The alpha-synuclein 5'untranslated region targeted translation blockers: anti-alpha synuclein efficacy of cardiac glycosides and Posiphen

Increased brain α-synuclein (SNCA) protein expression resulting from gene duplication and triplication can cause a familial form of Parkinson's disease (PD). Dopaminergic neurons exhibit elevated iron levels that can accelerate toxic SNCA fibril formation. Examinations of human post mortem brain have shown that while mRNA levels for SNCA in PD have been shown to be either unchanged or decreased with respect to healthy controls, higher levels of insoluble protein occurs during PD progression. We show evidence that SNCA can be regulated via the 5'untranslated region (5'UTR) of its transcript, which we modeled to fold into a unique RNA stem loop with a CAGUGN apical loop similar to that encoded in the canonical iron-responsive element (IRE) of L- and H-ferritin mRNAs. The SNCA IRE-like stem loop spans the two exons that encode its 5'UTR, whereas, by contrast, the H-ferritin 5'UTR is encoded by a single first exon. We screened a library of 720 natural products (NPs) for their capacity to inhibit SNCA 5'UTR driven luciferase expression. This screen identified several classes of NPs, including the plant cardiac glycosides, mycophenolic acid (an immunosuppressant and Fe chelator), and, additionally, posiphen was identified to repress SNCA 5'UTR conferred translation. Western blotting confirmed that Posiphen and the cardiac glycoside, strophanthidine, selectively blocked SNCA expression (~1 μM IC(50)) in neural cells. For Posiphen this inhibition was accelerated in the presence of iron, thus providing a known APP-directed lead with potential for use as a SNCA blocker for PD therapy. These are candidate drugs with the potential to limit toxic SNCA expression in the brains of PD patients and animal models in vivo

Right Here Right Now (RHRN) pilot study: testing a method of near-real-time data collection on the social determinants of health

Background: Informing policy and practice with up-to-date evidence on the social determinants of health is an ongoing challenge. One limitation of traditional approaches is the time-lag between identification of a policy or practice need and availability of results. The Right Here Right Now (RHRN) study piloted a near-real-time data-collection process to investigate whether this gap could be bridged. Methods: A website was developed to facilitate the issue of questions, data capture and presentation of findings. Respondents were recruited using two distinct methods – a clustered random probability sample, and a quota sample from street stalls. Weekly four-part questions were issued by email, Short Messaging Service (SMS or text) or post. Quantitative data were descriptively summarised, qualitative data thematically analysed, and a summary report circulated two weeks after each question was issued. The pilot spanned 26 weeks. Results: It proved possible to recruit and retain a panel of respondents providing quantitative and qualitative data on a range of issues. The samples were subject to similar recruitment and response biases as more traditional data-collection approaches. Participants valued the potential to influence change, and stakeholders were enthusiastic about the findings generated, despite reservations about the lack of sample representativeness. Stakeholders acknowledged that decision-making processes are not flexible enough to respond to weekly evidence. Conclusion: RHRN produced a process for collecting near-real-time data for policy-relevant topics, although obtaining and maintaining representative samples was problematic. Adaptations were identified to inform a more sustainable model of near-real-time data collection and dissemination in the future

The geometrical pattern of the evolution of cooperation in the Spatial Prisoner's Dilemma: an intra-group model

The Prisoner's Dilemma (PD) deals with the cooperation/defection conflict between two agents. The agents are represented by a cell of $L \times L$ square lattice. The agents are initially randomly distributed according to a certain proportion $\rho_c(0)$ of cooperators. Each agent does not have memory of previous behaviors and plays the PD with eight nearest neighbors and then copies the behavior of who had the greatest payoff for next generation. This system shows that, when the conflict is established, cooperation among agents may emerge even for reasonably high defection temptation values. Contrary to previous studies, which treat mean inter-group interaction, here a model where the agents are not allowed to self-interact, representing intra-group interaction, is proposed. This leads to short time and asymptotic behaviors similar to the one found when self-interaction is considered. Nevertheless, the intermediate behavior is different, with no possible data collapse since oscillations are present. Also, the fluctuations are much smaller in the intra-group model. The geometrical configurations of cooperative clusters are distinct and explain the $\rho_c(t)$ differences between inter and intra-group models. The boundary conditions do not affect the results.Comment: 4 pages, 4 figure

The effects of inspiratory muscle training in older adults

Purpose: Declining inspiratory muscle function and structure and systemic low-level inflammation and oxidative stress may contribute to morbidity and mortality during normal ageing. Therefore, we examined the effects of inspiratory muscle training (IMT) in older adults on inspiratory muscle function and structure and systemic inflammation and oxidative stress, and re-examined the reported positive effects of IMT on respiratory muscle strength, inspiratory muscle endurance, spirometry, exercise performance, physical activity levels (PAL) and quality of life (QoL). Methods: Thirty-four healthy older adults (68 ± 3 years) with normal spirometry, respiratory muscle strength and physical fitness were divided equally into a pressure-threshold IMT or sham-hypoxic placebo group. Before and after an 8 week intervention, measurements were taken for dynamic inspiratory muscle function and inspiratory muscle endurance using a weighted plunger pressure-threshold loading device, diaphragm thickness using B-mode ultrasonography, plasma cytokine concentrations using immunoassays, DNA damage levels in peripheral blood mononuclear cells (PBMC) using Comet Assays, spirometry, maximal mouth pressures, exercise performance using a six minute walk test, PAL using a questionnaire and accelerometry, and QoL using a questionnaire

