Reactive Designs in Isabelle/UTP

Reactive designs combine the UTP theories of reactive processes and designs to characterise reactive programs. Whereas sequential imperative programs are expected to run until termination, reactive programs pause at instances to allow interaction with the environment using abstract events, and often do not terminate at all. Thus, whereas a design describes the precondition and postcondition for a program, to characterise initial and final states, a reactive design also has a “pericondition”, which characterises intermediate quiescent observations. This gives rise to a notion of “reactive contract”, which specifies the assumptions a program makes of its environment, and the guarantees it will make of its own behaviour in both intermediate and final observations. This Isabelle/UTP document mechanises the UTP theory of reactive designs, including its healthiness conditions, signature, and a large library of algebraic laws of reactive programming

A novel tool for evaluating non-cognitive traits of doctor of physical therapy learners in the United States

Purpose The primary aim of this study was to develop a survey addressing an individual’s non-cognitive traits, such as emotional intelligence, interpersonal skills, social intelligence, psychological flexibility, and grit. Such a tool would provide beneficial information for the continued development of admissions standards and would help better capture the full breadth of experience and capabilities of applicants applying to doctor of physical therapy (DPT) programs. Methods This was a cross-sectional survey study involving learners in DPT programs at 3 academic institutions in the United States. A survey was developed based on established non-proprietary, non-cognitive measures affiliated with success and resilience. The survey was assessed for face validity, and exploratory factor analysis (EFA) was used to identify subgroups of factors based on responses to the items. Results A total of 298 participants (90.3%) completed all elements of the survey. EFA yielded 39 items for dimensional assessment with regression coefficients < 0.4. Within the 39 items, 3 latent constructs were identified: adaptability (16 items), intuitiveness (12 items), and engagement (11 items). Conclusion This preliminary non-cognitive assessment survey will be able to play a valuable role in DPT admissions decisions following further examination and refinement

Permissive Transcriptional Activity at the Centromere through Pockets of DNA Hypomethylation

DNA methylation is a hallmark of transcriptional silencing, yet transcription has been reported at the centromere. To address this apparent paradox, we employed a fully sequence-defined ectopic human centromere (or neocentromere) to investigate the relationship between DNA methylation and transcription. We used sodium bisulfite PCR and sequencing to determine the methylation status of 2,041 CpG dinucleotides distributed across a 6.76-Mbp chromosomal region containing a neocentromere. These CpG dinucleotides were associated with conventional and nonconventional CpG islands. We found an overall hypermethylation of the neocentric DNA at nonconventional CpG islands that we designated as CpG islets and CpG orphans. The observed hypermethylation was consistent with the presence of a presumed transcriptionally silent chromatin state at the neocentromere. Within this neocentric chromatin, specific sites of active transcription and the centromeric chromatin boundary are defined by DNA hypomethylation. Our data demonstrate, for the first time to our knowledge, a correlation between DNA methylation and centromere formation in mammals, and that transcription and “chromatin-boundary activity” are permissible at the centromere through the selective hypomethylation of pockets of sequences without compromising the overall silent chromatin state and function of the centromere

Membrane-protein interactions in mechanosensitive channels

In this paper, we examine the mechanical role of the lipid bilayer in ion channel conformation and function with specific reference to the case of the mechanosensitive channel of large conductance (MscL). In a recent paper (Wiggins and Phillips, 2004), we argued that mechanotransduction very naturally arises from lipid-protein interactions by invoking a simple analytic model of the MscL channel and the surrounding lipid bilayer. In this paper, we focus on improving and expanding this analytic framework for studying lipid-protein interactions with special attention to MscL. Our goal is to generate simple scaling relations which can be used to provide qualitative understanding of the role of membrane mechanics in protein function and to quantitatively interpret experimental results. For the MscL channel, we find that the free energies induced by lipid-protein interaction are of the same order as the free energy differences between conductance states measured by Sukharev et al. (1999). We therefore conclude that the mechanics of the bilayer plays an essential role in determining the conformation and function of the channel. Finally, we compare the predictions of our model to experimental results from the recent investigations of the MscL channel by Perozo et al. (2002), Powl et al. (2003), Yoshimura et al. (2004), and others and suggest a suite of new experiments

