The disruption of proteostasis in neurodegenerative diseases

Cells count on surveillance systems to monitor and protect the cellular proteome which, besides being highly heterogeneous, is constantly being challenged by intrinsic and environmental factors. In this context, the proteostasis network (PN) is essential to achieve a stable and functional proteome. Disruption of the PN is associated with aging and can lead to and/or potentiate the occurrence of many neurodegenerative diseases (ND). This not only emphasizes the importance of the PN in health span and aging but also how its modulation can be a potential target for intervention and treatment of human diseases.info:eu-repo/semantics/publishedVersio

Comprehensive comparative analysis of strand-specific RNA sequencing methods

Strand-specific, massively parallel cDNA sequencing (RNA-seq) is a powerful tool for transcript discovery, genome annotation and expression profiling. There are multiple published methods for strand-specific RNA-seq, but no consensus exists as to how to choose between them. Here we developed a comprehensive computational pipeline to compare library quality metrics from any RNA-seq method. Using the well-annotated Saccharomyces cerevisiae transcriptome as a benchmark, we compared seven library-construction protocols, including both published and our own methods. We found marked differences in strand specificity, library complexity, evenness and continuity of coverage, agreement with known annotations and accuracy for expression profiling. Weighing each method's performance and ease, we identified the dUTP second-strand marking and the Illumina RNA ligation methods as the leading protocols, with the former benefitting from the current availability of paired-end sequencing. Our analysis provides a comprehensive benchmark, and our computational pipeline is applicable for assessment of future protocols in other organisms.Howard Hughes Medical InstituteUnited States-Israel Binational Science Foundatio

The Lancet Commission on Self-Harm

By delivering transformative shifts in societal attitudes and initiating a radical redesign of mental health care, we can fundamentally improve the lives of people who self-harm.This Lancet Commission is the product of a substantial team effort that has taken place over the last five years. It consolidates evidence and knowledge derived from empirical research and the lived experience of self-harm. Self-harm refers to intentional self-poisoning or injury, irrespective of apparent purpose, and can take many forms, including overdoses of medication, ingestion of harmful substances, cutting, burning, or punching. The focus of this Commission is on non-fatal self-harm—however, in some settings, distinctions are not this clear cut. Self-harm is a behaviour, not a psychiatric diagnosis, with a wide variety of underlying causes and contributing factors. It is shaped by culture and society, yet its definitions have arisen from research conducted mainly in high-income countries. The field has often overlooked the perspectives of people living in low-income and middle-income countries (LMICs) and Indigenous peoples. Furthermore, unlike suicide prevention, self-harm has been neglected by governments internationally. For these reasons, we set out to integrate missing perspectives about self-harm from across the world alongside existing mainstream scientific knowledge, with the aim of raising the profile of self-harm in the global policy arena and improving the treatment of people who self-harm internationally.There are at least 14 million episodes of self-harm annually across the world, representing a global rate of 60 per 100 000 people per year. This estimate is likely to be a considerable underestimate, because most people who self-harm do not present to clinical services and there are few routine surveillance systems, particularly in LMICs. Although self-harm can occur at any age, the incidence is much higher among young people and within this population, rates appear to be increasing. Repetition of self-harm is common, and suicide is much more common after self-harm than in the general population; 1·6% of people die by suicide within a year after presentation to hospital with an episode of self-harm. In LMICs, rates of repetition appear to be lower because pesticide self-poisoning (the most common method of self-harm in LMICs) has a high case fatality rate.For people who self-harm, the behaviour serves a variety of functions, including self-soothing, emotional management, communication, validation of identity, and self-expression. Self-harm practices are also shaped by social relationships and class dynamics. Indigenous peoples across the world, especially Indigenous youth, have high rates of self-harm, with colonisation and racism playing potentially important roles in driving the behaviour. Numerous psychological and social factors are associated with self-harm and the social determinants of health—poverty, in particular, heavily influences the distribution of self-harm within all communities. Yet we know little about how individual-level factors interact with social context to drive self-harm, or whether an individual might be more likely to engage in self-harm at a particular point in time. Furthermore, many of the biopsychosocial mechanisms underlying self-harm remain elusive. Granular data capture through Ecological Momentary Assessment, together with machine learning and triangulation of data sources, including qualitative data, could help to shed light on the nature and timing of self-harm.Psychological treatments can help some people who self-harm, but service users and practitioners often differ in their opinions of what constitutes effective treatment. Furthermore, treatment provision for self-harm remains highly variable and is often inaccessible, particularly within LMICs and to Indigenous peoples. Unfortunately, in many settings, there is a lack of a caring, empathic response towards people who self-harm, and those living in countries where self-harm with suicidal intent is deemed a criminal offence can find themselves liable to prosecution. Even in some liberal democracies, the police are sometimes used as a first line of response to people who self-harm, compounding feelings of stigma.We have identified 12 key recommendations that, if actioned, could transform the lives of people who self-harm (panel 1)

A rare exception to Haldane's rule: are X chromosomes key to hybrid incompatibilities?

