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Some hypothesize that aging in humans is a cumulative process of macromolecular and mitochondrial damage starting years, even decades before any symptoms arise. Aging may begin when the rate of damage exceeds the rate of continual repair and turnover. Quality control for damaged mitochondria entails cellular digestion by mitophagy, a specialized kind of autophagy. Insufficient protective autophagy could cause damaged cellular components to accumulate over many years until they affect normal function in the cell. Alternatively, aging could be the result of overactive, pathologic autophagy. Current knowledge supports both hypotheses with conflicting data, depending on which stage of autophagy is examined. To distinguish these opposite hypotheses, two criteria need to be observed. First, is there a buildup of undigested waste that can be removed by stimulation of autophagy? Or second, if autophagy is overactive, does inhibition of autophagy rescue cell, organ and organism demise. Both of these are best determined by rate measures rather than measures at a single time point. Here, we review the generalized process of autophagy, with a focus on the limited information available for neuron mitophagy, aging, and Alzheimer's disease (AD). In two mouse models, treatment with rapamycin abolishes the AD pathology and reverses memory deficits. As a working model, we hypothesize that insufficient protective autophagy accelerates both aging and AD pathology, possibly caused by defects in autophagosome fusion with lysosomes. [ABSTRACT FROM AUTHOR]

Alzheimer's disease is associated with synapse loss, memory dysfunction, and pathological accumulation of amyloid-β (Aβ) in plaques. However, an exclusively pathological role for Aβ is being challenged by new evidence for an essential function of Aβ at the synapse. Aβ protein exists in different assembly states in the central nervous system and plays distinct roles ranging from synapse and memory formation to memory loss and neuronal cell death. Aβ is present in the brain of symptom-free people where it likely performs important physiological roles. New evidence indicates that synaptic activity directly evokes the release of Aβ at the synapse. At physiological levels, Aβ is a normal, soluble product of neuronal metabolism that regulates synaptic function beginning early in life. Monomeric Aβ40 and Aβ42 are the predominant forms required for synaptic plasticity and neuronal survival. With age, some assemblies of Aβ are associated with synaptic failure and Alzheimer's disease pathology, possibly targeting the N-methyl-D-aspartic acid receptor through the nicotinic acetylcholine receptor, mitochondrial Aβ alcohol dehydrogenase, and cyclophilin D. But emerging data suggests a distinction between age effects on the target response in contrast to the assembly state or the accumulation of the peptide. Both aging and Aβ independently decrease neuronal plasticity. Our laboratory has reported that Aβ, glutamate, and lactic acid are each increasingly toxic with neuron age. The basis of the age-related toxicity partly resides in age-related mitochondrial dysfunction and an oxidative shift in mitochondrial and cytoplasmic redox potential. In turn, signaling through phosphorylated extracellular signal-regulated protein kinases is affected along with an age-independent increase in phosphorylated cAMP response element-binding protein. This review examines the long-awaited functional impact of Aβ on synaptic plasticity. [ABSTRACT FROM AUTHOR]

A new anticopper drug, tetrathiomolybdate (TM), developed for Wilson's disease, is a very promising antiangiogenic agent. Copper levels lowered into an antiangiogenic window by TM have shown efficacy against cancer in a variety of animal models as well as in patients. The only significant toxicity so far results from overtreatment and excessive bone marrow depletion of copper. The resulting anemia and/or leukopenia is easily treatable by dose reduction or drug holiday. The underlying concept for TM efficacy as an anticancer agent is that when the body's copper status is in the window, cellular copper needs are met and toxicity is avoided. Copper status is relatively easily monitored by following serum ceruloplasmin, a copper-containing protein secreted by the liver at a rate dependent upon the amount of copper in the liver available to incorporate into the protein. The authors speculate that the copper level is a primitive angiogenesis and growth-signaling regulator that has been retained throughout evolution. [ABSTRACT FROM AUTHOR]

Spindle-shaped waves of oscillations emerge in EEG scalp recordings during human and rodent non-REM sleep. The association of these 10-16 Hz oscillations with events during prior wakefulness suggests a role in memory consolidation. Human and rodent depth electrodes in the brain record strong spindles throughout the cortex and hippocampus, with possible origins in the thalamus. However, the source and targets of the spindle oscillations from the hippocampus are unclear. Here, we employed an in vitro reconstruction of four subregions of the hippocampal formation with separate microfluidic tunnels for single axon communication between subregions assembled on top of a microelectrode array. We recorded spontaneous 400-1000 ms long spindle waves at 10-16 Hz in single axons passing between subregions as well as from individual neurons in those subregions. Spindles were nested within slow waves. The highest amplitudes and most frequent occurrence suggest origins in CA3 neurons that send feed-forward axons into CA1 and feedback axons into DG. Spindles had 50-70% slower conduction velocities than spikes and were not phase-locked to spikes suggesting that spindle mechanisms are independent of action potentials. Therefore, consolidation of declarative-cognitive memories in the hippocampus may be separate from the more easily accessible consolidation of memories related to thalamic motor function., (© 2024. The Author(s).)

Background: Outdoor races introduce environmental stressors to runners, and core temperature changes may influence runners' movement patterns. This study assessed changes and determined relationships between sensor-derived running biomechanics and core temperature among runners across an 11.27-km road race., Hypothesis: Core temperatures would increase significantly across the race, related to changes in spatiotemporal biomechanical measures., Study Design: Cross-sectional cohort study., Level of Evidence: Level 3., Methods: Twenty runners (9 female, 11 male; age, 48 ± 12 years; height, 169.7 ± 9.1 cm; mass, 71.3 ± 13.4 kg) enrolled in the 2022 Falmouth Road Race were recruited. Participants used lightweight technologies (ingestible thermistors and wearable sensors) to monitor core temperature and running biomechanics throughout the race. Timestamps were used to align sensor-derived measures for 7 race segments. Observations were labeled as core temperatures generally within normal limits (<38°C) or at elevated core temperatures (≥38°C). Multivariate repeated measures analyses of variance were used to assess changes in sensor-derived measures across the race, with Bonferroni post hoc comparisons for significant findings. Pearson's r correlations were used to assess the relationship between running biomechanics and core temperature measures., Results: Eighteen participants developed hyperthermic core temperatures (39.0°C ± 0.5°C); core temperatures increased significantly across the race ( P < 0.01). Kinetic measures obtained from the accelerometers, including shock, impact, and braking g , all significantly increased across the race ( P < 0.01); other sensor-derived biomechanical measures did not change significantly. Core temperatures were weakly associated with biomechanics (| r range|, 0.02-0.16)., Conclusion: Core temperatures and kinetics increased significantly across a race, yet these outcomes were not strongly correlated. The observed kinetic changes may have been attributed to fatigue-related influences over the race., Clinical Relevance: Clinicians may not expect changes in biomechanical movement patterns to signal thermal responses during outdoor running in a singular event., Competing Interests: The following authors declared potential conflicts of interest: A.D.L. has received grant support from VALD Performance. W.M. has received grant support from the NHL Alumni Association and the NFL.

