Nuclear receptor signaling via NHR-49/MDT-15 regulates stress resilience and proteostasis in response to reproductive and metabolic cues.

The ability to sense and respond to proteotoxic insults declines with age, leaving cells vulnerable to chronic and acute stressors. Reproductive cues modulate this decline in cellular proteostasis to influence organismal stress resilience in Caenorhabditis elegans We previously uncovered a pathway that links the integrity of developing embryos to somatic health in reproductive adults. Here, we show that the nuclear receptor NHR-49, an ortholog of mammalian peroxisome proliferator-activated receptor α (PPARα), regulates stress resilience and proteostasis downstream from embryo integrity and other pathways that influence lipid homeostasis and upstream of HSF-1. Disruption of the vitelline layer of the embryo envelope, which activates a proteostasis-enhancing intertissue pathway in somatic cells, triggers changes in lipid catabolism gene expression that are accompanied by an increase in fat stores. NHR-49, together with its coactivator, MDT-15, contributes to this remodeling of lipid metabolism and is also important for the elevated stress resilience mediated by inhibition of the embryonic vitelline layer. Our findings indicate that NHR-49 also contributes to stress resilience in other pathways known to change lipid homeostasis, including reduced insulin-like signaling and fasting, and that increased NHR-49 activity is sufficient to improve proteostasis and stress resilience in an HSF-1-dependent manner. Together, our results establish NHR-49 as a key regulator that links lipid homeostasis and cellular resilience to proteotoxic stress.

A conserved SREBP-1/phosphatidylcholine feedback circuit regulates lipogenesis in metazoans.

Sterol regulatory element-binding proteins (SREBPs) activate genes involved in the synthesis and trafficking of cholesterol and other lipids and are critical for maintaining lipid homeostasis. Aberrant SREBP activity, however, can contribute to obesity, fatty liver disease, and insulin resistance, hallmarks of metabolic syndrome. Our studies identify a conserved regulatory circuit in which SREBP-1 controls genes in the one-carbon cycle, which produces the methyl donor S-adenosylmethionine (SAMe). Methylation is critical for the synthesis of phosphatidylcholine (PC), a major membrane component, and we find that blocking SAMe or PC synthesis in C. elegans, mouse liver, and human cells causes elevated SREBP-1-dependent transcription and lipid droplet accumulation. Distinct from negative regulation of SREBP-2 by cholesterol, our data suggest a feedback mechanism whereby maturation of nuclear, transcriptionally active SREBP-1 is controlled by levels of PC. Thus, nutritional or genetic conditions limiting SAMe or PC production may activate SREBP-1, contributing to human metabolic disorders.

Homeostatic control of stearoyl desaturase expression via patched-like receptor PTR-23 ensures the survival of C. elegans during heat stress.

Organismal responses to temperature fluctuations include an evolutionarily conserved cytosolic chaperone machinery as well as adaptive alterations in lipid constituents of cellular membranes. Using C. elegans as a model system, we asked whether adaptable lipid homeostasis is required for survival during physiologically relevant heat stress. By systematic analyses of lipid composition in worms during and before heat stress, we found that unsaturated fatty acids are reduced in heat-stressed animals. This is accompanied by the transcriptional downregulation of fatty acid desaturase enzymes encoded by fat-1, fat-3, fat-4, fat-5, fat-6, and fat-7 genes. Conversely, overexpression of the Δ9 desaturase FAT-7, responsible for the synthesis of PUFA precursor oleic acid, and supplementation of oleic acid causes accelerated death of worms during heat stress. Interestingly, heat stress causes permeability defects in the worm's cuticle. We show that fat-7 expression is reduced in the permeability defective collagen (PDC) mutant, dpy-10, known to have enhanced heat stress resistance (HSR). Further, we show that the HSR of dpy-10 animals is dependent on the upregulation of PTR-23, a patched-like receptor in the epidermis, and that PTR-23 downregulates the expression of fat-7. Consequently, abrogation of ptr-23 in wild type animals affects its survival during heat stress. This study provides evidence for the negative regulation of fatty acid desaturase expression in the soma of C. elegans via the non-canonical role of a patched receptor signaling component. Taken together, this constitutes a skin-gut axis for the regulation of lipid desaturation to promote the survival of worms during heat stress.

The fetal lineage is susceptible to Zika virus infection within days of fertilization.

