An unexpected path for Malat1 in neurons: trafficking out of the nucleus for translation.

The Malat1 (metastasis-associated lung adenocarcinoma transcript 1) long noncoding RNA is highly and broadly expressed in mammalian tissues, accumulating in the nucleus where it modulates expression and pre-mRNA processing of many protein-coding genes. In this issue of Genes & Development, Xiao and colleagues (doi:10.1101/gad.351557.124) report that a significant fraction of Malat1 transcripts in cultured mouse neurons are surprisingly exported from the nucleus. These transcripts are packaged with Staufen proteins in RNA granules and traffic down the lengths of neurites. They then can be released in a stimulus-dependent manner to be locally translated into a microprotein that alters neuronal gene expression patterns.

Overlapping genes in natural and engineered genomes.

Modern genome-scale methods that identify new genes, such as proteogenomics and ribosome profiling, have revealed, to the surprise of many, that overlap in genes, open reading frames and even coding sequences is widespread and functionally integrated into prokaryotic, eukaryotic and viral genomes. In parallel, the constraints that overlapping regions place on genome sequences and their evolution can be harnessed in bioengineering to build more robust synthetic strains and constructs. With a focus on overlapping protein-coding and RNA-coding genes, this Review examines their discovery, topology and biogenesis in the context of their genome biology. We highlight exciting new uses for sequence overlap to control translation, compress synthetic genetic constructs, and protect against mutation.

IRE1α Mediates the Hypertrophic Growth of Cardiomyocytes Through Facilitating the Formation of Initiation Complex to Promote the Translation of TOP-Motif Transcripts.

BACKGROUND: Cardiomyocyte growth is coupled with active protein synthesis, which is one of the basic biological processes in living cells. However, it is unclear whether the unfolded protein response transducers and effectors directly take part in the control of protein synthesis. The connection between critical functions of the unfolded protein response in cellular physiology and requirements of multiple processes for cell growth prompted us to investigate the role of the unfolded protein response in cell growth and underlying molecular mechanisms. METHODS: Cardiomyocyte-specific inositol-requiring enzyme 1α (IRE1α) knockout and overexpression mouse models were generated to explore its function in vivo. Neonatal rat ventricular myocytes were isolated and cultured to evaluate the role of IRE1α in cardiomyocyte growth in vitro. Mass spectrometry was conducted to identify novel interacting proteins of IRE1α. Ribosome sequencing and polysome profiling were performed to determine the molecular basis for the function of IRE1α in translational control. RESULTS: We show that IRE1α is required for cell growth in neonatal rat ventricular myocytes under prohypertrophy treatment and in HEK293 cells in response to serum stimulation. At the molecular level, IRE1α directly interacts with eIF4G and eIF3, 2 critical components of the translation initiation complex. We demonstrate that IRE1α facilitates the formation of the translation initiation complex around the endoplasmic reticulum and preferentially initiates the translation of transcripts with 5' terminal oligopyrimidine motifs. We then reveal that IRE1α plays an important role in determining the selectivity and translation of these transcripts. We next show that IRE1α stimulates the translation of epidermal growth factor receptor through an unannotated terminal oligopyrimidine motif in its 5' untranslated region. We further demonstrate a physiological role of IRE1α-governed protein translation by showing that IRE1α is essential for cardiomyocyte growth and cardiac functional maintenance under hemodynamic stress in vivo. CONCLUSIONS: These studies suggest a noncanonical, essential role of IRE1α in orchestrating protein synthesis, which may have important implications in cardiac hypertrophy in response to pressure overload and general cell growth under other physiological and pathological conditions.

Prospective associations of technostress at work, burnout symptoms, hair cortisol, and chronic low-grade inflammation.