Purpose: To investigate heat stress mitigation strategies on productivity and thermoregulatory responses during simulated occupational work in the heat., Methods: Thirteen physically active men (age, 25 ± 4 years; body mass,77.8 ± 14.7 kg; VO 2 peak, 44.5 ± 9.2 ml·kg -1 ·min -1 ) completed five randomized-controlled trials in a hot environment (40°C, 40% relative humidity). Each trial was 4.5 h in duration to simulate an outdoor occupational shift. Thermoregulatory responses (heart rate, HR; rectal temperature, Trec; mean skin temperature, Tsk), perceptual responses (rating of perceived exertion, RPE; thermal sensation; thermal comfort; fatigue) and productivity outcomes (box lifting repetitions, time to exhaustion) were examined in the following heat mitigation strategy interventions: (1) simulated solar radiation with limited fluid intake [SUN]; (2) simulated solar radiation with no fluid restrictions [SUN + H2O]; (3) shade (no simulated solar radiation during trial) with no fluid restrictions [SHADE + H 2 O]; (4) shade and cooling towels during rest breaks with no fluid restrictions [COOL + H 2 O]; and (5) shade with cooling towels, cooling vest during activity with no fluid restrictions [COOL + VEST + H 2 O]., Results: [COOL + VEST + H 2 O] had lower Trec compared to [SUN] [ p  = 0.004, effect size(ES) = 1.48], [SUN + H 2 O] ( p  < 0.001, ES = -1.87), and [SHADE + H 2 O] ( p  = 0.001, ES = 1.62). Average Tsk was lower during the treadmill and box lifting activities in the [COOL + VEST + H 2 O] compared to [SUN] ( p  < 0.001, ES = 7.92), [SUN + H 2 O] ( p  < 0.001,7.96), [SHADE + H 2 O] ( p  < 0.001), and [COOL + H 2 O] ( p  < 0.001, ES = 3.01). There were performance differences during the [COOL + VEST + H 2 O] (p = 0.033) and [COOL + H 2 O] ( p  = 0.023) conditions compared to [SUN] during phases of the experimental trial, however, there were no differences in total box lifting repetitions between trials ( p  > 0.05)., Conclusion: Our results suggest that during a simulated occupational shift in a laboratory setting, additional heat mitigation strategies ([COOL + VEST + H 2 O] and [COOL + H 2 O]) reduced physiological strain and improved box lifting performance to a greater degree than [SUN]. These differences may have been attributed to a larger core to skin temperature gradient or reduction in fatigue, thermal sensation, and RPE during [COOL + H 2 O] and [COOL + VEST + H 2 O]. These data suggest that body cooling, hydration, and "shade" (removal of simulated radiant heat) as heat stress mitigation strategies should be considered as it reduces physiological strain while producing no additional harm., Competing Interests: WA receives royalties from Springer Nature and sits on the following advisory boards; Medical and Science Advisory Board for the Korey Stringer Institute, Sport Advisory Council for the Wu Tsai Human Performance Alliance, Expert Advisory Board for Emerja Corporation, and Expert Advisory Board for My Normative. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Morrissey-Basler, Brewer, Anderson, Adams, Navarro, Marcelino, Martin and Casa.)

The sub-regions of the hippocampal formation are essential for episodic learning and memory formation, yet the spike dynamics of each region contributing to this function are poorly understood, in part because of a lack of access to the inter-regional communicating axons. Here, we reconstructed hippocampal networks confined to four subcompartments in 2D cultures on a multi-electrode array that monitors individual communicating axons. In our novel device, somal, and axonal activity was measured simultaneously with the ability to ascertain the direction and speed of information transmission. Each sub-region and inter-regional axons had unique power-law spiking dynamics, indicating differences in computational functions, with abundant axonal feedback. After stimulation, spiking, and burst rates decreased in all sub-regions, spikes per burst generally decreased, intraburst spike rates increased, and burst duration decreased, which were specific for each sub-region. These changes in spiking dynamics post-stimulation were found to occupy a narrow range, consistent with the maintenance of the network at a critical state. Functional connections between the sub-region neurons and communicating axons in our device revealed homeostatic network routing strategies post-stimulation in which spontaneous feedback activity was selectively decreased and balanced by decreased feed-forward activity. Post-stimulation, the number of functional connections per array decreased, but the reliability of those connections increased. The networks maintained a balance in spiking and bursting dynamics in response to stimulation and sharpened network routing. These plastic characteristics of the network revealed the dynamic architecture of hippocampal computations in response to stimulation by selective routing on a spatiotemporal scale in single axons., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lassers, Vakilna, Tang and Brewer.)

Background: Stable flies [Stomoxys calcitrans (L.)] are economically important pests of cattle and other livestock. As an alternative to conventional insecticides, we tested a push-pull management strategy using a coconut oil fatty acid repellent formulation and an attractant-added stable fly trap., Results: In our field trials we found that weekly applications of a push-pull strategy can reduce stable fly populations on cattle as well as a standard insecticide (permethrin). We also found that the efficacy periods of the push-pull and permethrin treatments following on-animal application were equivalent. Traps with an attractant lure used as the pull component of the push-pull strategy captured sufficient numbers of stable flies to reduce on-animal numbers by an estimated 17-21%., Conclusions: This is the first proof-of-concept field trial demonstrating the effectiveness of a push-pull strategy using a coconut oil fatty acid-based repellent formulation and traps with an attractant lure to manage stable flies on pasture cattle. Also notable is that the push-pull strategy had an efficacy period equivalent to that of a standard, conventional insecticide under field conditions. © 2023 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry., (© 2023 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.)

In hybrid sunflower, bee pollination can improve productivity, but the contribution of bees to productivity may be over or underestimated. To estimate bee effects (seed trait gains from exposure to bees during anthesis), single capitula are commonly covered with a porous material to exclude bees. However, depending on the exclosure porosity, estimates of the magnitude of bee effects will vary. In two studies, porosity size and bee effect gains in two sunflower types were tested. In the exclosure study, Delnet exclosures severely reduced seed set and exclosures with larger porosities and had smaller and similar effects. However, since a few small bees penetrated the largest porosity size tested, exclosures with porosity sizes < 7 mm are recommended. With an exclosure porosity of 5 X 5 mm, the estimated bee effect contribution to the yield was 323 kg per hectare. Effects of exclosures on seed traits were similar in the oilseed and confectionary hybrids tested. Insecticide use did not affect seed traits but did lower insect damage to seeds. Bees from three families, mostly Apidae, were collected while foraging on sunflower. In summary, we recommend the use of exclosures with porosities of about 3 to 5 mm to avoid over or underestimating bee effects. And we recommend holistic insect management for sunflower cropping systems that balances the benefits of bee effects on seed traits with management of pest insects., Competing Interests: The authors declare no conflicts of interest.

Purpose: To quantify the current literature and limitations associated with research examining thermoregulatory and cardiovascular strain in laborers working in the heat., Methods: PubMed, SCOPUS, and SPORTDiscus were searched for terms related to the cardiovascular system, heat stress, and physical work. Qualifying studies included adult participants (18-65 years old), a labor-intensive environment or exercise protocol simulating a labor environment, a minimum duration of 120 min of physical work, and environmental heat stress (ambient temperature ≥26.0°C and ≥30% relative humidity). Studies included at least one of the following outcomes: pre- and peak physical work, core temperature, heart rate (HR), systolic blood pressure, diastolic blood pressure, HR variability, and rate pressure product., Results: Twenty-one out of 1559 potential studies qualified from our search. There was a total of 598 participants (mean = 28 ± 50 participants per study, range = 4-238 participants per study), which included 51 females (8.5%) and 547 males (91.5%). Of the participants, 3.8% had cardiovascular risk factors (diabetes: n = 10; hypertension: n = 13) and 96.2% were characterized as "healthy". Fifty-seven percent of the included studies were performed in a laboratory setting., Conclusions: Studies were predominantly in men (91.5%), laboratory settings (57%), and "healthy" individuals (96.2%). To advance equity in protection against occupational heat stress and better inform future heat safety recommendations to protect all workers, future studies must focus on addressing these limitations. Employers, supervisors, and other safety stakeholders should consider these limitations while implementing current heat safety recommendations., (© 2023 Wiley Periodicals LLC.)