Adults contracting Zika virus (ZIKV) typically exhibit mild symptoms, yet ZIKV infection of pregnant individuals can cause miscarriage or birth defects in their offspring. Many studies have focused on maternal-to-fetal ZIKV transmission via blood and placenta. Notably, however, ZIKV is also transmitted sexually, raising the possibility that ZIKV could infect the embryo shortly after fertilization, long before the placenta is established. Here, we evaluate the consequences of ZIKV infection in mouse embryos during the first few days of embryogenesis. We show that divergent strains of ZIKV can infect the fetal lineage and can cause developmental arrest, raising concern for the developmental consequences of sexual ZIKV transmission. This article has an associated 'The people behind the papers' interview.

Ether lipid deficiency disrupts lipid homeostasis leading to ferroptosis sensitivity.

Ferroptosis is an iron-dependent form of regulated cell death associated with uncontrolled membrane lipid peroxidation and destruction. Previously, we showed that dietary dihomo-gamma-linolenic acid (DGLA; 20: 3(n-6)) triggers ferroptosis in the germ cells of the model organism, Caenorhabditis elegans. We also demonstrated that ether lipid-deficient mutant strains are sensitive to DGLA-induced ferroptosis, suggesting a protective role for ether lipids. The vinyl ether bond unique to plasmalogen lipids has been hypothesized to function as an antioxidant, but this has not been tested in animal models. In this study, we used C. elegans mutants to test the hypothesis that the vinyl ether bond in plasmalogens acts as an antioxidant to protect against germ cell ferroptosis as well as to protect from whole-body tert-butyl hydroperoxide (TBHP)-induced oxidative stress. We found no role for plasmalogens in either process. Instead, we demonstrate that ether lipid-deficiency disrupts lipid homeostasis in C. elegans, leading to altered ratios of saturated and monounsaturated fatty acid (MUFA) content in cellular membranes. We demonstrate that ferroptosis sensitivity in both wild type and ether-lipid deficient mutants can be rescued in several ways that change the relative abundance of saturated fats, MUFAs and specific polyunsaturated fatty acids (PUFAs). Specifically, we reduced ferroptosis sensitivity by (1) using mutant strains unable to synthesize DGLA, (2) using a strain carrying a gain-of-function mutation in the transcriptional mediator MDT-15, or (3) by dietary supplementation of MUFAs. Furthermore, our studies reveal important differences in how dietary lipids influence germ cell ferroptosis versus whole-body peroxide-induced oxidative stress. These studies highlight a potentially beneficial role for endogenous and dietary MUFAs in the prevention of ferroptosis.

Simulating the healthcare workforce impact and capacity for pancreatic cancer care in Victoria: a model-based analysis.

BACKGROUND: The incidence of pancreatic cancer is rising. With improvements in knowledge for screening and early detection, earlier detection of pancreatic cancer will continue to be more common. To support workforce planning, our aim is to perform a model-based analysis that simulates the potential impact on the healthcare workforce, assuming an earlier diagnosis of pancreatic cancer. METHODS: We developed a simulation model to estimate the demand (i.e. new cases of pancreatic cancer) and supply (i.e. the healthcare workforce including general surgeons, medical oncologists, radiation oncologists, pain medicine physicians, and palliative care physicians) between 2023 and 2027 in Victoria, Australia. The model compares the current scenario to one in which pancreatic cancer is diagnosed at an earlier stage. The incidence of pancreatic cancer in Victoria, five-year survival rates, and Victoria's population size were obtained from Victorian Cancer Registry, Cancer Council NSW, and Australian Bureau of Statistics respectively. The healthcare workforce data were sourced from the Australian Government Department of Health and Aged Care's Health Workforce Data. The model was constructed at the remoteness level. We analysed the new cases and the number of healthcare workforce by profession together to assess the impact on the healthcare workforce. RESULTS: In the status quo, over the next five years, there will be 198 to 220 stages I-II, 297 to 330 stage III, and 495 to 550 stage IV pancreatic cancer cases diagnosed annually, respectively. Assuming 20-70% of the shift towards pancreatic cancer's earlier diagnosis (shifting from stage IV to stages I-II pancreatic cancer within one year), the stages I-II cases could increase to 351 to 390 or 598 to 665 per year. The shift to early diagnosis led to substantial survival gains, translating into an additional 284 or 795 out of 5246 patients with pancreatic cancer remaining alive up to year 5 post-diagnosis. Workforce supply decreases significantly by the remoteness levels, and remote areas face a shortage of key medical professionals registered in delivering pancreatic cancer care, suggesting travel necessities by patients or clinicians. CONCLUSION: Improving the early detection and diagnosis of pancreatic cancer is expected to bring significant survival benefits, although there are workforce distribution imbalances in Victoria that may affect the ability to achieve the anticipated survival gain.

