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Abstract Wildfire impacts the global carbon cycle, property, harvestable timber, and public health. Canada saw a record fire season in 2023 with 14.9 Mha burned—over seven times the 1986–2022 average of 2.1 Mha. Here we utilize a new process-based wildfire module that explicitly represents fire weather, fuel type and availability, ignition sources, fire suppression, and vegetation’s climate response to project the future of wildfire in Canada. Under rapid climate change (shared socioeconomic pathway [SSP] 370 & 585) simulated annual burned area in the 2090 s reaches 10.2 ± 2.1 to 11.7 ± 2.4 Mha, approaching the 2023 fire season total. However, climate change below a 2 °C global target (SSP126), keeps the 2090 s area burned near modern (2004–2014) norms. The simulated area burned and carbon emissions are most sensitive to climate drivers and lightning but future lightning activity is a key uncertainty.

Abstract Background There is an urgent need to increase colorectal cancer screening (CRCS) uptake in Texas federally qualified health centers (FQHCs), which serve a predominantly vulnerable population with high demands. Empirical support exists for evidence-based interventions (EBIs) that are proven to increase CRCS; however, as with screening, their use remains low in FQHCs. This study aimed to identify barriers to and facilitators of implementing colorectal cancer screening (CRCS) evidence-based interventions (EBIs) in federally qualified health centers (FQHCs), guided by the Consolidated Framework for Implementation Research (CFIR). Methods We recruited employees involved in implementing CRCS EBIs (e.g., physicians) using data from a CDC-funded program to increase the CRCS in Texas FQHCs. Through 23 group interviews, we explored experiences with practice change, CRCS promotion and quality improvement initiatives, organizational readiness, the impact of COVID-19, and the use of CRCS EBIs (e.g., provider reminders). We used directed content analysis with CFIR constructs to identify the critical facilitators and barriers. Results The analysis revealed six primary CFIR constructs that influence implementation: information technology infrastructure, innovation design, work infrastructure, performance measurement pressure, assessing needs, and available resources. Based on experiences with four recommended EBIs, participants described barriers, including data limitations of electronic health records and the design of reminder alerts targeted at deliverers and recipients of patient or provider reminders. Implementation facilitators include incentivized processes to increase provider assessment and feedback, existing clinic processes (e.g., screening referrals), and available resources to address patient needs (e.g., transportation). Staff buy-in emerged as an implementation facilitator, fostering a conducive environment for change within clinics. Conclusions Using CFIR, we identified barriers, such as the burden of technology infrastructure, and facilitators, such as staff buy-in. The results, which enhance our understanding of CRCS EBI implementation in FQHCs, provide insights into designing nuanced, practical implementation strategies to improve cancer control in a critical setting.

The global growth of an aging population is expected to coincide with an increase in aging-related pathologies, including those related to brain health. Thus, the potential for accelerated cognitive health declines due to adverse aging is expected to have profound social and economic implications. However, the progression to pathological conditions is not an inevitable part of aging. In fact, engaging in activities that improve cardiovascular fitness appears to be a means that offers the benefits of maintaining and/or improving cognitive health in older age. However, to date, the underlying mechanisms responsible for improved central nervous system health and function with exercise are not yet fully elucidated. Consequently, there is considerable interest in studies aimed at understanding the neurophysiological benefits of exercise on aging. One such area of study suggests that the improvements in brain health via exercise are, in part, driven by the recovery of inhibitory processes related to the neurotransmitter gamma-aminobutyric acid (GABA). In the present review, we highlight the opposing effects of aging and exercise on cortical inhibition and the GABAergic system’s functional integrity. We highlight these changes in GABA function by reviewing work with in vivo measurements: transcranial magnetic stimulation (TMS) and magnetic resonance spectroscopy (MRS). We also highlight recent and significant technological and methodological advances in assessing the GABAergic system’s integrity with TMS and MRS. We then discuss potential future research directions to inform mechanistic GABA study targeted to improve health and function in aging. We conclude by highlighting the significance of understanding the effects of exercise and aging, its influence on GABA levels, and why a better understanding is crucial to allow for more targeted and effective interventions aimed to ultimately improve age-related decline in aging.