Increased interest in the aging and Alzheimer's disease (AD)-related impairments in autophagy in the brain raise important questions about regulation and treatment. Since many steps in endocytosis and autophagy depend on GTPases, new measures of cellular GTP levels are needed to evaluate energy regulation in aging and AD. The recent development of ratiometric GTP sensors (GEVALS) and findings that GTP levels are not homogenous inside cells raise new issues of regulation of GTPases by the local availability of GTP. In this review, we highlight the metabolism of GTP in relation to the Rab GTPases involved in formation of early endosomes, late endosomes, and lysosomal transport to execute the autophagic degradation of damaged cargo. Specific GTPases control macroautophagy (mitophagy), microautophagy, and chaperone-mediated autophagy (CMA). By inference, local GTP levels would control autophagy, if not in excess. Additional levels of control are imposed by the redox state of the cell, including thioredoxin involvement. Throughout this review, we emphasize the age-related changes that could contribute to deficits in GTP and AD. We conclude with prospects for boosting GTP levels and reversing age-related oxidative redox shift to restore autophagy. Therefore, GTP levels could regulate the numerous GTPases involved in endocytosis, autophagy, and vesicular trafficking. In aging, metabolic adaptation to a sedentary lifestyle could impair mitochondrial function generating less GTP and redox energy for healthy management of amyloid and tau proteostasis, synaptic function, and inflammation., (© 2023. The Author(s).)

Laborers are particularly vulnerable to exertional injuries and illnesses, as they often engage in heavy physical work for prolonged hours, yet no studies have examined the top causes of catastrophic exertional injuries and fatalities among this population. The purpose of the investigation was to characterize the top causes of exertional injury and fatality within open access, Occupational Safety and Health Administration (OSHA) reportable data. A secondary analysis of OSHA reported injury and fatality data was performed through open access records from OSHA Severe Injury Reports (2015-2022) and OSHA fatality inspection data (2017-2020), respectively. The research team characterized each reported injury and fatality as "exertion-related" or "non-exertion-related. Injury and fatality rates were reported per 100,000 equivalent full-time worker years and included 95% confidence intervals (95% CI). Of 58,648 cases in the OSHA Severe Injury Report database from 2015-2020, 1682 cases (2.9%) were characterized as exertional (0.20 injuries per 100,000 full-time worker years, 95% CI: 0.19, 0.22). Heat-related injuries encompassed 91.9% of the exertional injuries ( n = 1546). From the 2017-2022 OSHA fatality inspection database, 89 (1.9%) of 4598 fatalities were characterized as exertion-related (fatality rate: 0.0160 per 100,000 full-time equivalent workers, 95% CI: 0.009, 0.0134). The exertion-related fatalities primarily consisted of heat-related cases (87.6%). Exertion-related injuries and fatalities were most reported in Southeast states, in the construction and excavation industry, and among nonunionized workers. As heat stress continues to be recognized as an occupational health and safety hazard, this analysis further highlights the need for targeted interventions or further evaluation of the impact of heat stress on construction and excavation workers, nonunionized workers, and workers in Southeastern states.

Few investigations have evaluated the validity of current body composition technology among racially and ethnically diverse populations. This study assessed the validity of common body composition methods in a multi-ethnic sample stratified by race and ethnicity. One hundred and ten individuals (55 % female, age: 26·5 (sd 6·9) years) identifying as Asian, African American/Black, Caucasian/White, Hispanic, Multi-racial and Native American were enrolled. Seven body composition models (dual-energy X-ray absorptiometry (DXA), air displacement plethysmography (ADP), two bioelectrical impedance devices (BIS, IB) and three multi-compartment models) were evaluated against a four-compartment criterion model by assessing total error (TE) and standard error of the estimate. For the total sample, measures of % fat and fat-free mass (FFM) from multi-compartment models were all excellent to ideal (% fat: TE = 0·94-2·37 %; FFM: TE = 0·72-1·78 kg) compared with the criterion. % fat measures were very good to excellent for DXA, ADP and IB (TE = 2·52-2·89 %) and fairly good for BIS (TE = 4·12 %). For FFM, single device estimates were good (BIS; TE = 3·12 kg) to ideal (DXA, ADP, IB; TE = 1·21-2·15 kg). Results did not vary meaningfully between each race and ethnicity, except BIS was not valid for African American/Black, Caucasian/White and Multi-racial participants for % fat (TE = 4·3-4·9 %). The multi-compartment models evaluated can be utilised in a multi-ethnic sample and in each individual race and ethnicity to obtain highly valid results for % fat and FFM. Estimates from DXA, ADP and IB were also valid. The BIS may demonstrate greater TE for all racial and ethnic cohorts and results should be interpreted cautiously.

Objectives: Fat-free mass (FFM) accounts for ~80% of the variance in resting energy expenditure (REE), and this relationship is complicated by adiposity. The objective was to compare adjusted REE and contributions of skeletal lean mass and fat mass (FM) to adjusted REE in women with varying adiposity levels using a novel approach., Methods: Women were divided into tertiles by body fat percent (%fat): Tertile 1 (T1): %fat = 18.5%-28.4%; Tertile 2 (T2): %fat = 28.5%-33.8%; Tertile 3 (T3): %fat = 34.0%-61.0%. Outcome measures were measured and adjusted REE, body composition (skeletal lean mass, FM, %fat) from dual-energy X-ray absorptiometry, and percent contribution of skeletal lean mass and FM to adjusted REE., Results: The main effect for tertiles (T1 vs. T2 vs. T3) was significant (p = .001); REE was significantly higher in T3 versus both T1 by 281 kcal/day (p = .001) and T2 by 215 kcal/day (p = .001). Expenditure from skeletal lean mass in T1 was significantly higher than T3 by 3.2% (p = .001). T3 had a significantly higher FM contribution than T1 by 5.1% (p = .001) and T2 by 3.9% (p = .001)., Conclusions: Women with elevated %fat experienced lower skeletal lean mass contribution and higher FM contribution to adjusted REE. FM may explain more of the variance in REE between women of different levels of adiposity., (© 2021 Wiley Periodicals LLC.)

Background: Many identified mechanisms could be upstream of the prominent amyloid-β (Aβ) plaques in Alzheimer's disease (AD)., Objective: To profile the progression of pathology in AD., Methods: We monitored metabolic signaling, redox stress, intraneuronal amyloid-β (iAβ) accumulation, and extracellular plaque deposition in the brains of 3xTg-AD mice across the lifespan., Results: Intracellular accumulation of aggregated Aβ in the CA1 pyramidal cells at 9 months preceded extracellular plaques that first presented in the CA1 at 16 months of age. In biochemical assays, brain glutathione (GSH) declined with age in both 3xTg-AD and non-transgenic controls, but the decline was accelerated in 3xTg-AD brains from 2 to 4 months. The decline in GSH correlated exponentially with the rise in iAβ. Integrated metabolic signaling as the ratio of phospho-Akt (pAkt) to total Akt (tAkt) in the PI3kinase and mTOR pathway declined at 6, 9, and 12 months, before rising at 16 and 20 months. These pAkt/tAkt ratios correlated with both iAβ and GSH levels in a U-shaped relationship. Selective vulnerability of age-related AD-genotype-specific pAkt changes was greatest in the CA1 pyramidal cell layer. To demonstrate redox causation, iAβ accumulation was lowered in cultured middle-age adult 3xTg-AD neurons by treatment of the oxidized redox state in the neurons with exogenous cysteine., Conclusion: The order of pathologic progression in the 3xTg-AD mouse was loss of GSH (oxidative redox shift) followed by a pAkt/tAkt metabolic shift in CA1, iAβ accumulation in CA1, and extracellular Aβ deposition. Upstream targets may prove strategically more effective for therapy before irreversible changes.

