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Complete representation of rainfall–runoff responses in complex, large watersheds using a single-objective parameterization approach in watershed models is often unachievable. In this study we present a calibration approach for the SWAT+ model that independently fits model parameters for different flow segments of the hydrograph. The approach is demonstrated for the Feather River, California, USA, using daily streamflow from the Lake Oroville Reservoir outlet gage. Results show that when model parameters were independently fitted for different flow segments the KGE, NSE, PBIAS, and RSR values improved to 0.96, 0.99, −3.3, and 0.10, respectively, compared to 0.72, 0.66, −9.30, and 0.53, respectively, achieved under a multiobjective and full hydrograph (average hydrograph) calibration. The results highlight that when considering the average hydrograph and flow duration curves, a more balanced representation of both poorly and well-performing segments is achieved, emphasizing the importance of segment-specific parameterization and multi-objective evaluation for accurately representing different flow conditions.

Using the regionally refined mesh (RRM) configuration of the US Department of Energy's Simple Cloud-Resolving Energy Exascale Earth System Model (E3SM) Atmosphere Model (SCREAM), we simulate and evaluate four meteorologically distinct atmospheric river events over California. We test five different RRM configurations, each differing in terms of the areal extent of the refined mesh and the resolution (ranging from 800 m to 3.25 km). We find that SCREAM RRM generally has a good representation of the AR-generated precipitation in CA, even for the control simulation which has a very small 3 km refined patch, and is able to capture the fine-scale regional distributions that are controlled largely by the fine-scale topography of the state. It is found that SCREAM generally has a wet bias over topography, most prominently over the Sierra Nevada mountain range, with a corresponding dry bias on the lee side. We find that refining the resolution beyond 3 km (specifically 1.6 km and 800 m) has virtually no benefit towards reducing systematic precipitation biases but that improvements can be found when increasing the areal extent of the upstream refined mesh. However, these improvements are relatively modest and only realized if the size of the refined mesh is expanded to the scale where employing RRM no longer achieves the substantial cost benefit it was intended for.

The spatial heterogeneity related to complex topography in California demands high-resolution (< 5 km) modeling, but global convection-permitting climate models are computationally too expensive to run multi-decadal simulations. We developed a 3.25 km California climate modeling framework by leveraging regional mesh refinement (CARRM) using the U.S. Department of Energy (DOE)'s global Simple Cloud-Resolving E3SM Atmosphere Model (SCREAM) version 0. Four 5-year time periods (2015–2020, 2029–2034, 2044–2049, and 2094–2099) were simulated by nudging CARRM outside California to 1° coupled simulation of E3SMv1 under the Shared Socioeconomic Pathways (SSP)5-8.5 future scenario. The 3.25 km grid spacing adds considerable value to the prediction of the California climate changes, including more realistic high temperatures in the Central Valley and much improved spatial distributions of precipitation and snowpack in the Sierra Nevada and coastal stratocumulus. Under the SSP5-8.5 scenario, CARRM simulation predicts widespread warming of 6–10 °C over most of California, a 38 % increase in statewide average 30 d winter–spring precipitation, a near-complete loss of the alpine snowpack, and a sharp reduction in shortwave cloud radiative forcing associated with marine stratocumulus by the end of the 21st century. We note a climatological wet precipitation bias for the CARRM and discuss possible reasons. We conclude that SCREAM RRM is a technically feasible and scientifically valid tool for climate simulations in regions of interest, providing an excellent bridge to global convection-permitting simulations.

Summary: Acetylcholine (ACh) is thought to play a role in driving the rapid, spontaneous brain-state transitions that occur during wakefulness; however, the spatiotemporal properties of cortical ACh activity during these state changes are still unclear. We perform simultaneous imaging of GRAB-ACh sensors, GCaMP-expressing basal forebrain axons, and behavior to address this question. We observed a high correlation between axon and GRAB-ACh activity around periods of locomotion and pupil dilation. GRAB-ACh fluorescence could be accurately predicted from axonal activity alone, and local ACh activity decreased at farther distances from an axon. Deconvolution of GRAB-ACh traces allowed us to account for sensor kinetics and emphasized rapid clearance of small ACh transients. We trained a model to predict ACh from pupil size and running speed, which generalized well to unseen data. These results contribute to a growing understanding of the precise timing and spatial characteristics of cortical ACh during fast brain-state transitions.

Community screening for sarcopenia is complex, with barriers including access to specialized equipment and trained staff to conduct body composition, strength and function assessment. In the current study, self-reported dietary protein intake and physical activity (PA) in adults ≥65 years was assessed relative to sarcopenia risk, as determined by body composition, strength and physical function assessments, consistent with the European Working Group on Sarcopenia in Older People (EWGSOP) definition. Of those screened (n = 632), 92 participants (77% female) were assessed as being at high risk of developing sarcopenia on the basis of dietary protein intake ≤1 g∙kg−1∙day−1 [0.9 (0.7–0.9) g∙kg−1∙day−1] and moderate intensity physical activity −1. A further 31 participants (65% female) were defined as being at low risk, with both protein intake [1.2 (1.1–1.5) g∙kg−1∙day−1] and PA greater than the cut-off values. High-risk participants had reduced % lean mass [53.5 (7.8)% versus 54.8 (6.1)%, p < 0.001] and impaired strength and physical function. Notably, high-risk females exhibited greater deficits in lean mass and strength, with minimal differences between groups for males. In community-dwelling older adults, self-reported low protein intake and low weekly PA is associated with heightened risk for sarcopenia, particularly in older women. Future research should determine whether early intervention in older adults with low protein intake and PA attenuates functional decline.

Abstract Understanding the genetic risk and mechanisms through which SARS-CoV-2 infection outcomes and comorbidities interact to impact acute and long-term sequelae is essential if we are to reduce the ongoing health burdens of the COVID-19 pandemic. Here we use a de novo protein diffusion network analysis coupled with tissue-specific gene regulatory networks, to examine putative mechanisms for associations between SARS-CoV-2 infection outcomes and comorbidities. Our approach identifies a shared genetic aetiology and molecular mechanisms for known and previously unknown comorbidities of SARS-CoV-2 infection outcomes. Additionally, genomic variants, genes and biological pathways that provide putative causal mechanisms connecting inherited risk factors for SARS-CoV-2 infection and coronary artery disease and Parkinson’s disease are identified for the first time. Our findings provide an in depth understanding of genetic impacts on traits that collectively alter an individual’s predisposition to acute and post-acute SARS-CoV-2 infection outcomes. The existence of complex inter-relationships between the comorbidities we identify raises the possibility of a much greater post-acute burden arising from SARS-CoV-2 infection if this genetic predisposition is realised.

