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Multiple sclerosis (MS) is an autoimmune disorder characterised by demyelination of central nervous system neurons with subsequent damage, cell death and disability. While mechanisms exist in the CNS to repair this damage, they are disrupted in MS and currently there are no treatments to address this deficit. In recent years, increasing attention has been paid to the influence of the small, non-coding RNA molecules, microRNAs (miRNAs), in autoimmune disorders, including MS. In this review, we examine the role of miRNAs in remyelination in the different cell types that contribute to MS. We focus on key miRNAs that have a central role in mediating the repair process, along with several more that play either secondary or inhibitory roles in one or more aspects. Finally, we consider the current state of miRNAs as therapeutic targets in MS, acknowledging current challenges and potential strategies to overcome them in developing effective novel therapeutics to enhance repair mechanisms in MS.

Mitochondria are important regulators of macrophage polarisation. Here, we show that arginase-2 (Arg2) is a microRNA-155 (miR-155) and interleukin-10 (IL-10) regulated protein localized at the mitochondria in inflammatory macrophages, and is critical for IL-10-induced modulation of mitochondrial dynamics and oxidative respiration. Mechanistically, the catalytic activity and presence of Arg2 at the mitochondria is crucial for oxidative phosphorylation. We further show that Arg2 mediates this process by increasing the activity of complex II (succinate dehydrogenase). Moreover, Arg2 is essential for IL-10-mediated downregulation of the inflammatory mediators succinate, hypoxia inducible factor 1α (HIF-1α) and IL-1β in vitro. Accordingly, HIF-1α and IL-1β are highly expressed in an LPS-induced in vivo model of acute inflammation using Arg2 −/− mice. These findings shed light on a new arm of IL-10-mediated metabolic regulation, working to resolve the inflammatory status of the cell. IL-10 can limit inflammation in part by inhibiting miR-155. Here the authors show how this axis induces mitochondrial arginase-2 to alter the mitochondrial dynamics and bioenergetics of macrophages and make these cells less pro-inflammatory.

\"The van very clearly says 'provided with the support of UNICEF and the European Union' and there was another picture also which wasn't published, but which I saw that said 'in support of child friendly justice',\" he said. \"The idea that these centres are child friendly justice is really outrageous. These centres are abusive and they're torturing kids.\" Authorities are accused of taking children off the streets and delivering them to detention centres.; Human Rights Watch accuses Cambodia of locking up and torturing thousands of people a year in drug detention centres. The human rights group also accuses UNICEF of involvement in one of the eleven detention centres and says a UNICEF vehicle was used to transport children to the drug treatment centre

Efficient coupling of soft robotic cardiac assist devices to the external surface of the heart is crucial to augment cardiac function and represents a hurdle to translation of this technology. In this work, we compare various fixation strategies for local and global coupling of a direct cardiac compression sleeve to the heart. For basal fixation, we find that a sutured Velcro band adheres the strongest to the epicardium. Next, we demonstrate that a mesh-based sleeve coupled to the myocardium improves function in an acute porcine heart failure model. Then, we analyze the biological integration of global interface material candidates (medical mesh and silicone) in a healthy and infarcted murine model and show that a mesh interface yields superior mechanical coupling via pull-off force, histology, and microcomputed tomography. These results can inform the design of a therapeutic approach where a mesh-based soft robotic DCC is implanted, allowed to biologically integrate with the epicardium, and actuated for active assistance at a later timepoint. This strategy may result in more efficient coupling of extracardiac sleeves to heart tissue, and lead to increased augmentation of heart function in end-stage heart failure patients.

