Association of Gait Quality With Daily-Life Mobility: An Actigraphy and Global Positioning System Based Analysis in Older Adults.

OBJECTIVE: Walking is a key component of daily-life mobility. We examined associations between laboratory-measured gait quality and daily-life mobility through Actigraphy and Global Positioning System (GPS). We also assessed the relationship between two modalities of daily-life mobility i.e., Actigraphy and GPS. METHODS: In community-dwelling older adults (N = 121, age = 77±5 years, 70% female, 90% white), we obtained gait quality from a 4-m instrumented walkway (gait speed, walk-ratio, variability) and accelerometry during 6-Minute Walk (adaptability, similarity, smoothness, power, and regularity). Physical activity measures of step-count and intensity were captured from an Actigraph. Time out-of-home, vehicular time, activity-space, and circularity were quantified using GPS. Partial Spearman correlations between laboratory gait quality and daily-life mobility were calculated. Linear regression was used to model step-count as a function of gait quality. ANCOVA and Tukey analysis compared GPS measures across activity groups [high, medium, low] based on step-count. Age, BMI, and sex were used as covariates. RESULTS: Greater gait speed, adaptability, smoothness, power, and lower regularity were associated with higher step-counts (0.20<|ρp| < 0.26, p < .05). Age(ß = -0.37), BMI(ß = -0.30), speed(ß = 0.14), adaptability(ß = 0.20), and power(ß = 0.18), explained 41.2% variance in step-count. Gait characteristics were not related to GPS measures. Participants with high (>4800 steps) compared to low activity (steps<3100) spent more time out-of-home (23 vs 15%), more vehicular travel (66 vs 38 minutes), and larger activity-space (5.18 vs 1.88 km2), all p < .05. CONCLUSIONS: Gait quality beyond speed contributes to physical activity. Physical activity and GPS-derived measures capture distinct aspects of daily-life mobility. Wearable-derived measures should be considered in gait and mobility-related interventions.

Integration of metabolic flux with hepatic glucagon signaling and gene expression profiles in the conscious dog.

Glucagon rapidly and profoundly simulates hepatic glucose production (HGP), but for reasons which are unclear, this effect normally wanes after a few hours, despite sustained plasma glucagon levels. This study characterized the time course and relevance (to metabolic flux) of glucagon mediated molecular events in the livers of conscious dogs. Glucagon was either infused into the hepato-portal vein at a 6-fold basal rate in the presence of somatostatin and basal insulin, or it was maintained at a basal level in control studies. In one control group glucose remained at basal while in the other glucose was infused to match the hyperglycemia that occurred in the hyperglucagonemic group. Elevated glucagon caused a rapid (30 min) but only partially sustained increase in hepatic cAMP over 4h, a continued elevation in G6P, and activation and deactivation of glycogen phosphorylase and synthase activities, respectively. Net hepatic glycogenolysis and HGP increased rapidly, peaking at 30 min, then returned to baseline over the next 3h (although glucagons stimulatory effect on HGP was sustained relative to the hyperglycemic control group). Hepatic gluconeogenic flux did not increase due to lack of glucagon effect on substrate supply to the liver. Global gene expression profiling highlighted glucagon-regulated activation of genes involved in cellular respiration, metabolic processes, and signaling, and downregulation of genes involved in extracellular matrix assembly and development.

Cardiorespiratory fitness is associated with hippocampal resting state connectivity in women newly diagnosed with breast cancer.

Background: Breast cancer and its treatment are associated with aberrant patterns of resting state functional connectivity (rsFC) between the hippocampus and several areas of the brain, which may account for poorer cognitive outcomes in patients. Higher cardiorespiratory fitness (CRF) has been associated with enhanced rsFC and cognitive performance; however, these associations have not been well studied in breast cancer. We examined the relationship between CRF, rsFC of the hippocampus, and cognitive performance among women newly diagnosed with breast cancer. Methods: Thirty-four postmenopausal women newly diagnosed with Stage 0-IIIa breast cancer (Mage = 63.59 ± 5.73) were enrolled in a 6-month randomized controlled trial of aerobic exercise vs. usual care. During baseline assessments, participants completed functional brain imaging, a submaximal CRF test, and cognitive testing. Whole-brain, seed-based analyses were used to examine the relationship between CRF and hippocampal rsFC, with age, years of education, and framewise displacement included as covariates. Cognition was measured with a battery of validated neurocognitive measures, reduced to seven composite factors. Results: Higher CRF was positively associated with greater rsFC of the hippocampus to a cluster within the dorsomedial and dorsolateral frontal cortex (z-max = 4.37, p = 0.003, cluster extent = 1,020 voxels). Connectivity within cluster peaks was not significantly related to cognitive factors (all ps > 0.05). Discussion: CRF was positively associated with hippocampal rsFC to frontal cortex structures, comprising a network of regions commonly suppressed in breast cancer. Future longitudinal research is needed to explore whether baseline rsFC predicts long-term cognitive resilience in breast cancer.