L’histoire nationale américaine a été largement mythifiée : a contrario de l’image d’un pays de liberté et de justice, les États-Unis ont en réalité fondé leur développement économique d’abord sur l’esclavage racialisé, ensuite sur la ségrégation raciale. Persistant même après la fin de la ségrégation, l’oppression sur la longue durée des Noirs par les Blancs constitue un phénomène de « racisme systémique », dont l’auteur analyse ici les tenants et les aboutissants. Encore aujourd’hui, les Américains évoluent mentalement dans un « cadre racial blanc ». Un tel cadre permet aux Blancs d’accumuler richesses et capital social, et perpétue les discriminations vis-à-vis des minorités non blanches.America’s national history has been largely mythologized: contrary to the image of a country of freedom and justice, this its economic development first on racialized slavery, then on racial segregation. Even after the end of segregation, the long-term oppression of Blacks by Whites constitutes a phenomenon of “systemic racism”, the author studies here. Even today, Americans mentally evolve within a "white racial framework". This framework allows Whites to accumulate wealth and social capital, and perpetuates discrimination discrimination against non-white minorities.

The thermal performance of rural building envelopes is mostly non-standardized in Northern China, resulting in significant heat loss. In this study, we take, as an example, the central area of Liaoning province, with the objective of proposing some low-cost and energy-efficient solutions. Through our investigations, we found that heating energy consumption was reduced by 20% and construction costs increased by less than CNY 8000 (USD 1108), which can be accepted by rural residents. In order to achieve this target, the NSGA-II algorithm integrated with Rhino + Grasshopper and EnergyPlus simulation kernel was used to establish a thermal performance optimization model for the heat transfer of rural building envelopes in this severe cold region. Among the above-calculated Pareto optimal solutions, the recommended thickness of insulation layers for room floors, roofs, and external walls was about 70 mm, 50 mm, and 40 mm, respectively. Furthermore, we tried to reduce the window-to-wall ratio as much as possible. Finally, based on both the lower building renovation cost and energy-saving rate, three technical solutions from which rural residents could select, according to their specific needs, are put forward.

Abstract Aberrant enhancer activation is a key mechanism driving oncogene expression in many cancers. While much is known about the regulation of larger chromosome domains in eukaryotes, the details of enhancer-promoter interactions remain poorly understood. Recent work suggests co-activators like BRD4 and Mediator have little impact on enhancer-promoter interactions. In leukemias controlled by the MLL-AF4 fusion protein, we use the ultra-high resolution technique Micro-Capture-C (MCC) to show that MLL-AF4 binding promotes broad, high-density regions of enhancer-promoter interactions at a subset of key targets. These enhancers are enriched for transcription elongation factors like PAF1C and FACT, and the loss of these factors abolishes enhancer-promoter contact. This work not only provides an additional model for how MLL-AF4 is able to drive high levels of transcription at key genes in leukemia but also suggests a more general model linking enhancer-promoter crosstalk and transcription elongation.

Abstract Protein arginine methyltransferase 5 (PRMT5) catalyzes mono-methylation and symmetric di-methylation on arginine residues and has emerged as a potential antitumor target with inhibitors being tested in clinical trials. However, it remains unknown how the efficacy of PRMT5 inhibitors is regulated. Here we report that autophagy blockage enhances cellular sensitivity to PRMT5 inhibitor in triple negative breast cancer cells. Genetic ablation or pharmacological inhibition of PRMT5 triggers cytoprotective autophagy. Mechanistically, PRMT5 catalyzes monomethylation of ULK1 at R532 to suppress ULK1 activation, leading to attenuation of autophagy. As a result, ULK1 inhibition blocks PRMT5 deficiency-induced autophagy and sensitizes cells to PRMT5 inhibitor. Our study not only identifies autophagy as an inducible factor that dictates cellular sensitivity to PRMT5 inhibitor, but also unearths a critical molecular mechanism by which PRMT5 regulates autophagy through methylating ULK1, providing a rationale for the combination of PRMT5 and autophagy inhibitors in cancer therapy.

BackgroundChanges in regional levels of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) may indicate the potential for favorable responses to the treatment of stroke affecting the upper extremity. By selectively altering GABA levels during training, we may induce long-term potentiation and adjust excitatory/inhibitory balance (E/I balance). However, the impact of this alteration may be limited by neural damage or aging. Aerobic exercise has been shown to increase GABA levels in the sensorimotor cortex and improve motor learning by widening the dynamic range of E/I balance. The cross-sectional project, Effects of Acute Exercise on Functional Magnetic Resonance Spectroscopy Measures of GABA in Aging and Chronic Stroke (EASE), is designed to assess the functional relevance of changes in GABA concentration within the sensorimotor cortex before and after an acute aerobic exercise session.Methods/designEASE will enroll 30 participants comprised of healthy younger adults (18-35 years; n = 10), older adults (60+ years; n = 10), and persons with chronic stroke (n = 10) affecting distal upper extremity function. We will use resting magnetic resonance spectroscopy to measure all participants' GABA levels at rest before and after aerobic exercise. In addition, we will employ functional magnetic resonance spectroscopy using motor skill acquisition and recall tasks in healthy adults. We hypothesize that acute aerobic exercise will increase resting sensorimotor GABA concentration and that higher GABA resting levels will predict better motor learning performance on measures taken both inside and outside the magnet. We also hypothesize that a higher dynamic range of GABA during task-based spectroscopy in healthy adults will predict better motor skill acquisition and recall.DiscussionThe EASE project will evaluate the effect of acute exercise on GABA levels as a biomarker of upper extremity motor skill learning with two populations (aging adults and those with chronic stroke). We predict that acute exercise, higher sensorimotor GABA levels, and broader dynamic range will be related to better motor skill acquisition.

