A bifurcation study to guide the design of a landing gear with a combined uplock/downlock mechanism

This paper discusses the insights that a bifurcation analysis can provide when designing mechanisms. A model, in the form of a set of coupled steady-state equations, can be derived to describe the mechanism. Solutions to this model can be traced through the mechanism's state versus parameter space via numerical continuation, under the simultaneous variation of one or more parameters. With this approach, crucial features in the response surface, such as bifurcation points, can be identified. By numerically continuing these points in the appropriate parameter space, the resulting bifurcation diagram can be used to guide parameter selection and optimization. In this paper, we demonstrate the potential of this technique by considering an aircraft nose landing gear, with a novel locking strategy that uses a combined uplock/downlock mechanism. The landing gear is locked when in the retracted or deployed states. Transitions between these locked states and the unlocked state (where the landing gear is a mechanism) are shown to depend upon the positions of two fold point bifurcations. By performing a two-parameter continuation, the critical points are traced to identify operational boundaries. Following the variation of the fold points through parameter space, a minimum spring stiffness is identified that enables the landing gear to be locked in the retracted state. The bifurcation analysis also shows that the unlocking of a retracted landing gear should use an unlock force measure, rather than a position indicator, to de-couple the effects of the retraction and locking actuators. Overall, the study demonstrates that bifurcation analysis can enhance the understanding of the influence of design choices over a wide operating range where nonlinearity is significant

Absolute quantification of the host-to-parasite DNA ratio in Theileria parva-infected lymphocyte cell lines

Theileria parva is a tick-transmitted intracellular apicomplexan pathogen of cattle in sub-Saharan Africa that causes East Coast fever (ECF). ECF is an acute fatal disease that kills over one million cattle annually, imposing a tremendous burden on African small-holder cattle farmers. The pathology and level of T. parva infections in its wildlife host, African buffalo (Syncerus caffer), and in cattle are distinct. We have developed an absolute quantification method based on quantitative PCR (qPCR) in which recombinant plasmids containing single copy genes specific to the parasite (apical membrane antigen 1 gene, ama1) or the host (hypoxanthine phosphoribosyltransferase 1, hprt1) are used as the quantification reference standards. Our study shows that T. parva and bovine cells are present in similar numbers in T. parva-infected lymphocyte cell lines and that consequently, due to its much smaller genome size, T. parva DNA comprises between 0.9% and 3% of the total DNA samples extracted from these lines. This absolute quantification assay of parasite and host genome copy number in a sample provides a simple and reliable method of assessing T. parva load in infected bovine lymphocytes, and is accurate over a wide range of host-to-parasite DNA ratios. Knowledge of the proportion of target DNA in a sample, as enabled by this method, is essential for efficient high-throughput genome sequencing applications for a variety of intracellular pathogens. This assay will also be very useful in future studies of interactions of distinct host-T. parva stocks and to fully characterize the dynamics of ECF infection in the field

Social physique anxiety and physical activity in early adolescent girls : the influence of maturation and physical activity motives

This study considered the influence of maturation on social physique anxiety (SPA), the relationship between SPA and current and future physical activity (PA) levels and the influence of motives for physical activity on this relationship in early adolescent girls (n=162; mean age=11.80±0.33 years). Participants completed the Pubertal Development Scale, the modified Social Physique Anxiety Scale and the Motives for Physical Activity Scale at baseline and the Physical Activity Questionnaire for Older Children at baseline and 6 months later. The girls became less active across the 6 months and girls in the early stages of maturation had significantly lower SPA than the girls in the middle and late stages of maturation. SPA was not related to current or future physical activity in the sample as a whole. Cluster analysis identified four groups with different motive profiles and the High Appearance and Fitness group demonstrated a moderate negative relationship between SPA and PA at phase 1, whereas the other groups did not. These findings indicate that SPA may increase with maturation and the relationship between SPA and PA is dependent on reasons for being active. For girls who are motivated to be active primarily by body-related reasons SPA is likely to lead to lower levels of PA

Understanding variation in ambulance service non-conveyance rates: a mixed methods study