The Phase Diagram of Fluid Random Surfaces with Extrinsic Curvature

We present the results of a large-scale simulation of a Dynamically Triangulated Random Surface with extrinsic curvature embedded in three-dimensional flat space. We measure a variety of local observables and use a finite size scaling analysis to characterize as much as possible the regime of crossover from crumpled to smooth surfaces.Comment: 29 pages. There are also 19 figures available from the authors but not included here - sorr

The Vehicle, Fall 1993

Table of Contents 7/10ths SynthesisPeter F. Essigpage 5 Aug 1992 (My Small Catechism)Jon Montgomerypage 6 Chaos Is-J. Dylan McNeillpage 7 UntouchedTraci Williamspage 8 The JustificationJohn C. Carminepage 8 LincolnJon Montgomerypage 9 Untitled (Photo)Nicole Niemanpage 10 Park PoemJohn Brillhartpage 11 SmokeJulia Ann Canhampage 12 Warming the BenchAnn Moutraypage 12 Cereal KillerJay Harnackpage 13 The Dutiful SonsTom McGrathpage 14 UntitledCatherine DeGraafpage 17 7-up bottleWalt Howardpage 17 BreedDan Trutterpage 18 An Argument Against LoveTony Martinezpage 19 UntitledT. Scott Laniganpage 19 Glassblowers BallStephanie Franzenpage 20 Portrait of a Young GirlJohn C. Carminepage 20 Untitled (artwork)Dan Trutterpage 21 Death of a FriendLizabeth Kulkapage 22 Submission BluesMartin Paul Brittpage 23 To the Fourteen Year Old SuicideScott Langenpage 23 The Flabby PilgrimTom McGrathpage 24 The Fall of ImmortalityBrian Wheelerpage 25 Merging with AirThom Schnarrepage 26 UntitledCatherine DeGraafpage 27 Tree FishSandra Beauchamppage 28 Country SlumberJ. Dylan McNeillpage 29 Untitled (artwork)Dan Trutterpage 33 Authors\u27 Pagepage 34https://thekeep.eiu.edu/vehicle/1060/thumbnail.jp

Use of whole genome sequencing to determine genetic basis of suspected mitochondrial disorders: cohort study.

OBJECTIVE: To determine whether whole genome sequencing can be used to define the molecular basis of suspected mitochondrial disease. DESIGN: Cohort study. SETTING: National Health Service, England, including secondary and tertiary care. PARTICIPANTS: 345 patients with suspected mitochondrial disorders recruited to the 100 000 Genomes Project in England between 2015 and 2018. INTERVENTION: Short read whole genome sequencing was performed. Nuclear variants were prioritised on the basis of gene panels chosen according to phenotypes, ClinVar pathogenic/likely pathogenic variants, and the top 10 prioritised variants from Exomiser. Mitochondrial DNA variants were called using an in-house pipeline and compared with a list of pathogenic variants. Copy number variants and short tandem repeats for 13 neurological disorders were also analysed. American College of Medical Genetics guidelines were followed for classification of variants. MAIN OUTCOME MEASURE: Definite or probable genetic diagnosis. RESULTS: A definite or probable genetic diagnosis was identified in 98/319 (31%) families, with an additional 6 (2%) possible diagnoses. Fourteen of the diagnoses (4% of the 319 families) explained only part of the clinical features. A total of 95 different genes were implicated. Of 104 families given a diagnosis, 39 (38%) had a mitochondrial diagnosis and 65 (63%) had a non-mitochondrial diagnosis. CONCLUSION: Whole genome sequencing is a useful diagnostic test in patients with suspected mitochondrial disorders, yielding a diagnosis in a further 31% after exclusion of common causes. Most diagnoses were non-mitochondrial disorders and included developmental disorders with intellectual disability, epileptic encephalopathies, other metabolic disorders, cardiomyopathies, and leukodystrophies. These would have been missed if a targeted approach was taken, and some have specific treatments

