Literature-based discovery of diabetes- and ROS-related targets

Abstract Background Reactive oxygen species (ROS) are known mediators of cellular damage in multiple diseases including diabetic complications. Despite its importance, no comprehensive database is currently available for the genes associated with ROS. Methods We present ROS- and diabetes-related targets (genes/proteins) collected from the biomedical literature through a text mining technology. A web-based literature mining tool, SciMiner, was applied to 1,154 biomedical papers indexed with diabetes and ROS by PubMed to identify relevant targets. Over-represented targets in the ROS-diabetes literature were obtained through comparisons against randomly selected literature. The expression levels of nine genes, selected from the top ranked ROS-diabetes set, were measured in the dorsal root ganglia (DRG) of diabetic and non-diabetic DBA/2J mice in order to evaluate the biological relevance of literature-derived targets in the pathogenesis of diabetic neuropathy. Results SciMiner identified 1,026 ROS- and diabetes-related targets from the 1,154 biomedical papers (http://jdrf.neurology.med.umich.edu/ROSDiabetes/). Fifty-three targets were significantly over-represented in the ROS-diabetes literature compared to randomly selected literature. These over-represented targets included well-known members of the oxidative stress response including catalase, the NADPH oxidase family, and the superoxide dismutase family of proteins. Eight of the nine selected genes exhibited significant differential expression between diabetic and non-diabetic mice. For six genes, the direction of expression change in diabetes paralleled enhanced oxidative stress in the DRG. Conclusions Literature mining compiled ROS-diabetes related targets from the biomedical literature and led us to evaluate the biological relevance of selected targets in the pathogenesis of diabetic neuropathy.http://deepblue.lib.umich.edu/bitstream/2027.42/78315/1/1755-8794-3-49.xmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/78315/2/1755-8794-3-49-S7.XLShttp://deepblue.lib.umich.edu/bitstream/2027.42/78315/3/1755-8794-3-49-S10.XLShttp://deepblue.lib.umich.edu/bitstream/2027.42/78315/4/1755-8794-3-49-S8.XLShttp://deepblue.lib.umich.edu/bitstream/2027.42/78315/5/1755-8794-3-49-S3.XLShttp://deepblue.lib.umich.edu/bitstream/2027.42/78315/6/1755-8794-3-49-S1.XLShttp://deepblue.lib.umich.edu/bitstream/2027.42/78315/7/1755-8794-3-49-S4.XLShttp://deepblue.lib.umich.edu/bitstream/2027.42/78315/8/1755-8794-3-49-S2.XLShttp://deepblue.lib.umich.edu/bitstream/2027.42/78315/9/1755-8794-3-49-S12.XLShttp://deepblue.lib.umich.edu/bitstream/2027.42/78315/10/1755-8794-3-49-S11.XLShttp://deepblue.lib.umich.edu/bitstream/2027.42/78315/11/1755-8794-3-49-S9.XLShttp://deepblue.lib.umich.edu/bitstream/2027.42/78315/12/1755-8794-3-49-S5.XLShttp://deepblue.lib.umich.edu/bitstream/2027.42/78315/13/1755-8794-3-49-S6.XLShttp://deepblue.lib.umich.edu/bitstream/2027.42/78315/14/1755-8794-3-49.pdfPeer Reviewe

Un-oriented Quiver Theories for Majorana Neutrons

In the context of un-oriented open string theories, we identify quivers whereby a Majorana mass for the neutron is indirectly generated by exotic instantons. We discuss two classes of (Susy) Standard Model like quivers, depending on the embedding of SU(2)_W in the Chan-Paton group. In both cases, the main mechanism involves a vector-like pair mixing through a non-perturbative mass term. We also discuss possible relations between the phenomenology of Neutron-Antineutron oscillations and LHC physics in these models. In particular, a vector-like pair of color-triplet scalars or color-triplet fermions could be directly detected at LHC, compatibly with n-\bar{n} limits. Finally we briefly comment on Pati-Salam extensions of our models.Comment: More comments on phenomenology and fluxes, Re-discussion of SM-quivers compatible with n-cycles conditions Version accepted by JHE

Control of wrist movement in deafferented man: evidence for a mixed strategy of position and amplitude control

© 2017 The Author(s) There is a continuing debate about control of voluntary movement, with conflicted evidence about the balance between control of movement vectors (amplitude control) that implies knowledge of the starting position for accuracy, and equilibrium point or final position control, that is independent of the starting conditions. We tested wrist flexion and extension movements in a man with a chronic peripheral neuronopathy that deprived him of proprioceptive knowledge of his wrist angles. In a series of experiments, we demonstrate that he could scale the amplitude of his wrist movements in flexion/extension, even without visual feedback, and appeared to adopt a strategy of moving via a central wrist position when asked to reach target angles from unknown start locations. When examining the relationship between positional error at the start and end of each movement in long sequences of movements, we report that he appears to have three canonical positions that he can reach relatively successfully, in flexion, in extension and in the centre. These are consistent with end-point or position control. Other positions were reached with errors that suggest amplitude control. Recording wrist flexor and extensor EMG confirmed that the flexion and extension canonical positions were reached by strong flexor and extensor activity, without antagonist activity, and other positions were reached with graded muscle activation levels. The central canonical position does not appear to be reached by either maximal co-contraction or by complete relaxation, but may have been reached by matched low-level co-contraction

