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BackgroundOccupational therapy (OT) is a vital service that supports older adults’ ability to age in place. Given the barriers to accessing care, video telehealth is a means of providing OT. Even within Veterans Health Administration (VHA), a pioneer in telehealth, video telehealth by OT practitioners to serve older adults is not well understood. ObjectiveThis study examines VHA OT practice using video telehealth with older veterans using an implementation framework. MethodsA web-based national survey of VHA OT practitioners conducted between September and October 2019 contained a mix of mostly closed questions with some open-text options. The questions were developed using the Promoting Action on Research Implementation in Health Services model with input from subject matter experts. The questions gathered the extent to which VHA OT practitioners use video telehealth with older veterans; are comfortable with video telehealth to deliver specific OT services; and, for those using video telehealth with older veterans, the barriers, facilitators of change, and perceived benefits of video telehealth. ResultsOf approximately 1455 eligible VHA OT practitioners, 305 participated (21.0% response rate). Most were female (196/259, 75.7%) occupational therapists (281/305, 92.1%) with a master’s degree (147/259, 56.8%) and 10 years or fewer (165/305, 54.1%) of VHA OT practice. Less than half (125/305, 41.0%) had used video telehealth with older veterans, and users and nonusers of video telehealth were demographically similar. When asked to rate perceived comfort with video telehealth to deliver OT services, participants using video telehealth expressed greater comfort than nonusers, which was significant for 9 of the 13 interventions: activities of daily living (P

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.

The mechanisms underlying metabolic adaptation of pancreatic ductal adenocarcinoma (PDA) cells to pharmacologic inhibition of RAS-MAPK signaling are largely unknown. Using transcriptome and chromatin immunoprecipitation profiling of PDA cells treated with the MEK inhibitor (MEKi) trametinib, we identify transcriptional antagonism between c-MYC and the master transcription factors for lysosome gene expression, the MiT/TFE proteins. Under baseline conditions, c-MYC and MiT/TFE factors compete for binding to lysosome gene promoters to fine-tune gene expression. Treatment of PDA cells or patient organoids with MEKi leads to c-MYC downregulation and increased MiT/TFE-dependent lysosome biogenesis. Quantitative proteomics of immunopurified lysosomes uncovered reliance on ferritinophagy, the selective degradation of the iron storage complex ferritin, in MEKi-treated cells. Ferritinophagy promotes mitochondrial iron-sulfur cluster protein synthesis and enhanced mitochondrial respiration. Accordingly, suppressing iron utilization sensitizes PDA cells to MEKi, highlighting a critical and targetable reliance on lysosome-dependent iron supply during adaptation to KRAS-MAPK inhibition.SignificanceReduced c-MYC levels following MAPK pathway suppression facilitate the upregulation of autophagy and lysosome biogenesis. Increased autophagy-lysosome activity is required for increased ferritinophagy-mediated iron supply, which supports mitochondrial respiration under therapy stress. Disruption of ferritinophagy synergizes with KRAS-MAPK inhibition and blocks PDA growth, thus highlighting a key targetable metabolic dependency. See related commentary by Jain and Amaravadi, p. 2023. See related article by Santana-Codina et al., p. 2180. This article is highlighted in the In This Issue feature, p. 2007.

Cognitive control operates via two distinct mechanisms, proactive and reactive control. These control states are engaged differentially, depending on a number of within-subject factors, but also between-group variables. While research has begun to explore if shifts in control can be experimentally modulated, little is known about whether context impacts which control state is utilized. Thus, we test if contextual factors temporarily bias the use of a particular control state long enough to impact performance on a subsequent task. Our methodology involves two parts: first participants are exposed to a context manipulation designed to promote proactive or reactive processing through amount or availability of advanced preparation within a task-switching paradigm. Then, they complete an AX-CPT task, where we assess immediate transfer on preferential adoption of one control mode over another. We present results from a Pilot Study that revealed anecdotal evidence of proactive versus reactive processing for a context manipulation using long and short preparation times. We also present data from a follow-up Registered Experiment that implements a context manipulation using long or no preparation times to assess if a more extreme context leads to pronounced differences on AX-CPT performance. Together, the results suggest that contextual representations do not impact the engagement of a particular control state, but rather, there is a general preference for the engagement of proactive control.

Copper is an essential nutrient for sustaining vital cellular processes spanning respiration, metabolism, and proliferation. However, loss of copper homeostasis, particularly misregulation of loosely bound copper ions which are defined as the labile copper pool, occurs in major diseases such as cancer, where tumor growth and metastasis have a heightened requirement for this metal. To help decipher the role of copper in the etiology of cancer, we report a histochemical activity-based sensing approach that enables systematic, high-throughput profiling of labile copper status across many cell lines in parallel. Coppermycin-1 reacts selectively with Cu(I) to release puromycin, which is then incorporated into nascent peptides during protein translation, thus leaving a permanent and dose-dependent marker for labile copper that can be visualized with standard immunofluorescence assays. We showcase the utility of this platform for screening labile Cu(I) pools across the National Cancer Institute's 60 (NCI-60) human tumor cell line panel, identifying cell types with elevated basal levels of labile copper. Moreover, we use Coppermycin-1 to show that lung cancer cells with heightened activation of nuclear factor-erythroid 2-related factor 2 (NRF2) possess lower resting labile Cu(I) levels and, as a result, have reduced viability when treated with a copper chelator. This work establishes that methods for labile copper detection can be used to assess cuproplasia, an emerging form of copper-dependent cell growth and proliferation, providing a starting point for broader investigations into the roles of transition metal signaling in biology and medicine. [ABSTRACT FROM AUTHOR]

