A tandem activity-based sensing and labeling strategy reveals antioxidant response element regulation of labile iron pools.

Iron is an essential element for life owing to its ability to participate in a diverse array of oxidation-reduction reactions. However, misregulation of iron-dependent redox cycling can also produce oxidative stress, contributing to cell growth, proliferation, and death pathways underlying aging, cancer, neurodegeneration, and metabolic diseases. Fluorescent probes that selectively monitor loosely bound Fe(II) ions, termed the labile iron pool, are potentially powerful tools for studies of this metal nutrient; however, the dynamic spatiotemporal nature and potent fluorescence quenching capacity of these bioavailable metal stores pose challenges for their detection. Here, we report a tandem activity-based sensing and labeling strategy that enables imaging of labile iron pools in live cells through enhancement in cellular retention. Iron green-1 fluoromethyl (IG1-FM) reacts selectively with Fe(II) using an endoperoxide trigger to release a quinone methide dye for subsequent attachment to proximal biological nucleophiles, providing a permanent fluorescent stain at sites of elevated labile iron. IG1-FM imaging reveals that degradation of the major iron storage protein ferritin through ferritinophagy expands the labile iron pool, while activation of nuclear factor-erythroid 2-related factor 2 (NRF2) antioxidant response elements (AREs) depletes it. We further show that lung cancer cells with heightened NRF2 activation, and thus lower basal labile iron, have reduced viability when treated with an iron chelator. By connecting labile iron pools and NRF2-ARE activity to a druggable metal-dependent vulnerability in cancer, this work provides a starting point for broader investigations into the roles of transition metal and antioxidant signaling pathways in health and disease.

Treatment of Organophosphorus Poisoning with 6-Alkoxypyridin-3-ol Quinone Methide Precursors: Resurrection of Methylphosphonate-Aged Acetylcholinesterase.

Organophosphorus (OP) nerve agents inhibit acetylcholinesterase (AChE), creating a cholinergic crisis in which death can occur. The phosphylated serine residue spontaneously dealkylates to the OP-aged form, which current therapeutics cannot reverse. Soman's aging half-life is 4.2 min, so immediate recovery (resurrection) of OP-aged AChE is needed. In 2018, we showed pyridin-3-ol-based quinone methide precursors (QMPs) can resurrect OP-aged electric eel AChE in vitro, achieving 2% resurrection after 24 h of incubation (pH 7, 4 mM). We prepared 50 unique 6-alkoxypyridin-3-ol QMPs with 10 alkoxy groups and five amine leaving groups to improve AChE resurrection. These compounds are predicted in silico to cross the blood-brain barrier and treat AChE in the central nervous system. This library resurrected 7.9% activity of OP-aged recombinant human AChE after 24 h at 250 µM, a 4-fold increase from our 2018 report. The best QMP (1b), with a 6-methoxypyridin-3-ol core and a diethylamine leaving group, recovered 20.8% (1 mM), 34% (4 mM), and 42.5% (predicted maximum) of methylphosphonate-aged AChE activity over 24 h. Seven QMPs recovered activity from AChE aged with Soman and a VX degradation product (EA-2192). We hypothesize that QMPs form the quinone methide (QM) to realkylate the phosphylated serine residue as the first step of resurrection. We calculated thermodynamic energetics for QM formation, but there was no trend with the experimental biochemical data. Molecular docking studies revealed that QMP binding to OP-aged AChE is not the determining factor for the observed biochemical trends; thus, QM formation may be enzyme-mediated.

On the illusion of auxotrophy: met15Δ yeast cells can grow on inorganic sulfur, thanks to the previously uncharacterized homocysteine synthase Yll058w.