Comparative Evaluation of Synthetic Cytokines for Enhancing Production and Performance of NK92 Cell-Based Therapies.

Off-the shelf immune cell therapies are potentially curative and may offer cost and manufacturing advantages over autologous products, but further development is needed. The NK92 cell line has a natural killer-like phenotype, has efficacy in cancer clinical trials, and is safe after irradiation. However, NK92 cells lose activity post-injection, limiting efficacy. This may be addressed by engineering NK92 cells to express stimulatory factors, and comparative analysis is needed. Thus, we systematically explored the expression of synthetic cytokines for enhancing NK92 cell production and performance. All synthetic cytokines evaluated (membrane-bound IL2 and IL15, and engineered versions of Neoleukin-2/15, IL15, IL12, and decoy resistant IL18) enhanced NK92 cell cytotoxicity. Engineered cells were preferentially expanded by expressing membrane-bound but not soluble synthetic cytokines, without compromising the radiosensitivity required for safety. Some membrane-bound cytokines conferred cell-contact independent paracrine activity, partly attributable to extracellular vesicles. Finally, we characterized interactions within consortia of differently engineered NK92 cells.

Peak Expiratory Flow Predicts Incident Dementia in a Representative Sample of U.S. Older Adults: The National Health and Aging Trends Study (NHATS).

BACKGROUND: Dementia is an increasingly important public health problem with various risk factors. Respiratory function, measured via peak expiratory flow (PEF), may be a modifiable dementia risk factor. METHODS: We investigated the association between PEF and incident dementia in 5 935 older adults from the National Health and Aging Trends Study (NHATS) from 2011 to 2014. Baseline PEF, expressed as a standardized residual (SR) percentile, was analyzed as a predictor of incident dementia using discrete-time proportional hazards models, while controlling for several health and sociodemographic covariates. RESULTS: After 14 332 person-years of follow-up, 9.0% (N = 536) had incident cases of dementia. Compared to the lowest PEF category (SR-percentile < 10%), the highest PEF category (SR-percentile ≥ 80%) had 49% lower risk of incident dementia (hazard ratio [HR] = 0.51; 95% confidence interval [CI; 0.37, 0.71]), and the second highest PEF category (SR-percentile 50%-80%) had 25% lower risk of incident dementia (HR = 0.75; 95% CI [0.56, 1.00]). A sensitivity analysis using multiple imputation to account for missing PEF measurements yielded similar associations with incident dementia. CONCLUSION: These associations suggest a dose-dependent relationship such that higher PEF categories were more protective against incident dementia. PEF may be considered as an easily administered, low-cost measure of respiratory function and a potentially modifiable dementia risk factor. Improving PEF may reduce dementia risk through vascular mechanisms, such as increased brain oxygenation. Future research should explore potential causal pathways between PEF and dementia.

Obesity, Psychological Distress, and Resting State Connectivity of the Hippocampus and Amygdala Among Women With Early-Stage Breast Cancer.

