Modelling the functional genomics of Parkinson’s disease in Caenorhabditis elegans: LRRK2 and beyond

For decades, Parkinson’s disease (PD) cases have been genetically categorised into familial, when caused by mutations in single genes with a clear inheritance pattern in affected families, or idiopathic, in the absence of an evident monogenic determinant. Recently, genome-wide association studies (GWAS) have revealed how common genetic variability can explain up to 36% of PD heritability and that PD manifestation is often determined by multiple variants at different genetic loci. Thus, one of the current challenges in PD research stands in modelling the complex genetic architecture of this condition and translating this into functional studies. Caenorhabditis elegans provide a profound advantage as a reductionist, economical model for PD research, with a short lifecycle, straightforward genome engineering and high conservation of PD relevant neural, cellular and molecular pathways. Functional models of PD genes utilising C. elegans show many phenotypes recapitulating pathologies observed in PD. When contrasted with mammalian in vivo and in vitro models, these are frequently validated, suggesting relevance of C. elegans in the development of novel PD functional models. This review will discuss how the nematode C. elegans PD models have contributed to the uncovering of molecular and cellular mechanisms of disease, with a focus on the genes most commonly found as causative in familial PD and risk factors in idiopathic PD. Specifically, we will examine the current knowledge on a central player in both familial and idiopathic PD, Leucine-rich repeat kinase 2 (LRRK2) and how it connects to multiple PD associated GWAS candidates and Mendelian disease-causing genes

Online Disturbance Estimation for Improving Kinematic Accuracy in Continuum Manipulators

Continuum manipulators are flexible robots which undergo continuous deformation as they are actuated. To describe the elastic deformation of such robots, kinematic models have been developed and successfully applied to a large variety of designs and to various levels of constitutive stiffness. Independent of the design, kinematic models need to be calibrated to best describe the deformation of the manipulator. However, even after calibration, unmodeled effects such as friction, nonlinear elastic and/or spatially varying material properties as well as manufacturing imprecision reduce the accuracy of these models. In this letter, we present a method for improving the accuracy of kinematic models of continuum manipulators through the incorporation of orientation sensor feedback. We achieve this through the use of a “disturbance wrench,” which is used to compensate for these unmodeled effects, and is continuously estimated based on orientation sensor feedback as the robot moves through its workspace. The presented method is applied to the HydroJet, a waterjet-actuated soft continuum manipulator, and shows an average of 40% reduction in root mean square position and orientation error in the two most common types of kinematic models for continuum manipulators, a Cosserat rod model and a pseudo-rigid body model

The impact of an intervention to introduce malaria rapid diagnostic tests on fever case management in a high transmission setting in Uganda: A mixed-methods cluster-randomized trial (PRIME).

Rapid diagnostic tests for malaria (mRDTs) have been scaled-up widely across Africa. The PRIME study evaluated an intervention aiming to improve fever case management using mRDTs at public health centers in Uganda. A cluster-randomized trial was conducted from 2010-13 in Tororo, a high malaria transmission setting. Twenty public health centers were randomized in a 1:1 ratio to intervention or control. The intervention included training in health center management, fever case management with mRDTs, and patient-centered services; plus provision of mRDTs and artemether-lumefantrine (AL) when stocks ran low. Three rounds of Interviews were conducted with caregivers of children under five years of age as they exited health centers (N = 1400); reference mRDTs were done in children with fever (N = 1336). Health worker perspectives on mRDTs were elicited through semi-structured questionnaires (N = 49) and in-depth interviews (N = 10). The primary outcome was inappropriate treatment of malaria, defined as the proportion of febrile children who were not treated according to guidelines based on the reference mRDT. There was no difference in inappropriate treatment of malaria between the intervention and control arms (24.0% versus 29.7%, adjusted risk ratio 0.81 95\% CI: 0.56, 1.17 p = 0.24). Most children (76.0\%) tested positive by reference mRDT, but many were not prescribed AL (22.5\% intervention versus 25.9\% control, p = 0.53). Inappropriate treatment of children testing negative by reference mRDT with AL was also common (31.3\% invention vs 42.4\% control, p = 0.29). Health workers appreciated mRDTs but felt that integrating testing into practice was challenging given constraints on time and infrastructure. The PRIME intervention did not have the desired impact on inappropriate treatment of malaria for children under five. In this high transmission setting, use of mRDTs did not lead to the reductions in antimalarial prescribing seen elsewhere. Broader investment in health systems, including infrastructure and staffing, will be required to improve fever case management

A cost-effectiveness analysis of provider and community interventions to improve the treatment of uncomplicated malaria in Nigeria: study protocol for a randomized controlled trial.