Abstract Earth System Models (ESMs) project that the terrestrial carbon sink will continue to grow as atmospheric CO2 increases, but this projection is uncertain due to biases in the simulated climate and how ESMs represent ecosystem processes. In particular, the strength of the CO2‐fertilization effect, which is modulated by nutrient cycles, varies substantially across models. This study evaluates land carbon balance uncertainties for the Canadian Earth System Model (CanESM) by conducting simulations where the latest version of CanESM's land surface component is driven offline with raw and bias‐adjusted CanESM5 climate forcing data. To quantify the impact of nutrient limitation, we complete simulations where the nitrogen cycle is enabled or disabled. Results show that bias adjustment improves model performance across most ecosystem variables, primarily due to reduced biases in precipitation. Turning the nitrogen cycle on increases the global land carbon sink during the historical period (1995–2014) due to enhanced nitrogen deposition, placing it within the Global Carbon Budget uncertainty range. During the future period (2080–2099), the simulated land carbon sink increases in response to bias adjustment and decreases in response to the dynamic carbon‐nitrogen interaction, leading to a net decrease when both factors are acting together. The dominating impact of the nitrogen cycle demonstrates the importance of representing nutrient limitation in ESMs. Such efforts may produce more robust carbon balance projections in support of global climate change mitigation policies such as the 2015 Paris Agreement.

Abstract Animals select habitats based on food, water, space, and cover. Each of those components are essential to the ability of an individual to survive and reproduce in a particular habitat. Selection of resources is linked to reproductive fitness and individuals likely vary in how they select resources relative to their reproductive state: during pregnancy, while provisioning young when nutritional needs of the mother are high, but offspring are vulnerable to predation, or if they lose young to mortality. We investigated the effects of reproductive state on selection of resources by maternal female desert bighorn sheep (Ovis canadensis nelsoni) by comparing selection during the last trimester of gestation, following parturition when females were provisioning dependent young, and if the female lost an offspring. We captured, and recaptured each year, 32 female bighorn sheep at Lone Mountain, Nevada, during 2016–2018. Captured females were fit with GPS collars and those that were pregnant received vaginal implant transmitters. We used a Bayesian approach to estimate differences in selection between females provisioning and not provisioning offspring, as well as the length of time it took for females with offspring to return levels of selection similar to that observed prior to parturition. Females that were not provisioning offspring selected areas with higher risk of predation, but greater nutritional resources than those that were provisioning dependent young. When females were provisioning young immediately following parturition, females selected areas that were safe from predators, but had lower nutritional resources. Females displayed varying rates of return to selection strategies associated with access to nutritional resources as young grew and became more agile and less dependent on mothers. We observed clear and substantial shifts in selection of resources associated with reproductive state, and females exhibited tradeoffs in favor of areas that were safer from predators when provisioning dependent young despite loss of nutritional resources to support lactation. As young grew and became less vulnerable to predators, females returned to levels of selection that provided access to nutritional resources to restore somatic reserves lost during lactation.

MIT (magnetic induction tomography) image reconstruction from data acquired with a single, small inductive sensor has unique requirements not found in other imaging modalities. During the course of scanning over a target, measured inductive loss decreases rapidly with distance from the target boundary. Since inductive loss exists even at infinite separation due to losses internal to the sensor, all other measurements made in the vicinity of the target require subtraction of the infinite-separation loss. This is accomplished naturally by treating infinite-separation loss as an unknown. Furthermore, since contributions to inductive loss decline with greater depth into a conductive target, regularization penalties must be decreased with depth. A pair of squared L2 penalty norms are combined to form a 2-term Sobolev norm, including a zero-order penalty that penalizes solution departures from a default solution and a first-order penalty that promotes smoothness. While constraining the solution to be non-negative and bounded from above, the algorithm is used to perform image reconstruction on scan data obtained over a 4.3 cm thick phantom consisting of bone-like features embedded in agarose gel, with the latter having a nominal conductivity of 1.4 S/m.