BACKGROUND: Working conditions in the age of digitalization harbor risks for chronic stress and burnout. However, real-world investigations into biological effects of technostress, that is stress in the context of digital technology use, are sparse. This study prospectively assessed associations between technostress, general work stress, burnout symptoms, hair cortisol, and chronic low-grade inflammation. METHODS: Hospital employees (N = 238, 182 females, Mage = 28.5 years) participated in a prospective cohort study with two follow-ups six months apart (T2, T3). Participants answered standardized questionnaires on general job strain (job demand-control ratio), technostressors (work interruptions, multitasking, information overload), burnout symptoms (exhaustion, mental distance), and relevant confounders. Moreover, they provided capillary blood samples for C-reactive protein (CRP) and hair strands for hair cortisol concentration (HCC) analysis. Structural equation modelling was performed. RESULTS: The factorial structure of survey measures was confirmed. Burnout symptoms (MT2 = 2.17, MT3 = 2.33) and HCC (MT2 = 4.79, MT3 = 9.56; pg/mg) increased over time, CRP did not (MT2 = 1.15, MT3 = 1.21; mg/L). Adjusted path models showed that technostress was negatively associated with HCC (ß = -0.16, p =.003), but not with burnout and CRP. General work stress in contrast, was not significantly associated with burnout, HCC or CRP. Furthermore, there were reciprocal effects of CRP on HCC (ß = 0.28, p =.001) and of HCC on CRP (ß = -0.10, p ≤.001). Associations were robust in additional analyses including further confounders. CONCLUSION: This is the first study on prospective effects of technostress on employees' endocrine and inflammatory systems. Results suggest differential effects of technostress on the hypothalamic-pituitary-adrenocortical axis activity. Given its key role for long-term health, the findings have important implications for occupational health and safety in digitalized work environments.

The brain-derived neurotrophic factor Val66met polymorphism is associated with better attention and working memory performance and resilience to mild chronic stress.

The val66met polymorphism of the brain-derived neurotrophic factor (BDNF) gene has been identified as a potential moderator for the relationship between chronic stress and executive functioning. However, whether the presence of the met allele increases cognitive vulnerability or resilience to stress has yet to be determined. Given the established effects of autonomic activity and psychological arousal on executive functioning, in the present study, 56 healthy university students completed self-report measures of chronic stress, positive arousal (vigour) and negative arousal (anxiety) and measured heart-rate variability to quantify autonomic activity. Participants then completed a cognitive test battery that measured attention, decision-making, visual learning and working memory. Regression analyses demonstrated that Val/met participants performed better on attention and working memory tasks than Val/val participants, but no differences were seen in decision-making and visual learning. Further, Val/met participants were protected from stress-related differences in attention seen in Val/val participants. Val66met was not associated with physiological or psychological arousal. This study demonstrates that val66met plays an important but selective role in cognitive performance.

A Systematic Review and Revised Meta-analysis of the Effort-Reward Imbalance Model of Workplace Stress and Hypothalamic-Pituitary-Adrenal Axis Measures of Stress.

OBJECTIVE: Despite considerable research in the past 20 years into associations between the effort-reward imbalance (ERI) model and various health outcomes, the mechanisms responsible for the association remain unclear. Our meta-analysis assessed the associations of ERI and overcommitment (OC) in the workplace with measures from the hypothalamic-pituitary-adrenal (HPA) axis. METHODS: Electronic databases were searched with the phrase "effort * reward * imbalance," which yielded 319 studies leading to 56 full-text studies being screened. Thirty-two studies within 14 articles met the inclusion criteria and were meta-analyzed using mixed- and random-effects models. RESULTS: Greater ERI was associated with increased HPA axis activity (r = 0.05, p = .02, k = 14, n = 2461). The cortisol waking concentrations (r = 0.11, p = .02, k = 6, n = 493) were the only subgroup associated with ERI. Meta-regression revealed that studies that contained more men had stronger ERI to HPA marker associations. When all HPA markers were considered collectively, OC was not associated with greater HPA axis activity (r = 0.01, p = .70, k = 10, n = 1684), with only cortisol (pm) associated with OC (r = -0.24, p = .02, k = 2, n = 95). CONCLUSIONS: ERI and OC were associated with HPA responsivity. Although the cortisol waking concentrations and not the CAR were associated with ERI, this may be due to heterogeneity in the experience of stress between studies. Future studies should consider the concurrent assessment of burnout to better assist the interpretation of ERI with HPA responsivity.

Cognitive performance in older people after mild traumatic brain injury: Trauma effects and other risk factors.

