Type-Inference Based Short Cut Deforestation (nearly) without Inlining

Deforestation optimises a functional program by transforming it into another one that does not create certain intermediate data structures. In [ICFP'99] we presented a type-inference based deforestation algorithm which performs extensive inlining. However, across module boundaries only limited inlining is practically feasible. Furthermore, inlining is a non-trivial transformation which is therefore best implemented as a separate optimisation pass. To perform short cut deforestation (nearly) without inlining, Gill suggested to split definitions into workers and wrappers and inline only the small wrappers, which transfer the information needed for deforestation. We show that Gill's use of a function build limits deforestation and note that his reasons for using build do not apply to our approach. Hence we develop a more general worker/wrapper scheme without build. We give a type-inference based algorithm which splits definitions into workers and wrappers. Finally, we show that we can deforest more expressions with the worker/wrapper scheme than the algorithm with inlining

α-Catenin-dependent cytoskeletal tension controls Yap activity in the heart.

Shortly after birth, muscle cells of the mammalian heart lose their ability to divide. At the same time, the N-cadherin/catenin cell adhesion complex accumulates at the cell termini, creating a specialized type of cell-cell contact called the intercalated disc (ICD). To investigate the relationship between ICD maturation and proliferation, αE-catenin (Ctnna1) and αT-catenin (Ctnna3) genes were deleted to generate cardiac-specific α-catenin double knockout (DKO) mice. DKO mice exhibited aberrant N-cadherin expression, mislocalized actomyosin activity and increased cardiomyocyte proliferation that was dependent on Yap activity. To assess effects on tension, cardiomyocytes were cultured on deformable polyacrylamide hydrogels of varying stiffness. When grown on a stiff substrate, DKO cardiomyocytes exhibited increased cell spreading, nuclear Yap and proliferation. A low dose of either a myosin or RhoA inhibitor was sufficient to block Yap accumulation in the nucleus. Finally, activation of RhoA was sufficient to increase nuclear Yap in wild-type cardiomyocytes. These data demonstrate that α-catenins regulate ICD maturation and actomyosin contractility, which, in turn, control Yap subcellular localization, thus providing an explanation for the loss of proliferative capacity in the newborn mammalian heart

Optimal management of an insurer's exposure in a competitive general insurance market

The qualitative behavior of the optimal premium strategy is determined for an insurer in a finite and an infinite market using a deterministic general insurance model. The optimization problem leads to a system of forward-backward differential equations obtained from Pontryagin’s Maximum Principle. The focus of the modelling is on how this optimization problem can be simplified by the choice of demand function and the insurer’s objective. Phase diagrams are used to characterize the optimal control. When the demand is linear in the relative premium, the structure of the phase diagram can be determined analytically. Two types of premium strategy are identified for an insurer in an infinite market, and which is optimal depends on the existence of equilibrium points in the phase diagram. In a finite market there are four more types of premium strategy, and optimality depends on the initial exposure of the insurer and the position of a saddle point in the phase diagram. The effect of a nonlinear demand function is examined by perturbing the linear price function. An analytical optimal premium strategy is also found using inverse methods when the price function is nonlinear

Patient journey following lumbar spinal fusion surgery (LSFS): protocol for a multicentre qualitative analysis of the patient rehabilitation experience (FuJourn)

INTRODUCTION: There has been a 65% increase in lumbar spinal fusion surgery (LSFS) worldwide over the last 13 years, with costs of £26 million to the UK National Health Service annually. Patient dissatisfaction with outcome and persistent pain and disability incurs further costs. Three trials provide low-quality evidence for the role of physiotherapy. Our UK surveys investigating physiotherapy/surgeon practice concluded rehabilitation should be tailored to the individual patient owing to considerable clinical heterogeneity. This study will explore the perceptions of patients who undergo LSFS to inform precision rehabilitation. METHODS AND ANALYSIS: A qualitative study, using interpretive phenomenological analysis, will recruit a purposive sample (n=40) to ensure patterns of similarity and difference in their journeys can be explored. In-depth semistructured interviews will be undertaken following discharge from hospital and at 12 months postsurgery. Patients' preoperative and postoperative experiences, underlying attitudes and beliefs towards the surgical intervention, facilitators and barriers to recovery, adherence to advice and physiotherapy, experiences of rehabilitation and return to normal function/activity/work will be explored. A 12-month patient diary will provide real time access to patient data, capturing a weekly record of life as lived, including symptoms, medication, experiences of stages of recovery, rehabilitation adherence, healthcare professional appointments, attitudes, their feelings and experiences throughout their journey. Data will be analysed in a number of stages in accordance with interpretive phenomenological analysis, supported using NVivo software. Analysis of the first interviews and patient diaries will afford a rich density of data to build an overall understanding of the patients' lived experiences, informing the 12-month interview. Strategies (eg, reflexivity) will ensure trustworthiness. ETHICS AND DISSEMINATION: The study has ethical approval (IRAS 223283). Findings will ensure that patient-driven data inform precision rehabilitation by understanding the patient journey. Findings will be disseminated through peer-reviewed journals and conferences

Development and validation of two clinical prediction models to inform clinical decision-making for lumbar spinal fusion surgery for degenerative disorders and rehabilitation following surgery: protocol for a prospective observational study