Objective: Overweight and obesity [body mass index (BMI) ≥ 25 kg/m2] are associated with poorer prognosis among women with breast cancer, and weight gain is common during treatment. Symptoms of depression and anxiety are also highly prevalent in women with breast cancer and may be exacerbated by post-diagnosis weight gain. Altered brain function may underlie psychological distress. Thus, this secondary analysis examined the relationship between BMI, psychological health, and resting state functional connectivity (rsFC) among women with breast cancer. Methods: The sample included 34 post-menopausal women newly diagnosed with Stage 0-IIa breast cancer (Mage = 63.59 ± 5.73) who were enrolled in a 6-month randomized controlled trial of aerobic exercise vs. usual care. At baseline prior to randomization, whole-brain analyses were conducted to evaluate the relationship between BMI and seed-to-voxel rsFC of the hippocampus and amygdala. Connectivity values from significant clusters were then extracted and examined as predictors of self-reported depression and anxiety. Results: Mean BMI was in the obese range (M = 31.83 ± 6.62). For both seeds examined, higher BMI was associated with lower rsFC with regions of prefrontal cortex (PFC), including ventrolateral PFC (vlPFC), dorsolateral PFC, and superior frontal gyrus (z range = 2.85-4.26). Hippocampal connectivity with the vlPFC was negatively correlated with self-reported anxiety (ß = 0.47, p < 0.01). Conclusion: Higher BMI was associated with lower hippocampal and amygdala connectivity to regions of PFC implicated in cognitive control and emotion regulation. BMI-related differences in hippocampal and amygdala connectivity following a recent breast cancer diagnosis may relate to future worsening of psychological functioning during treatment and remission. Additional longitudinal research exploring this hypothesis is warranted.

Estimating the financial costs associated with a phase III, multi-site exercise intervention trial: Investigating Gains in Neurocognition in an Intervention Trial of Exercise (IGNITE).

INTRODUCTION: Supervised exercise interventions are expensive and time intensive. However, there are financial costs to consider in addition to the intervention itself, namely: advertising and recruitment, outcome assessments, and other trial-related costs. OBJECTIVES: In this analysis, we examine the financial costs associated with the administration of Investigating Gains in Neurocognition in an Intervention Trial of Exercise (IGNITE) to quantify the costs associated with large exercise intervention trials and to provide future investigators with financial estimates if they wish to pursue studies of a similar design. METHODS: Cost per randomized participant were calculated in four areas: (1) advertising and recruitment, (2) outcome assessments, (3) delivery of the intervention, and (4) other trial-related expenses. Overall trial costs associated with data analysis, faculty salaries, and indirect costs were estimated as well. RESULTS: The total cost per randomized participant was estimated to be $16,494. Outcome assessments accounted for the highest proportion of per-participant (75%) and total trial (38%) costs. Neuroimaging assessments (MRI & PET) cost $8247 per randomized participant, accounting for two-thirds (67%) of outcome assessment costs and half (50%) of per-participant costs. CONCLUSION: Large clinical trials of exercise are expensive (~$21 million), particularly when administering several visits to assess study aims. Outcome assessments, specifically those involving neuroimaging, accounted for a significant proportion of total costs in this analysis. Future investigators must budget accordingly if they wish to conduct a comprehensive, multi-site exercise intervention trial that examines numerous physiological and psychological outcomes.

Ultrahigh capacitive energy density in ion-bombarded relaxor ferroelectric films.

Dielectric capacitors can store and release electric energy at ultrafast rates and are extensively studied for applications in electronics and electric power systems. Among various candidates, thin films based on relaxor ferroelectrics, a special kind of ferroelectric with nanometer-sized domains, have attracted special attention because of their high energy densities and efficiencies. We show that high-energy ion bombardment improves the energy storage performance of relaxor ferroelectric thin films. Intrinsic point defects created by ion bombardment reduce leakage, delay low-field polarization saturation, enhance high-field polarizability, and improve breakdown strength. We demonstrate energy storage densities as high as ~133 joules per cubic centimeter with efficiencies exceeding 75%. Deterministic control of defects by means of postsynthesis processing methods such as ion bombardment can be used to overcome the trade-off between high polarizability and breakdown strength.

The COMET toolkit for composing customizable genetic programs in mammalian cells.

Engineering mammalian cells to carry out sophisticated and customizable genetic programs requires a toolkit of multiple orthogonal and well-characterized transcription factors (TFs). To address this need, we develop the COmposable Mammalian Elements of Transcription (COMET)-an ensemble of TFs and promoters that enable the design and tuning of gene expression to an extent not, to the best of our knowledge, previously possible. COMET currently comprises 44 activating and 12 inhibitory zinc-finger TFs and 83 cognate promoters, combined in a framework that readily accommodates new parts. This system can tune gene expression over three orders of magnitude, provides chemically inducible control of TF activity, and enables single-layer Boolean logic. We also develop a mathematical model that provides mechanistic insights into COMET performance characteristics. Altogether, COMET enables the design and construction of customizable genetic programs in mammalian cells.