For the second consecutive year, The Canadian Journal for New Scholars in Education (CJNSE) and the Canadian Committee of Graduate Students in Education (CCGSE) have united to bring forth a Special Issue that showcases the innovative work of Canada's graduate students in education. Stemming from some of the enlightening presentations at the 2023 CCGSE/CSSE conference, this issue aims to amplify the voices of emerging scholars, providing them with a platform where their research undergoes a rigorous peer-review process and reaches a wider academic audience.

Stratospheric ozone affects climate directly as the predominant heat source in the stratosphere and indirectly through chemical reactions controlling other greenhouse gases. The U.S. Department of Energy’s Energy Exascale Earth System Model version 1 (E3SMv1) implemented a new ozone chemistry module that improves the simulation of the sharp tropopause gradients, replacing a version based partly on long-term average climatologies that poorly represented heating rates in the lowermost stratosphere. The new O3v2 module extends seamlessly into the troposphere and preserves the naturally sharp cross-tropopause gradient, with 20 %–40 % less ozone in this region. Additionally, O3v2 enables the diagnosis of stratosphere–troposphere exchange flux of ozone, a key budget term lacking in E3SMv1. Here, we evaluate key features in ozone abundance and other closely related quantities in atmosphere-only E3SMv1 simulations driven by observed sea surface temperatures (SSTs, years 1990–2014), comparing them with satellite observations of ozone and also with the University of California, Irvine chemistry transport model (UCI CTM) using the same stratospheric chemistry scheme but driven by European Centre forecast fields for the same period. In terms of stratospheric column ozone, O3v2 shows reduced mean bias and improved northern midlatitude variability, but it is not quite as good as the UCI CTM. As expected, SST-forced E3SMv1 simulations cannot synchronize with observed quasi-biennial oscillations (QBOs), but they do show the typical QBO pattern seen in column ozone. This new O3v2 E3SMv1 model mostly retains the same climate state and climate sensitivity as the previous version, and we recommend its use for other climate models that still use ozone climatologies.

Stellar occultation observations from space can probe the stratosphere and mesosphere at a fine vertical scale around the globe. Unlike other measurement techniques like radiosondes and aircraft, stellar occultation has the potential to observe the atmosphere above 30 km, and unlike radio occultation, stellar occultation probes fine-scale phenomena with potential to observe atmospheric turbulence. We imaged the refractive bending angle of a star centroid for a series of occultations by the atmosphere. Atmospheric refractivity, density, and then temperature are retrieved from the bending observations with the Abel transformation and Edlén's law, the hydrostatic equation, and the ideal gas law. The retrieval technique is applied to data collected by two nanosatellites operated by Terran Orbital. Measurements were primarily taken by the GEOStare SV2 mission, with a dedicated imaging telescope, supplemented with images captured by spacecraft bus sensors, namely the star trackers on other Terran Orbital missions. The bending angle noise floor is 10 and 30 arcsec for the star tracker and GEOStare SV2 data, respectively. The most significant sources of uncertainty are due to centroiding errors due to the fairly low-resolution stellar images and telescope pointing knowledge derived from noisy satellite attitude sensors. The former mainly affects the star tracker data, while the latter limits the GEOStare SV2 accuracy, with both providing low vertical resolution. This translates to a temperature profile retrieval up to roughly 20 km for both star tracker and GEOStare SV2 datasets. In preparation of an upcoming 2023 mission designed to correct these deficiencies, SOHIP, we simulated bending angle measurements with varying magnitudes of error. The expected maximum altitude of retrieved temperature is 41 km on average for these simulated measurements with a noise floor of 0.39 arcsec. Our work highlights the capabilities of stellar occultation observations from nanosatellites for atmospheric sounding. Future work will investigate high-frequency observations of atmospheric gravity waves and turbulence, mitigating the major uncertainties observed in these datasets.

Abstract Human brain development starts in the embryonic period. Maternal preconception nutrition and nutrient availability to the embryo may influence brain development at this critical period following conception and early cellular differentiation, thereby affecting offspring neurodevelopmental and behavioural disorder risk. However, studying this is challenging due to difficulties in characterizing preconception nutritional status and few studies have objective neurodevelopmental imaging measures in children. We investigated the associations of maternal preconception circulating blood nutrient-related biomarker mixtures (~15 weeks before conception) with child behavioural symptoms (Child Behaviour Checklist (CBCL), aged 3 years) within the Singapore Preconception Study of Long-Term Maternal and Child Outcomes (S-PRESTO) study. The CBCL preschool form evaluates child behaviours based on syndrome scales and Diagnostic and Statistical Manual of Mental Disorders (DSM) oriented scales. These scales consist of internalizing problems, externalizing problems, anxiety problems, pervasive developmental problems, oppositional defiant, etc. We applied data-driven clustering and a method for modelling mixtures (Bayesian kernel machine regression, BKMR) to account for complex, non-linear dependencies between 67 biomarkers. We used effect decomposition analyses to explore the potential mediating role of neonatal (week 1) brain microstructure, specifically orientation dispersion indices (ODI) of 49 cortical and subcortical grey matter regions. We found that higher levels of a nutrient cluster including thiamine, thiamine monophosphate (TMP), pyridoxal phosphate, pyridoxic acid, and pyridoxal were associated with a higher CBCL score for internalizing problems (posterior inclusion probability (PIP) = 0.768). Specifically, thiamine independently influenced CBCL (Conditional PIP = 0.775). Higher maternal preconception thiamine level was also associated with a lower right subthalamic nucleus ODI (P-value = 0.01) while a lower right subthalamic nucleus ODI was associated with higher CBCL scores for multiple domains (P-value

Healthy aging can be promoted by enhanced metabolic fitness and physical capacity. Mitochondria are chief metabolic organelles with strong implications in aging that also coordinate broad physiological functions, in part, using peptides that are encoded within their independent genome. However, mitochondrial-encoded factors that actively regulate aging are unknown. Here, we report that mitochondrial-encoded MOTS-c can significantly enhance physical performance in young (2 mo.), middle-age (12 mo.), and old (22 mo.) mice. MOTS-c can regulate (i) nuclear genes, including those related to metabolism and proteostasis, (ii) skeletal muscle metabolism, and (iii) myoblast adaptation to metabolic stress. We provide evidence that late-life (23.5 mo.) initiated intermittent MOTS-c treatment (3x/week) can increase physical capacity and healthspan in mice. In humans, exercise induces endogenous MOTS-c expression in skeletal muscle and in circulation. Our data indicate that aging is regulated by genes encoded in both of our co-evolved mitochondrial and nuclear genomes.

