Just-in-Time Prompts for Running, Walking, and Performing Strength Exercises in the Built Environment: 4-Week Randomized Feasibility Study.

BACKGROUND: App-based mobile health exercise interventions can motivate individuals to engage in more physical activity (PA). According to the Fogg Behavior Model, it is important that the individual receive prompts at the right time to be successfully persuaded into PA. These are referred to as just-in-time (JIT) interventions. The Playful Active Urban Living (PAUL) app is among the first to include 2 types of JIT prompts: JIT adaptive reminder messages to initiate a run or walk and JIT strength exercise prompts during a walk or run (containing location-based instruction videos). This paper reports on the feasibility of the PAUL app and its JIT prompts. OBJECTIVE: The main objective of this study was to examine user experience, app engagement, and users' perceptions and opinions regarding the PAUL app and its JIT prompts and to explore changes in the PA behavior, intrinsic motivation, and the perceived capability of the PA behavior of the participants. METHODS: In total, 2 versions of the closed-beta version of the PAUL app were evaluated: a basic version (Basic PAUL) and a JIT adaptive version (Smart PAUL). Both apps send JIT exercise prompts, but the versions differ in that the Smart PAUL app sends JIT adaptive reminder messages to initiate running or walking behavior, whereas the Basic PAUL app sends reminder messages at randomized times. A total of 23 participants were randomized into 1 of the 2 intervention arms. PA behavior (accelerometer-measured), intrinsic motivation, and the perceived capability of PA behavior were measured before and after the intervention. After the intervention, participants were also asked to complete a questionnaire on user experience, and they were invited for an exit interview to assess user perceptions and opinions of the app in depth. RESULTS: No differences in PA behavior were observed (Z=-1.433; P=.08), but intrinsic motivation for running and walking and for performing strength exercises significantly increased (Z=-3.342; P<.001 and Z=-1.821; P=.04, respectively). Furthermore, participants increased their perceived capability to perform strength exercises (Z=2.231; P=.01) but not to walk or run (Z=-1.221; P=.12). The interviews indicated that the participants were enthusiastic about the strength exercise prompts. These were perceived as personal, fun, and relevant to their health. The reminders were perceived as important initiators for PA, but participants from both app groups explained that the reminder messages were often not sent at times they could exercise. Although the participants were enthusiastic about the functionalities of the app, technical issues resulted in a low user experience. CONCLUSIONS: The preliminary findings suggest that the PAUL apps are promising and innovative interventions for promoting PA. Users perceived the strength exercise prompts as a valuable addition to exercise apps. However, to be a feasible intervention, the app must be more stable.

Caspase-mediated cleavage of miRNA processing proteins Drosha, DGCR8, Dicer, and TRBP2 in heat-shocked cells and its inhibition by HSP70 overexpression.

Cells respond to stress through adaptive mechanisms that limit cellular damage and prevent cell death. MicroRNAs act as regulators of stress responses and stress can impact the functioning of miRNA biogenesis pathways. We were interested in the effect that severe proteotoxic stress capable of inducing apoptosis may have on miRNA biogenesis and the impact of the molecular chaperone protein HSP70 under these conditions. We found that the miRNA processing enzymes Drosha and Dicer and their accessory proteins DGCR8 and TRBP2 are cleaved by caspases in apoptotic cells. Overexpression of HSP70 prevented caspase activation and the degradation of these processing proteins. Caspase cleavage of TRBP2 was mapped to amino acid 234 which separates the two dsRNA-binding domains from the C-terminal Dicer interacting domain. Overexpression of TRBP2 was found to increase miRNA maturation, while expression of either of the fragments generated by caspase cleavage impaired maturation. These results indicate that inactivation of miRNA biogenesis is a critical feature of apoptosis and that cleavage of TRBP2, rather than simply a loss of function, serves to create positive acting inhibitors of pre-miRNA maturation.

Trauma exposure, alcohol consumption, and sleep quality: a latent growth curve model.