Organisms must either synthesize or assimilate essential organic compounds to survive. The homocysteine synthase Met15 has been considered essential for inorganic sulfur assimilation in yeast since its discovery in the 1970s. As a result, MET15 has served as a genetic marker for hundreds of experiments that play a foundational role in eukaryote genetics and systems biology. Nevertheless, we demonstrate here through structural and evolutionary modeling, in vitro kinetic assays, and genetic complementation, that an alternative homocysteine synthase encoded by the previously uncharacterized gene YLL058W enables cells lacking Met15 to assimilate enough inorganic sulfur for survival and proliferation. These cells however fail to grow in patches or liquid cultures unless provided with exogenous methionine or other organosulfurs. We show that this growth failure, which has historically justified the status of MET15 as a classic auxotrophic marker, is largely explained by toxic accumulation of the gas hydrogen sulfide because of a metabolic bottleneck. When patched or cultured with a hydrogen sulfide chelator, and when propagated as colony grids, cells without Met15 assimilate inorganic sulfur and grow, and cells with Met15 achieve even higher yields. Thus, Met15 is not essential for inorganic sulfur assimilation in yeast. Instead, MET15 is the first example of a yeast gene whose loss conditionally prevents growth in a manner that depends on local gas exchange. Our results have broad implications for investigations of sulfur metabolism, including studies of stress response, methionine restriction, and aging. More generally, our findings illustrate how unappreciated experimental variables can obfuscate biological discovery.

Web-based physical activity promotion in young people with CF: a randomised controlled trial.

BACKGROUND: Physical activity levels are known to decline following hospitalisation for people with cystic fibrosis (pwCF). However, optimal physical activity promotion strategies are unclear. This study investigated the effect of a web-based application (ActivOnline) in promoting physical activity in young pwCF. METHODS: Multicentre randomised controlled trial with assessor blinding and qualitative evaluation. People with CF (12-35 years) admitted to hospital for a respiratory cause were eligible and randomised to the 12-week ActivOnline intervention (AO) or usual care (UC). The primary outcome was change in device-based time spent in moderate-to-vigorous physical activity (MVPA) from baseline to post-intervention. Follow-up was at 6 months from hospital discharge when qualitative evaluation was undertaken. RESULTS: 107 participants were randomised to AO (n=52) or UC (n=55). Sixty-three participants (59%) contributed to the intention-to-treat analysis. Mean (SD) age was 21 (6) years (n=46, <18 years). At baseline, physical activity levels were high in both groups (AO 102 (52) vs UC 127 (73) min/day). There was no statistically significant difference in MVPA between groups at either timepoint (post-intervention mean difference (95% CI) -14 mins (-45 to 16)). Uptake of the intervention was low with only 40% (n=21) of participants accessing the web application. CONCLUSION: A web-based application, including individualised goal setting, real-time feedback and motivation for behavioural change, was no better than usual care at promoting physical activity in young pwCF following hospital discharge. High levels of baseline physical activity levels in both groups, and limited engagement with the intervention, suggest alternative strategies may be necessary to identify and support young pwCF who would benefit from enhanced physical activity. TRIAL REGISTRATION NUMBER: ACTRN12617001009303, 13 July 13 2017.

Exercise and Airway Clearance Techniques in Cystic Fibrosis.

Exercise and airway clearance techniques (ACTs) have been a cornerstone of treatment for people with cystic fibrosis (pwCF) for many decades. Exercise may confer both respiratory and nonrespiratory benefits for pwCF, with greater exercise capacity associated with improved survival. A wide variety of exercise interventions for pwCF have been investigated. ACTs may assist in reducing respiratory symptoms for pwCF and are currently recommended to be performed daily, with the types of ACTs used varying globally. While recommended components of care, both exercise and ACTs are time-intensive and maintaining adherence to the recommendations over the longer term can be challenging. It has been proposed that with advances in the therapeutic options for pwCF, a rationalization of the therapeutic regimen may be possible. We summarize the current evidence for the use of exercise and ACTs by pwCF, discuss the implications of the introduction of cystic fibrosis transmembrane conductance regulator modulators on both exercise and ACTs, and highlight areas for further research.

Factors Influencing Barriers and Facilitators to In-home Video Telehealth for Dementia Management.