Pan-Arctic soil moisture control on tundra carbon sequestration and plant productivity.

Long-term atmospheric CO2 concentration records have suggested a reduction in the positive effect of warming on high-latitude carbon uptake since the 1990s. A variety of mechanisms have been proposed to explain the reduced net carbon sink of northern ecosystems with increased air temperature, including water stress on vegetation and increased respiration over recent decades. However, the lack of consistent long-term carbon flux and in situ soil moisture data has severely limited our ability to identify the mechanisms responsible for the recent reduced carbon sink strength. In this study, we used a record of nearly 100 site-years of eddy covariance data from 11 continuous permafrost tundra sites distributed across the circumpolar Arctic to test the temperature (expressed as growing degree days, GDD) responses of gross primary production (GPP), net ecosystem exchange (NEE), and ecosystem respiration (ER) at different periods of the summer (early, peak, and late summer) including dominant tundra vegetation classes (graminoids and mosses, and shrubs). We further tested GPP, NEE, and ER relationships with soil moisture and vapor pressure deficit to identify potential moisture limitations on plant productivity and net carbon exchange. Our results show a decrease in GPP with rising GDD during the peak summer (July) for both vegetation classes, and a significant relationship between the peak summer GPP and soil moisture after statistically controlling for GDD in a partial correlation analysis. These results suggest that tundra ecosystems might not benefit from increased temperature as much as suggested by several terrestrial biosphere models, if decreased soil moisture limits the peak summer plant productivity, reducing the ability of these ecosystems to sequester carbon during the summer.

Carbon uptake in Eurasian boreal forests dominates the high-latitude net ecosystem carbon budget.

Arctic-boreal landscapes are experiencing profound warming, along with changes in ecosystem moisture status and disturbance from fire. This region is of global importance in terms of carbon feedbacks to climate, yet the sign (sink or source) and magnitude of the Arctic-boreal carbon budget within recent years remains highly uncertain. Here, we provide new estimates of recent (2003-2015) vegetation gross primary productivity (GPP), ecosystem respiration (Reco ), net ecosystem CO2 exchange (NEE; Reco - GPP), and terrestrial methane (CH4 ) emissions for the Arctic-boreal zone using a satellite data-driven process-model for northern ecosystems (TCFM-Arctic), calibrated and evaluated using measurements from >60 tower eddy covariance (EC) sites. We used TCFM-Arctic to obtain daily 1-km2 flux estimates and annual carbon budgets for the pan-Arctic-boreal region. Across the domain, the model indicated an overall average NEE sink of -850 Tg CO2 -C year-1 . Eurasian boreal zones, especially those in Siberia, contributed to a majority of the net sink. In contrast, the tundra biome was relatively carbon neutral (ranging from small sink to source). Regional CH4 emissions from tundra and boreal wetlands (not accounting for aquatic CH4 ) were estimated at 35 Tg CH4 -C year-1 . Accounting for additional emissions from open water aquatic bodies and from fire, using available estimates from the literature, reduced the total regional NEE sink by 21% and shifted many far northern tundra landscapes, and some boreal forests, to a net carbon source. This assessment, based on in situ observations and models, improves our understanding of the high-latitude carbon status and also indicates a continued need for integrated site-to-regional assessments to monitor the vulnerability of these ecosystems to climate change.

A compendium of kinetic modulatory profiles identifies ferroptosis regulators.