Background Prevention of violence due to severe mental disorders in psychiatric hospitals may require intrusive, restrictive and coercive therapeutic practices. Research concerning appropriate use of such interventions is limited by lack of a system for description and measurement. We set out to devise and validate a tool for clinicians and secure hospitals to assess necessity and proportionality between imminent violence and restrictive practices including de-escalation, seclusion, restraint, forced medication and others. Methods In this retrospective observational cohort study, 28 patients on a 12 bed male admissions unit in a secure psychiatric hospital were assessed daily for six months. Data on adverse incidents were collected from case notes, incident registers and legal registers. Using the functional assessment sequence of antecedents, behaviours and consequences (A, B, C) we devised and applied a multivariate framework of structured professional assessment tools, common adverse incidents and preventive clinical interventions to develop a tool to analyse clinical practice. We validated by testing assumptions regarding the use of restrictive and intrusive practices in the prevention of violence in hospital. We aimed to provide a system for measuring contextual and individual factors contributing to adverse events and to assess whether the measured seriousness of threating and violent behaviours is proportionate to the degree of restrictive interventions used. General Estimating Equations tested preliminary models of contexts, decisions and pathways to interventions. Results A system for measuring adverse behaviours and restrictive, intrusive interventions for prevention had good internal consistency. Interventions were proportionate to seriousness of harmful behaviours. A ‘Pareto’ group of patients (5/28) were responsible for the majority (80%) of adverse events, outcomes and interventions. The seriousness of the precipitating events correlated with the degree of restrictions utilised to safely manage or treat such behaviours. Conclusion Observational scales can be used for restrictive, intrusive or coercive practices in psychiatry even though these involve interrelated complex sequences of interactions. The DRILL tool has been validated to assess the necessity and demonstrate proportionality of restrictive practices. This tool will be of benefit to services when reviewing practices internally, for mandatory external reviewing bodies and for future clinical research paradigms.

In this work, we present a comprehensive theoretical and experimental study of quantum confinement in layered platinum diselenide (PtSe 2 ) films as a function of film thickness. Our electrical measurements, in combination with density functional theory calculations, show distinct layer-dependent semimetal-to-semiconductor evolution in PtSe 2 films, and highlight the importance of including van der Waals interactions, Green’s function calibration, and screened Coulomb interactions in the determination of the thickness-dependent PtSe 2 energy gap. Large-area PtSe 2 films of varying thickness (2.5–6.5 nm) were formed at 400 °C by thermally assisted conversion of ultra-thin platinum films on Si/SiO 2 substrates. The PtSe 2 films exhibit p -type semiconducting behavior with hole mobility values up to 13 cm 2 /V·s. Metal-oxide-semiconductor field-effect transistors have been fabricated using the grown PtSe 2 films and a gate field-controlled switching performance with an I ON / I OFF ratio of >230 has been measured at room temperature for a 2.5–3 nm PtSe 2 film, while the ratio drops to <2 for 5–6.5 nm-thick PtSe 2 films, consistent with a semiconducting-to-semimetallic transition with increasing PtSe 2 film thickness. These experimental observations indicate that the low-temperature growth of semimetallic or semiconducting PtSe 2 could be integrated into the back-end-of-line of a silicon complementary metal-oxide-semiconductor process.

The clinical translation of regenerative therapy for the diseased heart, whether in the form of cells, macromolecules or small molecules, is hampered by several factors: the poor retention and short biological half-life of the therapeutic agent, the adverse side effects from systemic delivery, and difficulties with the administration of multiple doses. Here, we report the development and application of a therapeutic epicardial device that enables sustained and repeated administration of small molecules, macromolecules and cells directly to the epicardium via a polymer-based reservoir connected to a subcutaneous port. In a myocardial infarct rodent model, we show that repeated administration of cells over a four-week period using the epicardial reservoir provided functional benefits in ejection fraction, fractional shortening and stroke work, compared to a single injection of cells and to no treatment. The pre-clinical use of the therapeutic epicardial reservoir as a research model may enable insights into regenerative cardiac therapy, and assist the development of experimental therapies towards clinical use. An epicardial device that enables sustained and repeated administration of small molecules, macromolecules and cells directly to the epicardium provides therapeutic benefits in a rat model of myocardial infarction.