Abstract Cold water immersion (CWI) following intense exercise is a common athletic recovery practice. However, CWI impacts muscle adaptations to exercise training, with attenuated muscle hypertrophy and increased angiogenesis. Tissue temperature modulates the abundance of specific miRNA species and thus CWI may affect muscle adaptations via modulating miRNA expression following a bout of exercise. The current study focused on the regulatory mechanisms involved in cleavage and nuclear export of mature miRNA, including DROSHA, EXPORTIN‐5, and DICER. Muscle biopsies were obtained from the vastus lateralis of young males (n = 9) at rest and at 2, 4, and 48 h of recovery from an acute bout of resistance exercise, followed by either 10 min of active recovery (ACT) at ambient temperature or CWI at 10°C. The abundance of key miRNA species in the regulation of intracellular anabolic signaling (miR‐1 and miR‐133a) and angiogenesis (miR‐15a and miR‐126) were measured, along with several gene targets implicated in satellite cell dynamics (NCAM and PAX7) and angiogenesis (VEGF and SPRED‐1). When compared to ACT, CWI suppressed mRNA expression of DROSHA (24 h p = 0.025 and 48 h p = 0.017), EXPORTIN‐5 (24 h p = 0.008), and DICER (24 h p = 0.0034). Of the analyzed miRNA species, miR‐133a (24 h p

Leachable investigations are routinely undertaken across a range of sectors (e.g., pharmaceuticals, medical devices, etc.) to determine whether chemicals from a container closure system transfer into a product under normal conditions of use. For Electronic Nicotine Delivery Systems (ENDS) the container closure system includes all materials in contact with the e-liquid that is aerosolized and subsequently inhaled by the user. Currently, there is no guidance for conducting leachable studies for ENDS products, however, there are relevant guidance documents for orally inhaled drug products that can be applied to an ENDS container closure system. We present a case study of the analytical investigation of two leachable compounds identified in simulated leachable studies using aged JUULpods filled with unflavored e-liquid (PG/VG/nicotine/benzoic acid). Both compounds had limited toxicological information and were considered data deficient. A qualitative analysis of the aerosol collected from aged commercial JUULpods (Virginia Tobacco and Menthol), using a similar analytical method (LC-MS/MS) used in the simulated leachable studies, showed no trace or detectable levels of either leachable compound. Therefore, this qualitative analysis did not provide semi-quantitative values for the data-deficient leachable compounds necessary to support toxicological risk assessment. Further, no commercial authentic standards or reasonable synthetic route were available due to the molecular size and structural complexity of the compounds. Instead, method limits were established using an alternative approach to standard ICH guidelines. The experimentally determined method limit of quantitation, using spiked samples of simulated leachable e-liquid, provided conservative semi-quantitative values for each data deficient leachable compound in the aerosol that enabled a transfer efficiency from e-liquid to aerosol to be estimated. The transfer efficiency of each leachable compound was experimentally determined to be less than 3% based on the limit of quantitation, which then could be used to define a relevant exposure limit for the toxicological risk assessment. This work details a novel analytical approach for determining the transfer efficiency of data deficient leachable compounds from ENDS container closure systems into the ENDS aerosol to support toxicological health risk assessments.

This paper documents the biogeochemistry configuration of the Energy Exascale Earth System Model (E3SM), E3SMv1.1-BGC. The model simulates historical carbon cycle dynamics, including carbon losses predicted in response to land use and land cover change, and the responses of the carbon cycle to changes in climate. In addition, we introduce several innovations in the treatment of soil nutrient limitation mechanisms, including explicit dependence on phosphorus availability. The suite of simulations described here includes E3SM contributions to the Coupled Climate-Carbon Cycle Model Intercomparison Project and other projects, as well as simulations to explore the impacts of structural uncertainty in representations of nitrogen and phosphorus limitation. We describe the model spin-up and evaluation procedures, provide an overview of results from the simulation campaign, and highlight key features of the simulations. Cumulative warming over the twentieth century is similar to observations, with a midcentury cold bias offset by stronger warming in recent decades. Ocean biomass production and carbon uptake are underpredicted, likely due to biases in ocean transport leading to widespread anoxia and undersupply of nutrients to surface waters. The inclusion of nutrient limitations in the land biogeochemistry results in weaker carbon fertilization and carbon-climate feedbacks than exhibited by other Earth System Models that exclude those limitations. Finally, we compare with an alternative representation of terrestrial biogeochemistry, which differs in structure and in initialization of soil phosphorus. While both configurations agree well with observational benchmarks, they differ significantly in their distribution of carbon among different pools and in the strength of nutrient limitations.

This study provides an overview of the coupled high-resolution Version 1 of the Energy Exascale Earth System Model (E3SMv1) and documents the characteristics of a 50-year-long high-resolution control simulation with time-invariant 1950 forcings following the HighResMIP protocol. In terms of global root-mean-squared error metrics, this high-resolution simulation is generally superior to results from the low-resolution configuration of E3SMv1 (due to resolution, tuning changes, and possibly initialization procedure) and compares favorably to models in the CMIP5 ensemble. Ocean and sea ice simulation is particularly improved, due to better resolution of bathymetry, the ability to capture more variability and extremes in winds and currents, and the ability to resolve mesoscale ocean eddies. The largest improvement in this regard is an ice-free Labrador Sea, which is a major problem at low resolution. Interestingly, several features found to improve with resolution in previous studies are insensitive to resolution or even degrade in E3SMv1. Most notable in this regard are warm bias and associated stratocumulus deficiency in eastern subtropical oceans and lack of improvement in El Niño. Another major finding of this study is that resolution increase had negligible impact on climate sensitivity (measured by net feedback determined through uniform +4K prescribed sea surface temperature increase) and aerosol sensitivity. Cloud response to resolution increase consisted of very minor decrease at all levels. Large-scale patterns of precipitation bias were also relatively unaffected by grid spacing.