Elucidation and refinement of synthetic receptor mechanisms.

Synthetic receptors are powerful tools for engineering mammalian cell-based devices. These biosensors enable cell-based therapies to perform complex tasks such as regulating therapeutic gene expression in response to sensing physiological cues. Although multiple synthetic receptor systems now exist, many aspects of receptor performance are poorly understood. In general, it would be useful to understand how receptor design choices influence performance characteristics. In this study, we examined the modular extracellular sensor architecture (MESA) and systematically evaluated previously unexamined design choices, yielding substantially improved receptors. A key finding that might extend to other receptor systems is that the choice of transmembrane domain (TMD) is important for generating high-performing receptors. To provide mechanistic insights, we adopted and employed a Förster resonance energy transfer-based assay to elucidate how TMDs affect receptor complex formation and connected these observations to functional performance. To build further insight into these phenomena, we developed a library of new MESA receptors that sense an expanded set of ligands. Based upon these explorations, we conclude that TMDs affect signaling primarily by modulating intracellular domain geometry. Finally, to guide the design of future receptors, we propose general principles for linking design choices to biophysical mechanisms and performance characteristics.

Light-Induced Currents at Domain Walls in Multiferroic BiFeO3.

Multiferroic BiFeO3 (BFO) films with spontaneously formed periodic stripe domains can generate above-gap open circuit voltages under visible light illumination; nevertheless the underlying mechanism behind this intriguing optoelectronic response has not been understood to date. Here, we make contact-free measurements of light-induced currents in epitaxial BFO films via detecting terahertz radiation emanated by these currents, enabling a direct probe of the intrinsic charge separation mechanisms along with quantitative measurements of the current amplitudes and their directions. In the periodic stripe samples, we find that the net photocurrent is dominated by the charge separation across the domain walls, whereas in the monodomain samples the photovoltaic response arises from a bulk shift current associated with the non-centrosymmetry of the crystal. The peak current amplitude driven by the charge separation at the domain walls is found to be 2 orders of magnitude higher than the bulk shift current response, indicating the prominent role of domain walls acting as nanoscale junctions to efficiently separate photogenerated charges in the stripe domain BFO films. These findings show that domain-wall-engineered BFO thin films offer exciting prospects for ferroelectric-based optoelectronics, as well as bias-free strong terahertz emitters.

Weight-Loss Outcomes from a Pilot Study of African Dance in Older African Americans.

OBJECTIVE: Obesity is a risk factor for both cognitive and physical impairment in late adulthood. Though the rates of obesity are high in many groups, older African Americans are disproportionately affected. A randomized pilot intervention of African Dance was conducted with 28 African American older adults with obesity (mean age = 68.4 ± 5.1 years; mean BMI = 33.4 ± 6.2). The goal of the study was to evaluate the physiological outcomes of a culturally sensitive exercise intervention and specifically changes in weight. METHODS: Participants were randomly assigned to an African Dance (experimental) or Culture Education (control) group. They attended their assigned class for 1 hour per session, 3 days per week, for 6 months. RESULTS: There was a significant group × time interaction on weight (P  = 0.005) such that the African Dance group lost weight (mean = 4.0 ± 6.0 lb) while the Culture Education group gained weight (mean = 2.6 ± 3.9 lb). CONCLUSIONS: These results suggest that a culturally sensitive form of physical activity, African Dance, may be effective for promoting weight loss in a population at increased risk for obesity and cognitive decline.

Protocol for Exercise Program in Cancer and Cognition (EPICC): A randomized controlled trial of the effects of aerobic exercise on cognitive function in postmenopausal women with breast cancer receiving aromatase inhibitor therapy.