This study examined the relations among precollege trauma exposure, alcohol use upon entering college, growth in alcohol use, and sleep quality in a sample of undergraduate students. Participants were 932 students from a large, urban, public university. Participants completed a survey upon entering college and then subsequent follow-up surveys each Spring semester. Precollege trauma exposure was associated with both baseline and growth in alcohol use, whereby higher levels of trauma were associated with higher baseline alcohol use, but with less steep increases in growth rate, as compared to those with lower levels of trauma. Baseline alcohol use was associated with sleep quality whereby those with higher levels of consumption demonstrated worsened sleep quality. This study provides longitudinal evidence for the relations among trauma, alcohol use, and sleep quality. Although the relationship between trauma and alcohol is well-established, further work is needed to identify how this relationship impacts additional health outcomes.

Measuring coping in people with amyotrophic lateral sclerosis using the Coping Index-ALS: A patient derived, Rasch compliant scale.

OBJECTIVE: The progressively disabling and terminal nature of ALS/MND imposes major coping demands on patients. We wished to improve the psychometric properties of our previously published MND-Coping Scale, so that parametric analyses were valid, and to make it simpler for patients to complete and clinicians to score. METHODS: After a new qualitative analysis of 26 patients with ALS/MND, the draft Coping Index-ALS (CI-ALS) was administered to 465 additional patients, alongside COPE-60, General Perceived Self Efficacy scale, and WHOQOL-BREF. Validity of the CI-ALS was assessed using the Rasch model. External validity was checked against comparator measures. RESULTS: Thirteen centres contributed 465 patients, mean age 64.9 years (SD 10.8), mean disease duration 28.4 months (SD 37.5). The CI-ALS-Self and CI-ALS-Others both satisfied Rasch model expectations and showed invariance across age, gender, marital status and type of onset. Expected correlations were observed with comparator scales. A nomogram is available to convert the raw scores to interval level measures suitable for parametric analysis. CONCLUSIONS: Coping abilities in ALS/MND can now be measured using a simple 21 item self-report measure, offering two subscales with a focus of 'coping by self ' and 'coping with others'. This allows clinicians to identify individuals with poor coping and facilitates research on interventions that may improve coping skills.

The dichotomous effects of caffeine on homologous recombination in mammalian cells.

This study was initiated to examine the effects of caffeine on the DNA damage response (DDR) and homologous recombination (HR) in mammalian cells. A 5 mM caffeine treatment caused the cell cycle to stall at G2/M and cells eventually underwent apoptosis. Caffeine exposure also induced a strong DDR along with subsequent activation of wildtype p53 protein. An unexpected observation was the caffeine-induced depletion of Rad51 (and Brca2) proteins. Consequently, caffeine-treated cells were expected to be inefficient in HR. However, a dichotomy in the HR response of cells to caffeine treatment was revealed. Caffeine treatment rendered cells significantly better at performing the nascent DNA synthesis that accompanies the early strand invasion steps of HR. Additionally, caffeine treatment increased chromatin accessibility and elevated the efficiency of illegitimate recombination. Conversely, the increase in nascent DNA synthesis did not translate into a higher number of gene targeting events. Thus, prolonged caffeine exposure stalls the cell cycle, induces a p53-mediated apoptotic response and a down-regulation of critical HR proteins, and for reasons discussed, stimulates early steps of HR, but not the formation of complete recombination products.

Immune-unreactive urinary albumin as a predictor of cardiovascular events: the Hortega Study.

BACKGROUND: We aimed to determine if immune-unreactive albumin excretion (IURAE) is associated with cardiovascular (CV) events in a representative sample of a general population from Spain. METHODS: We included 1297 subjects (mean age ± standard error 48.0 ± 0.2 years, 48% females), who participated in the Hortega Follow-Up Study. The primary endpoint was incidence of fatal and non-fatal CV events. Urinary albumin excretion (UAE) was measured in spot voided urine, frozen at -80°C, by immunonephelometry [immune-reactive albumin excretion (IRAE)] and by high-performance liquid chromatography (HPLC) [total albumin excretion (AE)]. IURAE was calculated as the difference between HPLC measurements and IRAE. We estimated fully adjusted hazard ratios (HRs) of CV incidence by Cox regression for IRAE, IURAE and total AE. RESULTS: After an average at-risk follow-up of 13 years, we observed 172 CV events. urinary albumin to creatinine ratio (UACR) of ≥30 mg/g assessed by IRAE, IURAE or total AE concentrations was observed in 74, 273 and 417 participants, respectively. Among discordant pairs, there were 49 events in those classified as micro- and macroalbuminuric by IURAE, but normoalbuminuric by IRAE. Only the IRAE was a significant independent factor for the incidence of CV events [HR (95% confidence interval) 1.15 (1.04-1.27)]. The association of UAE with CV events was mainly driven by heart failure (HF) [HR 1.33 (1.15-1.55) for IRAE; HR 1.38 (1.06-1.79) for IURAE; HR 1.62 (1.22-2.13) for total AE]. Those subjects who were micro- and macroalbuminuric by both IRAE and IURAE had a significant increase in risk for any CV event, and especially for HF. CONCLUSIONS: IRAE, IURAE and AE were associated with an increased risk for CV events, but IRAE offered better prognostic assessment.