OBJECTIVE: Cognitive symptoms are common in the initial weeks after mTBI, but recovery is generally expected within three months. However, there is limited information about recovery specifically in older age cohorts. Therefore, this study investigated cognitive outcome three months after mTBI in older adults (≥ 65 years) compared to trauma and community age-matched controls and explored risk factors for outcome after traumatic injury. METHODS: Older mTBI patients (n = 40) and older adults with mild traumatic injury but without head injury (n = 66) were compared to a noninjured community control group (n = 47). Cognitive assessment included neuropsychological and computerized tests. Group differences were compared on individual tasks and overall cognitive performances using composite scores. Regression analyses identified predictors of outcome for trauma patients and moderator analyses explored possible interactions of mTBI severity with age and cognition. RESULTS: As well as lower performances in processing speed and memory, both trauma groups had significantly lower performance on composite neuropsychological (d = .557 and .670) and computerized tasks (d = .783 and .824) compared to noninjured controls. Age, education, and history of depression were direct predictors of cognitive performance after mild traumatic injury (with or without head injury). Further moderation analysis demonstrated that mTBI severity (Glasgow Coma Scale < 15) moderated the impact of older age on computerized assessment (ß = -.138). CONCLUSIONS: Three months after mild trauma (regardless of head injury), older people demonstrate lower cognition compared to noninjured peers. However, severity of mTBI (Glasgow Coma Scale < 15) can interact with older age to predict poorer cognitive outcomes.

Mild Traumatic Brain Injury and Functional Outcome in Older Adults: Pain Interference But Not Cognition Mediates the Relationship Between Traumatic Injury and Functional Difficulties.

OBJECTIVE: To examine functional status of older people 3 months after mild traumatic brain injury (mTBI) and identify whether pain interference or cognition mediates any relationship found between injury status and functional outcomes. SETTING: Patients admitted to a Melbourne-based emergency department. PARTICIPANTS: Older adults 65 years and older: 40 with mTBI, 66 with orthopedic injury without mTBI (TC), and 47 healthy controls (CC) without injury. DESIGN: Observational cohort study. MAIN MEASURES: Functional outcome was measured using the World Health Organization Disability Assessment Schedule (WHODAS 2.0) and single- and dual-task conditions of the Timed-Up-and-Go task. Pain interference and cognitive performance at 3 months post-injury were examined as mediators of the relationship between injury status (injured vs noninjured) and functional outcome. RESULTS: Patients with mTBI and/or orthopedic injury reported greater difficulties in overall functioning, including community participation, compared with noninjured older people (CC group). Both trauma groups walked slower than the CC group on the mobility task, but all groups were similar on the dual-task condition. Pain interference mediated the relationship between injury status and overall functioning [ b = 0.284; 95% CI = 0.057, 0.536), community participation ( b = 0.259; 95% CI = 0.051, 0.485), and mobility ( b = 0.116; 95% CI = 0.019, 0.247). However, cognition did not mediate the relationship between injury status and functional outcomes. CONCLUSIONS: Three months after mild traumatic injury (with and without mTBI), patients 65 years and older had greater functional difficulties compared with noninjured peers. Pain interference, but not cognition, partially explained the impact of traumatic injury on functional outcomes. This highlights the importance of reducing pain interference for older patients after injury (including mTBI) to support better functional recovery.

Quality of life and psychological health after mild traumatic brain injury in older people: Three- and six-month follow up.

OBJECTIVES: Examine quality of life (QoL) and psychological health after mild traumatic brain injury (mTBI) in older people (65+ years) at 3- and 6-month follow-up and explore which injury factors predicted QoL. METHODS: mTBI patients were compared to trauma comparison (TC) and community comparison (CC) groups. QoL and psychological health were measured at both timepoints. After accounting for 3-month psychological health, injury severity, neuroimaging, and 3-month neuropsychological performance were assessed as predictors of 6-month QoL. RESULTS: Overall 3-month QoL was lower for mTBI (Cohen's d = 0.938) and TC (Cohen's d = 0.485) groups compared to CCs, but by 6 months only mTBI patients continued to report poorer overall QoL (Cohen's d = 0.577) and physical QoL (Cohen's d = 0.656). Despite group differences, QoL for most (~92%) was within normative limits. 3-month psychological health predicted QoL 6-months postinjury (ß = -.377, 95% CI -.614, -.140) but other proposed risk factors (GCS <15, neuroimaging, 3-month neuropsychological performance) did not uniquely predict QoL. CONCLUSIONS: Older adults following mTBI reported lower QoL up to 6-months postinjury compared to non-injured peers, indicating that mTBI patients were particularly susceptible to ongoing differences in QoL 6-months postinjury.