The Exercise Program in Cancer and Cognition (EPICC) Study is a randomized controlled trial designed to test the effects of moderate-intensity aerobic exercise on cognitive function in postmenopausal women with early-stage breast cancer during the first six months of aromatase inhibitor therapy. It is estimated that up to 75% of survivors of breast cancer experience cognitive impairment related to disease and treatment. At present, there are no known interventions to improve or manage cognitive function for women with breast cancer. Here, we describe a single-blinded, randomized controlled trial with allocation of 254 postmenopausal women with early-stage breast cancer to a supervised six-month aerobic exercise intervention or usual care. Prior to beginning aromatase inhibitor (AI) therapy, participants complete baseline assessments of cognitive function, cardiorespiratory fitness, blood-based biomarkers, physical activity and sleep, and symptoms (fatigue, sleep problems, depressive symptoms, anxiety). A random subset of participants (n = 150) undergoes neuroimaging procedures that include structural and functional magnetic resonance imaging assessments. All participants maintain an activity diary; physical activity and sleep monitoring is repeated three and seven months post-randomization. The remaining baseline assessments are repeated seven months post-randomization. If successful, exercise could be a low-cost method to improve cognitive function in women with breast cancer that is easily adaptable to the home or community. TRIAL REGISTRATION: Clinicaltrials.govNCT02793921. Registered 20 May 2016.

Energy Expenditure in Vinyasa Yoga Versus Walking.

BACKGROUND: Whether the energy cost of vinyasa yoga meets the criteria for moderate-to-vigorous physical activity has not been established. PURPOSE: To compare energy expenditure during acute bouts of vinyasa yoga and 2 walking protocols. METHODS: Participants (20 males, 18 females) performed 60-minute sessions of vinyasa yoga (YOGA), treadmill walking at a self-selected brisk pace (SELF), and treadmill walking at a pace that matched the heart rate of the YOGA session (HR-Match). Energy expenditure was assessed via indirect calorimetry. RESULTS: Energy expenditure was significantly lower in YOGA compared with HR-Match (difference = 79.5 ± 44.3 kcal; P < .001) and SELF (difference = 51.7 ± 62.6 kcal; P < .001), but not in SELF compared with HR-Match (difference = 27.8 ± 72.6 kcal; P = .054). A similar pattern was observed for metabolic equivalents (HR-Match = 4.7 ± 0.8, SELF = 4.4 ± 0.7, YOGA = 3.6 ± 0.6; P < .001). Analyses using only the initial 45 minutes from each of the sessions, which excluded the restorative component of YOGA, showed energy expenditure was significantly lower in YOGA compared with HR-Match (difference = 68.0 ± 40.1 kcal; P < .001) but not compared with SELF (difference = 15.1 ± 48.7 kcal; P = .189). CONCLUSIONS: YOGA meets the criteria for moderate-intensity physical activity. Thus, YOGA may be a viable form of physical activity to achieve public health guidelines and to elicit health benefits.

Building with intent: technologies and principles for engineering mammalian cell-based therapies to sense and respond.

The engineering of cells as programmable devices has enabled therapeutic strategies that could not otherwise be achieved. Such strategies include recapitulating and enhancing native cellular functions and composing novel functions. These novel functions may be composed using both natural and engineered biological components, with the latter exemplified by the development of synthetic receptor and signal transduction systems. Recent advances in implementing these approaches include the treatment of cancer, where the most clinical progress has been made to date, and the treatment of diabetes. Principles for engineering cell-based therapies that are safe and effective are increasingly needed and beginning to emerge, and will be essential in the development of this new class of therapeutics.

Thermodynamic signature of DNA damage: characterization of DNA with a 5-hydroxy-2'-deoxycytidine·2'-deoxyguanosine base pair.

Oxidation of DNA due to exposure to reactive oxygen species is a major source of DNA damage. One of the oxidation lesions formed, 5-hydroxy-2'-deoxycytidine, has been shown to miscode by some replicative DNA polymerases but not by error prone polymerases capable of translesion synthesis. The 5-hydroxy-2'-deoxycytidine lesion is repaired by DNA glycosylases that require the 5-hydroxycytidine base to be extrahelical so it can enter into the enzyme's active site where it is excised off the DNA backbone to afford an abasic site. The thermodynamic and nuclear magnetic resonance results presented here describe the effect of a 5-hydroxy-2'-deoxycytidine·2'-deoxyguanosine base pair on the stability of two different DNA duplexes. The results demonstrate that the lesion is highly destabilizing and that the energy barrier for the unstacking of 5-hydroxy-2'-deoxycytidine from the DNA duplex may be low. This could provide a thermodynamic mode of adduct identification by DNA glycosylases that requires the lesion to be extrahelical.