OBJECTIVES: Quality dementia care, which recognizes caregivers as vital care partners, is a scarce resource. Innovative solutions like video telehealth may increase the reach of extant clinicians; however, little is known about perceived barriers and facilitators to in-home video telehealth for dementia management from the perspectives of caregivers. METHODS: Twenty-four caregivers of community-dwelling Veterans with dementia participated in semi-structured interviews. Questions gathered perceived facilitators and barriers to in-home video telehealth for dementia management through experience with related technology. Transcripts were analyzed using directed content analysis which was guided by factors previously identified as influencing older adults' adoption of technology. RESULTS: Caregiver experience with related technology was mostly facilitative to video telehealth, which was thought best suited for follow-up care. Increased access and decreased patient-caregiver stress were potential benefits. Barriers included perceived limitations of video and the belief that persons with dementia would have limited ability to manage technological aspects and to engage in video telehealth on their own. CONCLUSIONS: This study improves our understanding of the factors that caregivers perceive as barriers and facilitators to in-home video telehealth for dementia management. CLINICAL IMPLICATIONS: Strategies to optimize video telehealth include capitalizing on caregivers' social network and providing targeted training.

Driver Rehabilitation Utilization and Need Among Community-Dwelling Older Adults.

IMPORTANCE: Driving is one of the most important instrumental activities of daily living. As adults age, many face challenges with maintaining independent driving, leading to risk for decreased occupational engagement and quality of life. The extent to which occupational therapy services meet the driver rehabilitation needs of older adults is unknown. OBJECTIVE: To characterize driver rehabilitation service utilization among a nationally representative sample of community-dwelling older adults. DESIGN: Exploratory, descriptive cross-sectional study using the National Health and Aging Trends Study 2016 wave. PARTICIPANTS: Community-dwelling adults age 65 and older who received rehabilitation services in the past year (N = 1,173). OUTCOMES AND MEASURES: Sociodemographic information, comorbidities, rehabilitation use, community mobility, and participation restrictions were collected using self-report and performance-based measures. RESULTS: Of this sample of older adults, 63.0% reported driving as their primary mode of transportation, 25.8% reported limitations in community participation related to transportation, and 9.2% reported having received rehabilitation focused on driving or other transportation goals in the past year. Findings from this study suggest a discrepancy between utilization of driver rehabilitation and self-reported need. CONCLUSIONS AND RELEVANCE: Many older adults reported limitations in community participation for transportation-related reasons, yet driver rehabilitation represented only a small proportion of services used. As experts in driver rehabilitation, occupational therapy practitioners should lead the way in advocating for increased utilization of driver rehabilitation and development of innovative, accessible transportation options to promote community mobility and participation among older adults. WHAT THIS ARTICLE ADDS: The results of this study illustrate an important discrepancy between self-reported need for and utilization of driver rehabilitation services. Occupational therapy practitioners can play an important role in meeting older adults' driving and transportation needs to enable them to fully participate in their community and daily routines.

Exercise as a substitute for traditional airway clearance in cystic fibrosis: a systematic review.

BACKGROUND: Exercise and traditional airway clearance techniques (ACTs) are both routinely recommended for people with cystic fibrosis (CF), with some people using exercise as a substitute for traditional ACTs. The effectiveness of this is unclear. We systematically reviewed the evidence for using exercise as a substitute for traditional ACTs in people with CF. METHODS: A systematic database and literature search were undertaken of studies comparing exercise to rest or traditional ACTs. Primary outcomes were respiratory function, respiratory exacerbations and health-related quality of life. Secondary outcomes included mucociliary clearance (MCC), sputum weight and ease of expectoration. Data are mean difference (95% CI). RESULTS: A total of 12 studies (15 reports) were included, all of short duration (single session to 2 weeks). In crossover trials, exercise did not improve forced expiratory volume in one second in comparison to rest, but peak expiratory flow was increased during treadmill exercise (mean difference (MD) range 1.00-1.16 L/s) and cycle ergometry (1.19 (0.96 to 1.42) L/s). Treadmill exercise improved MCC (2.6 (1.6 to 3.6)%) and ease of expectoration (MD range 1.3-1.8 cm) compared with rest. No consistent differences in respiratory function were evident when exercise was compared with traditional ACTs (four crossover studies). There was no significant difference in MCC or sputum weight in studies where forced expirations were included in the exercise intervention. CONCLUSIONS: Exercise improves ease of expectoration and sputum clearance compared with rest. Exercise, incorporating forced expirations, may have similar effects to traditional ACTs over the short term. There are no data comparing exercise to traditional ACTs over the longer term. PROSPERO REGISTRATION NUMBER: CRD42018102780.

