In vivo rate-determining steps of tau seed accumulation in Alzheimer's disease

Both the replication of protein aggregates and their spreading throughout the brain are implicated in the progression of Alzheimer’s disease (AD). However, the rates of these processes are unknown and the identity of the rate-determining process in humans has therefore remained elusive. By bringing together chemical kinetics with measurements of tau seeds and aggregates across brain regions, we can quantify their replication rate in human brains. Notably, we obtain comparable rates in several different datasets, with five different methods of tau quantification, from postmortem seed amplification assays to tau PET studies in living individuals. Our results suggest that from Braak stage III onward, local replication, rather than spreading between brain regions, is the main process controlling the overall rate of accumulation of tau in neocortical regions. The number of seeds doubles only every ∼5 years. Thus, limiting local replication likely constitutes the most promising strategy to control tau accumulation during AD

Deceptive body movements reverse spatial cueing in soccer

This article has been made available through the Brunel Open Access Publishing Fund.The purpose of the experiments was to analyse the spatial cueing effects of the movements of soccer players executing normal and deceptive (step-over) turns with the ball. Stimuli comprised normal resolution or point-light video clips of soccer players dribbling a football towards the observer then turning right or left with the ball. Clips were curtailed before or on the turn (-160, -80, 0 or +80 ms) to examine the time course of direction prediction and spatial cueing effects. Participants were divided into higher-skilled (HS) and lower-skilled (LS) groups according to soccer experience. In experiment 1, accuracy on full video clips was higher than on point-light but results followed the same overall pattern. Both HS and LS groups correctly identified direction on normal moves at all occlusion levels. For deceptive moves, LS participants were significantly worse than chance and HS participants were somewhat more accurate but nevertheless substantially impaired. In experiment 2, point-light clips were used to cue a lateral target. HS and LS groups showed faster reaction times to targets that were congruent with the direction of normal turns, and to targets incongruent with the direction of deceptive turns. The reversed cueing by deceptive moves coincided with earlier kinematic events than cueing by normal moves. It is concluded that the body kinematics of soccer players generate spatial cueing effects when viewed from an opponent's perspective. This could create a reaction time advantage when anticipating the direction of a normal move. A deceptive move is designed to turn this cueing advantage into a disadvantage. Acting on the basis of advance information, the presence of deceptive moves primes responses in the wrong direction, which may be only partly mitigated by delaying a response until veridical cues emerge

Co-creation workshops for work life oriented ICT education

ICT Companies in Finland today are facing problems in recruiting the right skilled workforce to meet their needs [1]. There is particular shortage of application developers, application designers, web professionals and coders in the South Ostrobothnia area of Finland [2]. Typical degree courses offered by universities would not work because there is a mismatch between the university degrees offered and the needs of these companies. There is a need to develop a new approach to address this shortage. In response to this, local University of Applied Sciences has developed a new ICT education programme using co-creation methods. The new approach is based on the concepts of co-creation of value from service science. This paper discusses the importance of this new approach in education and how it can be implemented. Empirical data is gathered through observation of and reflection on the development of the ICT programme which follows the principles of co-creation

Moderate and heavy metabolic stress interval training improve arterial stiffness and heart rate dynamics in humans

Traditional continuous aerobic exercise training attenuates age-related increases of arterial stiffness, however, training studies have not determined whether metabolic stress impacts these favourable effects. Twenty untrained healthy participants (n = 11 heavy metabolic stress interval training, n = 9 moderate metabolic stress interval training) completed 6 weeks of moderate or heavy intensity interval training matched for total work and exercise duration. Carotid artery stiffness, blood pressure contour analysis, and linear and non-linear heart rate variability were assessed before and following training. Overall, carotid arterial stiffness was reduced (p  0.05). This study demonstrates the effectiveness of interval training at improving arterial stiffness and autonomic function, however, the metabolic stress was not a mediator of this effect. In addition, these changes were also independent of improvements in aerobic capacity, which were only induced by training that involved a high metabolic stress

Experimental loophole-free violation of a Bell inequality using entangled electron spins separated by 1.3 km

