A Survey on Continuous Time Computations

We provide an overview of theories of continuous time computation. These theories allow us to understand both the hardness of questions related to continuous time dynamical systems and the computational power of continuous time analog models. We survey the existing models, summarizing results, and point to relevant references in the literature

Outcomes associated with matching patients' treatment preferences to physicians' recommendations: study methodology

<p>Abstract</p> <p>Background</p> <p>Patients often express strong preferences for the forms of treatment available for their disease. Incorporating these preferences into the process of treatment decision-making might improve patients' adherence to treatment, contributing to better outcomes. We describe the methodology used in a study aiming to assess treatment outcomes when patients' preferences for treatment are closely matched to recommended treatments.</p> <p>Method</p> <p>Participants included patients with moderate and severe psoriasis attending outpatient dermatology clinics at the University Medical Centre Mannheim, University of Heidelberg, Germany. A self-administered online survey used conjoint analysis to measure participants' preferences for psoriasis treatment options at the initial study visit. Physicians' treatment recommendations were abstracted from each participant's medical records. The Preference Matching Index (PMI), a measure of concordance between the participant's preferences for treatment and the physician's recommended treatment, was determined for each participant at t₁(initial study visit). A clinical outcome measure, the Psoriasis Area and Severity Index, and two participant-derived outcomes assessing treatment satisfaction and health related quality of life were employed at t₁, t₂(twelve weeks post-t₁) and t₃(twelve weeks post-t₂). Change in outcomes was assessed using repeated measures analysis of variance. The association between participants' PMI scores at t₁and outcomes at t₂and t₃was evaluated using multivariate regressions analysis.</p> <p>Discussion</p> <p>We describe methods for capturing concordance between patients' treatment preferences and recommended treatment and for assessing its association with specific treatment outcomes. The methods are intended to promote the incorporation of patients' preferences in treatment decision-making, enhance treatment satisfaction, and improve treatment effectiveness through greater adherence.</p

Maximizing the general success of cecal intubation during propofol sedation in a multi-endoscopist academic centre

<p>Abstract</p> <p>Background</p> <p>Achieving the target of 95% colonoscopy completion rate at centres conducting colorectal screening programs is an important issue. Large centres and teaching hospitals employing endoscopists with different levels of training and expertise risk achieving worse results. Deep sedation with propofol in routine colonoscopy could maximize the results of cecal intubation.</p> <p>Methods</p> <p>The present study on the experience of a single centre focused on estimating the overall completion rate of colonoscopies performed under routine propofol sedation at a large teaching hospital with many operators involved, and on assessing the factors that influence the success rate of the procedure and how to improve this performance, analyzing the aspects relating to using of deep sedation. Twenty-one endoscopists, classified by their level of specialization in colonoscopic practice, performed 1381 colonoscopies under deep sedation. All actions needed for the anaesthesiologist to restore adequate oxygenation or hemodynamics, even for transient changes, were recorded.</p> <p>Results</p> <p>The "crude" overall completion rate was 93.3%. This finding shows that with routine deep sedation, the colonoscopy completion rate nears, but still does not reach, the target performance for colonoscopic screening programs, at centers where colonoscopists of difference experience are employed in such programs.</p> <p>Factors interfering with cecal intubation were: inadequate colon cleansing, endoscopists' expertise in colonoscopic practice, patients' body weight under 60 kg or age over 71 years, and the need for active intervention by the anaesthesiologist. The most favourable situation - a patient less than 71 years old with a body weight over 60 kg, an adequate bowel preparation, a "highly experienced specialist" performing the test, and no need for active anaesthesiological intervention during the procedure - coincided with a 98.8% probability of the colonoscopy being completed.</p> <p>Conclusions</p> <p>With routine deep sedation, the colonoscopy completion rate nears the target performance for colonoscopic screening programs, at centers where colonoscopists of difference experience are employed in such programs. Organizing the daily workload to prevent negative factors affecting the success rate from occurring in combination may enable up to 85% of incomplete procedures to be converted into successful colonoscopies.</p

Regulation of p14ARF expression by miR-24: a potential mechanism compromising the p53 response during retinoblastoma development

