardPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/84155/1/Cooke - ICD9 validity in COPD.pd

The Reform of Employee Compensation in China’s Industrial Enterprises

Although employee compensation reform in Chinese industrial sector has been discussed in the literature, the real changes in compensation system and pay practices have received insufficient attention and warrant further examination. This paper briefly reviews the pre- and post-reform compensation system, and reports the results of a survey of pay practices in the four major types of industrial enterprises in China. The research findings indicate that the type of enterprise ownership has little influence on general compensation practices, adoption of profit-sharing plans, and subsidy and allowance packages. In general, pay is linked more to individual performance and has become an important incentive to Chinese employees. However, differences are found across the enterprise types with regard to performance-related pay. Current pay practices are positively correlated to overall effectiveness of the enterprise

LEMUR: Large European Module for solar Ultraviolet Research. European contribution to JAXA's Solar-C mission

Understanding the solar outer atmosphere requires concerted, simultaneous solar observations from the visible to the vacuum ultraviolet (VUV) and soft X-rays, at high spatial resolution (between 0.1" and 0.3"), at high temporal resolution (on the order of 10 s, i.e., the time scale of chromospheric dynamics), with a wide temperature coverage (0.01 MK to 20 MK, from the chromosphere to the flaring corona), and the capability of measuring magnetic fields through spectropolarimetry at visible and near-infrared wavelengths. Simultaneous spectroscopic measurements sampling the entire temperature range are particularly important. These requirements are fulfilled by the Japanese Solar-C mission (Plan B), composed of a spacecraft in a geosynchronous orbit with a payload providing a significant improvement of imaging and spectropolarimetric capabilities in the UV, visible, and near-infrared with respect to what is available today and foreseen in the near future. The Large European Module for solar Ultraviolet Research (LEMUR), described in this paper, is a large VUV telescope feeding a scientific payload of high-resolution imaging spectrographs and cameras. LEMUR consists of two major components: a VUV solar telescope with a 30 cm diameter mirror and a focal length of 3.6 m, and a focal-plane package composed of VUV spectrometers covering six carefully chosen wavelength ranges between 17 and 127 nm. The LEMUR slit covers 280" on the Sun with 0.14" per pixel sampling. In addition, LEMUR is capable of measuring mass flows velocities (line shifts) down to 2 km/s or better. LEMUR has been proposed to ESA as the European contribution to the Solar C mission.Comment: 35 pages, 14 figures. To appear on Experimental Astronom

Adjustment for time-invariant and time-varying confounders in ‘unexplained residuals’ models for longitudinal data within a causal framework and associated challenges

‘Unexplained residuals’ models have been used within lifecourse epidemiology to model an exposure measured longitudinally at several time points in relation to a distal outcome. It has been claimed that these models have several advantages, including: the ability to estimate multiple total causal effects in a single model, and additional insight into the effect on the outcome of greater-than-expected increases in the exposure compared to traditional regression methods. We evaluate these properties and prove mathematically how adjustment for confounding variables must be made within this modelling framework. Importantly, we explicitly place unexplained residual models in a causal framework using directed acyclic graphs. This allows for theoretical justification of appropriate confounder adjustment and provides a framework for extending our results to more complex scenarios than those examined in this paper. We also discuss several interpretational issues relating to unexplained residual models within a causal framework. We argue that unexplained residual models offer no additional insights compared to traditional regression methods, and, in fact, are more challenging to implement; moreover, they artificially reduce estimated standard errors. Consequently, we conclude that unexplained residual models, if used, must be implemented with great care

Early prediction of median survival among a large AIDS surveillance cohort

<p>Abstract</p> <p>Background</p> <p>For individuals with AIDS, data exist relatively soon after diagnosis to allow estimation of "early" survival quantiles (<it>e.g.</it>, the 0.10, 0.15, 0.20 and 0.30 quantiles, etc.). Many years of additional observation must elapse before median survival, a summary measure of survival, can be estimated accurately. In this study, a new approach to predict AIDS median survival is presented and its accuracy tested using AIDS surveillance data.</p> <p>Methods</p> <p>The data consisted of 96,373 individuals who were reported to the HIV/AIDS Reporting System of the California Department of Health Services Office of AIDS as of December 31, 1996. We defined cohorts based on quarter year of diagnosis (<it>e.g.</it>, the "931" cohort consists of individuals diagnosed with AIDS in the first quarter of 1993). We used early quantiles (estimated using the Inverse Probability of Censoring Weighted estimator) of the survival distribution to estimate median survival by assuming a linear relationship between the earlier quantiles and median survival. From this model, median survival was predicted for cohorts for which a median could not be estimated empirically from the available data. This prediction was compared with the actual medians observed when using updated survival data reported at least five years later.</p> <p>Results</p> <p>Using the 0.15 quantile as the predictor and the data available as of December 31, 1996, we were able to predict the median survival of four cohorts (933, 934, 941, and 942) to be 34, 34, 31, and 29 months. Without this approach, there were insufficient data with which to make any estimate of median survival. The actual median survival of these four cohorts (using data as of December 31, 2001) was found to be 32, 40, 46, and 80 months, suggesting that the accuracy for this approach requires a minimum of three years to elapse from diagnosis to the time an accurate prediction can be made.</p> <p>Conclusion</p> <p>The results of this study suggest that early and accurate prediction of median survival time after AIDS diagnosis may be possible using early quantiles of the survival distribution. The methodology did not seem to work well during a period of significant change in survival as observed with highly active antiretroviral treatment, but results suggest that it may work well in a time of more gradual improvement in survival.</p

Autoimmune and autoinflammatory mechanisms in uveitis

The eye, as currently viewed, is neither immunologically ignorant nor sequestered from the systemic environment. The eye utilises distinct immunoregulatory mechanisms to preserve tissue and cellular function in the face of immune-mediated insult; clinically, inflammation following such an insult is termed uveitis. The intra-ocular inflammation in uveitis may be clinically obvious as a result of infection (e.g. toxoplasma, herpes), but in the main infection, if any, remains covert. We now recognise that healthy tissues including the retina have regulatory mechanisms imparted by control of myeloid cells through receptors (e.g. CD200R) and soluble inhibitory factors (e.g. alpha-MSH), regulation of the blood retinal barrier, and active immune surveillance. Once homoeostasis has been disrupted and inflammation ensues, the mechanisms to regulate inflammation, including T cell apoptosis, generation of Treg cells, and myeloid cell suppression in situ, are less successful. Why inflammation becomes persistent remains unknown, but extrapolating from animal models, possibilities include differential trafficking of T cells from the retina, residency of CD8(+) T cells, and alterations of myeloid cell phenotype and function. Translating lessons learned from animal models to humans has been helped by system biology approaches and informatics, which suggest that diseased animals and people share similar changes in T cell phenotypes and monocyte function to date. Together the data infer a possible cryptic infectious drive in uveitis that unlocks and drives persistent autoimmune responses, or promotes further innate immune responses. Thus there may be many mechanisms in common with those observed in autoinflammatory disorders