A continuous 305-year (1711–2016) monthly rainfall series (IoI_1711) is created for the Island of Ireland. The post 1850 series draws on an existing quality assured rainfall network for Ireland, while pre-1850 values come from instrumental and documentary series compiled, but not published by the UK Met Office. The series is evaluated by comparison with independent long-term observations and reconstructions of precipitation, temperature and circulation indices from across the British–Irish Isles. Strong decadal consistency of IoI_1711 with other long-term observations is evident throughout the annual, boreal spring and autumn series. Annually, the most recent decade (2006–2015) is found to be the wettest in over 300 years. The winter series is probably too dry between the 1740s and 1780s, but strong consistency with other long-term observations strengthens confidence from 1790 onwards. The IoI_1711 series has remarkably wet winters during the 1730s, concurrent with a period of strong westerly airflow, glacial advance throughout Scandinavia and near unprecedented warmth in the Central England Temperature record – all consistent with a strongly positive phase of the North Atlantic Oscillation. Unusually wet summers occurred in the 1750s, consistent with proxy (tree-ring) reconstructions of summer precipitation in the region. Our analysis shows that inter-decadal variability of precipitation is much larger than previously thought, while relationships with key modes of climate variability are time-variant. The IoI_1711 series reveals statistically significant multi-centennial trends in winter (increasing) and summer (decreasing) seasonal precipitation. However, given uncertainties in the early winter record, the former finding should be regarded as tentative. The derived record, one of the longest continuous series in Europe, offers valuable insights for understanding multi-decadal and centennial rainfall variability in Ireland, and provides a firm basis for benchmarking other long-term records and reconstructions of past climate. Correlation of Irish rainfall with other parts of Europe increases the utility of the series for understanding historical climate in further regions.

The charge distribution of aerosol is an important factor for accurate prediction of aerosol behavior as it influences particle transport, settling, deposition, and coagulation. In the production of aerosol for pulmonary drug delivery, charging of aerosol particles is influenced by both the generation method and chemical properties of the drug. Electrostatic charging of add-on devices such as plastic spacers and holding chambers will reduce the delivery to the lung, while charged particles can also enhance deposition to the respiratory system by inducing an image charge to airway surfaces. Typical target particle size for delivery devices in terms of mass median aerodynamic diameter (MMAD) is 1–5 μm, and therefore up to 50% of the dose includes submicron particles in the fine (100–1000 nm) and ultrafine (<100 nm) size range. Measurement of the charge distribution of submicron particles produced using a vibrating mesh nebulizer is presented using a tandem differential mobility analyzer (TDMA). It is found that the charge distribution is not at equilibrium, but instead has an increase in the fraction of charged particles below 200 nm and a decrease in the charged fraction above 200 nm. In general the charge distribution will be dependent on the specific aerosol nebulizer setup being used and the chemical properties of the nebulized solution, and it could be further quantified by using the methods discussed here.

Background: Prevention of violence due to severe mental disorders in psychiatric hospitals may require intrusive, restrictive and coercive therapeutic practices. Research concerning appropriate use of such interventions is limited by lack of a system for description and measurement. We set out to devise and validate a tool for clinicians and secure hospitals to assess necessity and proportionality between imminent violence and restrictive practices including de-escalation, seclusion, restraint, forced medication and others. Methods: In this retrospective observational cohort study, 28 patients on a 12 bed male admissions unit in a secure psychiatric hospital were assessed daily for six months. Data on adverse incidents were collected from case notes, incident registers and legal registers. Using the functional assessment sequence of antecedents, behaviours and consequences (A, B, C) we devised and applied a multivariate framework of structured professional assessment tools, common adverse incidents and preventive clinical interventions to develop a tool to analyse clinical practice. We validated by testing assumptions regarding the use of restrictive and intrusive practices in the prevention of violence in hospital. We aimed to provide a system for measuring contextual and individual factors contributing to adverse events and to assess whether the measured seriousness of threating and violent behaviours is proportionate to the degree of restrictive interventions used. General Estimating Equations tested preliminary models of contexts, decisions and pathways to interventions. Results: A system for measuring adverse behaviours and restrictive, intrusive interventions for prevention had good internal consistency and inter-rater reliability. Interventions were proportionate to seriousness of harmful behaviours. A ‘Pareto’ group of patients (5/28) were responsible for the majority (80%) of adverse events, outcomes and interventions. The seriousness of the precipitating events correlated with the degree of restrictions utilised to safely manage or treat such behaviours. Conclusion: Observational scales can be used for restrictive, intrusive or coercive practices in psychiatry even though these involve interrelated complex sequences of interactions. The DRILL tool has been validated to assess the necessity and demonstrate proportionality of restrictive practices. This tool will be of benefit to services when reviewing practices internally, for mandatory external reviewing bodies and for future clinical research paradigms.