<p>Abstract</p> <p>Background</p> <p>Most human cancers show inactivation of both pRB- and p53-pathways. While retinoblastomas are initiated by loss of the <it>RB1 </it>tumor suppressor gene, <it>TP53 </it>mutations have not been found. High expression of the p53-antagonist MDM2 in human retinoblastomas may compromise p53 tumor surveillance so that <it>TP53 </it>mutations are not selected for in retinoblastoma tumorigenesis. We previously showed that p14^ARFprotein, which activates p53 by inhibiting MDM2, is low in retinoblastomas despite high mRNA expression.</p> <p>Methods</p> <p>In human fetal retinas, adult retinas, and retinoblastoma cells, we determined endogenous <it>p14^ARF</it>mRNA, ARF protein, and miR-24 expression, while integrity of p53 signalling in WERI-Rb1 cells was tested using an adenovirus vector expressing p14^ARF. To study p14^ARFbiogenesis, retinoblastoma cells were treated with the proteasome inhibitor, MG132, and siRNA against miR-24.</p> <p>Results</p> <p>In human retinoblastoma cell lines, <it>p14^ARF</it>mRNA was disproportionally high relative to the level of p14^ARFprotein expression, suggesting a perturbation of p14^ARFregulation. When p14^ARFwas over-expressed by an adenovirus vector, expression of p53 and downstream targets increased and cell growth was inhibited indicating an intact p14^ARF-p53 axis. To investigate the discrepancy between <it>p14^ARF</it>mRNA and protein in retinoblastoma, we examined p14^ARFbiogenesis. The proteasome inhibitor, MG132, did not cause p14^ARFaccumulation, although p14^ARFnormally is degraded by proteasomes. miR-24, a microRNA that represses p14^ARFexpression, is expressed in retinoblastoma cell lines and correlates with lower protein expression when compared to other cell lines with high <it>p14^ARF</it>mRNA. Transient over-expression of siRNA against miR-24 led to elevated p14^ARFprotein in retinoblastoma cells.</p> <p>Conclusions</p> <p>In retinoblastoma cells where high levels of <it>p14^ARF</it>mRNA are not accompanied by high p14^ARFprotein, we found a correlation between miR-24 expression and low p14^ARFprotein. p14^ARFprotein levels were restored without change in mRNA abundance upon miR-24 inhibition suggesting that miR-24 could functionally repress expression, effectively blocking p53 tumor surveillance. During retinal tumorigenesis, miR-24 may intrinsically compromise the p53 response to <it>RB1 </it>loss.</p

The Glycosylphosphatidylinositol-PLC in Trypanosoma brucei Forms a Linear Array on the Exterior of the Flagellar Membrane Before and After Activation

Bloodstream forms of Trypanosoma brucei contain a glycosylphosphatidylinositol-specific phospholipase C (GPI-PLC) that cleaves the GPI-anchor of the variable surface glycoprotein (VSG). Its location in trypanosomes has been controversial. Here, using confocal microscopy and surface labelling techniques, we show that the GPI-PLC is located exclusively in a linear array on the outside of the flagellar membrane, close to the flagellar attachment zone, but does not co-localize with the flagellar attachment zone protein, FAZ1. Consequently, the GPI-PLC and the VSG occupy the same plasma membrane leaflet, which resolves the topological problem associated with the cleavage reaction if the VSG and the GPI-PLC were on opposite sides of the membrane. The exterior location requires the enzyme to be tightly regulated to prevent VSG release under basal conditions. During stimulated VSG release in intact cells, the GPI-PLC did not change location, suggesting that the release mechanism involves lateral diffusion of the VSG in the plane of the membrane to the fixed position of the GPI-PLC

Depauperate Avifauna in Plantations Compared to Forests and Exurban Areas

Native forests are shrinking worldwide, causing a loss of biological diversity. Our ability to prioritize forest conservation actions is hampered by a lack of information about the relative impacts of different types of forest loss on biodiversity. In particular, we lack rigorous comparisons of the effects of clearing forests for tree plantations and for human settlements, two leading causes of deforestation worldwide. We compared avian diversity in forests, plantations and exurban areas on the Cumberland Plateau, USA, an area of global importance for biodiversity. By combining field surveys with digital habitat databases, and then analyzing diversity at multiple scales, we found that plantations had lower diversity and fewer conservation priority species than did other habitats. Exurban areas had higher diversity than did native forests, but native forests outscored exurban areas for some measures of conservation priority. Overall therefore, pine plantations had impoverished avian communities relative to both native forests and to exurban areas. Thus, reports on the status of forests give misleading signals about biological diversity when they include plantations in their estimates of forest cover but exclude forested areas in which humans live. Likewise, forest conservation programs should downgrade incentives for plantations and should include settled areas within their purview

Molecular identification of 1-Cys peroxiredoxin and anthocyanidin/flavonol 3-O-galactosyltransferase from proanthocyanidin-rich young fruits of persimmon (Diospyros kaki Thunb.)

Fruits of persimmon (Diospyros kaki Thunb.) accumulate large amounts of proanthocyanidins (PAs) in the early stages of development. Astringent (A)-type fruits remain rich in soluble PAs even after they reach full-mature stage, whereas non-astringent (NA)-type fruits lose these compounds before full maturation. As a first step to elucidate the mechanism of PA accumulation in this non-model species, we used suppression subtractive hybridization to identify transcripts accumulating differently in young fruits of A- and NA-type. Interestingly, only a few clones involved in PA biosynthesis were identified in A–NA libraries. Represented by multiple clones were those encoding a novel 1-Cys peroxiredoxin and a new member of family 1 glycosyltransferases. Quantitative RT-PCR analyses confirmed correlation of the amount of PAs and accumulation of transcripts encoding these proteins in young persimmon fruits. Furthermore, the new family 1 glycosyltransferase was produced in Escherichia coli and shown to efficiently catalyze galactosylation at 3-hydroxyl groups of several anthocyanidins and flavonols. These findings suggest a complex mechanism of PA accumulation in persimmon fruits