Abstract Wetlands are responsible for 20%–31% of global methane (CH4) emissions and account for a large source of uncertainty in the global CH4 budget. Data‐driven upscaling of CH4 fluxes from eddy covariance measurements can provide new and independent bottom‐up estimates of wetland CH4 emissions. Here, we develop a six‐predictor random forest upscaling model (UpCH4), trained on 119 site‐years of eddy covariance CH4 flux data from 43 freshwater wetland sites in the FLUXNET‐CH4 Community Product. Network patterns in site‐level annual means and mean seasonal cycles of CH4 fluxes were reproduced accurately in tundra, boreal, and temperate regions (Nash‐Sutcliffe Efficiency ∼0.52–0.63 and 0.53). UpCH4 estimated annual global wetland CH4 emissions of 146 ± 43 TgCH4 y−1 for 2001–2018 which agrees closely with current bottom‐up land surface models (102–181 TgCH4 y−1) and overlaps with top‐down atmospheric inversion models (155–200 TgCH4 y−1). However, UpCH4 diverged from both types of models in the spatial pattern and seasonal dynamics of tropical wetland emissions. We conclude that upscaling of eddy covariance CH4 fluxes has the potential to produce realistic extra‐tropical wetland CH4 emissions estimates which will improve with more flux data. To reduce uncertainty in upscaled estimates, researchers could prioritize new wetland flux sites along humid‐to‐arid tropical climate gradients, from major rainforest basins (Congo, Amazon, and SE Asia), into monsoon (Bangladesh and India) and savannah regions (African Sahel) and be paired with improved knowledge of wetland extent seasonal dynamics in these regions. The monthly wetland methane products gridded at 0.25° from UpCH4 are available via ORNL DAAC (https://doi.org/10.3334/ORNLDAAC/2253).

Cu-Mn hopcalite, as a conventional catalyst showing potential in many chemical reactions, has been rarely researched for its applications in H2O2-activated Fenton-like reactions for the decomposition of refractory pollutants. In this work, an amorphous Cu-Mn hopcalite catalyst (CMO-200) was prepared by simple calcination of their precursors at 200 °C. At circumneutral pH, CMO-200 behaved more efficiently than several commercial manganese oxides, CuO, and Fe2O3, as well as its crystalline analogues in catalytic degradation of tetracycline (TC) with H2O2 as oxidant. The excellent performance can be kept without remarkable loss during its 6 cycles of reuse. Singlet oxygen, superoxide anion radical and hydroxyl radical were found to be active species for the degradation reaction. The amorphous structure and high contents of chemically adsorbed oxygen, Cu+ and Mn4+ species are speculated as the reasons for its high catalytic performance.

Summary: Translocation sequencing can be used to assess mechanisms of DNA repair and identify genome-wide double-strand breaks (DSBs) accessible to DNA repair machinery. Here, we present a protocol for mapping double-strand DNA break sites across the genome with translocation capture sequencing. Bait DSBs are introduced using a Cas9 nuclease and repaired by the host cell, connecting bait DSBs to other DSBs. Repair sites are detected by isolating bait site DNA, cleaving normal sequence to enrich off-site repair, and next-generation sequencing.For complete details on the use and execution of this protocol, please refer to Switonski et al. (2021).1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Global wetlands are the largest and most uncertain natural source of atmospheric methane (CH _4 ). The FLUXNET-CH _4 synthesis initiative has established a global network of flux tower infrastructure, offering valuable data products and fostering a dedicated community for the measurement and analysis of methane flux data. Existing studies using the FLUXNET-CH _4 Community Product v1.0 have provided invaluable insights into the drivers of ecosystem-to-regional spatial patterns and daily-to-decadal temporal dynamics in temperate, boreal, and Arctic climate regions. However, as the wetland CH _4 monitoring network grows, there is a critical knowledge gap about where new monitoring infrastructure ought to be located to improve understanding of the global wetland CH _4 budget. Here we address this gap with a spatial representativeness analysis at existing and hypothetical observation sites, using 16 process-based wetland biogeochemistry models and machine learning. We find that, in addition to eddy covariance monitoring sites, existing chamber sites are important complements, especially over high latitudes and the tropics. Furthermore, expanding the current monitoring network for wetland CH _4 emissions should prioritize, first, tropical and second, sub-tropical semi-arid wetland regions. Considering those new hypothetical wetland sites from tropical and semi-arid climate zones could significantly improve global estimates of wetland CH _4 emissions and reduce bias by 79% (from 76 to 16 TgCH _4 y ^−1 ), compared with using solely existing monitoring networks. Our study thus demonstrates an approach for long-term strategic expansion of flux observations.