A web-based intervention to promote physical activity in adolescents and young adults with cystic fibrosis: protocol for a randomized controlled trial.

BACKGROUND: Regular participation in physical activity by people with cystic fibrosis (CF) promotes positive clinical and health outcomes including reduced rate of decline in lung function, fewer hospitalizations and greater wellbeing. However adherence to exercise and activity programs is low, in part due to the substantial daily therapy burden for young people with CF. Strict infection control requirements limit the role of group exercise programs that are commonly used in other clinical groups. Investigation of methods to promote physical activity in this group has been limited. The Active Online Physical Activity in Cystic fibrosis Trial (ActionPACT) is an assessor-blinded, multi-centre, randomized controlled trial designed to compare the efficacy of a novel web-based program (ActivOnline) compared to usual care in promoting physical activity participation in adolescents and young adults with CF. METHODS: Adolescents and young adults with CF will be recruited on discharge from hospital for a respiratory exacerbation. Participants randomized to the intervention group will have access to a web-based physical activity platform for the 12-week intervention period. ActivOnline allows users to track their physical activity, set goals, and self-monitor progress. All participants in both groups will be provided with standardised information regarding general physical activity recommendations for adolescents and young adults. Outcomes will be assessed by a blinded assessor at baseline, after completion of the intervention, and at 3-months followup. Healthcare utilization will be assessed at 12 months from intervention completion. The primary outcome is change in moderate-to-vigorous physical activity participation measured objectively by accelerometry. Secondary outcomes include aerobic fitness, health-related quality of life, anxiety and depression and sleep quality. DISCUSSION: This trial will establish whether a web-based application can improve physical activity participation more effectively than usual care in the period following hospitalization for a respiratory exacerbation. The web-based application under investigation can be made readily and widely available to all individuals with CF, to support physical activity and exercise participation at a time and location of the user's choosing, regardless of microbiological status. TRIAL REGISTRATION: Clinical trial registered on July 13, 2017 with the Australian and New Zealand Clinical Trials Register at (ACTRN12617001009303).

Older Adult Multitasking Performance Using a Gaze-Contingent Useful Field of View.

Objective We implemented a gaze-contingent useful field of view paradigm to examine older adult multitasking performance in a simulated driving environment. Background Multitasking refers to the ability to manage multiple simultaneous streams of information. Recent work suggests that multitasking declines with age, yet the mechanisms supporting these declines are still debated. One possible framework to better understand this phenomenon is the useful field of view, or the area in the visual field where information can be attended and processed. In particular, the useful field of view allows for the discrimination of two competing theories of real-time multitasking, a general interference account and a tunneling account. Methods Twenty-five older adult subjects completed a useful field of view task that involved discriminating the orientation of lines in gaze-contingent Gabor patches appearing at varying eccentricities (based on distance from the fovea) as they operated a vehicle in a driving simulator. In half of the driving scenarios, subjects also completed an auditory two-back task to manipulate cognitive workload, and during some trials, wind was introduced as a means to alter general driving difficulty. Results Consistent with prior work, indices of driving performance were sensitive to both wind and workload. Interestingly, we also observed a decline in Gabor patch discrimination accuracy under high cognitive workload regardless of eccentricity, which provides support for a general interference account of multitasking. Conclusion The results showed that our gaze-contingent useful field of view paradigm was able to successfully examine older adult multitasking performance in a simulated driving environment. Application This study represents the first attempt to successfully measure dynamic changes in the useful field of view for older adults completing a multitasking scenario involving driving.

Effectiveness of a 16-Week High-Intensity Cardioresistance Training Program in Adults.