Cell death can be executed by regulated apoptotic and nonapoptotic pathways, including the iron-dependent process of ferroptosis. Small molecules are essential tools for studying the regulation of cell death. Using time-lapse imaging and a library of 1,833 bioactive compounds, we assembled a large compendium of kinetic cell death modulatory profiles for inducers of apoptosis and ferroptosis. From this dataset we identify dozens of ferroptosis suppressors, including numerous compounds that appear to act via cryptic off-target antioxidant or iron chelating activities. We show that the FDA-approved drug bazedoxifene acts as a potent radical trapping antioxidant inhibitor of ferroptosis both in vitro and in vivo. ATP-competitive mechanistic target of rapamycin (mTOR) inhibitors, by contrast, are on-target ferroptosis inhibitors. Further investigation revealed both mTOR-dependent and mTOR-independent mechanisms that link amino acid metabolism to ferroptosis sensitivity. These results highlight kinetic modulatory profiling as a useful tool to investigate cell death regulation.

Impact of the Medicare Benefits Schedule Rebate (MBSR) freeze on General Practice (GP) use: multivariable regression analysis.

BACKGROUND: In 2015, the Australian government froze the Medicare Benefits Schedule Rebate (MBSR) for General Practitioner (GP) service use. This paper aimed to explore the impact of the MBSR freeze on the demand for GP services in Victoria, Australia, for three years, from 2014 to 2016. METHOD: Annual data on GP service utilisation by the Victorian State Statistical Area Level 3 (SA3) were analysed using 2015 as the reference year (MBSR freeze year). We compared annual per-person GP service use before and after the MBSR freeze for each SA3. Socioeconomic Indexes for Areas (SEIFA) scores and regions of Victoria (Greater Melbourne and the Rest of Victoria) were used to identify the most disadvantaged SA3s in Victoria. We conducted a multivariable regression analysis for the number of GP services per patient by SA3, controlling for regions of Victoria, the number of GP services, the proportion of bulk-billed visits, age group, gender and year. FINDINGS: After adjusting for age group, gender, region, SEIFA, the number of GPs and the proportion of bulk-billed GP visits, mean GP services per person per year declined steadily between 2014 and 2016, with a 3% or 0.11 visit (-0.114, 95%CI: -0.134; -0.094, P = < 0.001) reduction in mean utilisation in 2016 compared to 2014. In disadvantaged SA3s, there was a fall in the number of GP services that were bulk-billed during and after the MBSR freeze compared to 2014, and this fall was large in LOW SEIFA SA3s, with a reduction in 17% of mean bulk-billed GP services. CONCLUSION: The MBSR freeze for GP consultations in 2015 resulted in a reduction in the annual per capita demand for GP visits, with the impact of reduced demand more significant in lower socioeconomic and regional/rural areas. The GP funding policies must consider the demand differences by social-economic status and location.

Vital sign assessment and nursing interventions in medical and surgical patients with rapid response system triggers.

AIM(S): To explore vital sign assessment (both complete and incomplete sets of vital signs), and escalation of care per policy and nursing interventions in response to clinical deterioration. DESIGN: This cohort study is a secondary analysis of data from the Prioritising Responses of Nurses To deteriorating patient Observations cluster randomised controlled trial of a facilitation intervention on nurses' vital sign measurement and escalation of care for deteriorating patients. METHODS: The study was conducted in 36 wards at four metropolitan hospitals in Victoria, Australia. Medical records of all included patients from the study wards during three randomly selected 24-h periods within the same week were audited at three time points: pre-intervention (June 2016), and at 6 (December 2016) and 12 months (June 1017) post-intervention. Descriptive statistics were used to summarise the study data, and relationships between variables were examined using chi-square test. RESULTS: A total of 10,383 audits were conducted. At least one vital sign measurement was documented every 8 h in 91.6% of audits, and a complete set of vital signs was documented every 8 h in 83.1% of audits. There were pre-Medical Emergency Team, Medical Emergency Team or Cardiac Arrest Team triggers in 25.8% of audits. When triggers were present, a rapid response system call occurred in 26.8% of audits. There were 1350 documented nursing interventions in audits with pre-Medical Emergency Team (n = 2403) or Medical Emergency Team triggers (n = 273). One or more nursing interventions were documented in 29.5% of audits with pre-Medical Emergency Team triggers and 63.7% of audits with Medical Emergency Team triggers. CONCLUSION: When rapid response system triggers were documented, there were gaps in escalation of care per policy; however, nurses undertook a range of interventions within their scope of practice in response to clinical deterioration. RELEVANCE TO CLINICAL PRACTICE: Medical and surgical ward nurses in acute care wards frequently engage in vital sign assessment. Interventions by medical and nurgical nurses may occur prior to, or in parallel with calling the rapid response system. Nursing interventions are a key but under-recognised element of the organisational response to deteriorating patients. IMPLICATIONS FOR THE PROFESSION AND/OR PATIENT CARE: Nurses engage in a range of nursing interventions to manage deteriorating patients, (aside from rapid response system activation) that are not well understood, nor well described in the literature to date. IMPACT: This study addresses the gap in the literature regarding nurses' management of deteriorating patients within their scope of practice (aside from RRS activation) in real world settings. When rapid response system triggers were documented, there were gaps in escalation of care per policy; however, nurses undertook a range of interventions within their scope of practice in response to clinical deterioration. The results of this research are relevant to nurses working on medical and surgical wards. REPORTING METHOD: The trial was reported according to the Consolidated Standards of Reporting Trials extension for Cluster Trials recommendations, and this paper is reported according to the Strengthening the Reporting of Observational Studies in Epidemiology Statement. PATIENT OR PUBLIC CONTRIBUTION: No Patient or Public Contribution.