Background In England in 2015/16, ambulance services responded to nearly 11 million calls. Ambulance Quality Indicators show that half of the patients receiving a response by telephone or face to face were not conveyed to an emergency department. A total of 11% of patients received telephone advice only. A total of 38% of patients were sent an ambulance but were not conveyed to an emergency department. For the 10 large ambulance services in England, rates of calls ending in telephone advice varied between 5% and 17%. Rates of patients who were sent an ambulance but not conveyed to an emergency department varied between 23% and 51%. Overall non-conveyance rates varied between 40% and 68%. Objective To explain variation in non-conveyance rates between ambulance services. Design A sequential mixed methods study with five work packages. Setting Ten of the 11 ambulance services serving > 99% of the population of England. Methods (1) A qualitative interview study of managers and paramedics from each ambulance service, as well as ambulance commissioners (totalling 49 interviews undertaken in 2015). (2) An analysis of 1 month of routine data from each ambulance service (November 2014). (3) A qualitative study in three ambulance services with different published rates of calls ending in telephone advice (120 hours of observation and 20 interviews undertaken in 2016). (4) An analysis of routine data from one ambulance service linked to emergency department attendance, hospital admission and mortality data (6 months of 2013). (5) A substudy of non-conveyance for people calling 999 with breathing problems. Results Interviewees in the qualitative study identified factors that they perceived to affect non-conveyance rates. Where possible, these perceptions were tested using routine data. Some variation in non-conveyance rates between ambulance services was likely to be due to differences in the way rates were calculated by individual services, particularly in relation to telephone advice. Rates for the number of patients sent an ambulance but not conveyed to an emergency department were associated with patient-level factors: age, sex, deprivation, time of call, reason for call, urgency level and skill level of attending crew. However, variation between ambulance services remained after adjustment for patient-level factors. Variation was explained by ambulance service-level factors after adjustment for patient-level factors: the percentage of calls attended by advanced paramedics [odds ratio 1.05, 95% confidence interval (CI) 1.04 to 1.07], the perception of ambulance service staff and commissioners that advanced paramedics were established and valued within the workforce of an ambulance service (odds ratio 1.84, 95% CI 1.45 to 2.33), and the perception of ambulance service staff and commissioners that senior management was risk averse regarding non-conveyance within an ambulance service (odds ratio 0.78, 95% CI 0.63 to 0.98). Limitations Routine data from ambulance services are complex and not consistently collected or analysed by ambulance services, thus limiting the utility of comparative analyses. Conclusions Variation in non-conveyance rates between ambulance services in England could be reduced by addressing variation in the types of paramedics attending calls, variation in how advanced paramedics are used and variation in perceptions of the risk associated with non-conveyance within ambulance service management. Linking routine ambulance data with emergency department attendance, hospital admission and mortality data for all ambulance services in the UK would allow comparison of the safety and appropriateness of their different non-conveyance rates. Funding The National Institute for Health Research Health Services and Delivery Research programme

Evidence that links loss of cyclooxygenase-2 with increased asymmetric dimethylarginine : novel explanation of cardiovascular side effects associated with anti-inflammatory drugs

© 2014 The Authors. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.BACKGROUND: Cardiovascular side effects associated with cyclooxygenase-2 inhibitor drugs dominate clinical concern. Cyclooxygenase-2 is expressed in the renal medulla where inhibition causes fluid retention and increased blood pressure. However, the mechanisms linking cyclooxygenase-2 inhibition and cardiovascular events are unknown and no biomarkers have been identified.METHODS AND RESULTS: Transcriptome analysis of wild-type and cyclooxygenase-2(-/-) mouse tissues revealed 1 gene altered in the heart and aorta, but >1000 genes altered in the renal medulla, including those regulating the endogenous nitric oxide synthase inhibitors asymmetrical dimethylarginine (ADMA) and monomethyl-l-arginine. Cyclo-oxygenase-2(-/-) mice had increased plasma levels of ADMA and monomethyl-l-arginine and reduced endothelial nitric oxide responses. These genes and methylarginines were not similarly altered in mice lacking prostacyclin receptors. Wild-type mice or human volunteers taking cyclooxygenase-2 inhibitors also showed increased plasma ADMA. Endothelial nitric oxide is cardio-protective, reducing thrombosis and atherosclerosis. Consequently, increased ADMA is associated with cardiovascular disease. Thus, our study identifies ADMA as a biomarker and mechanistic bridge between renal cyclooxygenase-2 inhibition and systemic vascular dysfunction with nonsteroidal anti-inflammatory drug usage.CONCLUSIONS: We identify the endogenous endothelial nitric oxide synthase inhibitor ADMA as a biomarker and mechanistic bridge between renal cyclooxygenase-2 inhibition and systemic vascular dysfunction.Peer reviewedFinal Published versio

P2Y Receptors Sensitize Mouse and Human Colonic Nociceptors.

