Light and circadian regulation of clock components aids flexible responses to environmental signals

The circadian clock measures time across a 24h period, increasing fitness by phasing biological processes to the most appropriate time of day. The interlocking feedback loop mechanism of the clock is conserved across species; however, the number of loops varies. Mathematical and computational analyses have suggested that loop complexity affects the overall flexibility of the oscillator, including its responses to entrainment signals. We used a discriminating experimental assay, at the transition between different photoperiods, in order to test this proposal in a minimal circadian network (in Ostreococcus tauri) and a more complex network (in Arabidopsis thaliana). Transcriptional and translational reporters in O.tauri primarily tracked dawn or dusk, whereas in A.thaliana, a wider range of responses were observed, consistent with its more flexible clock. Model analysis supported the requirement for this diversity of responses among the components of the more complex network. However, these and earlier data showed that the O.tauri network retains surprising flexibility, despite its simple circuit. We found that models constructed from experimental data can show flexibility either from multiple loops and/or from multiple light inputs. Our results suggest that O.tauri has adopted the latter strategy, possibly as a consequence of genomic reduction

The Prevalence of Psychological Side Effects of Concussions in Division II and III Athletes in Ohio

Background: Concussions are becoming an epidemic as millions of athletes are diagnosed with concussions each year. Concussions are not homogenous injuries and should be managed uniquely. Often health care providers focus on the physical side effects of concussions and ignore the psychological side effects. Methods: In order to determine the prevalence of psychological side effects resulting from concussions and the frequency of ATCs or team physicians managing their psychological symptoms we sent out a survey. The survey included seventeen questions related to demographics and concussion symptoms that were sent to Division II and III athletes in Ohio over the age of 18. Results: Fifteen surveys were received from participants that had experienced at least one concussion. The most common psychological symptom reported was a decrease in energy (10), followed by lack of motivation (5), mood swings (4), anxiety (3), and fits of rage (2). Two respondents did not experience any emotional symptoms related to their concussion(s). With five of the fifteen respondents have been asked about emotional symptoms by their athletic trainer or team physician. Conclusion: Our survey was limited by time restraints and limited responses. Our survey did not bring statistically significant results. However, it did show that psychological effects are present in those with concussions. In addition, it showed that athletic trainers and team physicians need to be more holistic in their management of concussions

`Zip codes' direct intracellular protein tyrosine phosphatases to the correct cellular `address'

The transmembrane and intracellular protein tyrosine phosphatases (PTPs) play an essential role as signal transduction proteins involved in various cellular processes including division, proliferation and differentiation. As such, their activity must be strictly regulated to avoid nonspecific tyrosine dephosphorylation of cellular proteins. The intracellular PTPs possess a diversity of protein sequences outside the catalytic domain that appear to serve as `zip codes' specifically `addressing' these proteins to defined subcellular compartments. These localization strategies are proposed to function as a regulatory mechanism, defining the substrate specificity and function of the intracellular PTPs.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/31657/1/0000591.pd

A Cluster Analysis of Challenging Behaviors in Autism Spectrum Disorder

We apply cluster analysis to a sample of 2,116 children with Autism Spectrum Disorder in order to identify patterns of challenging behaviors observed in home and centerbased clinical settings. The largest study of this type to date, and the first to employ machine learning, our results indicate that while the presence of multiple challenging behaviors is common, in most cases a dominant behavior emerges. Furthermore, the trend is also observed when we train our cluster models on the male and female samples separately. This work provides a basis for future studies to understand the relationship of challenging behavior profiles to learning outcomes, with the ultimate goal of providing personalized therapeutic interventions with maximum efficacy and minimum time and cost

Impact of HuR inhibition by the small molecule MS-444 on colorectal cancer cell tumorigenesis.