TEAD4, YAP1 and WWTR1 prevent the premature onset of pluripotency prior to the 16-cell stage.

In mice, pluripotent cells are thought to derive from cells buried inside the embryo around the 16-cell stage. Sox2 is the only pluripotency gene known to be expressed specifically within inside cells at this stage. To understand how pluripotency is established, we therefore investigated the mechanisms regulating the initial activation of Sox2 expression. Surprisingly, Sox2 expression initiated normally in the absence of both Nanog and Oct4 (Pou5f1), highlighting differences between embryo and stem cell models of pluripotency. However, we observed precocious ectopic expression of Sox2 prior to the 16-cell stage in the absence of Yap1, Wwtr1 and Tead4 Interestingly, the repression of premature Sox2 expression was sensitive to LATS kinase activity, even though LATS proteins normally do not limit activity of TEAD4, YAP1 and WWTR1 during these early stages. Finally, we present evidence for direct transcriptional repression of Sox2 by YAP1, WWTR1 and TEAD4. Taken together, our observations reveal that, while embryos are initially competent to express Sox2 as early as the four-cell stage, transcriptional repression prevents the premature expression of Sox2, thereby restricting the pluripotency program to the stage when inside cells are first created.

Clinical effectiveness and cost-effectiveness of ambulatory heart failure nurse-led services: an integrated review.

BACKGROUND: Globally the burden of heart failure is rising. Hospitalisation is one of the main contributors to the burden of heart failure and unfortunately, the majority of heart failure patients will experience multiple hospitalisations over their lifetime. Considering the high health care cost associated with heart failure, a review of economic evaluations of post-discharge heart failure services is warranted. AIM: An integrated review of the economic evaluations of post-discharge nurse-led heart failure services for patients hospitalised with acute heart failure. METHODS: Electronic databases were searched using EBSCOHost: CINAHL complete, Medline complete, Embase, Scopus, EconLit, Global Health, and Health source (Consumer and Nursing/Academic) for published articles until 22nd June 2021. The searches focussed on papers that examined the cost-effectiveness of nurse-led clinics or telemonitoring involving nurses to follow-up patients after hospitalisation for acute heart failure. GRADE criteria and CHEERS checklist were used to determine the quality of the evidence and the quality of reporting of the economic evaluation. RESULTS: Out of 453 studies identified, eight studies were included: four in heart failure clinics and four in telemonitoring programs. Five of the articles were cost-effectiveness analyses, one a cost comparison and two studies involved economic modelling The GRADE criteria were rated as high in five studies. In which, four studies examined the cost-effectiveness of telemonitoring programs. Based on the CHEERS checklist for reporting quality of economic evaluations, the majority of economic evaluations were rated between 86 and 96%. All the studies found the intervention to be cost-effective compared to usual care with Incremental Cost Effectiveness Ratios ranging from $18 259 (Canadian dollars)/life year gained to €40,321 per Quality Adjusted Life Years gained. CONCLUSION: Nurse-led heart failure clinics and telemonitoring programs were found to be cost-effective. Certainly, this review has shown that heart failure clinics and telemonitoring programs do represent value for money with their greatest impact and cost savings through reducing rehospitalisations.

Identifying patterns of potentially preventable hospitalisations in people living with dementia.