American football linemen are at an increased risk for developing obesity-related diseases. This study evaluated the impact of race and position on abdominal fat (visceral adipose tissue and android fat percentage) in football linemen. Thirty-four offensive and defensive linemen (%fat: 27.1±7.2%) completed a total body dual-energy X-ray absorptiometry scan to estimate visceral fat and android fat percentage. Participants were stratified by race [Black: n=23; White: n=11] and position (Offense: n=18; Defense: n=16). Two separate two-way ANOVA tests [race × position] were completed. For visceral adipose tissue, there was no interaction (p=0.056), but there was an effect of race (Black: 0.57±0.34 kg; White: 1.51±0.56 kg; p <0.001) and position (Offense: 1.22±0.60 kg; Defense: 0.49±0.34 kg; p<0.001). For android fat percentage, there was no interaction (p=0.855) or race effect (Black: 31.5±11.3%; White: 40.9±8.6%; p=0.123); there was a position effect (Offense: 42.1±5.6%; Defense: 26.0±9.9%; p<0.001). Offensive linemen, regardless of race, had greater visceral adipose tissue and android fat percent compared to defensive linemen. White linemen had greater visceral adipose tissue, regardless of position. These results suggest football linemen, especially offensive linemen with increased abdominal adiposity, may benefit from tracking metabolic health during their collegiate career to mitigate obesity-related disease risk once retired from sport., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Heat stress is a growing concern in the occupational setting as it endangers worker health, safety, and productivity. Heat-related reductions in physical work capacity and missed workdays directly and indirectly cause productivity losses and may substantially affect the economic wellbeing of the organization. This review highlights the physiological, physical, psychological, and financial harms of heat stress on worker productivity and proposes strategies to quantify heat-related productivity losses. Heat stress produces a vicious-cycle feedback loop that result in adverse outcomes on worker health, safety, and productivity. We propose a theoretical model for implementing an occupational heat safety plan that disrupts this loop, preventing heat-related productivity losses while improving worker health and safety., (© 2021 Wiley Periodicals LLC.)

High-intensity interval training (HIIT) promotes positive cardiometabolic and body composition changes. Essential amino acids (EAA) may support changes associated with HIIT, but evaluation of potential synergistic effects is lacking. The purpose of this study was to compare independent and combined effects of HIIT and EAA on total body composition and metabolism in men and women considered overweight/obese; an exploratory aim was to evaluate the modulatory effects of sex. Sixty-six healthy adults (50% female; Age: 36.7 ± 6.0 years; BMI: 32.0 ± 4.2 kg/m 2 ) completed 8 weeks of: (1) HIIT, 2 days/weeks; (2) EAA supplementation, 3.6 g twice daily; (3) HIIT + EAA; or (4) control. Body composition, resting metabolic rate (RMR), substrate metabolism (respiratory exchange ratio; RER), and cardiorespiratory fitness were measured at baseline, 4 weeks, and 8 weeks; cardiometabolic blood markers were measured at baseline and 8 weeks. Differences between groups were assessed by linear mixed models covaried for baseline values, followed by 95% confidence intervals (CI) on adjusted mean change scores. There were no significant changes in body composition (p > 0.05) for any group. Changes in RER, but not RMR, occurred with HIIT (mean change; [95% CI]: - 0.04; [- 0.07, - 0.02]) and EAA (- 0.03; [- 0.06, - 0.01]) after 8 weeks. Cardiorespiratory fitness increased following 8 weeks of HIIT (+ 5.1 ml/kg/min [3.3,6.8]) and HIIT + EAA (+ 4.1 ml/kg/min [1.0,6.4]). Changes with HIIT + EAA were not significantly different from HIIT. There were no changes in cardiometabolic markers (p > 0.05) and no sex interaction (p > 0.05). HIIT is efficacious for promoting positive changes in cardiorespiratory fitness and resting substrate metabolism in adults considered overweight/obese. Addition of EAA did not significantly enhance HIIT-induced adaptations. ClinicalTrials.gov ID#NCT04080102., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: This study aimed to identify the effects of early follicular (EF) and midfollicular (MF) menstrual phases on body composition, resting metabolic rate (RMR), and respiratory quotient (RQ) assessment accuracy to identify an optimal testing period., Methods: Body composition was obtained from a four-compartment (4C) criterion model (fat mass (FM), fat-free mass, body fat percent, and dual-energy x-ray absorptiometry (DXA; FM, lean mass (LM), trunk FM, and trunk LM) in 19 eumenorrheic females (mean ± SD: age, 21.3 ± 3.1 yr, body mass index, 23.6 ± 1.8 kg·m-2). RMR (kcal·d-1) and RQ (a.u.) were measured via indirect calorimetry for 25 min. Body composition, RMR, and RQ were measured during the EF and MF phases. Dependent-samples t-tests were used to compare outcomes between EF and MF., Results: 4C outcomes were similar between phases (P > 0.05). During EF, the following 4C components were significantly greater (P < 0.05): body volume (mean difference (MD) ± SD, 0.70 ± 1.05 L), extracellular fluid (MD ± SD, 0.27 ± 0.51 L), and body mass (MD ± SD, 0.56 ± 0.80 kg). DXA-measured LM, body fat percent, trunk LM, and trunk FM were similar (P > 0.05); however, DXA FM was significantly greater during EF (MD ± SD, 0.29 ± 0.40 kg; P = 0.005), yet within measurement error of the device. Although RMR was not significantly different between phases (MD ± SD, 6.0 ± 190.93 kcal·d-1; P > 0.05), RQ was significantly higher during EF (mean ± SD, 0.03 ± 0.06 a.u.; P = 0.029) compared with MF., Conclusions: Body composition from 4C and DXA do not seem to be affected beyond measurement error as a result of compartmental changes from the menstrual cycle. During MF, women oxidized more fat as demonstrated by a lower RQ. Researchers should aim to be more inclusive and schedule testing for females within 11-12 d from the onset of menstruation., (Copyright © 2021 by the American College of Sports Medicine.)

Background: While increased face mask use has helped reduce COVID-19 transmission, there have been concerns about its influence on thermoregulation during exercise in the heat, but consistent, evidence-based recommendations are lacking., Hypothesis: No physiological differences would exist during low-to-moderate exercise intensity in the heat between trials with and without face masks, but perceptual sensations could vary., Study Design: Crossover study., Level of Evidence: Level 2., Methods: Twelve physically active participants (8 male, 4 female; age = 24 ± 3 years) completed 4 face mask trials and 1 control trial (no mask) in the heat (32.3°C ± 0.04°C; 54.4% ± 0.7% relative humidity [RH]). The protocol was 60 minutes of walking and jogging between 35% and 60% of relative VO 2max . Rectal temperature (T rec ), heart rate (HR), temperature and humidity inside and outside of the face mask (T micro&#95;in , T micro&#95;out , RH micro&#95;in , RH micro&#95;out ) and perceptual variables (rating of perceived exertion (RPE), thermal sensation, thirst sensation, fatigue level, and overall breathing discomfort) were monitored throughout all trials., Results: Mean T rec and HR increased at 30- and 60-minute time points compared with 0-minute time points, but no difference existed between face mask trials and control trials ( P > 0.05). Mean T micro&#95;in , RH micro&#95;in , and humidity difference inside and outside of the face mask (ΔRH micro ) were significantly different between face mask trials ( P < 0.05). There was no significant difference in perceptual variables between face mask trials and control trials ( P > 0.05), except overall breathing discomfort ( P < 0.01). Higher RH micro&#95;in , RPE, and thermal sensation significantly predicted higher overall breathing discomfort ( r 2 = 0.418; P < 0.01)., Conclusion: Face mask use during 60 minutes of low-to-moderate exercise intensity in the heat did not significantly affect T rec or HR. Although face mask use may affect overall breathing discomfort due to the changes in the face mask microenvironment, face mask use itself did not cause an increase in whole body thermal stress., Clinical Relevance: Face mask use is feasible and safe during exercise in the heat, at low-to-moderate exercise intensities, for physically active, healthy individuals.