BackgroundFlexitarian, vegetarian and exclusively plant-based diets are increasingly popular, particularly amongst young adults. This is the first randomised dietary intervention to investigate the health, wellbeing, and behavioural implications of consuming a basal vegetarian diet that additionally includes low-to-moderate amounts of red meat (flexitarian) compared to one containing plant-based meat alternatives (PBMAs, vegetarian) in young adults (ClinicalTrials.gov NCT04869163). The objective for the current analysis is to measure adherence to the intervention, nutrition behaviours, and participants’ experience with their allocated dietary group.MethodsEighty healthy young adults participated in this 10-week dietary intervention as household pairs. Household pairs were randomised to receive either approximately three serves of red meat (average of 390 g cooked weight per individual, flexitarian group) or PBMAs (350–400 g per individual, vegetarian group) per week on top of a basal vegetarian diet. Participants were supported to adopt healthy eating behaviours, and this intervention was developed and implemented using a behaviour change framework. Adherence (eating allocated red meat or PBMA, abstaining from animal-based foods not provided by researchers) was continuously monitored, with total scores calculated at the end of the 10-week intervention period. Eating experiences were measured by the Positive Eating Scale and a purpose-designed exit survey, and a food frequency questionnaire measured dietary intake. Analyses used mixed effects modeling taking household clustering into account.ResultsThe total average adherence score was 91.5 (SD = 9.0) out of a possible 100, with participants in the flexitarian group scoring higher (96.1, SD = 4.6, compared to 86.7, SD = 10.0; p

The Energy Exascale Earth System Model Atmosphere Model version 1, the atmospheric component of the Department of Energy's Energy Exascale Earth System Model is described. The model began as a fork of the well-known Community Atmosphere Model, but it has evolved in new ways, and coding, performance, resolution, physical processes (primarily cloud and aerosols formulations), testing and development procedures now differ significantly. Vertical resolution was increased (from 30 to 72 layers), and the model top extended to 60 km (~0.1 hPa). A simple ozone photochemistry predicts stratospheric ozone, and the model now supports increased and more realistic variability in the upper troposphere and stratosphere. An optional improved treatment of light-absorbing particle deposition to snowpack and ice is available, and stronger connections with Earth system biogeochemistry can be used for some science problems. Satellite and ground-based cloud and aerosol simulators were implemented to facilitate evaluation of clouds, aerosols, and aerosol-cloud interactions. Higher horizontal and vertical resolution, increased complexity, and more predicted and transported variables have increased the model computational cost and changed the simulations considerably. These changes required development of alternate strategies for tuning and evaluation as it was not feasible to “brute force” tune the high-resolution configurations, so short-term hindcasts, perturbed parameter ensemble simulations, and regionally refined simulations provided guidance on tuning and parameterization sensitivity to higher resolution. A brief overview of the model and model climate is provided. Model fidelity has generally improved compared to its predecessors and the CMIP5 generation of climate models.

This work documents the first version of the U.S. Department of Energy (DOE) new Energy Exascale Earth System Model (E3SMv1). We focus on the standard resolution of the fully coupled physical model designed to address DOE mission-relevant water cycle questions. Its components include atmosphere and land (110-km grid spacing), ocean and sea ice (60 km in the midlatitudes and 30 km at the equator and poles), and river transport (55 km) models. This base configuration will also serve as a foundation for additional configurations exploring higher horizontal resolution as well as augmented capabilities in the form of biogeochemistry and cryosphere configurations. The performance of E3SMv1 is evaluated by means of a standard set of Coupled Model Intercomparison Project Phase 6 (CMIP6) Diagnosis, Evaluation, and Characterization of Klima simulations consisting of a long preindustrial control, historical simulations (ensembles of fully coupled and prescribed SSTs) as well as idealized CO2 forcing simulations. The model performs well overall with biases typical of other CMIP-class models, although the simulated Atlantic Meridional Overturning Circulation is weaker than many CMIP-class models. While the E3SMv1 historical ensemble captures the bulk of the observed warming between preindustrial (1850) and present day, the trajectory of the warming diverges from observations in the second half of the twentieth century with a period of delayed warming followed by an excessive warming trend. Using a two-layer energy balance model, we attribute this divergence to the model's strong aerosol-related effective radiative forcing (ERFari+aci = −1.65 W/m2) and high equilibrium climate sensitivity (ECS = 5.3 K).

This paper documents the experimental setup and general features of the coupled historical and future climate simulations with the first version of the US Department of Energy (DOE) Energy Exascale Earth System Model (E3SMv1.0). The future projected climate characteristics of E3SMv1.0 at the highest emission scenario (SSP5-8.5) designed in the Scenario Model Intercomparison Project (ScenarioMIP) and the SSP5-8.5 greenhouse gas (GHG) only forcing experiment are analyzed with a focus on regional responses of atmosphere, ocean, sea ice, and land. Due to its high equilibrium climate sensitivity (ECS of 5.3 K), E3SMv1.0 is one of the Coupled Model Intercomparison Project phase 6 (CMIP6) models with the largest surface warming by the end of the 21st century under the high-emission SSP5-8.5 scenario. The global mean precipitation change is highly correlated with the global temperature change, while the spatial pattern of the change in runoff is consistent with the precipitation changes. The oceanic mixed layer generally shoals throughout the global ocean. The annual mean Atlantic meridional overturning circulation (AMOC) is overly weak with a slower change from ∼ 11 to ∼ 6 Sv (Sverdrup) relative to other CMIP6 models. The sea ice, especially in the Northern Hemisphere, decreases rapidly with large seasonal variability. We detect a significant polar amplification in E3SMv1.0 from the atmosphere, ocean, and sea ice. Comparing the SSP5-8.5 all-forcing experiment with the GHG-only experiment, we find that the unmasking of the aerosol effects due to the decline of the aerosol loading in the future projection period causes transient accelerated warming in the all-forcing experiment in the first half of the 21st century. While the oceanic climate response is mainly controlled by the GHG forcing, the land runoff response is impacted primarily by forcings other than GHG over certain regions, e.g., southern North America, southern Africa, central Africa, and eastern Asia. However, the importance of the GHG forcing on the land runoff changes grows in the future climate projection period compared to the historical period.