Greenlee, TA, Greene, DR, Ward, NJ, Reeser, GE, Allen, CM, Baumgartner, NW, Cohen, NJ, Kramer, AF, Hillman, CH, and Barbey, AK. Effectiveness of a 16-week high-intensity cardioresistance training program in adults. J Strength Cond Res 31(9): 2528-2541, 2017-The purpose of this study was to determine the efficacy of a novel, 16-week high-intensity cardioresistance training (HICRT) program on measures of aerobic fitness, agility, aerobic power, muscular endurance, lower-body explosive power, and self-reported activity level. The intervention group (N = 129; 63 f, 24.65 ± 5.55 years) had a baseline V[Combining Dot Above]O2max of 39.83 ± 9.13. These individuals participated in 26, 70-minute exercise sessions, and 4 fitness testing sessions. Participants were matched with a nonexercise control group, paired by sex, age, and baseline V[Combining Dot Above]O2max. Matched controls (N = 129, 63 f, 24.26 ± 5.59 years) had a baseline V[Combining Dot Above]O2max of 39.86 ± 8.59 and completed preintervention and postintervention V[Combining Dot Above]O2max testing only. The results demonstrate that participants in the fitness intervention group significantly increased their V[Combining Dot Above]O2max (2.72 ± 0.31, Mdiff ± SE; p < 0.001) and reported being more physically active (0.42 ± 0.11, Mdiff ± SE; p < 0.001) after the intervention. The matched control group showed no significant pre-post intervention changes. Participants in the fitness intervention showed a significant improvement in 3 of 5 components of the fitness field tests. Specifically, significant improvements were observed for the 1-minute rower (5.32 ± 0.505, Mdiff ± SE; p < 0.001), 1-minute push-up (8.168 ± 0.709, Mdiff ± SE; p < 0.001), and 1.5-mile run tests (1.79 ± 0.169, Mdiff ± SE; p < 0.001). No significant improvements were observed for the shuttle run (p = 0.173) or standing long jump (p = 0.137). These findings demonstrate the efficacy of a novel, HICRT intervention across multiple dimensions of fitness for young- and middle-aged adults. High-intensity cardioresistance training affords flexibility for tailoring to meet desired health and fitness outcomes and makes perceivably daunting high-intensity functional training and multimodal sports training more accessible to general, traditionally nonathletic, populations.

Dissociable brain biomarkers of fluid intelligence.

Cognitive neuroscience has long sought to understand the biological foundations of human intelligence. Decades of research have revealed that general intelligence is correlated with two brain-based biomarkers: the concentration of the brain biochemical N-acetyl aspartate (NAA) measured by proton magnetic resonance spectroscopy (MRS) and total brain volume measured using structural MR imaging (MRI). However, the relative contribution of these biomarkers in predicting performance on core facets of human intelligence remains to be well characterized. In the present study, we sought to elucidate the role of NAA and brain volume in predicting fluid intelligence (Gf). Three canonical tests of Gf (BOMAT, Number Series, and Letter Sets) and three working memory tasks (Reading, Rotation, and Symmetry span tasks) were administered to a large sample of healthy adults (n=211). We conducted exploratory factor analysis to investigate the factor structure underlying Gf independent from working memory and observed two Gf components (verbal/spatial and quantitative reasoning) and one working memory component. Our findings revealed a dissociation between two brain biomarkers of Gf (controlling for age and sex): NAA concentration correlated with verbal/spatial reasoning, whereas brain volume correlated with quantitative reasoning and working memory. A follow-up analysis revealed that this pattern of findings is observed for males and females when analyzed separately. Our results provide novel evidence that distinct brain biomarkers are associated with specific facets of human intelligence, demonstrating that NAA and brain volume are independent predictors of verbal/spatial and quantitative facets of Gf.

Physiotherapy for cystic fibrosis in Australia and New Zealand: A clinical practice guideline.

Physiotherapy management is a key element of care for people with cystic fibrosis (CF) throughout the lifespan. Although considerable evidence exists to support physiotherapy management of CF, there is documented variation in practice. The aim of this guideline is to optimize the physiotherapy management of people with CF in Australia and New Zealand. A systematic review of the literature in key areas of physiotherapy practice for CF was undertaken. Recommendations were formulated based on National Health and Medical Research Council (Australia) guidelines and considered the quality, quantity and level of the evidence; the consistency of the body of evidence; the likely clinical impact; and applicability to physiotherapy practice in Australia and New Zealand. A total of 30 recommendations were made for airway clearance therapy, inhalation therapy, exercise assessment and training, musculoskeletal management, management of urinary incontinence, managing the newly diagnosed patient with CF, delivery of non-invasive ventilation, and physiotherapy management before and after lung transplantation. These recommendations can be used to underpin the provision of evidence-based physiotherapy care to people with CF in Australia and New Zealand.