Observed Strategies on Naturalistic Associative Memory Tasks in Healthy Older Adults and Amnestic Mild Cognitive Impairment.

BACKGROUND: Understanding the strategies people with amnestic mild cognitive impairment (aMCI) spontaneously use can inform targeted memory training. METHOD: Strategy use was observed for 99 people with aMCI and 100 healthy older adults (HOA) on two memory tasks. RESULTS: No differences were found between aMCI and HOA in the amount or types of strategies used, but strategy use varied with task. Association was more effective for one task, whereas on the other task, use of written notes or multiple strategies were detrimental to performance and related to poorer performance than active (spaced) retrieval, for aMCI. CONCLUSION: Our findings suggest the importance of identifying ineffective habits, in addition to instruction in more beneficial approaches.

Subjective Cognitive Decline: Level of Risk for Future Dementia and Mild Cognitive Impairment, a Meta-Analysis of Longitudinal Studies.

Subjective Cognitive Decline (SCD) in older adults has been identified as a risk factor for dementia, although the literature is inconsistent, and it is unclear which factors moderate progression from SCD to dementia. Through separate meta-analyses, we aimed to determine if SCD increased the risk of developing dementia or mild cognitive impairment (MCI). Furthermore, we examined several possible moderators. Longitudinal studies of participants with SCD at baseline, with data regarding incident dementia or MCI, were extracted from MEDLINE and PsycINFO. Articles were excluded if SCD occurred solely in the context of dementia, MCI, or as part of a specific disease. Pooled estimates were calculated using a random-effects model, with moderator analyses examining whether risk varied according to SCD definition, demographics, genetics, recruitment source, and follow-up duration. Risk of study bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2 tool. 46 studies with more than 74,000 unique participants were included. SCD was associated with increased risk of developing dementia (HR = 1.90, 95% CI 1.52-2.36; OR = 2.48, 95% CI 1.97-3.14) and MCI (HR = 1.73, 95% CI 1.18-2.52; OR = 1.83, 95% CI 1.56-2.16). None of the potential moderating factors examined influenced the HR or OR of developing dementia. In contrast, including worry in the definition of SCD, younger age, and recruitment source impacted the OR of developing MCI, with clinic samples demonstrating highest risk. SCD thus represents an at-risk phase, ideal for early intervention, with further research required to identify effective interventions for risk reduction, and cognitive-behavioural interventions for cognitive management. PROSPERO, protocol number: CRD42016037993.

Systematic Review and Meta-analysis of Outcome after Mild Traumatic Brain Injury in Older People.

OBJECTIVE: Older age is often identified as a risk factor for poor outcome from traumatic brain injury (TBI). However, this relates predominantly to mortality following moderate-severe TBI. It remains unclear whether increasing age exerts risk on the expected recovery from mild TBI (mTBI). In this systematic review of mTBI in older age (60+ years), a focus was to identify outcome through several domains - cognition, psychological health, and life participation. METHODS: Fourteen studies were identified for review, using PRISMA guidelines. Narrative synthesis is provided for all outcomes, from acute to long-term time points, and a meta-analysis was conducted for data investigating life participation. RESULTS: By 3-month follow-up, preliminary findings indicate that older adults continue to experience selective cognitive difficulties, but given the data it is possible these difficulties are due to generalised trauma or preexisting cognitive impairment. In contrast, there is stronger evidence across time points that older adults do not experience elevated levels of psychological distress following injury and endorse fewer psychological symptoms than younger adults. Meta-analysis, based on the Glasgow Outcome Scale at 6 months+ post-injury, indicates that a large proportion (67%; 95% CI 0.569, 0.761) of older adults can achieve good functional recovery, similar to younger adults. Nevertheless, individual studies using alternative life participation measures suggest more mixed rates of recovery. CONCLUSIONS: Although our initial review suggests some optimism in recovery from mTBI in older age, there is an urgent need for more investigations in this under-researched but growing demographic. This is critical for ensuring adequate health service provision, if needed.