BACKGROUND: There is mounting evidence of poor adherence by health service personnel to clinical guidelines for malaria following a symptomatic diagnosis. In response to this, the World Health Organization (WHO) recommends that in all settings clinical suspicion of malaria should be confirmed by parasitological diagnosis using microscopy or Rapid Diagnostic Test (RDT). The Government of Nigeria plans to introduce RDTs in public health facilities over the coming year. In this context, we will evaluate the effectiveness and cost-effectiveness of two interventions designed to support the roll-out of RDTs and improve the rational use of ACTs. It is feared that without supporting interventions, non-adherence will remain a serious impediment to implementing malaria treatment guidelines. METHODS/DESIGN: A three-arm stratified cluster randomized trial is used to compare the effectiveness and cost-effectiveness of: (1) provider malaria training intervention versus expected standard practice in malaria diagnosis and treatment; (2) provider malaria training intervention plus school-based intervention versus expected standard practice; and (3) the combined provider plus school-based intervention versus provider intervention alone. RDTs will be introduced in all arms of the trial. The primary outcome is the proportion of patients attending facilities that report a fever or suspected malaria and receive treatment according to malaria guidelines. This will be measured by surveying patients (or caregivers) as they exit primary health centers, pharmacies, and patent medicine dealers. Cost-effectiveness will be presented in terms of the primary outcome and a range of secondary outcomes, including changes in provider and community knowledge. Costs will be estimated from both a societal and provider perspective using standard economic evaluation methodologies. TRIAL REGISTRATION: Clinicaltrials.gov NCT01350752

Closed-loop control of soft continuum manipulators under tip follower actuation

Continuum manipulators, inspired by nature, have drawn significant interest within the robotics community. They can facilitate motion within complex environments where traditional rigid robots may be ineffective, while maintaining a reasonable degree of precision. Soft continuum manipulators have emerged as a growing subfield of continuum robotics, with promise for applications requiring high compliance, including certain medical procedures. This has driven demand for new control schemes designed to precisely control these highly flexible manipulators, whose kinematics may be sensitive to external loads, such as gravity. This article presents one such approach, utilizing a rapidly computed kinematic model based on Cosserat rod theory, coupled with sensor feedback to facilitate closed-loop control, for a soft continuum manipulator under tip follower actuation and external loading. This approach is suited to soft manipulators undergoing quasi-static deployment, where actuators apply a follower wrench (i.e., one that is in a constant body frame direction regardless of robot configuration) anywhere along the continuum structure, as can be done in water-jet propulsion. In this article we apply the framework specifically to a tip actuated soft continuum manipulator. The proposed control scheme employs both actuator feedback and pose feedback. The actuator feedback is utilized to both regulate the follower load and to compensate for non-linearities of the actuation system that can introduce kinematic model error. Pose feedback is required to maintain accurate path following. Experimental results demonstrate successful path following with the closed-loop control scheme, with significant performance improvements gained through the use of sensor feedback when compared with the open-loop case

Menstrual cycle phase does not predict political conservatism

Recent authors have reported a relationship between women's fertility status, as indexed by menstrual cycle phase, and conservatism in moral, social and political values. We conducted a survey to test for the existence of a relationship between menstrual cycle day and conservatism. 2213 women reporting regular menstrual cycles provided data about their political views. Of these women, 2208 provided information about their cycle date, 1260 provided additional evidence of reliability in self-reported cycle date, and of these, 750 also indicated an absence of hormonal disruptors such as recent hormonal contraception use, breastfeeding or pregnancy. Cycle day was used to estimate day-specific fertility rate (probability of conception); political conservatism was measured via direct self-report and via responses to the "Moral Foundations” questionnaire. We also recorded relationship status, which has been reported to interact with menstrual cycle phase in determining political preferences. We found no evidence of a relationship between estimated cyclical fertility changes and conservatism, and no evidence of an interaction between relationship status and cyclical fertility in determining political attitudes. Our findings were robust to multiple inclusion/exclusion criteria and to different methods of estimating fertility and measuring conservatism. In summary, the relationship between cycle-linked reproductive parameters and conservatism may be weaker or less reliable than previously thought