Cardiolipin exposure on the outer mitochondrial membrane modulates α-synuclein.

Neuronal loss in Parkinson's disease (PD) is associated with aberrant mitochondrial function and impaired proteostasis. Identifying the mechanisms that link these pathologies is critical to furthering our understanding of PD pathogenesis. Using human pluripotent stem cells (hPSCs) that allow comparison of cells expressing mutant SNCA (encoding α-synuclein (α-syn)) with isogenic controls, or SNCA-transgenic mice, we show that SNCA-mutant neurons display fragmented mitochondria and accumulate α-syn deposits that cluster to mitochondrial membranes in response to exposure of cardiolipin on the mitochondrial surface. Whereas exposed cardiolipin specifically binds to and facilitates refolding of α-syn fibrils, prolonged cardiolipin exposure in SNCA-mutants initiates recruitment of LC3 to the mitochondria and mitophagy. Moreover, we find that co-culture of SNCA-mutant neurons with their isogenic controls results in transmission of α-syn pathology coincident with mitochondrial pathology in control neurons. Transmission of pathology is effectively blocked using an anti-α-syn monoclonal antibody (mAb), consistent with cell-to-cell seeding of α-syn.

Development and validation of Spasticity Index-Amyotrophic Lateral Sclerosis.

OBJECTIVES: Spasticity is a common and disabling feature of amyotrophic lateral sclerosis (ALS). There are currently no validated ALS-specific measures of spasticity. The aim of this study was to develop and use a self-report outcome measure for spasticity in ALS. METHODS: Following semi-structured interviews with 11 ALS patients, a draft scale was administered across ALS clinics in the UK. Internal validity of the scale was examined using the Rasch model. The numerical rating scale (NRS) for spasticity and Leeds Spasticity scale (LSS) were co-administered. The final scale was used in a path model of spasticity and quality of life. RESULTS: A total of 465 patients (mean age 64.7 years (SD 10), 59% male) with ALS participated. Spasticity was reported by 80% of subjects. A pool of 71 items representing main themes of physical symptoms, negative impact and modifying factors was subject to an iterative process of item reduction by Rasch analysis resulting in a 20-item scale-the Spasticity Index for ALS (SI-ALS)-which was unidimensional and free from differential item functioning. Moderate correlations were found with LSS and NRS-spasticity. Incorporating the latent estimate of spasticity into a path model, greater spasticity reduced quality of life and motor function; higher motor function was associated with better quality of life. CONCLUSIONS: The SI-ALS is a disease-specific self-report scale, which provides a robust interval-level measure of spasticity in ALS. Spasticity has a substantial impact on quality of life in ALS.

Measuring sustainability of a grassroots program in a large integrated health care delivery system: the Warrior to Soul Mate Program.