Approximately 1.71 billion people globally live with musculoskeletal pain conditions, including low back pain, knee pain, and neck pain Cieza et al. (2020). In the US, an estimated 20.4% of U.S. adult had chronic pain and 8.0% of U.S. adults had high-impact chronic pain, with higher prevalence associated with advancing age Dahlhamer et al. (2018). On the other hand, between 50 and 70 million US adults have a sleep disorder (American Sleep Association). Although the link between sleep and pain is widely established, the neurobiological mechanisms underlying this relationship have yet to be fully elucidated, specifically within an aged population. As currently available sleep and chronic pain therapies are only partially effective, novel treatment approaches are urgently needed. Given the potential mechanistic role of γ-aminobutyric acid (GABA) in both conditions, and the availability of GABA supplements over the counter, the present proposal will determine the feasibility and acceptability of oral GABA administration in middle-to-older aged adults with chronic pain and sleep disorders as well as characterize the potential neurobiological mechanisms involved in both conditions. Results from the present investigation using a parallel, double-blinded, placebo-controlled study will provide novel preliminary information needed for future translational pain and sleep research.

Ectopic lipid accumulation, including intra-pancreatic fat deposition (IPFD), exacerbates type 2 diabetes risk in susceptible individuals. Dysregulated circulating microRNAs (miRNAs) have been identified as correlating with clinical measures of pancreatitis, pancreatic cancer and type 1 diabetes. The aim of the current study was therefore to examine the association between circulating abundances of candidate miRNAs, IPFD and liver fat deposition as quantified using magnetic resonance imaging (MRI) and spectroscopy (MRS). Asian Chinese (n = 34; BMI = 26.7 ± 4.2 kg/m2) and European Caucasian (n = 34; BMI = 28.0 ± 4.5 kg/m2) females from the TOFI_Asia cohort underwent MRI and MRS analysis of pancreas (MR-%IPFD) and liver fat (MR-%liver fat), respectively, to quantify ectopic lipid deposition. Plasma miRNA abundances of a subset of circulatory miRNAs associated with IPFD and liver fat deposition were quantified by qRT-PCR. miR-21-3p and miR-320a-5p correlated with MR-%IPFD, plasma insulin and HOMA2-IR, but not MR-%liver fat. MR-%IPFD remained associated with decreasing miR-21-3p abundance following multivariate regression analysis. miR-21-3p and miR-320a were demonstrated to be negatively correlated with MR-%IPFD, independent of ethnicity. For miR-21-3p, this relationship persists with the inclusion of MR-%liver fat in the model, suggesting the potential for a wider application as a specific circulatory correlate of IPFD.

BackgroundSheep milk (SM) is an alternate dairy source, which despite many similarities, has both compositional and structural differences in lipids compared to cow milk (CM). Studies are yet to examine the apparent digestibility of SM lipids, relative to CM, and the potential impact on the plasma lipidome.ObjectiveTo determine the response of the circulatory lipidome to equal volume servings of SM and CM, in females who avoid dairy products.MethodIn a double-blinded, randomized, cross-over trial, self-described dairy avoiding females (n = 30; 24.4 ± 1.1 years) drank SM or CM (650 mL; 33.4 vs. 21.3 g total lipid content; reconstituted from spray dried milk powders) following an overnight fast. Blood samples were collected at fasting and at regular intervals over 4 h after milk consumption. The plasma lipidome was analyzed by LC-MS and fatty acids were quantified by GC-FID.ResultsThe overall postprandial triglyceride (TG) response was similar between SM and CM. TG concentrations were comparable at fasting for both groups, however they were higher after CM consumption at 30 min (interaction milk × time p = 0.003), well before any postprandial lipemic response. This was despite greater quantities provided by SM. However, there were notable differences in the postprandial fatty acid response, with SM leading to an increase in short- and medium-chain fatty acids (MCFAs) (C6:0, C8:0, and C10:0) and several long-chain fatty acids (LCFAs) (C18:1 t11, c9, t11-CLA, and C20:0; interaction time × milk p < 0.05). This corresponded to a greater postprandial response for medium chain triglycerides (MCTs) C10:0, including TG(10:0/14:0/18:1), TG(16:0/10:0/12:0), and TG(16:0/10:0/14:0) (interaction time × milk p < 0.05).ConclusionsDespite a higher fat content, SM ingestion resulted in a greater circulating abundance of MCTs, without increasing total postprandial triglyceride response, when compared to CM. The greater abundance and postprandial appearance of MCTs may provide advantageous metabolic responses in children and adults.Unique identifier and registryU1111-1209-7768; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=375324.

Background: β-cryptoxanthin is a dietary carotenoid for which there have been few studies on the safety and pharmacokinetics following daily oral supplementation. Methods: 90 healthy Asian women between 21 and 35 years were randomized into three groups: 3 and 6 mg/day oral β-cryptoxanthin, and placebo. At 2, 4, and 8 weeks of supplementation, plasma carotenoid levels were measured. The effects of β-cryptoxanthin on blood retinoid-dependent gene expression, mood, physical activity and sleep, metabolic parameters, and fecal microbial composition were investigated. Results: β-cryptoxanthin supplementation for 8 weeks (3 and 6 mg/day) was found to be safe and well tolerated. Plasma β-cryptoxanthin concentration was significantly higher in the 6 mg/day group (9.0 ± 4.1 µmol/L) compared to 3 mg/day group (6.0 ± 2.6 µmol/L) (p < 0.03), and placebo (0.4 ± 0.1 µmol/L) (p < 0.001) after 8 weeks. Plasma all-trans retinol, α-cryptoxanthin, α-carotene, β-carotene, lycopene, lutein, and zeaxanthin levels were not significantly changed. No effects were found on blood retinol-dependent gene expression, mood, physical activity and sleep, metabolic parameters, and fecal microbial composition. Conclusions: Oral β-cryptoxanthin supplementation over 8 weeks lead to high plasma concentrations of β-cryptoxanthin, with no impact on other carotenoids, and was well tolerated in healthy women.