Memory Strategy Training Can Enhance Psychoeducation Outcomes for Dementia Family Caregivers: A Randomized Controlled Trial.

This study investigated caregiver outcomes when a psychoeducation program for older people with dementia and caregivers is modified to extend practice in memory strategies. Moderation effects of increased memory strategy use were also explored. Fifty-six care dyads participated in the multicenter, randomized controlled trial comparing psychoeducation (active control) with psychoeducation and memory strategy practice (intervention). Primary outcome was memory strategy use; secondary outcome was caregiver emotional reactivity (burden, depression, and anxiety). Results showed memory strategy use significantly increased following psychoeducation for both groups. However, psychoeducation combined with memory strategy practice resulted in a significant reduction in depression for caregivers reporting at least mild baseline symptoms. Greater use of memory strategies moderated the relationship between burden and depression following intervention. Psychoeducation programs that incorporate practical memory strategy training may offer more substantial outcomes.

Assessing the utility of a virtual-reality neuropsychological test battery, 'CONVIRT', in detecting alcohol-induced cognitive impairment.

New technologies such as virtual reality (VR) and eye-tracking software have paved the way for more sophisticated and ecologically valid measures of cognitive function. Testing the sensitivity and reliability of such measurements in response to acute alcohol intoxication provides a first step in establishing how these measures may operate in relation to cognitive impairments observed post-concussion. Healthy young adults (N = 54, M = 20.65, SD = 2.06, 30 females) completed the CONVIRT test battery (manual simple and choice reaction-time and saccade reaction-time) at three breath alcohol concentration (BrAC) levels: 0.00%T1, 0.05%T2, 0.08%T3. Participants consumed alcoholic beverages at 30-min intervals, with BrAC monitored at 15-min intervals using a breathalyser. All three CONVIRT measures were sensitive to changes in cognitive performance induced by alcohol at BrAC levels at or exceeding 0.05%. A composite measure was also sensitive to alcohol intoxication (Cohen's d = .85 at BrAC = 0.05%; d = 1.20 at BrAC = 0.08%). Strong test-retest reliability was observed (all r < .80), with no gender differences noted. CONVIRT measures were reliable and detected dose-dependent changes in alcohol-induced cognitive impairment. Potentially, the ecologically valid measures may assist in better quantifying the effects of conditions such as concussion, on cognitive performance.

Assessing the association of university stress and physiological reactivity with decision-making among students.

Compared with age-matched employees, university students report higher levels of chronic stress and this may affect their decision-making. The impact of chronic stress and physiological reactivity upon cognitive function is receiving more attention, but few studies have empirically assessed the associations of these variables concurrently. Our aim was to investigate if chronic student stress, as assessed by effort-reward imbalance (ERI) and overcommitment, and physiological reactivity, were related to decision-making. As measures of physiological reactivity, we collected salivary alpha-amylase (sAA) and continuously recorded heart rate variability (HRV) data from male students (n = 79) at pretest and immediately after some computerized decision-making tasks (simple and choice- reaction times). Our findings suggest that students who are higher in overcommitment and who are more physiologically reactive (sAA and HRV indices) at the pretest stage may be more "at-risk" of poor decision-making than others. If others can replicate our findings in more diverse samples, this will contribute to an evidence base for interventions targeted at reducing overcommitment, ERI, and dysregulated autonomic reactivity to improve decision-making.

Proteome profiling of Pseudomonas aeruginosa PAO1 identifies novel responders to copper stress.

BACKGROUND: The opportunistic pathogen, Pseudomonas aeruginosa is well known for its environmental and metabolic versatility, yet many of the functions of its gene-products remain to be fully elucidated. This study's objective was to illuminate the potential functions of under-described gene-products during the medically relevant copper-stress condition. RESULTS: We used data-independent acquisition mass spectrometry to quantitate protein expression changes associated with copper stress in P. aeruginosa PAO1. Approximately 2000 non-redundant proteins were quantified, with 78 proteins altering in abundance by +/- 1.5-fold or more when cultured to mid-log growth in the presence of 50 µM copper sulfate. One-third of those differentially expressed proteins have no prior established functional roles. CONCLUSIONS: This study provides evidence for the functional involvement of some specific proteins in enabling P. aeruginosa to survive under sub-lethal concentrations of copper. This further paves the way for targeted investigations into the specific mechanisms of their activity.