The global net land sink is relatively well constrained. However, the responsible drivers and above/below-ground partitioning are highly uncertain. Model issues regarding turnover of individual plant and soil components are responsible.

Abstract Canada's boreal forests and tundra ecosystems are responding to unprecedented climate change with implications for the global carbon (C) cycle and global climate. However, our ability to model the response of Canada's terrestrial ecosystems to climate change is limited and there has been no comprehensive, process‐based assessment of Canada's terrestrial C cycle. We tailor the Canadian Land Surface Scheme Including Biogeochemical Cycles (CLASSIC) to Canada and evaluate its C cycling performance against independent reference data. We utilize skill scores to assess model performance against reference data alongside benchmark scores that quantify the level of agreement between the reference data sets to aid in interpretation. Our results demonstrate CLASSIC's sensitivity to prescribed vegetation cover. They also show that the addition of five region‐specific Plant functional types (PFTs) improves CLASSIC's skill at simulating the Canadian C cycle. CLASSIC performs well when tailored to Canada, falls within the range of the reference data sets, and meets or exceeds the benchmark scores for most C cycling processes. New region‐specific land cover products, well‐informed PFT parameterizations, and more detailed reference data sets will facilitate improvements to the representation of the terrestrial C cycle in regional and global land surface models. Incorporating a parameterization for boreal disturbance processes and explicitly representing peatlands and permafrost soils will improve CLASSIC's future performance in Canada and other boreal regions. This is an important step toward a comprehensive process‐based assessment of Canada's terrestrial C cycle and evaluating Canada's net C balance under climate change.

Abstract Background Genomic instability and chemoresistance can arise in cancer due to a unique form of plasticity: that of polyploid giant cancer cells (PGCCs). These cells form under the stress of chemotherapy and have higher than diploid chromosome content. PGCCs are able to then repopulate tumors through an asymmetric daughter cell budding process. PGCCs have been observed in ovarian cancer histology, including the deadly and common form high-grade serous ovarian carcinoma (HGSC). We previously discovered that drugs which disrupt the cellular recycling process of autophagy are uniquely efficacious in pre-clinical HGSC models. While autophagy induction has been associated with PGCCs, it has never been previously investigated if autophagy modulation interacts with the PGCC life cycle and this form of tumor cell plasticity. Methods CAOV3 and OVCAR3 ovarian cancer cell lines were treated with carboplatin or docetaxel to induce PGCC formation. Microscopy was used to characterize and quantify PGCCs formed by chemotherapy. Two clinically available drugs that inhibit autophagy, hydroxychloroquine and nelfinavir, and a clinically available activator of autophagy, rapamycin, were employed to test the effect of these autophagy modulators on PGCC induction and subsequent colony formation from PGCCs. Crystal violet-stained colony formation assays were used to quantify the tumor-repopulating stage of the PGCC life cycle. Results Autophagy inhibitors did not prevent PGCC formation in OVCAR3 or CAOV3 cells. Rapamycin did not induce PGCC formation on its own nor did it exacerbate PGCC formation by chemotherapy. However, hydroxychloroquine prevented efficient colony formation in CAOV3 PGCCs induced by carboplatin (27% inhibition) or docetaxel (41% inhibition), as well as in OVCAR3 cells (95% and 77%, respectively). Nelfinavir similarly prevented colony formation in CAOV3 PGCCs induced by carboplatin (64% inhibition) or docetaxel (94% inhibition) as well as in OVCAR3 cells (89% and 80%, respectively). Rapamycin surprisingly also prevented PGCC colony outgrowth (52–84% inhibition). Conclusions While the autophagy previously observed to correlate with PGCC formation is unlikely necessary for PGCCs to form, autophagy modulating drugs severely impair the ability of HGSC PGCCs to form colonies. Clinical trials which utilize hydroxychloroquine, nelfinavir, and/or rapamycin after chemotherapy may be of future interest.

RUNX1 is a large and complex gene with two alternative promoters and multiple hematopoietic enhancers. Here the authors show that unlike smaller genes Runx1 becomes sub-compartmentalized during differentiation and gene activation. This subcompartmentalization partially depends on CTCF binding at promoter-proximal CTCF sites and transcription.