Colorectal cancer (CRC) is the third most common cancer and a leading cause of cancer-related mortality. Observed during CRC tumorigenesis is loss of post-transcriptional regulation of tumor-promoting genes such as COX-2, TNFα and VEGF. Overexpression of the RNA-binding protein HuR (ELAVL1) occurs during colon tumorigenesis and is abnormally present within the cytoplasm, where it post-transcriptionally regulates genes through its interaction with 3\u27UTR AU-rich elements (AREs). Here, we examine the therapeutic potential of targeting HuR using MS-444, a small molecule HuR inhibitor. Treatment of CRC cells with MS-444 resulted in growth inhibition and increased apoptotic gene expression, while similar treatment doses in non-transformed intestinal cells had no appreciable effects. Mechanistically, MS-444 disrupted HuR cytoplasmic trafficking and released ARE-mRNAs for localization to P-bodies, but did not affect total HuR expression levels. This resulted in MS-444-mediated inhibition of COX-2 and other ARE-mRNA expression levels. Importantly, MS-444 was well tolerated and inhibited xenograft CRC tumor growth through enhanced apoptosis and decreased angiogenesis upon intraperitoneal administration. In vivo treatment of MS-444 inhibited HuR cytoplasmic localization and decreased COX-2 expression in tumors. These findings provide evidence that therapeutic strategies to target HuR in CRC warrant further investigation in an effort to move this approach to the clinic

Light and circadian regulation of clock components aids flexible responses to environmental signals

PublishedJournal ArticleResearch Support, Non-U.S. Gov'tThe circadian clock measures time across a 24 h period, increasing fitness by phasing biological processes to the most appropriate time of day. The interlocking feedback loop mechanism of the clock is conserved across species; however, the number of loops varies. Mathematical and computational analyses have suggested that loop complexity affects the overall flexibility of the oscillator, including its responses to entrainment signals. We used a discriminating experimental assay, at the transition between different photoperiods, in order to test this proposal in a minimal circadian network (in Ostreococcus tauri) and a more complex network (in Arabidopsis thaliana). Transcriptional and translational reporters in O. tauri primarily tracked dawn or dusk, whereas in A. thaliana, a wider range of responses were observed, consistent with its more flexible clock. Model analysis supported the requirement for this diversity of responses among the components of the more complex network. However, these and earlier data showed that the O. tauri network retains surprising flexibility, despite its simple circuit. We found that models constructed from experimental data can show flexibility either from multiple loops and/or from multiple light inputs. Our results suggest that O. tauri has adopted the latter strategy, possibly as a consequence of genomic reduction.This research was supported by EU FP7 collaborative project TiMet (award 245143), BBSRC and EPSRC awards BB/F005237/1, BB/D019621/1 and BB/J009423 (to A.J.M. and others) and EPSRC award EP/I017445/1 (to O.E.A. and others). C.T.'s work was supported by the Human Frontiers Science Program and the Swedish Research Council (award 2010-5219)

A switchable light-input, light-output system modelled and constructed in yeast

<p>Abstract</p> <p>Background</p> <p>Advances in synthetic biology will require spatio-temporal regulation of biological processes in heterologous host cells. We develop a light-switchable, two-hybrid interaction in yeast, based upon the Arabidopsis proteins PHYTOCHROME A and FAR-RED ELONGATED HYPOCOTYL 1-LIKE. Light input to this regulatory module allows dynamic control of a light-emitting LUCIFERASE reporter gene, which we detect by real-time imaging of yeast colonies on solid media.</p> <p>Results</p> <p>The reversible activation of the phytochrome by red light, and its inactivation by far-red light, is retained. We use this quantitative readout to construct a mathematical model that matches the system's behaviour and predicts the molecular targets for future manipulation.</p> <p>Conclusion</p> <p>Our model, methods and materials together constitute a novel system for a eukaryotic host with the potential to convert a dynamic pattern of light input into a predictable gene expression response. This system could be applied for the regulation of genetic networks - both known and synthetic.</p

Short-Term Medical Costs of a VHA Health Information Exchange: A CHEERS-Compliant Article.