On stability of discretizations of the Helmholtz equation (extended version)

We review the stability properties of several discretizations of the Helmholtz equation at large wavenumbers. For a model problem in a polygon, a complete $k$-explicit stability (including $k$-explicit stability of the continuous problem) and convergence theory for high order finite element methods is developed. In particular, quasi-optimality is shown for a fixed number of degrees of freedom per wavelength if the mesh size $h$ and the approximation order $p$ are selected such that $kh/p$ is sufficiently small and $p = O(\log k)$, and, additionally, appropriate mesh refinement is used near the vertices. We also review the stability properties of two classes of numerical schemes that use piecewise solutions of the homogeneous Helmholtz equation, namely, Least Squares methods and Discontinuous Galerkin (DG) methods. The latter includes the Ultra Weak Variational Formulation

‘Dead people don’t claim’: A psychopolitical autopsy of UK austerity suicides

One of the symptoms of post financial crisis austerity in the UK has been an increase in the numbers of suicides, especially by people who have experienced welfare reform. This article develops and utilises an analytic framework of psychopolitical autopsy to explore media coverage of ‘austerity suicide’ and to take seriously the psychic life of austerity (internalisation, shame, anxiety), embedding it in a context of social dis-ease. Drawing on three distinct yet interrelated areas of literature (the politics of affect and psychosocial dynamics of welfare, post and anti-colonial psychopolitics, and critical suicidology), the article aims to better understand how austerity ‘kills’. Key findings include understanding austerity suicides as embedded within an affective economy of the anxiety caused by punitive welfare retrenchment, the stigmatisation of being a recipient of benefits, and the internalisation of market logic that assigns value through ‘productivity’ and conceptualises welfare entitlement as economic ‘burden’. The significance of this approach lies in its ability to widen analytic framing of suicide from an individual and psychocentric focus, to illuminate culpability of government reforms while still retaining the complexity of suicide, and thus to provide relevant policy insights about welfare reform

Metabolic phenotype of methylmalonic acidemia in mice and humans: the role of skeletal muscle

<p>Abstract</p> <p>Background</p> <p>Mutations in methylmalonyl-CoA mutase cause methylmalonic acidemia, a common organic aciduria. Current treatment regimens rely on dietary management and, in severely affected patients, liver or combined liver-kidney transplantation. For undetermined reasons, transplantation does not correct the biochemical phenotype.</p> <p>Methods</p> <p>To study the metabolic disturbances seen in this disorder, we have created a murine model with a null allele at the methylmalonyl-CoA mutase locus and correlated the results observed in the knock-out mice to patient data. To gain insight into the origin and magnitude of methylmalonic acid (MMA) production in humans with methylmalonyl-CoA mutase deficiency, we evaluated two methylmalonic acidemia patients who had received different variants of combined liver-kidney transplants, one with a complete liver replacement-kidney transplant and the other with an auxiliary liver graft-kidney transplant, and compared their metabolite production to four untransplanted patients with intact renal function.</p> <p>Results</p> <p>Enzymatic, Western and Northern analyses demonstrated that the targeted allele was null and correctable by lentiviral complementation. Metabolite studies defined the magnitude and tempo of plasma MMA concentrations in the mice. Before a fatal metabolic crisis developed in the first 24–48 hours, the methylmalonic acid content per gram wet-weight was massively elevated in the skeletal muscle as well as the kidneys, liver and brain. Near the end of life, extreme elevations in tissue MMA were present primarily in the liver. The transplant patients studied when well and on dietary therapy, displayed massive elevations of MMA in the plasma and urine, comparable to the levels seen in the untransplanted patients with similar enzymatic phenotypes and dietary regimens.</p> <p>Conclusion</p> <p>The combined observations from the murine metabolite studies and patient investigations indicate that during homeostasis, a large portion of circulating MMA has an extra-heptorenal origin and likely derives from the skeletal muscle. Our studies suggest that modulating skeletal muscle metabolism may represent a strategy to increase metabolic capacity in methylmalonic acidemia as well as other organic acidurias. This mouse model will be useful for further investigations exploring disease mechanisms and therapeutic interventions in methylmalonic acidemia, a devastating disorder of intermediary metabolism.</p