Activation of visceral nociceptors by inflammatory mediators contributes to visceral hypersensitivity and abdominal pain associated with many gastrointestinal disorders. Purine and pyrimidine nucleotides (e.g., ATP and UTP) are strongly implicated in this process following their release from epithelial cells during mechanical stimulation of the gut, and from immune cells during inflammation. Actions of ATP are mediated through both ionotropic P2X receptors and metabotropic P2Y receptors. P2X receptor activation causes excitation of visceral afferents; however, the impact of P2Y receptor activation on visceral afferents innervating the gut is unclear. Here we investigate the effects of stimulating P2Y receptors in isolated mouse colonic sensory neurons, and visceral nociceptor fibers in mouse and human nerve-gut preparations. Additionally, we investigate the role of Nav1.9 in mediating murine responses. The application of UTP (P2Y2 and P2Y4 agonist) sensitized colonic sensory neurons by increasing action potential firing to current injection and depolarizing the membrane potential. The application of ADP (P2Y1, P2Y12, and P2Y13 agonist) also increased action potential firing, an effect blocked by the selective P2Y1 receptor antagonist MRS2500. UTP or ADP stimulated afferents, including mouse and human visceral nociceptors, in nerve-gut preparations. P2Y1 and P2Y2 transcripts were detected in 80% and 56% of retrogradely labeled colonic neurons, respectively. Nav1.9 transcripts colocalized in 86% of P2Y1-positive and 100% of P2Y2-positive colonic neurons, consistent with reduced afferent fiber responses to UTP and ADP in Na(v)1.9(-/-) mice. These data demonstrate that P2Y receptor activation stimulates mouse and human visceral nociceptors, highlighting P2Y-dependent mechanisms in the generation of visceral pain during gastrointestinal disease.This work was supported by The Medical Research Council (D.C.B.), a Wellcome Trust University Award (L.A.B.), Neusentis (D.C.B.), The Royal College of Surgeons of England (G.B.), The Biotechnology and Biological Sciences Research Council (J.R.F.H.), Bowel & Cancer Research (M.A.T.), Pain Relief Foundation and Crohn's in Childhood Research Association (V.C.-G.), and The Dr Hadwen Trust for Humane Research (C.M.)

Owyhee Russet: AVariety with High Yields of U.S. No. 1 Tubers, Excellent Processing Quality, and Moderate Resistance to Fusarium Dry Rot (\u3ci\u3eFusarium solani var. coeruleum\u3c/i\u3e)

Owyhee Russet (AO96160-3) originated from a cross between A89384-10 and A89512-3 in 1996. Owyhee Russet was released in 2009 by Oregon State University, in cooperation with the USDA-ARS and the Agricultural Experiment Stations of Idaho and Washington and is a product of the Northwest Potato Variety (Tri-State) Development Program. Owyhee Russet has semi-erect medium sized vines with medium to late maturity. The tubers are long, with a tan skin, medium russeting, and attractive tuber appearance for fresh market. Owyhee Russet was evaluated in several locations across the Northwest for more than 15 years. Total yield of Owyhee Russet is similar to that of Russet Burbank and Ranger Russet but significantly higher than Russet Norkotah. U.S. No.1 tuber yield of Owyhee Russet is significantly higher than Russet Burbank and Russet Norkotah, resulting in substantially higher marketable yield. Owyhee Russet tubers have significantly higher specific gravity than Russet Burbank and Russet Norkotah. Fry color following tuber storage at 4°C and 9°C is significantly lighter for Owyhee Russet than the comparison varieties. Relative strengths include high yield with a very high proportion of U.S. No.1 tubers, good tuber appearance and excellent processing quality, resistance to cold sweetening, common scab and Fusarium dry rot. Weaknesses include susceptibility to foliar and tuber late blight and susceptibility to metribuzin herbicide injury. Allelic patterns of five SSR markers have shown that Owyhee Russet has a distinctive DNA genetic fingerprint from its russet type reference varieties which are Ranger Russet, Russet Burbank, and Russet Norkotah