BACKGROUND Chronic kidney disease (CKD) is characterized by chronic overactivation of the sympathetic nervous system (SNS), which increases the risk of cardiovascular (CV) disease and mortality. SNS overactivity increases CV risk by multiple mechanisms, including vascular stiffness. We tested the hypothesis that aerobic exercise training would reduce resting SNS activity and vascular stiffness in patients with CKD.METHODS In this randomized controlled trial, sedentary older adults with CKD underwent 12 weeks of exercise (cycling, n = 32) or stretching (an active control group, n = 26). Exercise and stretching interventions were performed 20–45 minutes/session at 3 days/week and were matched for duration. Primary endpoints include resting muscle sympathetic nerve activity (MSNA) via microneurography, arterial stiffness by central pulse wave velocity (PWV), and aortic wave reflection by augmentation index (AIx).RESULTS There was a significant group × time interaction in MSNA and AIx with no change in the exercise group but with an increase in the stretching group after 12 weeks. The magnitude of change in MSNA was inversely associated with baseline MSNA in the exercise group. There was no change in PWV in either group over the study period.CONCLUSION Our data demonstrate that 12 weeks of cycling exercise has beneficial neurovascular effects in patients with CKD. Specifically, exercise training safely and effectively ameliorated the increase in MSNA and AIx observed over time in the control group. This sympathoinhibitory effect of exercise training showed greater magnitude in patients with CKD with higher resting MSNA.TRIAL REGISTRATION ClinicalTrials.gov, NCT02947750.FUNDING NIH R01HL135183; NIH R61AT10457; NIH NCATS KL2TR002381; and NIH T32 DK00756; NIH F32HL147547; and VA Merit I01CX001065.

Selection of forage and habitats is driven by nutritional needs of individuals. Some species may sacrifice nutritional quality of forage for the mother in favor of safety of offspring (risk-averse strategy), immediately following parturition. We studied diet quality and forage selection by bighorn sheep before and following parturition to determine how nutritional demands associated with rearing offspring influenced forage acquisition. We used desert bighorn sheep, Ovis canadensis nelsoni, to investigate that potential tradeoff. We captured and radio-collared female bighorn sheep from 2016 to 2018. We used vaginal implant transmitters (VIT)s in pregnant females to identify parturition and to capture and radio-collar neonates to monitor survival of young. We collected fecal samples throughout the breeding season and throughout the year to understand diet quality and composition throughout those temporal periods. We determined diet quality and composition for pre-parturient females, females provisioning offspring, females that lost offspring, and non-pregnant individuals using fecal nitrogen and DNA metabarcoding analyses. Additionally, we compared the diet quality and composition of offspring and adult females during the spring, as well as summer and winter months. Our results indicated differences in diet quality between individuals provisioning offspring and those whose offspring had died. Females that were provisioning dependent young had lower quality diets than those that lost their offspring. Diet composition among those groups was also markedly different; females that had lost an offspring had a more diverse diet than did females with dependent young. Diet quality differed among seasons, wherein offspring and adult females had higher quality diets during the spring months, with decreasing quality as the year progressed. Diet diversity was similar across seasons, although spring months tended to be most diverse. Our results support tradeoffs associated with risk-averse strategies made by adult females associated with parturition. Nutritional quality of forage was linked to provisioning status, indicating that females were trading diet quality for safety of offspring, but those females whose offspring had died selected high quality forages. Those results help explain habitat selection observed in mountain ungulates around parturition and provide further insight into the evolutionary processes and adaptive significance exhibited by those specialized artiodactyls.

Subthreshold depressive symptoms are highly prevalent among older adults and are associated with numerous health risks including cognitive decline and decreased physical health. One brain region central to neuroanatomical models of depressive disorders is the anterior cingulate cortex (ACC). The rostral portion of the ACC—comprised of the pregenual ACC and subgenual ACC—is implicated in emotion control and reward processing. The goal of the current study was to examine how functional connectivity in subregions of the rostral ACC relate to depressive symptoms, measured by the Beck Depression Inventory-Second Edition, in an ethnically diverse sample of 28 community-dwelling older adults. Based on meta-analyses of previous studies in primarily young adults with clinical depression, we hypothesized that greater depressive symptoms would be associated with primarily increased resting-state functional connectivity from both the subgenual ACC and pregenual ACC to default mode network regions and the dorsolateral PFC. We instead found that higher depressive symptoms were associated with lower functional connectivity of the ACC to the dorsolateral PFC and regions within the default mode network, including from the subgenual ACC to the dorsolateral PFC and anterior cingulate and from the pregenual ACC to the middle cingulate gyrus. This preliminary study highlights brain alterations at subthreshold levels of depressive symptoms in older adults, which could serve as targets for interventions.