INTRODUCTION: Potential predictors of poor outcome will be measured at baseline: (1) preoperatively to develop a clinical prediction model to predict which patients are likely to have favourable outcome following lumbar spinal fusion surgery (LSFS) and (2) postoperatively to predict which patients are likely to have favourable long-term outcomes (to inform rehabilitation). METHODS AND ANALYSIS: Prospective observational study with a defined episode inception of the point of surgery. Electronic data will be collected through the British Spine Registry and will include patient-reported outcome measures (eg, Fear-Avoidance Beliefs Questionnaire) and data items (eg, smoking status). Consecutive patients (≥18 years) undergoing LSFS for back and/or leg pain of degenerative cause will be recruited. EXCLUSION CRITERIA: LSFS for spinal fracture, inflammatory disease, malignancy, infection, deformity and revision surgery. 1000 participants will be recruited (n=600 prediction model development, n=400 internal validation derived model; planning 10 events per candidate prognostic factor). The outcome being predicted is an individual's absolute risk of poor outcome (disability and pain) at 6 weeks (objective 1) and 12 months postsurgery (objective 2). Disability and pain will be measured using the Oswestry Disability Index (ODI), and severity of pain in the previous week with a Numerical Rating Scale (NRS 0-10), respectively. Good outcome is defined as a change of 1.7 on the NRS for pain, and a change of 14.3 on the ODI. Both linear and logistic (to dichotomise outcome into low and high risk) multivariable regression models will be fitted and mean differences or ORs for each candidate predictive factor reported. Internal validation of the derived model will use a further set of British Spine Registry data. External validation will be geographical using two spinal registries in The Netherlands and Switzerland. ETHICS AND DISSEMINATION: Ethical approval (University of Birmingham ERN_17-0446A). Dissemination through peer-reviewed journals and conferences

N-Acyloxymethyl-phthalimides deliver genotoxic formaldehyde to human cells

Formaldehyde is a pollutant and human metabolite that is toxic at high concentrations. Biological studies on formaldehyde are hindered by its high reactivity and volatility, which make it challenging to deliver quantitatively to cells. Here, we describe the development and validation of a set of N-acyloxymethyl-phthalimides as cell-relevant formaldehyde delivery agents. These esterase-sensitive compounds were similarly or less inhibitory to human cancer cell growth than free formaldehyde but the lead compound increased intracellular formaldehyde concentrations, increased cellular levels of thymidine derivatives (implying increased formaldehyde-mediated carbon metabolism), induced formation of cellular DNA-protein cross-links and induced cell death in pancreatic cancer cells. Overall, our N-acyloxymethyl-phthalimides and control compounds provide an accessible and broadly applicable chemical toolkit for formaldehyde biological research and have potential as cancer therapeutics

Non-destructive evaluation techniques and what they tell us about wood property variation

To maximize utilization of our forest resources, detailed knowledge of wood property variation and the impacts this has on end-product performance is required at multiple scales (within and among trees, regionally). As many wood properties are difficult and time-consuming to measure our knowledge regarding their variation is often inadequate as is our understanding of their responses to genetic and silvicultural manipulation. The emergence of many non-destructive evaluation (NDE) methodologies offers the potential to greatly enhance our understanding of the forest resource; however, it is critical to recognize that any technique has its limitations and it is important to select the appropriate technique for a given application. In this review, we will discuss the following technologies for assessing wood properties both in the field: acoustics, Pilodyn, Resistograph and Rigidimeter and the lab: computer tomography (CT) scanning, DiscBot, near infrared (NIR) spectroscopy, radial sample acoustics and SilviScan. We will discuss these techniques, explore their utilization, and list applications that best suit each methodology. As an end goal, NDE technologies will help researchers worldwide characterize wood properties, develop accurate models for prediction, and utilize field equipment that can validate the predictions. The continued advancement of NDE technologies will also allow researchers to better understand the impact on wood properties on product performance

In situ observations of coral bleaching in the central Saudi Arabian Red Sea during the 2015/2016 global coral bleaching event.

Coral bleaching continues to be one of the most devastating and immediate impacts of climate change on coral reef ecosystems worldwide. In 2015, a major bleaching event was declared as the “3rd global coral bleaching event” by the United States National Oceanic and Atmospheric Administration, impacting a large number of reefs in every major ocean. The Red Sea was no exception, and we present herein in situ observations of the status of coral reefs in the central Saudi Arabian Red Sea from September 2015, following extended periods of high temperatures reaching upwards of 32.5°C in our study area. We examined eleven reefs using line-intercept transects at three different depths, including all reefs that were surveyed during a previous bleaching event in 2010. Bleaching was most prevalent on inshore reefs (55.6% ± 14.6% of live coral cover exhibited bleaching) and on shallower transects (41% ± 10.2% of live corals surveyed at 5m depth) within reefs. Similar taxonomic groups (e.g., Agariciidae) were affected in 2015 and in 2010. Most interestingly, Acropora and Porites had similar bleaching rates (~30% each) and similar relative coral cover (~7% each) across all reefs in 2015. Coral genera with the highest levels of bleaching (>60%) were also among the rarest (<1% of coral cover) in 2015. While this bodes well for the relative retention of coral cover, it may ultimately lead to decreased species richness, often considered an important component of a healthy coral reef. The resultant long-term changes in these coral reef communities remain to be seen.N/

The Quest for Orthologs benchmark service and consensus calls in 2020.

The identification of orthologs-genes in different species which descended from the same gene in their last common ancestor-is a prerequisite for many analyses in comparative genomics and molecular evolution. Numerous algorithms and resources have been conceived to address this problem, but benchmarking and interpreting them is fraught with difficulties (need to compare them on a common input dataset, absence of ground truth, computational cost of calling orthologs). To address this, the Quest for Orthologs consortium maintains a reference set of proteomes and provides a web server for continuous orthology benchmarking (http://orthology.benchmarkservice.org). Furthermore, consensus ortholog calls derived from public benchmark submissions are provided on the Alliance of Genome Resources website, the joint portal of NIH-funded model organism databases