Solar-J is a comprehensive radiative transfer model for the solar spectrum that addresses the needs of both solar heating and photochemistry in Earth system models. Solar-J is a spectral extension of Cloud-J, a standard in many chemical models that calculates photolysis rates in the 0.18-0.8 μm region. The Cloud-J core consists of an eight-stream scattering, plane-parallel radiative transfer solver with corrections for sphericity. Cloud-J uses cloud quadrature to accurately average over correlated cloud layers. It uses the scattering phase function of aerosols and clouds expanded to eighth order and thus avoids isotropic-equivalent approximations prevalent in most solar heating codes. The spectral extension from 0.8 to 12 μm enables calculation of both scattered and absorbed sunlight and thus aerosol direct radiative effects and heating rates throughout the Earth's atmosphere. The Solar-J extension adopts the correlated-k gas absorption bins, primarily water vapor, from the shortwave Rapid Radiative Transfer Model for general circulation model (GCM) applications (RRTMG-SW). Solar-J successfully matches RRTMG-SW's tropospheric heating profile in a clear-sky, aerosol-free, tropical atmosphere. We compare both codes in cloudy atmospheres with a liquid-water stratus cloud and an ice-crystal cirrus cloud. For the stratus cloud, both models use the same physical properties, and we find a systematic low bias of about 3 % in planetary albedo across all solar zenith angles caused by RRTMG-SW's two-stream scattering. Discrepancies with the cirrus cloud using any of RRTMG-SW's three different parameterizations are as large as about 20-40 % depending on the solar zenith angles and occur throughout the atmosphere. Effectively, Solar-J has combined the best components of RRTMG-SW and Cloud-J to build a high-fidelity module for the scattering and absorption of sunlight in the Earth's atmosphere, for which the three major components - wavelength integration, scattering, and averaging over cloud fields - all have comparably small errors. More accurate solutions with Solar-J come with increased computational costs, about 5 times that of RRTMG-SW for a single atmosphere. There are options for reduced costs or computational acceleration that would bring costs down while maintaining improved fidelity and balanced errors.

Abstract. Solar-J is a comprehensive model for radiative transfer over the solar spectrum that addresses the needs of both photochemistry and solar heating in Earth system models. Solar-J includes an 8-stream scattering, plane-parallel radiative transfer solver with corrections for sphericity. It uses the scattering phase function of aerosols and clouds expanded to 8th order and thus makes no isotropic-equivalent approximations that are prevalent in most solar heating codes. It calculates both chemical photolysis rates and the absorption of sunlight and thus the heating rates throughout the Earth's atmosphere. Solar-J is a spectral extension of Fast-J, a standard in many chemical models that calculates photolysis rates in the 0.18–0.85 μm region. For solar heating, Solar-J extends its calculation out to 12 μm using correlated-k gas absorption bins in the infrared from the shortwave Rapid Radiative Transfer Model for GCM applications (RRTMG-SW). Solar-J successfully matches RRTMG's atmospheric heating profile in a clear-sky, aerosol-free, tropical atmosphere. We compare both codes in cloudy atmospheres with a liquid-water stratus cloud and an ice-crystal cirrus cloud. For the stratus cloud both models use the same physical properties, and we find a systematic low bias in the RRTMG-SW of about 3 % in planetary albedo across all solar zenith angles, caused by RRTMG-SW's 2-stream scattering. Discrepancies with the cirrus cloud using any of RRTMG's three different parameterizations are larger, less systematic, and occur throughout the atmosphere. Effectively, Solar-J has combined the best components of RRTMG and Fast-J to build a high-fidelity module for the scattering and absorption of sunlight in the Earth's atmosphere, for which the three major components – wavelength integration, scattering, and averaging over cloud fields all have comparably small errors. More accurate solutions come with increased computational costs, about 5x that of RRTMG, but there are options for reduced costs or computational acceleration that would bring costs down while maintaining balanced errors across components and improved fidelity.

We examined the multiyear mean and variability of dimethyl sulfide (DMS) and its relationship to sulfate aerosols, as well as cloud microphysical and radiative properties. We conducted a 150 year simulation using preindustrial conditions produced by the Community Earth System Model embedded with a dynamic DMS module. The model simulated the mean spatial distribution of DMS emissions and burden, as well as sulfur budgets associated with DMS, SO2, H2SO4, and sulfate that were generally similar to available observations and inventories for a variety of regions. Changes in simulated sea-to-air DMS emissions and associated atmospheric abundance, along with associated aerosols and cloud and radiative properties, were consistently dominated by El Niño–Southern Oscillation (ENSO) cycle in the tropical Pacific region. Simulated DMS, aerosols, and clouds showed a weak positive feedback on sea surface temperature. This feedback suggests a link among DMS, aerosols, clouds, and climate on interannual timescales. The variability of DMS emissions associated with ENSO was primarily caused by a higher variation in wind speed during La Niña events. The simulation results also suggest that variations in DMS emissions increase the frequency of La Niña events but do not alter ENSO variability in terms of the standard deviation of the Niño 3 sea surface temperature anomalies.

Stratospheric ozone affects climate directly as the predominant heat source in the stratosphere and indirectly through chemical reactions controlling other greenhouse gases. The U.S. Department of Energy's Energy Exascale Earth System Model version 1 (E3SMv1) implemented a new ozone chemistry module that improves the simulation of the sharp tropopause gradients, replacing a version based partly on long-term average climatologies that poorly represented heating rates in the lowermost stratosphere. The new O3v2 module extends seamlessly into the troposphere and preserves the naturally sharp cross-tropopause gradient, with 20 %–40 % less ozone in this region. Additionally, O3v2 enables the diagnosis of stratosphere–troposphere exchange flux of ozone, a key budget term lacking in E3SMv1. Here, we evaluate key features in ozone abundance and other closely related quantities in atmosphere-only E3SMv1 simulations driven by observed sea surface temperatures (SSTs, years 1990–2014), comparing them with satellite observations of ozone and also with the University of California, Irvine chemistry transport model (UCI CTM) using the same stratospheric chemistry scheme but driven by European Centre forecast fields for the same period. In terms of stratospheric column ozone, O3v2 shows reduced mean bias and improved northern midlatitude variability, but it is not quite as good as the UCI CTM. As expected, SST-forced E3SMv1 simulations cannot synchronize with observed quasi-biennial oscillations (QBOs), but they do show the typical QBO pattern seen in column ozone. This new O3v2 E3SMv1 model mostly retains the same climate state and climate sensitivity as the previous version, and we recommend its use for other climate models that still use ozone climatologies.