Stress carries diverse implications for perceptual, cognitive, and affective functions. One population particularly susceptible to acute stress-induced cognitive changes are individuals with high-stress jobs (e.g., military personnel). These individuals are often tasked with maintaining peak cognitive performance, including memory, spatial navigation, and decision-making under threatening and uncertain conditions. Previous research has separately examined decision-making under conditions of stress or uncertainty (i.e., ambiguous discrimination between friends and foes). However, questions remain about how operationally relevant stress impacts memory encoding and recall, or spatial learning, as well as how uncertainty may impact decision-making during stress. To address this gap, we examined the influence of a military-relevant emotional stressor on a series of cognitive tasks including recognition memory task (RMT), spatial orienting task (SOT), and shoot/don't shoot decision making (DMT). To examine the effects of uncertainty and stress we varied the stimulus clarity in the DMT. We utilized threat of shock (TOS) as a high-stakes outcome for decision errors. TOS increased sympathetic arousal but did not affect subjective emotional or HPA responses. TOS influenced decision times and confidence ratings in the DMT, but not response sensitivity or response bias. DMT performance varied by stimulus clarity (uncertainty) but did not differ between stress conditions. TOS did not influence recognition memory or spatial orienting. In sum, high levels of stress and uncertainty characterize military operations, yet stress experienced in military contexts can be difficult to induce in laboratory settings. We discuss several avenues for future research, including methodological considerations to better assess the magnitude and specificity of emotional stress-induction techniques in Soldiers. [ABSTRACT FROM AUTHOR]

Themotoric cognitive risk syndrome (MCR) is a syndrome characterized by subjective memory complaints and slowwalking speeds that can identify older adults at increased risk for developing Alzheimer's disease or a related dementia (ADRD). To date, the feasibility of community-based physical activity (PA) programs for improving outcomes in MCR have yet to be examined. To address this knowledge gap, we conducted a translational randomized controlled trial (RCT) comparing 24-weeks of PA to a healthy aging education (HE) control intervention delivered within the infrastructure of an urban senior center in Greater Boston (clincaltrials.gov identifier: NCT03750682). An existing senior center employee was trained to administer the multimodal groupbased PA program that included moderate-intensity aerobic walking, strength, flexibility and balance training. A total of 79 older adults attended the senior center for a screening visit, of whom 29met the MCR criteria and 25 were randomized to PA orHE(meanage: 74.4±7years; BMI: 32.4±7kg/m2;85%female; 3MSE score: 92.4± 7; gait speed: 0.52 ± 0.1 m/s; SPPB score 4.8 ± 1.9). Due to the Covid-19 pandemic the study was stopped prematurely. Participants could successfully adhere to the study interventions (overall attendance rate: PA: 69% vs. HE:70% at study termination). Participants also successfully completed baseline and follow-up study assessments that included a computerized cognitive testing battery and objective tests of physical performance and functional exercise capacity. No study-related adverse events occurred. Notable trends for improved cognitive performance, gait speed and 6- minwalk distancewere exhibited in PA compared to HE.Our study provides important preliminary information to aid the design of larger-scale RCTs of PA that may help to preserve the independence of vulnerable older adults at high risk for ADRD in community-based settings. [ABSTRACT FROM AUTHOR]

Performing two cognitive tasks at the same time can degrade performance for either domain-general reasons (e.g., both tasks require attention) or domain-specific reasons (e.g., both tasks require visual working memory). We tested predictions of these two accounts of interference on the task of driving while using language, a naturally occurring dual task. Using language and driving a vehicle use different perceptual and motor skills. As a consequence, a domain-general explanation for interference in this dual task appears most plausible. However, recent evidence from the language processing literature suggests that when people use language with motor content (e.g., language about actions) or visual content (e.g., language about visible objects and events), they engage their motor and perceptual systems in ways specifically reflecting the actions and percepts that the language is about. This raises the possibility that language might interfere with driving for domain-specific reasons when the language has visual or motor content. To test this, we had participants drive a simulated vehicle while simultaneously answering true-false statements that had motor, visual, or abstract content. A domain-general explanation for interference would predict greater distraction in each of these three conditions compared with control, while a domain-specific explanation would predict greater interference in the motor and visual conditions. Both of these predictions were borne out but on different measures of distraction, suggesting that language-driven distraction during driving and dual tasks involving language in general may be the result not only of domain-general causes but also specific interference caused by linguistic content. (Contains 3 figures, 1 table, and 1 footnote.)