The Virtual Lifetime Electronic Record (VLER) Health program provides the Veterans Health Administration (VHA) a framework whereby VHA providers can access the veterans’ electronic health record information to coordinate healthcare across multiple sites of care. As an early adopter of VLER, the Indianapolis VHA and Regenstrief Institute implemented a regional demonstration program involving bi-directional health information exchange (HIE) between VHA and non-VHA providers.The aim of the study is to determine whether implementation of VLER HIE reduces 1 year VHA medical costs.A cohort evaluation with a concurrent control group compared VHA healthcare costs using propensity score adjustment. A CHEERs compliant checklist was used to conduct the cost evaluation.Patients were enrolled in the VLER program onsite at the Indianapolis VHA in outpatient clinics or through the release-of-information office.VHA cost data (in 2014 dollars) were obtained for both enrolled and nonenrolled (control) patients for 1 year prior to, and 1 year after, the index date of patient enrollment.There were 6104 patients enrolled in VLER and 45,700 patients in the control group. The annual adjusted total cost difference per patient was associated with a higher cost for VLER enrollees $1152 (95$807–1433) (P < 0.01) (in 2014 dollars) than VLER nonenrollees.Short-term evaluation of this demonstration project did not show immediate reductions in healthcare cost as might be expected if HIE decreased redundant medical tests and treatments. Cost reductions from shared health information may be realized with longer time horizons

Randomized phase II study investigating pazopanib versus weekly paclitaxel in relapsed or progressive urothelial cancer

Purpose: Two previous single-arm trials have drawn conflicting conclusions regarding the activity of pazopanib in urothelial cancers after failure of platinum-based chemotherapy. Patients and Methods: This randomized (1:1) open-label phase II trial compared the efficacy of pazopanib 800 mg orally with paclitaxel (80 mg/m2 days 1, 8, and 15 every 28 days) in the second-line setting. The primary end point was overall survival (OS). Results: Between August 2012 and October 2014, 131 patients, out of 140 planned, were randomly assigned. The study was terminated early on the recommendation of the independent data monitoring committee because of futility. Final analysis after the preplanned number of deaths (n = 110) occurred after a median follow-up of 18 months. One hundred fifteen deaths had occurred at the final data extract presented here. Median OS was 8.0 months for paclitaxel (80% CI, 6.9 to 9.7 months) and 4.7 months for pazopanib (80% CI, 4.2 to 6.4 months). The hazard ratio (HR) adjusted for baseline stratification factors was 1.28 (80% CI, 0.99 to 1.67; one-sided P = .89). Median progression-free survival was 4.1 months for paclitaxel (80% CI, 3.0 to 5.6 months) and 3.1 months for pazopanib (80% CI, 2.7 to 4.6 months; HR, 1.09; 80% CI, 0.85 to 1.40; one-sided P = .67). Discontinuations for toxicity occurred in 7.8% and 23.1% for paclitaxel and pazopanib, respectively. Conclusion: Pazopanib did not have greater efficacy than paclitaxel in the second-line treatment of urothelial cancers. There was a trend toward superior OS for paclitaxel

Developing a Reliable Welfare Assessment Tool for Captive Hibernatory Bear Species

Animal welfare assessments are essential for the identification of welfare hazards and benchmarking of welfare improvements, though welfare assessments for zoo species are lacking. Bears are commonly housed in zoos but currently no composite welfare assessment tool exists for captive bears. This study describes the development of such a tool for use across hibernating bear species. A draft tool was developed using indicators derived from the literature and a modified Delphi analysis with an international group of bear keepers. A total of 18 bear keepers from 12 zoos were recruited to trial the tool on 24 brown bears and American black bears. The participating keepers assessed their bears three times across a period of nine days. Intraclass correlation coefficients analysis was used to analyse inter-, intra-rater and item reliability. The inter- and intra-rater reliability showed good to excellent levels of agreement (>0.7, p 0.05). Item reliability was also assessed and showed good to excellent levels of agreement (>0.75, p 0.05). The resulting bear welfare assessment is an important step in identifying and understanding challenges to bear welfare in captivity