Stratospheric ozone and water vapour are key components of the Earth system, and past and future changes to both have important impacts on global and regional climate. Here, we evaluate long-term changes in these species from the pre-industrial period (1850) to the end of the 21st century in Coupled Model Intercomparison Project phase 6 (CMIP6) models under a range of future emissions scenarios. There is good agreement between the CMIP multi-model mean and observations for total column ozone (TCO), although there is substantial variation between the individual CMIP6 models. For the CMIP6 multi-model mean, global mean TCO has increased from ∼ 300 DU in 1850 to ∼ 305 DU in 1960, before rapidly declining in the 1970s and 1980s following the use and emission of halogenated ozone-depleting substances (ODSs). TCO is projected to return to 1960s values by the middle of the 21st century under the SSP2-4.5, SSP3-7.0, SSP4-3.4, SSP4-6.0, and SSP5-8.5 scenarios, and under the SSP3-7.0 and SSP5-8.5 scenarios TCO values are projected to be ∼ 10 DU higher than the 1960s values by 2100. However, under the SSP1-1.9 and SSP1-1.6 scenarios, TCO is not projected to return to the 1960s values despite reductions in halogenated ODSs due to decreases in tropospheric ozone mixing ratios. This global pattern is similar to regional patterns, except in the tropics where TCO under most scenarios is not projected to return to 1960s values, either through reductions in tropospheric ozone under SSP1-1.9 and SSP1-2.6, or through reductions in lower stratospheric ozone resulting from an acceleration of the Brewer–Dobson circulation under other Shared Socioeconomic Pathways (SSPs). In contrast to TCO, there is poorer agreement between the CMIP6 multi-model mean and observed lower stratospheric water vapour mixing ratios, with the CMIP6 multi-model mean underestimating observed water vapour mixing ratios by ∼ 0.5 ppmv at 70 hPa. CMIP6 multi-model mean stratospheric water vapour mixing ratios in the tropical lower stratosphere have increased by ∼ 0.5 ppmv from the pre-industrial to the present-day period and are projected to increase further by the end of the 21st century. The largest increases (∼ 2 ppmv) are simulated under the future scenarios with the highest assumed forcing pathway (e.g. SSP5-8.5). Tropical lower stratospheric water vapour, and to a lesser extent TCO, shows large variations following explosive volcanic eruptions.

Abstract Background Translational capacity (i.e. ribosomal mass) is a key determinant of protein synthesis and has been associated with skeletal muscle hypertrophy. The role of translational capacity in muscle atrophy and regrowth from disuse is largely unknown. Therefore, we investigated the effect of muscle disuse and reloading on translational capacity in middle‐aged men (Study 1) and in rats (Study 2). Methods In Study 1, 28 male participants (age 50.03 ± 3.54 years) underwent 2 weeks of knee immobilization followed by 2 weeks of ambulatory recovery and a further 2 weeks of resistance training. Muscle biopsies were obtained for measurement of total RNA and pre‐ribosomal (r)RNA expression, and vastus lateralis cross‐sectional area (CSA) was determined via peripheral quantitative computed tomography. In Study 2, male rats underwent hindlimb suspension (HS) for either 24 h (HS 24 h, n = 4) or 7 days (HS 7d, n = 5), HS for 7 days followed by 7 days of reloading (Rel, n = 5) or remained as ambulatory weight bearing (WB, n = 5) controls. Rats received deuterium oxide throughout the study to determine RNA synthesis and degradation, and mTORC1 signalling pathway was assessed. Results Two weeks of immobilization reduced total RNA concentration (20%) and CSA (4%) in men (both P ≤ 0.05). Ambulatory recovery restored total RNA concentration to baseline levels and partially restored muscle CSA. Total RNA concentration and 47S pre‐rRNA expression increased above basal levels after resistance training (P ≤ 0.05). In rats, RNA synthesis was 30% lower while degradation was ~400% higher in HS 7d in soleus and plantaris muscles compared with WB (P ≤ 0.05). mTORC1 signalling was lower in HS compared with WB as was 47S pre‐rRNA (P ≤ 0.05). With reloading, the aforementioned parameters were restored to WB levels while RNA degradation was suppressed (P ≤ 0.05). Conclusions Changes in RNA concentration following muscle disuse and reloading were associated with changes in ribosome biogenesis and degradation, indicating that both processes are important determinants of translational capacity. The pre‐clinical data help explain the reduced translational capacity after muscle immobilization in humans and demonstrate that ribosome biogenesis and degradation might be valuable therapeutic targets to maintain muscle mass during disuse.

Exercise has beneficial effects on metabolism and overall physiologic fitness in aged organisms. Here the authors show that MOTS-c is a mitochondrial-encoded exercise-induced peptide that regulates skeletal muscle metabolism and improves healthspan of older mice.

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are neurodegenerative disorders that affect millions of individuals worldwide. As incidence of these conditions increases with age, there will undoubtedly be an increased prevalence of cases in the near future. Neuroinflammation is a hallmark in the development and progression of neurodegenerative diseases and prevention or resolution of chronic neuroinflammation may represent a novel approach to treatment. The present review highlights the potential of the anti-inflammatory and pro-resolving effects of polyunsaturated fatty acid (PUFA)-derived mediators (Specialized Pro-resolving Mediators—SPM) in neurodegenerative disorders. PUFA-derived SPM are biosynthesized in response to chemicals produced from acute inflammatory responses. Preclinical studies from both AD and PD models suggest a dysregulation of SPM and their receptors in neurological disorders. Decreased SPM may be due to inadequate substrate, an imbalance between SPM and pro-inflammatory mediators or a disruption in SPM synthesis. SPMs hold great promise for neuroprotection in AD by altering expression of pro-inflammatory genes, modulating macrophage function, serving as a biomarker for AD status, and promoting resolution of neuroinflammation. In PD, data suggest SPM are able to cross the blood-brain barrier, inhibit microglial activation and decrease induced markers of inflammation, possibly as a result of their ability to downregulate NFκB signaling pathways. Several in vivo and in vitro studies suggest a benefit from administration of SPMs in both neurodegenerative disorders. However, extrapolation of these outcomes to humans is difficult as no models are able to replicate all features of AD or PD. Minimal data evaluating these PUFA-derived metabolites in humans with neurodegenerative disorders are available and a gap in knowledge exists regarding behavior of SPM and their receptors in patients with these conditions. There is also large gap in our knowledge regarding which lipid mediator would be most effective in which model of AD or PD and how dietary intake or supplementation can impact SPM levels. Future direction should include focused, translational efforts to investigate SPM as an add-on (in addition to standard treatment) or as standalone agents in patients with neurodegenerative disorders.