Measuring the Useful Field of View During Simulated Driving With Gaze-Contingent Displays.

OBJECTIVE: We aimed to develop and test a new dynamic measure of transient changes to the useful field of view (UFOV), utilizing a gaze-contingent paradigm for use in realistic simulated environments. BACKGROUND: The UFOV, the area from which an observer can extract visual information during a single fixation, has been correlated with driving performance and crash risk. However, some existing measures of the UFOV cannot be used dynamically in realistic simulators, and other UFOV measures involve constant stimuli at fixed locations. We propose a gaze-contingent UFOV measure (the GC-UFOV) that solves the above problems. METHODS: Twenty-five participants completed four simulated drives while they concurrently performed an occasional gaze-contingent Gabor orientation discrimination task. Gabors appeared randomly at one of three retinal eccentricities (5°, 10°, or 15°). Cognitive workload was manipulated both with a concurrent auditory working memory task and with driving task difficulty (via presence/absence of lateral wind). RESULTS: Cognitive workload had a detrimental effect on Gabor discrimination accuracy at all three retinal eccentricities. Interestingly, this accuracy cost was equivalent across eccentricities, consistent with previous findings of "general interference" rather than "tunnel vision." CONCLUSION: The results showed that the GC-UFOV method was able to measure transient changes in UFOV due to cognitive load in a realistic simulated environment. APPLICATION: The GC-UFOV paradigm developed and tested in this study is a novel and effective tool for studying transient changes in the UFOV due to cognitive load in the context of complex real-world tasks such as simulated driving.

The Effects of Cell Phone and Text Message Conversations on Simulated Street Crossing.

OBJECTIVE: A fully immersive, high-fidelity street-crossing simulator was used to examine the effects of texting on pedestrian street-crossing performance. BACKGROUND: Research suggests that street-crossing performance is impaired when pedestrians engage in cell phone conversations. Less is known about the impact of texting on street-crossing performance. METHOD: Thirty-two young adults completed three distraction conditions in a simulated street-crossing task: no distraction, phone conversation, and texting. A hands-free headset and a mounted tablet were used to conduct the phone and texting conversations, respectively. Participants moved through the virtual environment via a manual treadmill, allowing them to select crossing gaps and change their gait. RESULTS: During the phone conversation and texting conditions, participants had fewer successful crossings and took longer to initiate crossing. Furthermore, in the texting condition, smaller percentage of time with head orientation toward the tablet, fewer number of head orientations toward the tablet, and greater percentage of total characters typed before initiating crossing predicted greater crossing success. CONCLUSION: Our results suggest that (a) texting is as unsafe as phone conversations for street-crossing performance and (b) when subjects completed most of the texting task before initiating crossing, they were more likely to make it safely across the street. APPLICATION: Sending and receiving text messages negatively impact a range of real-world behaviors. These results may inform personal and policy decisions.

Inactivation of Omi/HtrA2 protease leads to the deregulation of mitochondrial Mulan E3 ubiquitin ligase and increased mitophagy.

Omi/HtrA2 is a nuclear encoded mitochondrial serine protease with dual and opposite functions that depend entirely on its subcellular localization. During apoptosis, Omi/HtrA2 is released into the cytoplasm where it participates in cell death. While confined in the inter-membrane space of the mitochondria, Omi/HtrA2 has a pro-survival function that may involve the regulation of protein quality control (PQC) and mitochondrial homeostasis. Loss of Omi/HtrA2's protease activity causes the neuromuscular disorder of the mnd2 (motor neuron degeneration 2) mutant mice. These mice develop multiple defects including neurodegeneration with parkinsonian features. Loss of Omi/HtrA2 in non-neuronal tissues has also been shown to cause premature aging. The normal function of Omi/HtrA2 in the mitochondria and how its deregulation causes neurodegeneration or premature aging are unknown. Here we report that the mitochondrial Mulan E3 ubiquitin ligase is a specific substrate of Omi/HtrA2. During exposure to H(2)O(2), Omi/HtrA2 degrades Mulan, and this regulation is lost in cells that carry the inactive protease. Furthermore, we show accumulation of Mulan protein in various tissues of mnd2 mice as well as in Omi/HtrA2(-/-) mouse embryonic fibroblasts (MEFs). This causes a significant decrease of mitofusin 2 (Mfn2) protein, and increased mitophagy. Our work describes a new stress-signaling pathway that is initiated in the mitochondria and involves the regulation of Mulan by Omi/HtrA2 protease. Deregulation of this pathway, as it occurs in mnd2 mutant mice, causes mitochondrial dysfunction and mitophagy, and could be responsible for the motor neuron disease and the premature aging phenotype observed in these animals.