Background: There is an unmet need for non-medication approaches to illicit opioid discontinuation and relapse prevention. The NET (NeuroElectric Therapy) Device is a non-invasive, battery-operated, portable, re-useable device designed to deliver bilateral transcranial transcutaneous alternating current electrical stimulation, and is intended to treat opioid use disorder (OUD) without medication. The device is a CE-marked Class IIa, non-significant risk, investigational medical device. Objective: This prospective trial (NRC021) tests the hypothesis that the NET Device provides safe and effective neurostimulation treatment for persons with OUD who express a desire to be opioid abstinent without medications for opioid use disorder (MOUD). Methods: NRC021 is a randomized, parallel-group, sham-controlled, quintuple-blinded, single-site study. Persons with OUD entering a residential treatment facility for opioid detoxification are assigned to active or sham treatment (n = 50/group). Group assignment is stratified on presence of any current non-opioid substance use disorder and by sex. The biostatistician maintains the blinding so that the study sponsor, principal investigator, research assistants, treatment staff, and participants remain blinded. Following discharge from the inpatient facility, participants are assessed once weekly over 12 weeks for substance use (using timeline followback interview and video assessment of observed oral fluid sample provision and testing). The primary efficacy endpoint is each participant's overall percentage of weekly abstinence from illicit opioid use without use of MOUD. The secondary efficacy endpoint is each participant's percentage of non-opioid drug-free weeks. Safety outcomes are also measured. Conclusion: NRC021 is designed to assess the efficacy of a novel non-medication treatment for OUD. Clinical trial registration: ClinicalTrials.gov with the identifier NCT04916600.

Having a healthy sleep pattern plays a vital role in one’s overall health. Sleep in the elderly is characterized by decreased slow-wave sleep and an increase of REM sleep. Furthermore, quantitative electroencephalographic (qEEG) studies have shown an age-related attenuation of total EEG power in sleep. However, exercise has been shown to improve sleep across all age groups. In this study, we used the Sleep Profiler™ EEG Sleep Monitor to observe EEG changes occurring during sleep following an aerobic exercise intervention. This study was done on older adults (N = 18, with only five subjects containing both pre- and post-data of sufficient quality for analysis) with an age range 60–85 years. The aerobics regimen was performed three times weekly for 12-weeks commencing with 20-min sessions. The time of each session progressed by 1–2 min/session as needed to a maximum time of 45 min per session. The macro-architecture (sleep stages) and microarchitecture (EEG) results were analyzed using MATLAB. For the microarchitecture, our results showed more deep sleep following the aerobic exercise regimen. Furthermore, for the microarchitecture, out results shows an increase in total EEG power post-exercise in both light (N1 and L1) and deep sleep (N2 and N3). These preliminary changes in sleep the microarchitecture suggest that non-pharmacologic methods might mitigate age-related EEG changes with potential implications for neurocognitive health.

Older adults typically experience a decline in cognitive function, but improvements in physical health and lifestyle can be neuroprotective across the human lifespan. The primary objective of this study is to advance our basic understanding of how cardiorespiratory fitness and neurophysiological attributes relate to cognitive decline. While cerebral blood flow (CBF) is critical for the supply of nutrients to the tissue, the brain’s major neurotransmitters (i.e., gamma-aminobutyric acid, GABA, and glutamate-glutamine complex, Glx) are closely linked to oxidative metabolism. Within the context of flow-metabolism coupling, the critical question is how these neurophysiological parameters interplay, resulting in cognitive decline. Further, how cardiorespiratory fitness may impact aging neurophysiology and cognition is not well understood. To address these questions, we recruited 10 younger and 12 older cognitively intact participants to collect GABA and Glx using magnetic resonance spectroscopy (MRS), CBF using pseudo-continuous arterial spin labeling Magnetic Resonance Imaging (MRI), VO2max as a measure of cardiorespiratory fitness using the YMCA submax test, and cognitive and motor-cognitive measures using a battery of behavioral assessments. We observed expected differences in GABA+, Glx, and CBF between younger and older participants in pre-SMA, a frontal domain-general region. When GABA+ and Glx were related to CBF via multiple linear regression, Glx was identified as the main contributor to the model. For higher-order executive function (i.e., inhibition versus color naming), GABA*Glx*CBF interaction was critical in younger, while only Glx was involved in older participants. For unimanual motor dexterity, GABA*Glx interaction was the common denominator across both groups, but younger participants’ brain also engages CBF. In terms of selective motor inhibition, CBF from younger participants was the only major neurophysiological factor. In terms of fitness, cardiorespiratory fitness was significantly related to GABA, Glx, and motor performance when combining cohorts, but no group-specific relationships were observed. Taken together, our results indicate that Glx and CBF coupling decreases with aging, perhaps due to altered glial oxidative metabolism. Our data suggest that GABA, Glx, and CBF are engaged and weighted differently for different cognitive measures sensitized to aging, and higher fitness allows for a more efficient metabolic shift that facilitates improved performance on cognitive-motor tasks.