Do New Drugs Increase Life Expectancy? A Critique of a Manhattan Institute Paper

A recent study published by the Manhattan Institute “Why Has Longevity Increased More in Some States than in Others? The Role of Medical Innovation and Other Factors,” purported to show that the more rapid adoption of new drugs has substantial benefits in the form of increased life expectancy, higher productivity and lower non-drug health care expenditures. This study has been cited as evidence supporting the more rapid acceptance of new drugs in Medicaid, Medicare, and other public programs and has helped to shape public debate on the value of new drugs. This analysis questions the key conclusions of the study. It points out that the key statistical regressions appear to be misspecified, since they show anomalies such as a negative correlation between income growth and life expectancy and find no relationship between education and productivity growth. Methodological flaws addressed include lack of adjustment for infant mortality rates; inadequate proxy measures of health status; lack of adjustment for ages of individuals and other sociodemographic factors; inherent problems with the definition of drug age, or ‘vintage;’ and the failure to consider reverse causation as an obvious explanation for several findings. The Manhattan Institute study does not provide reliable evidence for favoring adoption of newer drugs in either public or private health care programs

A discrete choice experiment to explore patients’ willingness to risk disease relapse from treatment withdrawal in psoriatic arthritis

The objective of this study is to assess patient preferences for treatment-related benefits and risk of disease relapse in the management of low disease states of psoriatic arthritis (PsA). Focus groups with patients and a literature review were undertaken to determine the characteristics of treatment and symptoms of PsA important to patients. Patient preferences were assessed using a discrete choice experiment which compared hypothetical treatment profiles of the risk and benefits of treatment withdrawal. The risk outcome included increased risk of disease relapse, while benefit outcomes included reduced sickness/nausea from medication and changes in health-related quality of life. Each patient completed 12 choice sets comparing treatment profiles. Preference weights were estimated using a logic regression model, and the maximum acceptable risk in disease relapse for a given improvement in benefit outcomes was elicited. Final sample included 136 patients. Respondents attached the greatest importance to eliminating severe side effects of sickness/nausea and the least importance to a change in risk of relapse. Respondents were willing to accept an increase in the risk of relapse of 32.6 % in order to eliminate the side effects of sickness/nausea. For improvements in health status, the maximum acceptable risk in relapse was comparable to a movement from some to no sickness/nausea. The study suggests that patients in low disease states of PsA are willing to accept greater risks of relapse for improvements in side effects of sickness/nausea and overall health status, with the most important benefit attribute being the elimination of severe sickness or nausea

Pneumonic Tularemia in Rabbits Resembles the Human Disease as Illustrated by Radiographic and Hematological Changes after Infection

Background: Pneumonic tularemia is caused by inhalation of the gram negative bacterium, Francisella tularensis. Because of concerns that tularemia could be used as a bioterrorism agent, vaccines and therapeutics are urgently needed. Animal models of pneumonic tularemia with a pathophysiology similar to the human disease are needed to evaluate the efficacy of these potential medical countermeasures. Principal Findings: Rabbits exposed to aerosols containing Francisella tularensis strain SCHU S4 developed a rapidly progressive fatal pneumonic disease. Clinical signs became evident on the third day after exposure with development of a fever (>40.5°C) and a sharp decline in both food and water intake. Blood samples collected on day 4 found lymphopenia and a decrease in platelet counts coupled with elevations in erythrocyte sedimentation rate, alanine aminotransferase, cholesterol, granulocytes and monocytes. Radiographs demonstrated the development of pneumonia and abnormalities of intestinal gas consistent with ileus. On average, rabbits were moribund 5.1 days after exposure; no rabbits survived exposure at any dose (190-54,000 cfu). Gross evaluation of tissues taken at necropsy showed evidence of pathology in the lungs, spleen, liver, kidney and intestines. Bacterial counts confirmed bacterial dissemination from the lungs to the liver and spleen. Conclusions/Significance: The pathophysiology of pneumonic tularemia in rabbits resembles what has been reported for humans. Rabbits therefore are a relevant model of the human disease caused by type A strains of F. tularensis. © 2011 Reed et al

Complex Processes from Dynamical Architectures with Time-Scale Hierarchy

The idea that complex motor, perceptual, and cognitive behaviors are composed of smaller units, which are somehow brought into a meaningful relation, permeates the biological and life sciences. However, no principled framework defining the constituent elementary processes has been developed to this date. Consequently, functional configurations (or architectures) relating elementary processes and external influences are mostly piecemeal formulations suitable to particular instances only. Here, we develop a general dynamical framework for distinct functional architectures characterized by the time-scale separation of their constituents and evaluate their efficiency. Thereto, we build on the (phase) flow of a system, which prescribes the temporal evolution of its state variables. The phase flow topology allows for the unambiguous classification of qualitatively distinct processes, which we consider to represent the functional units or modes within the dynamical architecture. Using the example of a composite movement we illustrate how different architectures can be characterized by their degree of time scale separation between the internal elements of the architecture (i.e. the functional modes) and external interventions. We reveal a tradeoff of the interactions between internal and external influences, which offers a theoretical justification for the efficient composition of complex processes out of non-trivial elementary processes or functional modes