Protect your skin and let the fun begin: The results of an intervention to improve NSW primary schools' implementation of the SunSmart Program.

ISSUE ADDRESSED: The SunSmart Policy Support and Intervention Study (SSPSIS) (ACTRN12614000926639) investigated the feasibility of improving schools' implementation of the SunSmart Program, which is a resource for primary school communities to support their development of a comprehensive sun protection policy. METHODS: A cluster randomised controlled trial (RCT) was used to evaluate the SSPSIS, which was conducted in NSW SunSmart schools (n = 20). Objective measurements of students' sun-safe hat-wearing behaviours and sunscreen application, and teachers' role-modelling behaviours, were collected for baseline, post-test and follow-up data. Interviews with school community stakeholders, including students (n = 103), parents (n = 31), teachers (n = 11) and executive staff (n = 4), were conducted to inform the intervention design, which was implemented following baseline data collection. RESULTS: The results of baseline observations and interviews have been published previously. The intervention design aimed to combat negative perceptions of hat-wearing policy and create a trigger for sunscreen application by rewarding students practising these sun protection behaviours with play-based incentives. Although this intervention had no significant effect on the wearing of sun-safe hats among students or teachers, it did have a large effect on the consumption of sunscreen. CONCLUSIONS: Associating sunscreen and play-based incentives can create an effective trigger for students' sunscreen application behaviours. However, further evidence is needed to investigate how students' and teacher role models' hat-wearing behaviours could be increased. SO WHAT?: While combining a play-based incentive with a trigger for behaviour can promptly increase students' sunscreen application, it was unable to increase students' or teacher role models' hat-wearing behaviours.

A Systematic Review and Meta-analysis of the Effort-Reward Imbalance Model of Workplace Stress and Hypothalamic-Pituitary-Adrenal Axis Measures of Stress.

OBJECTIVE: The association between effort-reward imbalance (ERI) and various health outcomes has been well documented over the past 20 years, but the mechanisms responsible for this association remain unclear. The present meta-analysis assessed the associations of ERI and overcommitment (OC) in the workplace with hypothalamic-pituitary-adrenal (HPA) axis measures. METHODS: Electronic databases were searched with the phrase "effort*reward*imbalance," which yielded 319 studies leading to 56 full-text studies being screened. Thirty-two studies within 14 articles met inclusion criteria and were meta-analyzed using mixed and random effects models. RESULTS: Greater ERI was associated with increased HPA axis activity (r = .09, p < .001, k = 14, N = 2541). The cortisol awakening response (r = .14, p < .001, k = 9, N = 584) and cortisol waking concentrations (r = .12, p = .01, k = 6, N = 493) were the only HPA measures associated with ERI. OC was also associated with greater HPA axis activity (r = .06, p < .01, k = 10, N = 1918). Cortisol (PM) (r = .13, p = .02, k = 3, N = 295) was the only HPA measure associated with OC. CONCLUSIONS: ERI and OC were similarly related with HPA responsivity. However, because OC moderated the relationship between ERI and HPA axis markers, the importance of OC should not be overlooked. Because OC is likely more malleable than ERI to intervention, this may be a promising avenue for future research.

The salivary alpha amylase awakening response is related to over-commitment.

We assessed the relationship between physiological and psychological measures of workplace stress as measured by the effort-reward imbalance (ERI) model, with a seldom studied sample of owner-operator dairy farmers. Dairy farmers (N = 74) self-reported ERI, over-commitment (OC), dedication, and health then provided awakening saliva samples that were used to calculate the salivary alpha amylase awakening response (sAA-AR), cortisol awakening response (CAR), and salivary immunoglobulin A (sIgA) level. ERI, OC, and dedication levels were not related with sIgA or the CAR, but more over-committed farmers had a less pronounced sAA-AR. OC was more associated than ERI with the physiological indicators of stress, potentially due to the owner-operator sample used in this investigation. The suitability of sAA as a viable physiological measure of autonomic nervous system activity has been debated, but our findings promote its inclusion in future occupational stress research.