Large volcanic eruptions reaching the stratosphere have caused marked perturbations to the global climate including cooling at the Earth's surface, changes in large-scale circulation and precipitation patterns and marked temporary reductions in global ocean heat content. Many studies have investigated these effects using climate models; however, uncertainties remain in the modelled response to these eruptions. This is due in part to the diversity of forcing datasets that are used to prescribe the distribution of stratospheric aerosols resulting from these volcanic eruptions, as well as uncertainties in optical property derivations from these datasets. To improve this situation for the sixth phase of the Coupled Model Intercomparison Project (CMIP6), a two-step process was undertaken. First, a combined stratospheric aerosol dataset, the Global Space-based Stratospheric Aerosol Climatology (GloSSAC; 1979–2016), was constructed. Next, GloSSAC, along with information from ice cores and Sun photometers, was used to generate aerosol distributions, characteristics and optical properties to construct a more consistent stratospheric aerosol forcing dataset for models participating in CMIP6. This “version 3” of the stratospheric aerosol forcing has been endorsed for use in all contributing CMIP6 simulations. Recent updates to the underlying GloSSAC from version 1 to version 1.1 affected the 1991–1994 period and necessitated an update to the stratospheric aerosol forcing from version 3 to version 4. As version 3 remains the official CMIP6 input, quantification of the impact on radiative forcing and climate is both relevant and timely for interpreting results from experiments such as the CMIP6 historical simulations. This study uses two models, the Canadian Earth System Model version 5 (CanESM5) and the Energy Exascale Earth System Model (E3SM) Atmosphere Model version 1 (EAMv1), to estimate the difference in instantaneous radiative forcing in simulated post-Pinatubo climate response when using version 4 instead of version 3. Differences in temperature, precipitation and radiative forcings are generally found to be small compared to internal variability. An exception to this is differences in monthly temperature anomalies near 24 km altitude in the tropics, which can be as large as 3 ∘C following the eruption of Mt. Pinatubo.

Abstract Background Adult lactase non-persistence (LNP) is due to low lactase expression, resulting in lactose malabsorption (LM). LNP is a genetic trait, but is typically determined by LM markers including breath H2, blood glucose, and urinary galactose after a lactose tolerance test. Known validity of these markers using milk is limited, despite being common practice. Compositional variation, such as β-casein variants, in milk may impact diagnostic efficacy. This study aimed to evaluate the diagnostic accuracy to detect LNP using these commonly measured LM markers after both lactose and milk challenges. Methods Fourty healthy young women were challenged with 50 g lactose then randomized for separate cross-over visits to ingest 750 mL milk (37.5 g lactose) as conventional (both A1 and A2 β-casein) and A1 β-casein-free (a2 Milk™) milk. Blood, breath and urine were collected prior to and up to 3 h following each challenge. The presence of C/T13910 and G/A22018 polymorphisms, determined by restriction fragment length polymorphism, was used as the diagnostic reference for LNP. Results Genetic testing identified 14 out of 40 subjects as having LNP (C/C13910 and G/G22018). All three LM markers (breath H2, plasma glucose and urinary galactose/creatinine) discriminated between lactase persistence (LP) and LNP following lactose challenge with an area under the receiver operating characteristic (ROC) curve (AUC) of 1.00, 0.75 and 0.73, respectively. Plasma glucose and urinary galactose/creatinine were unreliable (AUC

The axon initial segment (AIS) is a specialized location in neurons with clustered ion channels which regulates the distribution of neuronal materials. Here, the authors use proximity biotinylation to examine the AIS proteome and better define its molecular organization.

Fluorescent organic dyes that absorb and emit in the near-infrared (NIR, 700–1000 nm) and shortwave infrared (SWIR, 1000–1700 nm) regions have the potential to produce noninvasive high-contrast biological images and videos. BODIPY dyes are well known for their high quantum yields in the visible energy region. To tune these chromophores to the NIR region, fused nitrogen-based heterocyclic indolizine donors were added to a BODIPY scaffold. The indolizine BODIPY dyes were synthesized via microwave-assisted Knoevenagel condensation with indolizine aldehydes. The non-protonated dyes showed NIR absorption and emission at longer wavelengths than an aniline benchmark. Protonation of the dyes produced a dramatic 0.35 eV bathochromic shift (230 nm shift from 797 nm to 1027 nm) to give a SWIR absorption and emission (λmaxemis = 1061 nm). Deprotonation demonstrates that material emission is reversibly switchable between the NIR and SWIR.

Abstract This study provides an overview of the coupled high‐resolution Version 1 of the Energy Exascale Earth System Model (E3SMv1) and documents the characteristics of a 50‐year‐long high‐resolution control simulation with time‐invariant 1950 forcings following the HighResMIP protocol. In terms of global root‐mean‐squared error metrics, this high‐resolution simulation is generally superior to results from the low‐resolution configuration of E3SMv1 (due to resolution, tuning changes, and possibly initialization procedure) and compares favorably to models in the CMIP5 ensemble. Ocean and sea ice simulation is particularly improved, due to better resolution of bathymetry, the ability to capture more variability and extremes in winds and currents, and the ability to resolve mesoscale ocean eddies. The largest improvement in this regard is an ice‐free Labrador Sea, which is a major problem at low resolution. Interestingly, several features found to improve with resolution in previous studies are insensitive to resolution or even degrade in E3SMv1. Most notable in this regard are warm bias and associated stratocumulus deficiency in eastern subtropical oceans and lack of improvement in El Niño. Another major finding of this study is that resolution increase had negligible impact on climate sensitivity (measured by net feedback determined through uniform +4K prescribed sea surface temperature increase) and aerosol sensitivity. Cloud response to resolution increase consisted of very minor decrease at all levels. Large‐scale patterns of precipitation bias were also relatively unaffected by grid spacing.