This work was funded by NERC (NE/G014906/1, NE/L011255/1, NE/I027800/1). Additional funding from the Orthopterists’ Society to PM is also gratefully acknowledged.The prevalence of Haldane’s rule suggests that sex chromosomes commonly have a key role in reproductive barriers and speciation. However, the majority of research on Haldane’s rule has been conducted in species with conventional sex determination systems (XY and ZW) and exceptions to the rule have been understudied. Here we test the role of X-linked incompatibilities in a rare exception to Haldane’s rule for female sterility in field cricket sister species (Teleogryllus oceanicus and T. commodus). Both have an XO sex determination system. Using three generations of crosses, we introgressed X chromosomes from each species onto different, mixed genomic backgrounds to test predictions about the fertility and viability of each cross type. We predicted that females with two different species X chromosomes would suffer reduced fertility and viability compared with females with two parental X chromosomes. However, we found no strong support for such X-linked incompatibilities. Our results preclude X–X incompatibilities and instead support an interchromosomal epistatic basis to hybrid female sterility. We discuss the broader implications of these findings, principally whether deviations from Haldane’s rule might be more prevalent in species without dimorphic sex chromosomes.PostprintPeer reviewe

Mentalisation-based treatment for antisocial personality disorder in males convicted of an offence on community probation in England and Wales (Mentalization for Offending Adult Males, MOAM):a multicentre, assessor-blinded, randomised controlled trial

BackgroundAntisocial personality disorder is a major health and social problem, but scepticism about its treatability has restricted development of the evidence base for psychological treatments. Mentalisation-based treatment (MBT) tailored for antisocial personality disorder (MBT-ASPD) can address problematic behaviours by improving the ability to understand and regulate the negative effects of thoughts and feelings. This study aimed to evaluate the clinical and cost-effectiveness of MBT-ASPD compared with probation as usual in reducing aggressive behaviours from baseline to 12 months of follow-up.MethodsThe Mentaliziation for Offending Adult Males (MOAM) trial was a multicentre, two-group, pragmatic, assessor-masked, randomised controlled superiority trial in England and Wales. Eligible participants were male, aged 21 years or older, convicted of an offence and under National Probation Service supervision at one of 13 sites, identified through the Community Personality Disorder Pathways Service, met DSM-5 criteria for antisocial personality disorder, and scored at least 15 on the Overt Aggression Scale-Modified (OAS-M). After a three-stage screening process, consenting participants were randomly allocated (1:1), stratified by site, age, probation order type, and remaining probation duration, to either MBT-ASPD plus probation as usual, or probation as usual alone. Participants in the MBT-ASPD group were offered 12 months of weekly 75-min group therapy sessions and monthly 50 min individual sessions. Probation as usual lasted up to 12 months, after which participants continued under National Probation Service supervision for the remainder of their term. Investigators and data collectors were masked to treatment allocation. The primary outcome was aggression measured by the OAS-M at 12 months after random allocation. Data were collected by a hybrid team of traditional researchers and researchers with lived experience of the criminal justice system. The primary analysis was conducted in the intention-to-treat population using a linear mixed-effects model, adjusted for baseline at each follow-up timepoint (months 3, 6, 9, 12, 15, 18, 21, and 24). This trial is registered with ISRCTN (ISRCTN 32309003), and all pre-planned follow-ups are complete.FindingsBetween Jan 2, 2016, and Aug 31, 2018, 1946 individuals were referred to the study; after the screening process, 313 participants were randomly allocated (156 [50%] to probation as usual and 157 [50%] to MBT-ASPD plus probation as usual). Participants had a mean age of 34·2 years (SD 9·3); the majority of participants (247 [79%]) identified as White British, Irish, or White Other; followed by Black British (Caribbean, African, or Other; 30 [10%]) or Mixed (29 [9%]). At 12 months after random allocation, mean OAS-M scores were significantly higher in the probation as usual group (mean score 186 [SD 153]) than in the MBT-ASPD group (90 [126]), with an adjusted mean difference between groups of –73·5 (95% CI –113·7 to –33·2); p<0·0001, with a medium-to-large effect size of 0·74. During the trial, seven participants died, and one presumed death occurred, all in the probation as usual group after random allocation, with none of the deaths deemed related to trial procedures.InterpretationMBT-ASPD holds promise as an effective intervention for individuals with antisocial personality disorder within a forensic population. Future research should explore these findings’ generalisability and the sustainability of treatment gains

Dopamine, affordance and active inference.