The tri-synaptic pathway in the mammalian hippocampus enables cognitive learning and memory. Despite decades of reports on anatomy and physiology, the functional architecture of the hippocampal network remains poorly understood in terms of the dynamics of axonal information transfer between subregions. Information inputs largely flow from the entorhinal cortex (EC) to the dentate gyrus (DG), and then are processed further in the CA3 and CA1 before returning to the EC. Here, we reconstructed elements of the rat hippocampus in a novel device over an electrode array that allowed for monitoring the directionality of individual axons between the subregions. The direction of spike propagation was determined by the transmission delay of the axons recorded between two electrodes in microfluidic tunnels. The majority of axons from the EC to the DG operated in the feed-forward direction, with other regions developing unexpectedly large proportions of feedback axons to balance excitation. Spike timing in axons between each region followed single exponential log-log distributions over two orders of magnitude from 0.01 to 1 s, indicating that conventional descriptors of mean firing rates are misleading assumptions. Most of the spiking occurred in bursts that required two exponentials to fit the distribution of inter-burst intervals. This suggested the presence of up-states and down-states in every region, with the least up-states in the DG to CA3 feed-forward axons and the CA3 subregion. The peaks of the log-normal distributions of intra-burst spike rates were similar in axons between regions with modes around 95 Hz distributed over an order of magnitude. Burst durations were also log-normally distributed around a peak of 88 ms over two orders of magnitude. Despite the diversity of these spike distributions, spike rates from individual axons were often linearly correlated to subregions. These linear relationships enabled the generation of structural connectivity graphs, not possible previously without the directional flow of axonal information. The rich axonal spike dynamics between subregions of the hippocampus reveal both constraints and broad emergent dynamics of hippocampal architecture. Knowledge of this network architecture may enable more efficient computational artificial intelligence (AI) networks, neuromorphic hardware, and stimulation and decoding from cognitive implants., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Vakilna, Tang, Wheeler and Brewer.)

The purpose of this consensus document was to develop feasible, evidence-based occupational heat safety recommendations to protect the US workers that experience heat stress. Heat safety recommendations were created to protect worker health and to avoid productivity losses associated with occupational heat stress. Recommendations were tailored to be utilized by safety managers, industrial hygienists, and the employers who bear responsibility for implementing heat safety plans. An interdisciplinary roundtable comprised of 51 experts was assembled to create a narrative review summarizing current data and gaps in knowledge within eight heat safety topics: (a) heat hygiene, (b) hydration, (c) heat acclimatization, (d) environmental monitoring, (e) physiological monitoring, (f) body cooling, (g) textiles and personal protective gear, and (h) emergency action plan implementation. The consensus-based recommendations for each topic were created using the Delphi method and evaluated based on scientific evidence, feasibility, and clarity. The current document presents 40 occupational heat safety recommendations across all eight topics. Establishing these recommendations will help organizations and employers create effective heat safety plans for their workplaces, address factors that limit the implementation of heat safety best-practices and protect worker health and productivity., Competing Interests: The authors declare no conflicts of interest relevant to this study., (© 2021. The Authors. GeoHealth published by Wiley Periodicals LLC on behalf of American Geophysical Union.)

Background: Multi-frequency bioelectrical impedance analysis (MF-BIA) offers enhanced body composition outcomes in a time-efficient manner. The accuracy of stand-up MF-BIA compared against a four-compartment (4C) criterion lacks evidence., Objectives: To validate a stand-up MF-BIA compared to a 4C criterion for fat mass (FM), fat-free mass (FFM) and body fat percentage (%fat)., Subjects/methods: Eighty-two healthy (32% men) normal-weight (BMI: 18.5-24.9 kg/m 2 ) young adults were measured for body composition determined from a stand-up MF-BIA and 4C model. Validity statistics included total error (TE) and standard error of the estimate (SEE) to examine prediction error between methods., Results: For the total sample, prediction error was the highest for %fat (TE = 4.2%; SEE = 3.9%) followed by FM (TE = 2.4 kg; SEE = 2.2 kg) and FFM (TE = 2.4 kg; SEE = 2.2 kg). In men, %fat (TE = 2.5%; SEE = 2.2%) and FM (TE = 1.9 kg; SEE = 1.6 kg) were ideal; FFM was similar to FM (TE = 1.9 kg; SEE = 1.6 kg). In women, %fat (TE = 4.7%; SEE = 4.4%) ranged from good to fairly good, and FM was very good to excellent (TE = 2.6 kg; SEE = 2.4 kg); FFM was similar to FM (TE = 2.6 kg; SEE = 2.3 kg)., Conclusions: Stand-up MF-BIA may overestimate %fat and FM, and underestimate FFM compared to a 4C model. FM and FFM estimates from MF-BIA demonstrate good agreement to a 4C model and may be a practical measure of body composition in normal-weight adults. The highest error was seen in %fat for both sexes, with greater error in women., (© 2021 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd.)

Three-dimensional (3D) body scanner technology for body composition assessment is expanding. The aim of this study was to assess the validity of a 3D body scanner. One hundred and ninety-four participants (43% male; age: 23.52 ± 5.47 years; body mass index: 23.98 ± 3.24 kg·m -2 ) were measured using 3D scanner and a 4-compartment (4C) model utilizing dual-energy X-ray absorptiometry (DXA), air displacement plethysmography, and bioelectrical impedance spectroscopy. Dependent t  tests, validity statistics including total error (TE), standard error of the estimate, constant error, and Bland-Altman analyses were utilized. Compared with 4C, 3D scanner fat mass (FM) [mean difference (MD; 3D-4C): 2.66 kg ± 3.32 kg] and percent body fat (%BF) (MD: 4.13% ± 5.36%) were significantly ( p  < 0.001) over-predicted; fat free mass (FFM) was significantly underpredicted (MD: -3.15 kg ± 4.75 kg; p  < 0.001). 3D demonstrated poor validity indicated by TE (%BF: 5.61%; FM: 4.50 kg; FFM: 5.69 kg). In contrast, there were no significant differences between 3D and DXA measures; 3D scanner demonstrated acceptable measurement for %BF (TE: 4.25%), FM (TE: 2.92 kg), and lean mass (TE: 3.86 kg). Compared with the 4C criterion, high TE values indicated 3D estimates were not valid. In contrast, 3D estimates produced acceptable measurement agreement when compared with DXA; an average overestimation of %BF by 5.31% (vs. 4C) and 4.20% (vs. DXA) may be expected. Novelty: 3D body composition estimates are not valid compared with the 4-C criterion model. 3D estimates appeared to be more valid in females, compared with males. When compared with DXA, 3D estimates were acceptable.

Although there is a plethora of information available regarding the impact of nutrition on exercise performance, many recommendations are based on male needs due to the dominance of male participation in the nutrition and exercise science literature. Female participation in sport and exercise is prevalent, making it vital for guidelines to address the sex-specific nutritional needs. Female hormonal levels, such as estrogen and progesterone, fluctuate throughout the mensural cycle and lifecycle requiring more attention for effective nutritional considerations. Sex-specific nutritional recommendations and guidelines for the active female and female athlete have been lacking to date and warrant further consideration. This review provides a practical overview of key physiological and nutritional considerations for the active female. Available literature regarding sex-specific nutrition and dietary supplement guidelines for women has been synthesized, offering evidenced-based practical information that can be incorporated into the daily lives of women to improve performance, body composition, and overall health.