BACKGROUND: Older Australians make up 46% of all potentially preventable hospitalisations (PPHs) and people living with dementia are at significantly greater risk. While policy reforms aim to reduce PPHs, there is currently little evidence available on what drives this, especially for people living with dementia. This study examines patterns of PPHs in people living with dementia to inform service delivery and the development of evidence-based interventions. METHODS: We used the Victorian Admitted Episodes Dataset from Victoria, Australia, to extract data for people aged 50 and over with a diagnosis of dementia between 2015 and 2016. Potentially avoidable admissions, known as ambulatory care sensitive conditions (ACSCs), were identified. The chi-square test was used to detect differences between admissions for ACSCs and non-ACSCs by demographic, geographical, and administrative factors. Predictors of ACSCs admissions were analysed using univariate and multiple logistic regression. RESULTS: Of the 8156 hospital records, there were 3884 (48%) ACSCs admissions, of which admissions for urinary tract infections accounted for 31%, followed by diabetes complications (21%). Mean bed-days were 8.26 for non-ACSCs compared with 9.74 for ACSCs (p ≤ 0.001). There were no differences between admissions for ACSCs and non-ACSCs by sex, marital status, region (rural vs metro), and admission source (private accommodation vs residential facility). Culture and language predicted ASCS admission rates in the univariate regression analyses, with ACSC admission rates increasing by 20 and 29% if English was not the preferred language or if an interpreter was required, respectively. Results from the multiple regression analysis confirmed that language was a significant predictor of ACSC admission rates. CONCLUSIONS: Improved primary health care may help to reduce the most common causes of PPHs for people living with dementia, particularly for those from culturally and linguistically diverse backgrounds.

Use of Outpatient Opioids Prescribed From a Pediatric Acute Care Setting.

OBJECTIVES: Deaths due to prescription opioid overdoses are at record high levels. Limiting the amount of opioid prescribed has been suggested as a prevention strategy, but little is known about how much is needed to adequately treat acutely painful conditions for outpatients. The purpose of this study was to quantify the usage of opioids prescribed from the pediatric emergency departments of a Midwestern tertiary care children's hospital system. METHODS: This was a prospective descriptive study in which patients aged 0 to 17 years seen in 2 pediatric emergency departments who received a prescription for an outpatient opioid were enrolled. The main outcome was opioid doses used at home, which was obtained via phone follow-up. Additional information, including patient demographics, location, prescriber specialty, diagnosis, and opioid name and amount prescribed, was obtained via chart review. RESULTS: A total of 295 patients were enrolled, with 281 completing the study (95%). The median numbers of opioid doses prescribed and used were 12 and 2 doses, respectively, with 9 doses in excess. Patients with lower extremity fractures used more opioids than other diagnoses, with a median of 8 doses. The majority of families reported keeping extra doses at home. CONCLUSIONS: Prescribed opioid doses exceeded used doses by a factor of 6. Lower extremity fractures required more doses than other acutely painful conditions. We should consider limiting doses prescribed to decrease excess opioids available for misuse and abuse.

Statistical upscaling of ecosystem CO2 fluxes across the terrestrial tundra and boreal domain: Regional patterns and uncertainties.

The regional variability in tundra and boreal carbon dioxide (CO2 ) fluxes can be high, complicating efforts to quantify sink-source patterns across the entire region. Statistical models are increasingly used to predict (i.e., upscale) CO2 fluxes across large spatial domains, but the reliability of different modeling techniques, each with different specifications and assumptions, has not been assessed in detail. Here, we compile eddy covariance and chamber measurements of annual and growing season CO2 fluxes of gross primary productivity (GPP), ecosystem respiration (ER), and net ecosystem exchange (NEE) during 1990-2015 from 148 terrestrial high-latitude (i.e., tundra and boreal) sites to analyze the spatial patterns and drivers of CO2 fluxes and test the accuracy and uncertainty of different statistical models. CO2 fluxes were upscaled at relatively high spatial resolution (1 km2 ) across the high-latitude region using five commonly used statistical models and their ensemble, that is, the median of all five models, using climatic, vegetation, and soil predictors. We found the performance of machine learning and ensemble predictions to outperform traditional regression methods. We also found the predictive performance of NEE-focused models to be low, relative to models predicting GPP and ER. Our data compilation and ensemble predictions showed that CO2 sink strength was larger in the boreal biome (observed and predicted average annual NEE -46 and -29 g C m-2  yr-1 , respectively) compared to tundra (average annual NEE +10 and -2 g C m-2  yr-1 ). This pattern was associated with large spatial variability, reflecting local heterogeneity in soil organic carbon stocks, climate, and vegetation productivity. The terrestrial ecosystem CO2 budget, estimated using the annual NEE ensemble prediction, suggests the high-latitude region was on average an annual CO2 sink during 1990-2015, although uncertainty remains high.