The role of dopamine in behaviour and decision-making is often cast in terms of reinforcement learning and optimal decision theory. Here, we present an alternative view that frames the physiology of dopamine in terms of Bayes-optimal behaviour. In this account, dopamine controls the precision or salience of (external or internal) cues that engender action. In other words, dopamine balances bottom-up sensory information and top-down prior beliefs when making hierarchical inferences (predictions) about cues that have affordance. In this paper, we focus on the consequences of changing tonic levels of dopamine firing using simulations of cued sequential movements. Crucially, the predictions driving movements are based upon a hierarchical generative model that infers the context in which movements are made. This means that we can confuse agents by changing the context (order) in which cues are presented. These simulations provide a (Bayes-optimal) model of contextual uncertainty and set switching that can be quantified in terms of behavioural and electrophysiological responses. Furthermore, one can simulate dopaminergic lesions (by changing the precision of prediction errors) to produce pathological behaviours that are reminiscent of those seen in neurological disorders such as Parkinson's disease. We use these simulations to demonstrate how a single functional role for dopamine at the synaptic level can manifest in different ways at the behavioural level

Varieties of living things: Life at the intersection of lineage and metabolism

publication-status: Publishedtypes: Articl

Vegan diets : practical advice for athletes and exercisers.

With the growth of social media as a platform to share information, veganism is becoming more visible, and could be becoming more accepted in sports and in the health and fitness industry. However, to date, there appears to be a lack of literature that discusses how to manage vegan diets for athletic purposes. This article attempted to review literature in order to provide recommendations for how to construct a vegan diet for athletes and exercisers. While little data could be found in the sports nutrition literature specifically, it was revealed elsewhere that veganism creates challenges that need to be accounted for when designing a nutritious diet. This included the sufficiency of energy and protein; the adequacy of vitamin B12, iron, zinc, calcium, iodine and vitamin D; and the lack of the long-chain n-3 fatty acids EPA and DHA in most plant-based sources. However, via the strategic management of food and appropriate supplementation, it is the contention of this article that a nutritive vegan diet can be designed to achieve the dietary needs of most athletes satisfactorily. Further, it was suggested here that creatine and β-alanine supplementation might be of particular use to vegan athletes, owing to vegetarian diets promoting lower muscle creatine and lower muscle carnosine levels in consumers. Empirical research is needed to examine the effects of vegan diets in athletic populations however, especially if this movement grows in popularity, to ensure that the health and performance of athletic vegans is optimised in accordance with developments in sports nutrition knowledge

Heritable symbionts in a world of varying temperature

Heritable microbes represent an important component of the biology, ecology and evolution of many plants, animals and fungi, acting as both parasites and partners. In this review, we examine how heritable symbiont–host interactions may alter host thermal tolerance, and how the dynamics of these interactions may more generally be altered by thermal environment. Obligate symbionts, those required by their host, are considered to represent a thermally sensitive weak point for their host, associated with accumulation of deleterious mutations. As such, these symbionts may represent an important determinant of host thermal envelope and spatial distribution. We then examine the varied relationship between thermal environment and the frequency of facultative symbionts that provide ecologically contingent benefits or act as parasites. We note that some facultative symbionts directly alter host thermotolerance. We outline how thermal environment will alter the benefits/costs of infection more widely, and additionally modulate vertical transmission efficiency. Multiple patterns are observed, with symbionts being cold sensitive in some species and heat sensitive in others, with varying and non-coincident thresholds at which phenotype and transmission are ablated. Nevertheless, it is clear that studies aiming to predict ecological and evolutionary dynamics of symbiont–host interactions need to examine the interaction across a range of thermal environments. Finally, we discuss the importance of thermal sensitivity in predicting the success/failure of symbionts to spread into novel species following natural/engineered introduction