INTRODUCTION: Veterans experience many physical and psychosocial adjustment problems that challenge personal relationships and social functioning and successful social reintegration. The Warrior to Soul Mate (W2SM) program uses a structured curriculum [i.e., the Practical Application of Intimate Relationships Skills (PAIRS)] to address veterans' interpersonal needs by teaching participants effective interpersonal skills. Veterans who attended the W2SM program reported lower anxiety levels, improvements in marital alterations and satisfaction, and increased intimacy, cohesion, and affection. Therefore, sustaining the W2SM program can have long-term positive effects for veterans, families, and the greater society. The purpose of this paper is to describe the sustainability of the W2SM program. METHODS: The Model of Community-based Program Sustainability conceptually guided the evaluation. Twenty-three VA hospitals in the U.S. that offer W2SM programs completed a self-report survey to measure sustainability. RESULTS: The highest scoring sustainability elements were "Demonstrating program results" (M=5.82, SD=1.23), "Staff involvement and integration" (M= 5.79, SD= 1.34), and "Program responsivity" (M=4.39, SD= 1.16); the lowest scoring element was "Strategic funding" (M=2.78, SD=1.75). Statistically significant associations were found between the global middle-range program results and three sustainability elements: leadership competence (r = .472, p = .023), effective collaboration (r = .470, p = .024), and strategic funding (r = .507, p = .014). DISCUSSION: Efforts to sustain programs should focus on leaders planning for sustainability at the onset of program implementation, collaborators must be involved in program design, implementation and evaluation, and long-term funding sources must be secured to support program operations and continuation.

Adherence to and effects on physical function parameters of a community-based standardised exercise programme for overweight or obese patients carried out by local sports clubs.

OBJECTIVES: To evaluate the adherence to a sports-club-based standardised real-life exercise programme for overweight or obese patients. The effects on physical function parameters, anthropometry and quality of life were also assessed. STUDY DESIGN: Within this prospective cohort study data from patients in Austrian sports-club-based programmes were analysed. METHODS: Sports-club-based programmes were held twice a week and carried out by local trainers. The target group was overweight or obese patients. Adherence was determined after 2 and 6 months, and physical function parameters were evaluated at baseline and after 2 months. RESULTS: A total of 71 patients (age: 52.0; standard deviation [SD: 12.1] years; body mass index [BMI]: 37.3 [SD: 8.2] kg/m2) took part in the study. Within the first 2 months the adherence rate was 62%, while 20% (14/71) participated in ≥75% of all offered sessions. After 6 months, 49% (17/35) of the retained sample still participated regularly in an exercise class. At baseline, muscle strength represented only 70% of the age- and sex-specific reference values and could be increased in a range from +4.0% (1.3 [SD: 3.0] kg; muscular endurance for the pectoral muscles) to +22.5% (16.1 [SD: 17.5] kg) (muscular endurance for the lower limb muscles). Concerning endurance capacity, the heart rate for a constant submaximal workload decreased from 126.4 (SD: 21.7) beats per minute at baseline to 120.9 (SD: 21.1) after 2 months (P < 0.001). CONCLUSIONS: Sports clubs, as a non-clinical setting, can offer attractive standardised exercise programmes for a minority of overweight or obese patients. Long term changes in life-style, that result in sufficient levels of health enhancing physical activity still remain a huge public health challenge.

An endophenotype approach to the genetics of alcohol dependence: a genome wide association study of fast beta EEG in families of African ancestry.

Fast beta (20-28 Hz) electroencephalogram (EEG) oscillatory activity may be a useful endophenotype for studying the genetics of disorders characterized by neural hyperexcitability, including substance use disorders (SUDs). However, the genetic underpinnings of fast beta EEG have not previously been studied in a population of African-American ancestry (AA). In a sample of 2382 AA individuals from 482 families drawn from the Collaborative Study on the Genetics of Alcoholism (COGA), we performed a genome-wide association study (GWAS) on resting-state fast beta EEG power. To further characterize our genetic findings, we examined the functional and clinical/behavioral significance of GWAS variants. Ten correlated single-nucleotide polymorphisms (SNPs) (r2>0.9) located in an intergenic region on chromosome 3q26 were associated with fast beta EEG power at P<5 × 10-8. The most significantly associated SNP, rs11720469 (ß: -0.124; P<4.5 × 10-9), is also an expression quantitative trait locus for BCHE (butyrylcholinesterase), expressed in thalamus tissue. Four of the genome-wide SNPs were also associated with Diagnostic and Statistical Manual of Mental Disorders Alcohol Dependence in COGA AA families, and two (rs13093097, rs7428372) were replicated in an independent AA sample (Gelernter et al.). Analyses in the AA adolescent/young adult (offspring from COGA families) subsample indicated association of rs11720469 with heavy episodic drinking (frequency of consuming 5+ drinks within 24 h). Converging findings presented in this study provide support for the role of genetic variants within 3q26 in neural and behavioral disinhibition. These novel genetic findings highlight the importance of including AA populations in genetics research on SUDs and the utility of the endophenotype approach in enhancing our understanding of mechanisms underlying addiction susceptibility.