The purpose of this study was to compare the independent and combined effects of high-intensity interval training (HIIT) and essential amino acids (EAA) on lean mass, muscle characteristics of the quadriceps, and 24-hr whole-body protein turnover (WBPT) in overweight and obese adults. An exploratory aim was to evaluate potential modulatory effects of sex. Sixty-six adults (50% female; Age: 36.7 ± 6.0 yrs; %BF: 36.0 ± 7.8%) were assigned to 8 wks of: (a) HIIT, 2 days/wk; (b) EAA supplementation, 3.6 g twice daily; (c) HIIT + EAA; or (d) control. At baseline, 4 wks, and 8 wks, total body, thigh LM and muscle characteristics were measured via dual-energy x-ray absorptiometry and B-mode ultrasound, respectively. In a subsample, changes in WBPT was measured using [N 15 ]alanine. Differences between groups were assessed using linear mixed models adjusted for baseline values, followed by 95% confidence intervals on adjusted mean change scores (Δ). HIIT and HIIT + EAA improved thigh LM (Δ: +0.17 ± 0.05 kg [0.08, 0.27]; +0.22 ± 0.05 kg [0.12,0.31]) and vastus lateralis cross-sectional area (Δ: +2.73 ± 0.52 cm 2 [1.69,3.77]; +2.64 ± 0.53 cm 2 [1.58,3.70]), volume (Δ: +54.50 ± 11.69 cm 3 [31.07, 77.92]; +62.39 ± 12.05 cm 3 [38.26, 86.52]), and quality (Δ: -5.46 ± 2.68a.u. [-10.84, -0.09]; -7.97 ± 2.76a.u.[-13.49, -2.45]). Protein synthesis, breakdown, and flux were greater with HIIT + EAA and EAA compared to HIIT (p < .05). Sex differences were minimal. Compared to women, men tended to respond more to HIIT, with or without EAA. For women, responses were greater with HIIT + EAA than HIIT. In overweight and obese adults, 8 weeks of HIIT, with or without EAA, improved thigh LM size and quality; EAA may enhance muscular adaptation via increases in protein turnover, supporting greater improvements in muscular size and quality., (© 2020 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Background & Aims: Body composition assessment has large variability. A dual-energy x-ray absorptiometry (DXA) derived four compartment (4C) method has been developed as an accurate and reliable method for assessing body composition in overweight/obese adults. This investigation was aimed at understanding the validity of the DXA-derived 4C equation for use in normal weight individuals, stratified by sex, and with varied levels of lean mass. Values were also compared against DXA alone., Methods: 78 men and women (68% female; Mean ± SD; Age: 19.2 ± 1.2 yrs; Ht: 168.8 ± 9.1 cm; Wt: 62.8 ± kg) completed a traditional 4C body composition reference assessment. Body composition was also assessed using a DXA-4C model. Validity was evaluated from total error (TE), constant error, and standard error of the estimate (SEE). Proportional bias was identified with Bland Altman plots., Results: Although significantly different (p < 0.05) the DXA-4C model produced ideal TE and SEE compared to the 4C criterion for all body composition outcomes of fat mass (TE: 2.1 kg; SEE: 1.9 kg), lean mass (TE: 2.1 kg; SEE: 1.8 kg), and percent body fat (TE: 3.6%; SEE: 3.4%). Validity results did not differ for men vs. women. DXA-4C estimates were slightly better in individuals with higher lean mass. DXA alone resulted in significantly greater error than DXA-4C (p < 0.05)., Conclusion: Body composition assessed from DXA-4C is an accurate approach, particularly in those with high levels of lean mass. This model appears to be more accurate than DXA alone., (Copyright © 2020 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)

Background: Stable flies are one of the most detrimental arthropod pests to livestock. With changing climates and agronomic practices, they expand their roles as pests and disease vectors as well. Their painful bites reduce livestock productivity, annoy companion animals, and interfere with human recreational activities. Current management technologies are unable to effectively control stable flies. The present study reports new results concerning the contact, spatial repellency, and toxicity of a bio-based product, coconut fatty acid and their methyl ester derivatives of free fatty acids of C 8:0 , C 10:0 and C 12:0 to stable flies., Results: Three medium chain fatty acid methyl esters (C 8:0 , C 10:0 and C 12:0 ) showed strong antifeedant activity against stable flies and their strengths were dose-dependent. Only the C 8:0 acid, C 8:0 - and C 10:0 methyl esters elicited significant antennal responses. Laboratory single cage olfactometer bioassays revealed that coconut fatty acid and C 8:0 methyl ester displayed active spatial repellency. All three methyl esters showed strong toxicity against stable flies., Conclusion: Antifeedant activity is the main method through which coconut fatty acid deters stable fly blood-feeding. The C 8:0 , C 10:0 and C 12:0 methyl esters act not only as strong antifeedants, but also possess strong toxicity against stable fly adults. Limited spatial repellency was observed from coconut fatty acid and C 8:0 methyl ester. © 2019 Society of Chemical Industry., (© 2019 Society of Chemical Industry.)

This work provides new insight into the age-related basis of Alzheimer's disease (AD), the composition of intraneuronal amyloid (iAβ), and the mechanism of an age-related increase in iAβ in adult AD-model mouse neurons. A new end-specific antibody for Aβ45 and another for aggregated forms of Aβ provide new insight into the composition of iAβ and the mechanism of accumulation in old adult neurons from the 3xTg-AD model mouse. iAβ levels containing aggregates of Aβ45 increased 30-50-fold in neurons from young to old age and were further stimulated upon glutamate treatment. iAβ was 8 times more abundant in 3xTg-AD than non-transgenic neurons with imaged particle sizes following the same log-log distribution, suggesting a similar snow-ball mechanism of intracellular biogenesis. Pathologically misfolded and mislocalized Alz50 tau colocalized with iAβ and rapidly increased following a brief metabolic stress with glutamate. AβPP-CTF, Aβ45, and aggregated Aβ colocalized most strongly with mitochondria and endosomes and less with lysosomes and autophagosomes. Differences in iAβ by sex were minor. These results suggest that incomplete carboxyl-terminal trimming of long Aβs by gamma-secretase produced large intracellular deposits which limited completion of autophagy in aged neurons. Understanding the mechanism of age-related changes in iAβ processing may lead to application of countermeasures to prolong dementia-free health span.

Brewer, GJ, Blue, MNM, Hirsch, KR, Peterjohn, AM, and Smith-Ryan, AE. Appendicular body composition analysis: Validity of bioelectrical impedance analysis compared with dual-energy x-ray absorptiometry in Division I college athletes. J Strength Cond Res 33(11): 2920-2925, 2019-The purpose of this study was to evaluate validity of appendicular body composition measurements measured from a multifrequency bioelectrical impedance analysis (MF-BIA) compared with a dual-energy x-ray absorptiometry (DXA) criterion in Division I athletes. One hundred sixty male (n = 44) and female (n = 116) collegiate athletes were enrolled: Men's Cross Country (n = 15), football linemen (n = 29), Women's Soccer (n = 27), Women's Field Hockey (n = 27), Women's Cross Country (n = 13), Women's Gymnastics (n = 16), and Women's Lacrosse (n = 33). Appendicular fat mass (FM) of the arms (AFM, right AFM, left AFM) and legs (LFM, right LFM, left LFM), appendicular fat-free mass (FFM) of the arms (AFFM, RAFFM, LAFFM) and legs (LFFM, RLFFM, LLFFM), total body FM and FFM, and total body %fat were collected from both devices. MF-BIA significantly underestimated appendicular FFM of the arms (AFFM mean difference [MD]: -0.7 kg; RAFFM: -0.4 kg; LAFFM: -0.4 kg, p < 0.001) and legs (LFFM MD: -3.8 kg; RLFFM: -1.9 kg; LLFFM: -1.9 kg, p < 0.001), and FM of the legs (LFM MD: -2.5 kg; RLFM: -1.3 kg; LLFM: -1.3 kg, p < 0.001). There was no significant difference in appendicular FM measures of the arms (p = 0.174). All measures held true for male subjects and female subjects. Female subjects produced smaller differences compared with male subjects. The lack of validity, from raw and relative error, between the devices for most appendicular measures (FFM of arms and FFM and FM legs) and all total body measures (FM, FFM, and %fat) suggest that this MF-BIA may not be accurate in measuring a lean, athletic, population compared with DXA.