Multi-wavelength diagnostic properties of Galactic Planetary Nebulae detected by GLIMPSE-I

We uniformly analyze 136 optically detected PNe and candidates from the GLIMPSE-I survey in order to to develop robust, multi-wavelength, classification criteria to augment existing diagnostics and provide pure PN samples. PNe represent powerful astrophysical probes. They are important dynamical tracers, key sources of ISM chemical enrichment, windows into late stellar evolution, and potent cosmological yardsticks. But their utility depends on separating them unequivocally from the many nebular mimics which can strongly resemble bona fide PNe in traditional optical images and spectra. We merge new PNe from the carefully evaluated, homogeneous MASH-I and MASH-II surveys, which offer a wider evolutionary range of PNe than hitherto available, with previously known PNe classified by SIMBAD. Mid-infrared (MIR) measurements vitally complement optical data because they reveal other physical processes and morphologies via fine-structure lines, molecular bands and dust. MIR colour-colour planes, optical emission line ratios and radio fluxes show the unambiguous classification of PNe to be complex, requiring all available evidence. Statistical trends provide predictive value and we offer quantitative MIR criteria to determine whether an emission nebula is most likely to be a PN or one of the frequent contaminants such as compact HII regions or symbiotic systems. Prerequisites have been optical images and spectra but MIR morphology, colours, environment and a candidate's MIR/radio flux ratio provide a more rigorous classification. Our ultimate goal is to recognize PNe using only MIR and radio characteristics, enabling us to trawl for PNe effectively even in heavily obscured regions of the Galaxy.Comment: 32 pages, 18 figures, 10 table

Capacity development for knowledge translation : evaluation of an experiential approach through secondment opportunities

Background - Experiential approaches to skills development using secondment models are shown to benefit healthcare organisations more generally, but little is known about the potential of this approach to develop capacity for knowledge translation (KT). Aim - To evaluate the success of KT capacity development secondments from the perspective of multiple stakeholders. Methods - A pluralistic evaluation design was used. Data were collected during 2011-12 using focus group and individual interviews with 14 clinical and academic secondees, and five managers from host and seconding organisations to gain insight into participants’ perceptions of the success of secondments and the criteria by which they judged success. Six After Action Reviews were undertaken with KT project teams to explore participants’ perceptions of the contribution secondees made to KT projects. Semi-structured interviews were undertaken with three healthcare managers on completion of projects to explore the impact of secondments on the organisation, staff and patients. Qualitative content analysis was used to identify criteria for success. The criteria provided a framework through which the overall success of secondments could be judged. Results - Six criteria for judging the success of the secondments at individual, team and organisation level were identified: KT skills development, effective workload management, team working, achieving KT objectives, enhanced care delivery, enhanced education delivery. Benefits to the individual, KT team, seconding and host organisations were identified. Implications for practice - Hosting teams should provide mentorship support to secondees, and be flexible to accommodate secondees’ needs as team members. On-going support of managers from seconding organisations is needed to maximise the benefits to individual secondees and the organisation. Conclusions - Experiential approaches to KT capacity development using secondments can benefit individual secondees, project teams, seconding and host organisations.</p

An Unbiased Itô Type Stochastic Representation for Transport PDEs: A Toy Example

We propose a stochastic representation for a simple class of transport PDEs based on Itô representations. We detail an algorithm using an estimator stemming for the representation that, unlike regularization by noise estimators, is unbiased. We rely on recent developments on branching diffusions, regime switching processes and their representations of PDEs. There is a loose relation between our technique and regularization by noise, but contrary to the latter, we add a perturbation and immediately its correction. The method is only possible through a judicious choice of the diffusion coefficient σ. A key feature is that our approach does not rely on the smallness of σ, in fact, our σ is strictly bounded from below which is in stark contrast with standard perturbation techniques. This is critical for extending this method to non-toy PDEs which have nonlinear terms in the first derivative where the usual perturbation technique breaks down. The examples presented show the algorithm outperforming alternative approaches. Moreover, the examples point toward a potential algorithm for the fully nonlinear case where the method of characteristics break down.</p

Police community support officers in England:a dramaturgical analysis

Police community support officers (PCSOs) have become an integral part of neighbourhood policing teams (NPTs) in England and Wales since the national roll-out of neighbourhood policing in 2008. Most research on PCSOs examines their outward-facing role, such as in the extent to which these police staff have become community engagement or enforcement-orientated. While this is important to consider, what is also important is the manner in which PCSOs have been accepted by the police organisation internally. This can have a bearing on the degree to which PCSOs are able to fulfil their roles in neighbourhood policing. The research reported here is based on a six-month observational study of PCSOs in England. Using Goffman's dramaturgical framework and concept of performance teams, this article argues that PCSOs and police constables (PCs) comprise separate performance teams within each NPT group, although the degree of separation between PC and PCSO teams varied from one NPT to another. One element of this relationship which was generally consistent was that police officers and supervisors tended to value more highly PCSO work which was enforcement-orientated. This challenges PCSOs to enhance this side of their performances in spite of their limited statutory powers. Some PCSOs experienced this as a daily pressure to justify their existence to police colleagues, leaving them as disillusioned and unsatisfied staff. This was clearly expressed in the use of space in these police stations in that PCSOs sought out spaces where they could relax in their own exclusive ‘back stage’ areas, away from police colleagues.</p

Mediation in the Law Curriculum

Cited by Lord Neuberger in ‘Educating Future Mediators’ at the 4th Civil Mediation Council National Conference, May 201