Prevalence and predictors of sexual assault among a college sample.

OBJECTIVE: This study examined the prevalence and correlates of precollege, college-onset, and repeat sexual assault (SA) within a representative student sample. PARTICIPANTS: A representative sample of 7,603 students. METHODS: Incoming first-year students completed a survey about their exposure to broad SA prior to college, prior trauma, personality, relationships, and mental health. Broad SA was then reassessed each spring semester while enrolled. RESULTS: Nearly 20% of the sample reported experiencing broad SA, with women endorsing significantly higher rates compared with males. Prior victimization before coming to college was related to a greater risk of victimization in college, and there was no statistically significant difference between males and females who reported revictimization. Correlates of college-onset broad SA were found and are discussed. CONCLUSIONS: Given the need for SA intervention and prevention on college campuses, identification of factors potentially contributing to exposure within this population is essential.

Integration of HIV in child survival platforms: a novel programmatic pathway towards the 90-90-90 targets.

INTRODUCTION: Integration of HIV into child survival platforms is an evolving territory with multiple connotations. Most literature on integration of HIV into other health services focuses on adults; however promising practices for children are emerging. These include the Double Dividend (DD) framework, a new programming approach with dual goal of improving paediatric HIV care and child survival. In this commentary, the authors discuss why integrating HIV testing, treatment and care into child survival platforms is important, as well as its potential to advance progress towards global targets that call for, by 2020, 90% of children living with HIV to know their status, 90% of those diagnosed to be on treatment and 90% of those on treatment to be virally suppressed (90-90-90). DISCUSSION: Integration is critical in improving health outcomes and efficiency gains. In children, integration of HIV in programmes such as immunization and nutrition has been associated with an increased uptake of HIV infant testing. Integration is increasingly recognized as a case-finding strategy for children missed from prevention of mother-to-child transmission programmes and as a platform for diffusing emerging technologies such as point-of-care diagnostics. These support progress towards the 90-90-90 targets by providing a pathway for early identification of HIV-infected children with co-morbidities, prompt initiation of treatment and improved survival. There are various promising practices that have demonstrated HIV outcomes; however, few have documented the benefits of integration on child survival interventions. The DD framework is well positioned to address the bidirectional impacts for both programmes. CONCLUSIONS: Integration provides an important programmatic pathway for accelerated progress towards the 90-90-90 targets. Despite this encouraging information, there are still challenges to be addressed in order to maximize the benefits of integration.

Patching the gaps towards the 90-90-90 targets: outcomes of Nigerian children receiving antiretroviral treatment who are co-infected with tuberculosis.

INTRODUCTION: Nigeria has a high burden of children living with HIV and tuberculosis (TB). This article examines the magnitude of TB among children receiving antiretroviral treatment (ART), compares their ART outcomes with their non-TB counterparts and argues that addressing TB among children on ART is critical for achieving the 90-90-90 targets. METHODS: This was a facility-based, retrospective analysis of medical records of children aged <15 years who were newly initiated on ART between 2011 and 2012. Structured tools were used to collect data. STATA software was used to perform descriptive, survival and multivariate analyses. RESULTS: A total of 1142 children with a median age of 3.5 years from 20 selected facilities were followed for 24 months. Of these, 95.8% were assessed for TB at ART initiation and 14.7% had TB. Children on ART were more likely to have TB if they were aged 5 years or older (p<0.01) and had delayed ART initiation (p<0.05). The cotrimoxazole and isoniazid prophylaxes were provided to 87.9 and 0.8% of children, respectively. The rate of new TB cases was 3 (2.2-4.0) per 100 person-years at six months and declined to 0.2 (0.06-1.4) per 100 person-years at 24 months. TB infection [adjusted hazard ratio (aHR): 4.3; 2.3-7.9], malnutrition (aHR: 5.1; 2.6-9.8), delayed ART initiation (aHR: 3.2; 1.5-6.7) and age less than 1 year at ART initiation (aHR: 4.0; 1.4-12.0) were associated with death. Additionally, patients with TB (aHR: 1.3; 1.1-1.6) and children below the age of 1 at ART initiation (aHR: 2.9; 1.7-5.2) were more likely to be lost to follow-up (LFU). CONCLUSIONS: Children on ART with TB are less likely to survive and more likely to be LFU. These risks, along with low isoniazid uptake and delayed ART initiation, present a serious challenge to achieving the 90-90-90 targets and underscore an urgent need for inclusion of childhood TB/HIV in global plans and reporting mechanisms.