For more than 80 years, the counterintuitive predictions of quantum theory have stimulated debate about the nature of reality. In his seminal work, John Bell proved that no theory of nature that obeys locality and realism can reproduce all the predictions of quantum theory. Bell showed that in any local realist theory the correlations between distant measurements satisfy an inequality and, moreover, that this inequality can be violated according to quantum theory. This provided a recipe for experimental tests of the fundamental principles underlying the laws of nature. In the past decades, numerous ingenious Bell inequality tests have been reported. However, because of experimental limitations, all experiments to date required additional assumptions to obtain a contradiction with local realism, resulting in loopholes. Here we report on a Bell experiment that is free of any such additional assumption and thus directly tests the principles underlying Bell's inequality. We employ an event-ready scheme that enables the generation of high-fidelity entanglement between distant electron spins. Efficient spin readout avoids the fair sampling assumption (detection loophole), while the use of fast random basis selection and readout combined with a spatial separation of 1.3 km ensure the required locality conditions. We perform 245 trials testing the CHSH-Bell inequality $S \leq 2$ and find $S = 2.42 \pm 0.20$. A null hypothesis test yields a probability of $p = 0.039$ that a local-realist model for space-like separated sites produces data with a violation at least as large as observed, even when allowing for memory in the devices. This result rules out large classes of local realist theories, and paves the way for implementing device-independent quantum-secure communication and randomness certification.Comment: Raw data will be made available after publicatio

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

The results of arthroscopic anterior stabilisation of the shoulder using the bioknotless anchor system

<p>Abstract</p> <p>Background</p> <p>Shoulder instability is a common condition, particularly affecting a young, active population. Open capsulolabral repair is effective in the majority of cases, however arthroscopic techniques, particularly using suture anchors, are being used with increasing success.</p> <p>Methods</p> <p>15 patients with shoulder instability were operated on by a single surgeon (VK) using BioKnotless anchors (DePuy Mitek, Raynham, MA). The average length of follow-up was 21 months (17 to 31) with none lost to follow-up. Constant scores in both arms, patient satisfaction, activity levels and recurrence of instability was recorded.</p> <p>Results</p> <p>80% of patients were satisfied with their surgery. 1 patient suffered a further dislocation and another had recurrent symptomatic instability. The average constant score returned to 84% of that measured in the opposite (unaffected) shoulder. There were no specific post-operative complications encountered.</p> <p>Conclusion</p> <p>In terms of recurrence of symptoms, our results show success rates comparable to other methods of shoulder stabilisation. This technique is safe and surgeons familiar with shoulder arthroscopy will not encounter a steep learning curve. Shoulder function at approximately 2 years post repair was good or excellent in the majority of patients and it was observed that patient satisfaction was correlated more with return to usual activities than recurrence of symptoms.</p

Cloning of the Repertoire of Individual Plasmodium falciparum var Genes Using Transformation Associated Recombination (TAR)

One of the major virulence factors of the malaria causing parasite is the Plasmodium falciparum encoded erythrocyte membrane protein 1 (PfEMP1). It is translocated to It the membrane of infected erythrocytes and expressed from approximately 60 var genes in a mutually exclusive manner. Switching of var genes allows the parasite to alter functional and antigenic properties of infected erythrocytes, to escape the immune defense and to establish chronic infections. We have developed an efficient method for isolating VAR genes from telomeric and other genome locations by adapting transformation-associated recombination (TAR) cloning, which can then be analyzed and sequenced. For this purpose, three plasmids each containing a homologous sequence representing the upstream regions of the group A, B, and C var genes and a sequence homologous to the conserved acidic terminal segment (ATS) of var genes were generated. Co-transfection with P. falciparum strain ITG2F6 genomic DNA in yeast cells yielded 200 TAR clones. The relative frequencies of clones from each group were not biased. Clones were screened by PCR, as well as Southern blotting, which revealed clones missed by PCR due to sequence mismatches with the primers. Selected clones were transformed into E. coli and further analyzed by RFLP and end sequencing. Physical analysis of 36 clones revealed 27 distinct types potentially representing 50% of the var gene repertoire. Three clones were selected for sequencing and assembled into single var gene containing contigs. This study demonstrates that it is possible to rapidly obtain the repertoire of var genes from P. falciparum within a single set of cloning experiments. This technique can be applied to individual isolates which will provide a detailed picture of the diversity of var genes in the field. This is a powerful tool to overcome the obstacles with cloning and assembly of multi-gene families by simultaneously cloning each member