Rare Copy Number Variants in \u3cem\u3eNRXN1\u3c/em\u3e and \u3cem\u3eCNTN6\u3c/em\u3e Increase Risk for Tourette Syndrome

Tourette syndrome (TS) is a model neuropsychiatric disorder thought to arise from abnormal development and/or maintenance of cortico-striato-thalamo-cortical circuits. TS is highly heritable, but its underlying genetic causes are still elusive, and no genome-wide significant loci have been discovered to date. We analyzed a European ancestry sample of 2,434 TS cases and 4,093 ancestry-matched controls for rare (\u3c 1% frequency) copy-number variants (CNVs) using SNP microarray data. We observed an enrichment of global CNV burden that was prominent for large (\u3e 1 Mb), singleton events (OR = 2.28, 95% CI [1.39–3.79], p = 1.2 × 10−3) and known, pathogenic CNVs (OR = 3.03 [1.85–5.07], p = 1.5 × 10−5). We also identified two individual, genome-wide significant loci, each conferring a substantial increase in TS risk (NRXN1 deletions, OR = 20.3, 95% CI [2.6–156.2]; CNTN6 duplications, OR = 10.1, 95% CI [2.3–45.4]). Approximately 1% of TS cases carry one of these CNVs, indicating that rare structural variation contributes significantly to the genetic architecture of TS

Capture-based enrichment of Theileria parva DNA enables full genome assembly of first buffalo-derived strain and reveals exceptional intra-specific genetic diversity

Theileria parva is an economically important, intracellular, tick-transmitted parasite of cattle. A live vaccine against the parasite is effective against challenge from cattle-transmissible T. parva but not against genotypes originating from the African Cape buffalo, a major wildlife reservoir, prompting the need to characterize genome-wide variation within and between cattle- and buffalo-associated T. parva populations. Here, we describe a capture-based target enrichment approach that enables, for the first time, de novo assembly of nearly complete T. parva genomes derived from infected host cell lines. This approach has exceptionally high specificity and sensitivity and is successful for both cattle- and buffalo-derived T. parva parasites. De novo genome assemblies generated for cattle genotypes differ from the reference by ~54K single nucleotide polymorphisms (SNPs) throughout the 8.31 Mb genome, an average of 6.5 SNPs/kb. We report the first buffalo-derived T. parva genome, which is ~20 kb larger than the genome from the reference, cattle-derived, Muguga strain, and contains 25 new potential genes. The average non-synonymous nucleotide diversity (πN) per gene, between buffalo-derived T. parva and the Muguga strain, was 1.3%. This remarkably high level of genetic divergence is supported by an average Wright’s fixation index (FST), genome-wide, of 0.44, reflecting a degree of genetic differentiation between cattle- and buffalo-derived T. parva parasites more commonly seen between, rather than within, species. These findings present clear implications for vaccine development, further demonstrated by the ability to assemble nearly all known antigens in the buffalo-derived strain, which will be critical in design of next generation vaccines. The DNA capture approach used provides a clear advantage in specificity over alternative T. parva DNA enrichment methods used previously, such as those that utilize schizont purification, is less labor intensive, and enables in-depth comparative genomics in this apicomplexan parasite

Degeneracy: a link between evolvability, robustness and complexity in biological systems

A full accounting of biological robustness remains elusive; both in terms of the mechanisms by which robustness is achieved and the forces that have caused robustness to grow over evolutionary time. Although its importance to topics such as ecosystem services and resilience is well recognized, the broader relationship between robustness and evolution is only starting to be fully appreciated. A renewed interest in this relationship has been prompted by evidence that mutational robustness can play a positive role in the discovery of adaptive innovations (evolvability) and evidence of an intimate relationship between robustness and complexity in biology. This paper offers a new perspective on the mechanics of evolution and the origins of complexity, robustness, and evolvability. Here we explore the hypothesis that degeneracy, a partial overlap in the functioning of multi-functional components, plays a central role in the evolution and robustness of complex forms. In support of this hypothesis, we present evidence that degeneracy is a fundamental source of robustness, it is intimately tied to multi-scaled complexity, and it establishes conditions that are necessary for system evolvability