Redox systems including extracellular cysteine/cystine (Cys/CySS), intracellular glutathione/oxidized glutathione (GSH/GSSG) and nicotinamide adenine dinucleotide reduced/oxidized forms (NADH/NAD + ) are critical for maintaining redox homeostasis. Aging as a major risk factor for Alzheimer's disease (AD) is associated with oxidative shifts, decreases in anti-oxidant protection and dysfunction of mitochondria. Here, we examined the flexibility of mitochondrial-specific free NADH in live neurons from non-transgenic (NTg) or triple transgenic AD-like mice (3xTg-AD) of different ages under an imposed extracellular Cys/CySS oxidative or reductive condition. We used phasor fluorescence lifetime imaging microscopy (FLIM) to distinguish free and bound NADH in mitochondria, nuclei and cytoplasm. Under an external oxidative stress, a lower capacity for maintaining mitochondrial free NADH levels was found in old compared to young neurons and a further decline with genetic load. Remarkably, an imposed Cys/CySS reductive state rejuvenated the mitochondrial free NADH levels of old NTg neurons by 71% and old 3xTg-AD neurons by 89% to levels corresponding to the young neurons. Using FLIM as a non-invasive approach, we were able to measure the reversibility of aging subcellular free NADH levels in live neurons. Our results suggest a potential reductive treatment to reverse the loss of free NADH in old and Alzheimer's neurons.

Nicotinamide adenine dinucleotide (reduced form: NADH) serves as a vital redox-energy currency for reduction-oxidation homeostasis and fulfilling energetic demands. While NADH exists as free and bound forms, only free NADH is utilized for complex I to power oxidative phosphorylation, especially important in neurons. Here, we studied how much free NADH remains available for energy production in mitochondria of old living neurons. We hypothesize that free NADH in neurons from old mice is lower than the levels in young mice and even lower in neurons from the 3xTg-AD Alzheimer's disease (AD) mouse model. To assess free NADH, we used lifetime imaging of NADH autofluorescence with 2-photon excitation to be able to resolve the pool of NADH in mitochondria, cytoplasm, and nuclei. Primary neurons from old mice were characterized by a lower free/bound NADH ratio than young neurons from both non-transgenic (NTg) and more so in 3xTg-AD mice. Mitochondrial compartments maintained 26 to 41% more reducing NADH redox state than cytoplasm for each age, genotype, and sex. Aging diminished the mitochondrial free NADH concentration in NTg neurons by 43% and in 3xTg-AD by 50%. The lower free NADH with age suggests a decline in capacity to regenerate free NADH for energetic supply to power oxidative phosphorylation which further worsens in AD. Applying this non-invasive approach, we showed the most explicit measures yet of bioenergetic deficits in free NADH with aging at the subcellular level in live neurons from in-bred mice and an AD model.

Impact Statement: The work described in this review is very important to scientists working on Alzheimer's disease (AD) because it reveals a cause for the explosive epidemic of this disease. It is also important to the public because it provides a method to avoid this newly revealed cause, and thereby avoid AD. The field is advanced because this review reveals new information about the mechanism of AD pathogenesis, namely copper, and specifically divalent copper, toxicity is important. New information about divalent copper toxicity in the brain affecting cognition is revealed. The field is impacted strongly because, in view of the frustrations that have occurred in treatment developed, now most AD can be prevented. This means the suffering of the patient, the prolonged and difficult care required by caregivers, and the enormous expenditures for this one disease, can now be avoided.

Age and Alzheimer's disease (AD) share some common features such as cognitive impairments, memory loss, metabolic disturbances, bioenergetic deficits, and inflammation. Yet little is known on how systematic shifts in metabolic networks depend on age and AD. In this work, we investigated the global metabolomic alterations in non-transgenic (NTg) and triple-transgenic (3xTg-AD) mouse brain hippocampus as a function of age by using untargeted Ultrahigh Performance Liquid Chromatography-tandem Mass Spectroscopy (UPLC-MS/MS). We observed common metabolic patterns with aging in both NTg and 3xTg-AD brains involved in energy-generating pathways, fatty acids oxidation, glutamate, and sphingolipid metabolism. We found age-related downregulation of metabolites from reactions in glycolysis that consumed ATP and in the TCA cycle, especially at NAD+/NADH-dependent redox sites, where age- and AD-associated limitations in the free NADH may alter reactions. Conversely, metabolites increased in glycolytic reactions in which ATP is produced. With age, inputs to the TCA cycle were increased including fatty acid β-oxidation and glutamine. Overall age- and AD-related changes were > 2-fold when comparing the declines of upstream metabolites of NAD+/NADH-dependent reactions to the increases of downstream metabolites (p = 10-5, n = 8 redox reactions). Inflammatory metabolites such as ceramides and sphingosine-1-phosphate also increased with age. Age-related decreases in glutamate, GABA, and sphingolipid were seen which worsened with AD genetic load in 3xTg-AD brains, possibly contributing to synaptic, learning- and memory-related deficits. The data support the novel hypothesis that age- and AD-associated metabolic shifts respond to NAD(P)+/NAD(P)H redox-dependent reactions, which may contribute to decreased energetic capacity.

Objective: Functions ascribed to the hippocampal sub-regions for encoding episodic memories include the separation of activity patterns propagated from the entorhinal cortex (EC) into the dentate gyrus (DG) and pattern completion in CA3 region. Since a direct assessment of these functions is lacking at the level of specific axonal inputs, our goal is to directly measure the separation and completion of distinct axonal inputs in engineered pairs of hippocampal sub-regional circuits., Approach: We co-cultured EC-DG, DG-CA3, CA3-CA1 or CA1-EC neurons in a two-chamber PDMS device over a micro-electrode array (MEA60), inter-connected via distinct axons that grow through the micro-tunnels between the compartments. Taking advantage of the axonal accessibility, we quantified pattern separation and completion of the evoked activity transmitted through the tunnels from source into target well. Since pattern separation can be inferred when inputs are more correlated than outputs, we first compared the correlations among axonal inputs with those of target somata outputs. We then compared, in an analog approach, the distributions of correlation distances between rate patterns of the axonal inputs inside the tunnels with those of the somata outputs evoked in the target well. Finally, in a digital approach, we measured the spatial population distances between binary patterns of the same axonal inputs and somata outputs., Main Results: We found the strongest separation of the propagated axonal inputs when EC was axonally connected to DG, with a decline in separation to CA3 and to CA1 for both rate and digital approaches. Furthermore, the digital approach showed stronger pattern completion in CA3, then CA1 and EC., Significance: To the best of our knowledge, these are the first direct measures of pattern separation and completion for axonal transmission to the somata target outputs at the rate and digital population levels in each of four stages of the EC-DG-CA3-CA1 circuit.

CA3 and dentate gyrus (DG) neurons are cultured in two-chamber devices on multi-electrode arrays (MEAs) and connected via micro-tunnels. In order to evoke time-locked activity, paired-pulse stimulation is applied to 22 different sites and repeated 25 times in each well in 5 MEA co-cultures and results compared to CA3-CA3 and DG-DG networks homologous controls. In these hippocampal sub-regions, we focus on the mechanisms underpinning a network's ability to decode the identity of site specific stimulation from analysis of evoked network responses using a support vector machine classifier. Our results indicate that a pool of CA3 neurons is able to reliably decode the identity of DG stimulation site information.