Results of a randomized, double blind, placebo controlled, crossover trial of melatonin for treatment of Nocturia in adults with multiple sclerosis (MeNiMS)

© 2018 The Author(s). Background: Nocturia is a common urinary symptom of multiple sclerosis (MS) which can affect quality of life (QoL) adversely. Melatonin is a hormone known to regulate circadian rhythm and reduce smooth muscle activity such as in the bladder. There is limited evidence supporting use of melatonin to alleviate urinary frequency at night in the treatment of nocturia. The aim of this study was to evaluate the effect of melatonin on the mean number of nocturia episodes per night in patients with MS. Methods: A randomized, double blind, placebo controlled crossover trial was conducted. 34 patients with nocturia secondary to multiple sclerosis underwent a 4-day pre-treatment monitoring phase. The patients were randomized to receive either 2 mg per night (taken at bedtime) of capsulated sustained-release melatonin (Circadin®) or 1 placebo capsule for 6 weeks followed by a crossover to the other regimen for an additional 6 weeks after a 1-month washout period. Results: From the 26 patients who completed the study, there was no significant difference observed in the signs or symptoms of nocturia when taking 2 mg melatonin compared to placebo. The primary outcome measure, mean number of nocturia episodes on bladder diaries, was 1.8/night at baseline, and 1.4/night on melatonin, compared with 1.6 for placebo (Medians 1.70, 1.50, and 1.30 respectively, p = 0.85). There was also no significant difference seen in LUTS, QoL and sleep quality when taking melatonin. No significant safety concerns arose. Conclusions: This small study suggests that a low dose of melatonin taken at bedtime may be ineffective therapy for nocturia in MS. Trial registration: (EudraCT reference) 2012-00418321 registered: 25/01/13. ISRCTN Registry: ISRCTN38687869

Comparability: manufacturing, characterization and controls, report of a UK Regenerative Medicine Platform Pluripotent Stem Cell Platform Workshop, Trinity Hall, Cambridge, 14–15 September 2015

This paper summarizes the proceedings of a workshop held at Trinity Hall, Cambridge to discuss comparability and includes additional information and references to related information added subsequently to the workshop. Comparability is the need to demonstrate equivalence of product after a process change; a recent publication states that this ‘may be difficult for cell-based medicinal products’. Therefore a well-managed change process is required which needs access to good science and regulatory advice and developers are encouraged to seek help early. The workshop shared current thinking and best practice and allowed the definition of key research questions. The intent of this report is to summarize the key issues and the consensus reached on each of these by the expert delegates

Culture Adaptation Alters Transcriptional Hierarchies among Single Human Embryonic Stem Cells Reflecting Altered Patterns of Differentiation

We have used single cell transcriptome analysis to re-examine the substates of early passage, karyotypically Normal, and late passage, karyotypically Abnormal (‘Culture Adapted’) human embryonic stem cells characterized by differential expression of the cell surface marker antigen, SSEA3. The results confirmed that culture adaptation is associated with alterations to the dynamics of the SSEA3(+) and SSEA3(-) substates of these cells, with SSEA3(-) Adapted cells remaining within the stem cell compartment whereas the SSEA3(-) Normal cells appear to have differentiated. However, the single cell data reveal that these substates are characterized by further heterogeneity that changes on culture adaptation. Notably the Adapted population includes cells with a transcriptome substate suggestive of a shift to a more naïve-like phenotype in contrast to the cells of the Normal population. Further, a subset of the Normal SSEA3(+) cells expresses genes typical of endoderm differentiation, despite also expressing the undifferentiated stem cell genes, POU5F1 (OCT4) and NANOG, whereas such apparently lineage-primed cells are absent from the Adapted population. These results suggest that the selective growth advantage gained by genetically variant, culture adapted human embryonic stem cells may derive in part from a changed substate structure that influences their propensity for differentiation