Monogalactosyldiacylglycerols as Host Recognition Cues for Western Corn Rootworm Larvae (Coleoptera: Chrysomelidae).

Monogalactosyldiacylglycerol (MGDG) was identified as a host recognition cue for larvae of the western corn rootworm Diabrotica virgifera virgifera LeConte. An active glycolipid fraction obtained from an extract of germinating maize roots was isolated with thin layer chromatography using a bioassay-driven approach. When analyzed with LC-MS (positive ion scanning), the assay-active spot was found to contain four different MGDG species: 18:3-18:3 (1,2-dilinolenoyl), 18:2-18:3 (1-linoleoyl, 2-linolenoyl), 18:2-18:2 (1,2-dilinoleoyl), and 18:2-16:0 (1-linoleoyl, 2-palmitoyl). A polar fraction was also needed for activity. When combined with a polar fraction containing a blend of sugars (glucose:fructose:sucrose:myoinositol), the isolated MGDG elicited a unique tight-turning behavior by neonate western corn rootworm larvae that is indicative of host recognition. In behavioral bioassays where disks treated with the active blend were exposed to successive sets of rootworm larvae, the activity of MGDG increased over four exposures, suggesting that larvae may be responding to compounds produced after enzymatic breakdown of MGDG. In subsequent tests with synthetic blends composed of theoretical MGDG-breakdown products, larval responses to four synthetic blends were not significantly different (P<0.5) than the response to isolated MGDG. GC-MS analysis showed modest increases in the amounts of the 16:0, 18:0, and 18:3 free fatty acids released from MGDG after a 30-min exposure to rootworm larvae, which is consistent with the enzymatic breakdown hypothesis.

An Endophyte Constructs Fungicide-Containing Extracellular Barriers for Its Host Plant.

Surface cracks create sites for pathogen invasion. Yew trees (Taxus) hyperbranch from long-lived buds that lie underneath the bark [1], resulting in persistent bark cracking and deep air pockets, potentially allowing pathogens to enter the nutrient-rich vascular system (vertical phloem and inter-connected radial medullary rays [MR]). Yew is famous as the source of the anti-cancer diterpenoid drug Taxol. A mystery has been why both the tree and its resident non-pathogenic fungi (endophytes) synthesize Taxol, apparently redundantly [2-7]. These endophytes, as well as pure Taxol, suppress fungal pathogens including wood-decaying fungi (WDF) [8-11]. Here we show that a Taxol-producing fungal endophyte, Paraconiothyrium SSM001 [12], migrates to pathogen entry points including branch cracks. The fungus sequesters Taxol in intracellular hydrophobic bodies that are induced by WDF for release by exocytosis, after which the bodies can coalesce to form remarkable extracellular barriers, laced with the fungicide. We propose that microbial construction of fungicide-releasing hydrophobic barriers might be a novel plant defense mechanism. We further propose that the endophyte might be evolutionarily analogous to animal immune cells, in that it might expand plant immunity by acting as an autonomous, anti-pathogen sentinel that monitors the vascular system.

Genome-wide association data suggest ABCB1 and immune-related gene sets may be involved in adult antisocial behavior.