Randomised controlled trial of thermostatic mixer valves in reducing bath hot tap water temperature in families with young children in social housing: A protocol

<p>Abstract</p> <p>Background</p> <p>Each year in the UK 2000 children attend emergency departments and 500 are admitted to hospital following a bath water scald. The long term effects can include disability, disfigurement or psychological harm and repeated skin grafts may be required as the child grows. The costs of treating a severe scald are estimated at 250,000 GBP. Children living in the most deprived wards are at greatest risk of thermal injuries; hospital admission rates are three times that for children living in the least deprived wards.</p> <p>Domestic hot water, which is usually stored at around 60 degrees Celsius, can result in a second-degree burn after 3 seconds and a third-degree burn after 5 seconds. Educational strategies to encourage testing of tap water temperature and reduction of hot water thermostat settings have largely proved unsuccessful. Legislation in the USA mandating pre-setting hot water heater thermostats at 49 degrees Celsius was effective in reducing scald injuries, suggesting passive measures may have a greater impact. Thermostatic mixer valves (TMVs), recently developed for the domestic market, fitted across the hot and cold water supply pipes of the bath, allow delivery of water set at a fixed temperature from the hot bath tap. These valves therefore offer the potential to reduce scald injuries.</p> <p>Design/Methods</p> <p>A pragmatic, randomised controlled trial to assess the effectiveness of TMVs in reducing bath hot tap water temperatures in the homes of families with young children in rented social housing. Two parallel arms include an intervention group and a control group where the intervention will be deferred.</p> <p>The intervention will consist of fitting a TMV (set at 44 degrees Celsius) by a qualified plumber and provision of educational materials. The control arm will not receive a TMV or the educational materials for the study duration but will be offered the intervention after collection of follow-up data 12 months post randomisation.</p> <p>The primary outcome measure will be the bath hot tap water temperature. Fifteen families per arm are required to detect a reduction in the mean bath hot tap water temperature from 60.4 degrees Celsius (SD 9.1) in the control group to 46 degrees Celsius in the intervention group, with 90% power and a 5% significance level (2 sided). Secondary outcome measures including acceptability will require a sample size of 120 participants.</p> <p>Discussion</p> <p>Whilst TMVs have the potential to reduce scald injuries, to date there have been no randomised controlled trials assessing their effectiveness, acceptability and cost effectiveness.</p> <p>Trial Registration</p> <p>ISRCTN21179067</p

X-Ray Spectroscopy of Stars

(abridged) Non-degenerate stars of essentially all spectral classes are soft X-ray sources. Low-mass stars on the cooler part of the main sequence and their pre-main sequence predecessors define the dominant stellar population in the galaxy by number. Their X-ray spectra are reminiscent, in the broadest sense, of X-ray spectra from the solar corona. X-ray emission from cool stars is indeed ascribed to magnetically trapped hot gas analogous to the solar coronal plasma. Coronal structure, its thermal stratification and geometric extent can be interpreted based on various spectral diagnostics. New features have been identified in pre-main sequence stars; some of these may be related to accretion shocks on the stellar surface, fluorescence on circumstellar disks due to X-ray irradiation, or shock heating in stellar outflows. Massive, hot stars clearly dominate the interaction with the galactic interstellar medium: they are the main sources of ionizing radiation, mechanical energy and chemical enrichment in galaxies. High-energy emission permits to probe some of the most important processes at work in these stars, and put constraints on their most peculiar feature: the stellar wind. Here, we review recent advances in our understanding of cool and hot stars through the study of X-ray spectra, in particular high-resolution spectra now available from XMM-Newton and Chandra. We address issues related to coronal structure, flares, the composition of coronal plasma, X-ray production in accretion streams and outflows, X-rays from single OB-type stars, massive binaries, magnetic hot objects and evolved WR stars.Comment: accepted for Astron. Astrophys. Rev., 98 journal pages, 30 figures (partly multiple); some corrections made after proof stag

Cognitive skills and literacy performance of Chinese adolescents with and without dyslexia

The present study sought to identify cognitive abilities that might distinguish Hong Kong Chinese adolescents with dyslexia and to assess how these abilities were associated with Chinese word reading, word dictation, and reading comprehension. The cognitive skills of interest were morphological awareness, visual-orthographic knowledge, rapid naming, and verbal working memory. A total of 90 junior secondary school students, 30 dyslexic, 30 chronological age controls, and 30 reading level controls was tested on a range of cognitive and literacy tasks. Dyslexic students were less competent than the control students in all cognitive and literacy measures. The regression analyses also showed that verbal working memory, rapid naming, morphological awareness, and visual-orthographic knowledge were significantly associated with literacy performance. Findings underscore the importance of these cognitive skills for Chinese literacy acquisition. Overall, this study highlights the persistent difficulties of Chinese dyslexic adolescents who seem to have multiple causes for reading and spelling difficulties