Communication between different sub regions of the hippocampus is fundamental to learning and memory. However accurate knowledge about information transfer between sub regions from access to the activity in individual axons is lacking. MEMS devices with microtunnels connecting two sub networks have begun to approach this problem but the commonly used 10 μm wide tunnels frequently measure signals from multiple axons. To reduce this complexity, we compared polydimethylsiloxane (PDMS) microtunnel devices each with a separate tunnel width of 2.5, 5 or 10 μm bridging two wells aligned over a multi electrode array (MEA). Primary rat neurons were grown in the chambers with neurons from the dentate gyrus on one side and hippocampal CA3 on the other. After 2-3 weeks of culture, spontaneous activity in the axons inside the tunnels was recorded. We report electrophysiological, exploratory data analysis for feature clustering and visual evidence to support the expectation that 2.5 μm wide tunnels have fewer axons per tunnel and therefore more clearly delineated signals than 10 or 5 μm wide tunnels. Several measures indicated that fewer axons per electrode enabled more accurate detection of spikes. A clustering analysis comparing the variations of spike height and width for different tunnel widths revealed tighter clusters representing unique spikes with less height and width variation when measured in narrow tunnels. Wider tunnels tended toward more diffuse clusters from a continuum of spike heights and widths. Standard deviations for multiple cluster measures, such as Average Dissimilarity, Silhouette Value (S) and Separation Factor (average dissimilarity/S value), support a conclusion that 2.5 μm wide tunnels containing fewer axons enable more precise determination of individual action potential peaks, their propagation direction, timing, and information transfer between sub networks.

Alzheimer's disease, the most common cause of dementia, is at epidemic proportions (15 to 44% depending on age, of those age 65 to 84) in the U.S. and other developed countries but remains relatively rare in undeveloped countries. Surprisingly, solid historical data reveal the epidemic is a creature of the last century. That is, the disease was also rare in developed countries, until the 20th century. It is disappointing that these historical and demographic facts have been ignored by the Alzheimer's disease scientific community. Disappointing because these facts clearly point at an environmental change in the 20th century in developed countries as a major factor in causing the epidemic. Some scientists have discarded the claimed rarity of the disease in the 19th century as incorrect, saying that Alzheimer's disease is a disease of aging and that the increasing lifespan of people accounts for the current high prevalence of the disease, but this cavalier attitude ignores historical data indicating there were many elderly people in the 19th century who were not getting Alzheimer's disease with any significant frequency. In this review, after documenting that the observed assertions about historical and demographic facts are correct, evidence is amassed that the main environmental culprit causing the Alzheimer's epidemic is ingestion of divalent copper or copper-2. The two sources of copper-2 ingestion are drinking water and multimineral supplement pills containing copper. The increase in copper plumbing use in developed countries parallels the increasing prevalence of Alzheimer's disease. It has been shown that enough copper is leached from copper plumbing in most households to cause Alzheimer's disease, using the Alzheimer's disease animal model studies as a guide to toxic levels. It is relatively easy to avoid or greatly diminish copper-2 ingestion by not using copper containing supplement pills and testing drinking water for copper levels. If the copper in water is too high, a simple device can be put on the tap to remove copper. In addition to the copper-2 hypothesis, this review covers dietary changes that enhance the epidemic.

To better understand encoding and decoding of stimulus information in two specific hippocampal sub-regions, we isolated and co-cultured rat primary dentate gyrus (DG) and CA3 neurons within a two-chamber device with axonal connectivity via micro-tunnels. We tested the hypothesis that, in these engineered networks, decoding performance of stimulus site information would be more accurate when stimuli and information flow occur in anatomically correct feed-forward DG to CA3 vs. CA3 back to DG. In particular, we characterized the neural code of these sub-regions by measuring sparseness and uniqueness of the responses evoked by specific paired-pulse stimuli. We used the evoked responses in CA3 to decode the stimulation sites in DG (and vice-versa) by means of learning algorithms for classification (support vector machine, SVM). The device was placed over an 8 × 8 grid of extracellular electrodes (micro-electrode array, MEA) in order to provide a platform for monitoring development, self-organization, and improved access to stimulation and recording at multiple sites. The micro-tunnels were designed with dimensions 3 × 10 × 400 μm allowing axonal growth but not migration of cell bodies and long enough to exclude traversal by dendrites. Paired-pulse stimulation (inter-pulse interval 50 ms) was applied at 22 different sites and repeated 25 times in each chamber for each sub-region to evoke time-locked activity. DG-DG and CA3-CA3 networks were used as controls. Stimulation in DG drove signals through the axons in the tunnels to activate a relatively small set of specific electrodes in CA3 (sparse code). CA3-CA3 and DG-DG controls were less sparse in coding than CA3 in DG-CA3 networks. Using all target electrodes with the three highest spike rates (14%), the evoked responses in CA3 specified each stimulation site in DG with optimum uniqueness of 64%. Finally, by SVM learning, these evoked responses in CA3 correctly decoded the stimulation sites in DG for 43% of the trials, significantly higher than the reverse, i.e., how well-recording in DG could predict the stimulation site in CA3. In conclusion, our co-cultured model for the in vivo DG-CA3 hippocampal network showed sparse and specific responses in CA3, selectively evoked by each stimulation site in DG.

In a letter to the editor, Meunier [1] apparently attempts to discredit the copper-2 hypothesis for causation of the Alzheimer's disease (AD) epidemic in developed countries proposed by myself in a review in this journal [2].[...].

Anatomical and behavioral studies, and in vivo and slice electrophysiology of the hippocampus suggest specific functions of the dentate gyrus (DG) and the CA3 subregions, but the underlying activity dynamics and repeatability of information processing remains poorly understood. To approach this problem, we engineered separate living networks of the DG and CA3 neurons that develop connections through 51 tunnels for axonal communication. Growing these networks on top of an electrode array enabled us to determine whether the subregion dynamics were separable and repeatable. We found spontaneous development of polarized propagation of 80% of the activity in the native direction from DG to CA3 and different spike and burst dynamics for these subregions. Spatial-temporal differences emerged when the relationships of target CA3 activity were categorized with to the number and timing of inputs from the apposing network. Compared to times of CA3 activity when there was no recorded tunnel input, DG input led to CA3 activity bursts that were 7× more frequent, increased in amplitude and extended in temporal envelope. Logistic regression indicated that a high number of tunnel inputs predict CA3 activity with 90% sensitivity and 70% specificity. Compared to no tunnel input, patterns of >80% tunnel inputs from DG specified different patterns of first-to-fire neurons in the CA3 target well. Clustering dendrograms revealed repeating motifs of three or more patterns at up to 17 sites in CA3 that were importantly associated with specific spatial-temporal patterns of tunnel activity. The number of these motifs recorded in 3 min was significantly higher than shuffled spike activity and not seen above chance in control networks in which CA3 was apposed to CA3 or DG to DG. Together, these results demonstrate spontaneous input-dependent repeatable coding of distributed activity in CA3 networks driven by engineered inputs from DG networks. These functional configurations at measured times of activation (motifs) emerge from anatomically accurate feed-forward connections from DG through tunnels to CA3.

Transient propagation of information across neuronal assembles is thought to underlie many cognitive processes. However, the nature of the neural code that is embedded within these transmissions remains uncertain. Much of our understanding of how information is transmitted among these assemblies has been derived from computational models. While these models have been instrumental in understanding these processes they often make simplifying assumptions about the biophysical properties of neurons that may influence the nature and properties expressed. To address this issue we created an in vitro analog of a feed-forward network composed of two small populations (also referred to as assemblies or layers) of living dissociated rat cortical neurons. The populations were separated by, and communicated through, a microelectromechanical systems (MEMS) device containing a strip of microscale tunnels. Delayed culturing of one population in the first layer followed by the second a few days later induced the unidirectional growth of axons through the microtunnels resulting in a primarily feed-forward communication between these two small neural populations. In this study we systematically manipulated the number of tunnels that connected each layer and hence, the number of axons providing communication between those populations. We then assess the effect of reducing the number of tunnels has upon the properties of between-layer communication capacity and fidelity of neural transmission among spike trains transmitted across and within layers. We show evidence based on Victor-Purpura's and van Rossum's spike train similarity metrics supporting the presence of both rate and temporal information embedded within these transmissions whose fidelity increased during communication both between and within layers when the number of tunnels are increased. We also provide evidence reinforcing the role of synchronized activity upon transmission fidelity during the spontaneous synchronized network burst events that propagated between layers and highlight the potential applications of these MEMs devices as a tool for further investigation of structure and functional dynamics among neural populations.