Adult antisocial behavior (AAB) is moderately heritable, relatively common and has adverse consequences for individuals and society. We examined the molecular genetic basis of AAB in 1379 participants from a case-control study in which the cases met criteria for alcohol dependence. We also examined whether genes of interest were expressed in human brain. AAB was measured using a count of the number of Antisocial Personality Disorder criteria endorsed under criterion A from the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV). Participants were genotyped on the Illumina Human 1M BeadChip. In total, all single-nucleotide polymorphisms (SNPs) accounted for 25% of the variance in AAB, although this estimate was not significant (P=0.09). Enrichment tests indicated that more significantly associated genes were over-represented in seven gene sets, and most were immune related. Our most highly associated SNP (rs4728702, P=5.77 × 10(-7)) was located in the protein-coding adenosine triphosphate-binding cassette, sub-family B (MDR/TAP), member 1 (ABCB1). In a gene-based test, ABCB1 was genome-wide significant (q=0.03). Expression analyses indicated that ABCB1 was robustly expressed in the brain. ABCB1 has been implicated in substance use, and in post hoc tests we found that variation in ABCB1 was associated with DSM-IV alcohol and cocaine dependence criterion counts. These results suggest that ABCB1 may confer risk across externalizing behaviors, and are consistent with previous suggestions that immune pathways are associated with externalizing behaviors. The results should be tempered by the fact that we did not replicate the associations for ABCB1 or the gene sets in a less-affected independent sample.

Heat shock inhibition of CDK5 increases NOXA levels through miR-23a repression.

Hyperthermia is a proteotoxic stress that is lethal when exposure is extreme but also cytoprotective in that sublethal exposure leads to the synthesis of heat shock proteins, including HSP70, which are able to inhibit stress-induced apoptosis. CDK5 is an atypical cyclin-dependent kinase family member that regulates many cellular functions including motility and survival. Here we show that exposure of a human lymphoid cell line to hyperthermia causes CDK5 insolubilization and loss of tyrosine-15 phosphorylation, both of which were prevented in cells overexpressing HSP70. Inhibition of CDK5 activity with roscovitine-sensitized cells to heat induced apoptosis indicating a protective role for CDK5 in inhibiting heat-induced apoptosis. Both roscovitine and heat shock treatment caused increased accumulation of NOXA a pro-apoptotic BH3-only member of the BCL2 family. The increased abundance of NOXA by CDK5 inhibition was not a result of changes in NOXA protein turnover. Instead, CDK5 inhibition increased NOXA mRNA and protein levels by decreasing the expression of miR-23a, whereas overexpressing the CDK5 activator p35 attenuated both of these effects on NOXA and miR-23a expression. Lastly, overexpression of miR-23a prevented apoptosis under conditions in which CDK5 activity was inhibited. These results demonstrate that CDK5 activity provides resistance to heat-induced apoptosis through the expression of miR-23a and subsequent suppression of NOXA synthesis. Additionally, they indicate that hyperthermia induces apoptosis through the insolubilization and inhibition of CDK5 activity.

Zebra body myopathy is caused by a mutation in the skeletal muscle actin gene (ACTA1).

We present follow up data on the original case of 'zebra body myopathy' published by Lake and Wilson in 1975. Pathological features in a second biopsy performed at the age of 29 years included a wide variation in fibre size, multiple split fibres, excess internal nuclei and endomysial connective tissue, rimmed vacuoles, accumulation of myofibrillar material and large 'wiped out' areas lacking stain for oxidative enzymes. The presence of nemaline rods and actin-like filaments in addition to small zebra bodies suggested ACTA1 as a candidate gene. This has been confirmed by the identification of a novel c.1043T.p.Leu348Gln mutation, which probably occurred de novo. This case illustrates that the myopathy associated with zebra bodies is part of the spectrum of myopathies associated with the ACTA1 gene. It also highlights that accumulation of actin filaments is not confined to severe neonatal ACTA1 cases and that progression of weakness can occur in congenital myopathies, as the patient is now wheelchair bound and can only stand with the aid of a walking frame.

Regulation of apoptosis by heat shock proteins.

Thermotolerance, the acquired resistance of cells to stress, is a well-established phenomenon. Studies of the key mediators of this response, the heat shock proteins (HSPs), have led to the discovery of the important roles played by these proteins in the regulation of apoptotic cell death. Apoptosis is critical for normal tissue homeostasis and is involved in diverse processes including development and immune clearance. Apoptosis is tightly regulated by both proapoptotic and antiapoptotic factors, and dysregulation of apoptosis plays a significant role in the pathophysiology of many diseases. In the recent years, HSPs have been identified as key determinants of cell survival, which can modulate apoptosis by directly interacting with components of the apoptotic machinery. Therefore, manipulation of the HSPs could represent a viable strategy for the treatment of diseases. Here, we review the current knowledge with regard to the mechanisms of HSP-mediated regulation of apoptosis.