Background: Combination therapy of targeted drugs in cancer treatment is a field in constant flux, with research balancing side effects with efficacy. Efficacy from combination therapy is improved either through synthetic lethality or through prevention of recurrent clones. Previous research has shown (hydroxy-)chloroquine is insufficient to disrupt autophagy in tumors. Hence, either combinations or novel autophagy agents are desired. In vivo studies of ovarian cancer have revealed that chloroquine can be combined with up to four other autophagy drugs to suppress ovarian cancer growth. While cancer efficacy is now established for the autophagy drug combination, it is unclear what toxicities may require monitoring in human trials. Additive toxicity with chemotherapy is also unknown.Methods: To address toxicity in more depth than previous weight-monitoring studies, biochemical and histopathology studies were performed. Mouse groups were treated with autophagy drugs for 2 weeks, with or without the chemotherapy Doxil. After the last dose, mice were processed for blood biochemistry, white blood cell markers, and histopathology.Results: Data from a comprehensive blood biochemistry panel, flow cytometric measurements of blood cell markers, and histopathology are herein reported. While Doxil presented clear bone marrow and immunologic toxicity, autophagy drugs were overall less toxic and more variable in their presentation of potential toxicities. Only minor additive effects of autophagy drugs with Doxil were observed.Conclusion: Combinations of autophagy drugs may be considered for therapy in human oncology trials, with possible side effects to monitor informed by these murine pre-clinical data.

Gait dysfunction and fall risk have been well documented in people with Alzheimer's Disease (AD) and individuals with mild cognitive impairment (MCI). Normal locomotor adaptation may be an important prerequisite for normal and safe community walking function, especially in older adults with age-related neural, musculoskeletal, or cardiovascular changes and cognitive impairments. The split-belt walking task is a well-studied and robust method to evaluate locomotor adaptation (e.g., the ability to adjust stepping movements to changing environmental demands). Here, we capitalized on the split-belt adaptation task to test our hypothesis that a decreased capacity for locomotor adaptation may be an important contributing factor and indicator of increased fall risk and cognitive decline in older individuals with MCI and AD. The objectives of this study were to (1) compare locomotor adaptation capacity in MCI and AD compared to healthy older adults (HOA) during split-belt treadmill walking, and (2) evaluate associations between locomotor adaptation and cognitive impairments. Our results demonstrated a significant decrease in split-belt locomotor adaptation magnitude in older individuals with MCI and AD compared to HOA. In addition, we found significant correlations between the magnitude of early adaptation and de-adaptation vs. cognitive test scores, demonstrating that individuals with greater cognitive impairment also display a reduced capacity to adapt their walking in response to the split-belt perturbation. Our study takes an important step toward understanding mechanisms underlying locomotor dysfunction in older individuals with cognitive impairment.

Abstract The Global Carbon Project estimates that the terrestrial biosphere has absorbed about one‐third of anthropogenic CO2 emissions during the 1959–2019 period. This sink‐estimate is produced by an ensemble of terrestrial biosphere models and is consistent with the land uptake inferred from the residual of emissions and ocean uptake. The purpose of our study is to understand how well terrestrial biosphere models reproduce the processes that drive the terrestrial carbon sink. One challenge is to decide what level of agreement between model output and observation‐based reference data is adequate considering that reference data are prone to uncertainties. To define such a level of agreement, we compute benchmark scores that quantify the similarity between independently derived reference data sets using multiple statistical metrics. Models are considered to perform well if their model scores reach benchmark scores. Our results show that reference data can differ considerably, causing benchmark scores to be low. Model scores are often of similar magnitude as benchmark scores, implying that model performance is reasonable given how different reference data are. While model performance is encouraging, ample potential for improvements remains, including a reduction in a positive leaf area index bias, improved representations of processes that govern soil organic carbon in high latitudes, and an assessment of causes that drive the inter‐model spread of gross primary productivity in boreal regions and humid tropics. The success of future model development will increasingly depend on our capacity to reduce and account for observational uncertainties.