Assessing Cognitive Distraction in the Automobile.

OBJECTIVE: The objective was to establish a systematic framework for measuring and understanding cognitive distraction in the automobile. BACKGROUND: Driver distraction from secondary in-vehicle activities is increasingly recognized as a significant source of injuries and fatalities on the roadway. METHOD: Across three studies, participants completed eight in-vehicle tasks commonly performed by the driver of an automobile. Primary, secondary, subjective, and physiological measures were collected and integrated into a cognitive distraction scale. RESULTS: In-vehicle activities, such as listening to the radio or an audio book, were associated with a low level of cognitive workload; the conversation activities of talking to a passenger in the vehicle or conversing with a friend on a handheld or hands-free cell phone were associated with a moderate level of cognitive workload; and using a speech-to-text interfaced e-mail system involved a high level of cognitive workload. CONCLUSION: The research established that there are significant impairments to driving that stem from the diversion of attention from the task of operating a motor vehicle and that the impairments to driving are directly related to the cognitive workload of these in-vehicle activities. Moreover, the adoption of voice-based systems in the vehicle may have unintended consequences that adversely affect traffic safety. APPLICATION: These findings can be used to help inform scientifically based policies on driver distraction, particularly as they relate to cognitive distraction stemming from the diversion of attention to other concurrent activities in the vehicle.

The relationship between sustained attention and parasympathetic functioning.

Sustained attention (SA) is an important cognitive ability that plays a crucial role in successful cognitive control. Resting vagally-mediated heart rate variability (vmHRV) has emerged as an informative index of parasympathetic nervous system activity and a sensitive correlate of individual differences in cognitive control. However, it is unclear how resting vmHRV is associated with individual differences in sustained attention. The primary aim of the current study was to assess if resting vmHRV was associated with individual differences in performance on a neuropsychological assessment of sustained attention. We further aimed to characterize the relationship between resting vmHRV and dispositional factors related to sustained attention, specifically attentional errors in daily life, self-regulation, mindfulness and media-multitasking. Based on previous work, we hypothesized higher resting vmHRV would be associated with better sustained attention across task-based and self-report measures. We did not find resting vmHRV to be significantly associated with performance measures on a task-based assessment of sustained attention. Further, resting vmHRV was not significantly associated with attention errors, self-regulation, mindfulness, or media-multitasking. This work stands to expand the current understanding between parasympathetic functioning, cognition, and behavior, investigating the unexplored domain of sustained attention and related dispositional factors.

Mitochondrial respiratory function is preserved under cysteine starvation via glutathione catabolism in NSCLC.

Cysteine metabolism occurs across cellular compartments to support diverse biological functions and prevent the induction of ferroptosis. Though the disruption of cytosolic cysteine metabolism is implicated in this form of cell death, it is unknown whether the substantial cysteine metabolism resident within the mitochondria is similarly pertinent to ferroptosis. Here, we show that despite the rapid depletion of intracellular cysteine upon loss of extracellular cystine, cysteine-dependent synthesis of Fe-S clusters persists in the mitochondria of lung cancer cells. This promotes a retention of respiratory function and a maintenance of the mitochondrial redox state. Under these limiting conditions, we find that glutathione catabolism by CHAC1 supports the mitochondrial cysteine pool to sustain the function of the Fe-S proteins critical to oxidative metabolism. We find that disrupting Fe-S cluster synthesis under cysteine restriction protects against the induction of ferroptosis, suggesting that the preservation of mitochondrial function is antagonistic to survival under starved conditions. Overall, our findings implicate mitochondrial cysteine metabolism in the induction of ferroptosis and reveal a mechanism of mitochondrial resilience in response to nutrient stress.