Reconciling carbon-cycle processes from ecosystem to global scales.

Understanding carbon (C) dynamics from ecosystem to global scales remains a challenge. Although expansion of global carbon dioxide (CO2) observatories makes it possible to estimate C-cycle processes from ecosystem to global scales, these estimates do not necessarily agree. At the continental US scale, only 5% of C fixed through photosynthesis remains as net ecosystem exchange (NEE), but ecosystem measurements indicate that only 2% of fixed C remains in grasslands, whereas as much as 30% remains in needleleaf forests. The wet and warm Southeast has the highest gross primary productivity and the relatively wet and cool Midwest has the highest NEE, indicating important spatial mismatches. Newly available satellite and atmospheric data can be combined in innovative ways to identify potential C loss pathways to reconcile these spatial mismatches. Independent datasets compiled from terrestrial and aquatic environments can now be combined to advance C-cycle science across the land-water interface.

Impacts of chronic disease prevention programs implemented by private health insurers: a systematic review.

BACKGROUND: Chronic diseases contribute to a significant proportion (71%) of all deaths each year worldwide. Governments and other stakeholders worldwide have taken various actions to tackle the key risk factors contributing to the prevalence and impact of chronic diseases. Private health insurers (PHI) are one key stakeholders, particularly in Australian health system, and their engagement in chronic disease prevention is growing. Therefore, we investigated the impacts of chronic disease prevention interventions implemented by PHI both in Australia and internationally. METHOD: We searched multiple databases (Business Source Complete, CINAHL, Global Health, Health Business Elite, Medline, PsycINFO, and Scopus) and grey literature for studies/reports published in English until September 2020 using search terms on the impacts of chronic disease prevention interventions delivered by PHIs. Two reviewers assessed the risk of bias using a quality assessment tool developed by Effective Public Healthcare Panacea Project. After data extraction, the literature was synthesised thematically based on the types of the interventions reported across studies. The study protocol was registered in PROSPERO, CRD42020145644. RESULTS: Of 7789 records, 29 studies were eligible for inclusion. There were predominantly four types of interventions implemented by PHIs: Financial incentives, health coaching, wellness programs, and group medical appointments. Outcome measures across studies were varied, making it challenging to compare the difference between the effectiveness of different intervention types. Most studies reported that the impacts of interventions, such as increase in healthy eating, physical activity, and lower hospital admissions, last for a shorter term if the length of the intervention is shorter. INTERPRETATION: Although it is challenging to conclude which intervention type was the most effective, it appeared that, regardless of the intervention types, PHI interventions of longer duration (at least 2 years) were more beneficial and outcomes were more sustained than those PHI interventions that lasted for a shorter period. FUNDING: Primary source of funding was Geelong Medical and Hospital Benefits Association (GMHBA), an Australian private health insurer.

Mouse maternal protein restriction during preimplantation alone permanently alters brain neuron proportion and adult short-term memory.

Maternal protein malnutrition throughout pregnancy and lactation compromises brain development in late gestation and after birth, affecting structural, biochemical, and pathway dynamics with lasting consequences for motor and cognitive function. However, the importance of nutrition during the preimplantation period for brain development is unknown. We have previously shown that maternal low-protein diet (LPD) confined to the preimplantation period (Emb-LPD) in mice, with normal nutrition thereafter, is sufficient to induce cardiometabolic and locomotory behavioral abnormalities in adult offspring. Here, using a range of in vivo and in vitro techniques, we report that Emb-LPD and sustained LPD reduce neural stem cell (NSC) and progenitor cell numbers at E12.5, E14.5, and E17.5 through suppressed proliferation rates in both ganglionic eminences and cortex of the fetal brain. Moreover, Emb-LPD causes remaining NSCs to up-regulate the neuronal differentiation rate beyond control levels, whereas in LPD, apoptosis increases to possibly temper neuron formation. Furthermore, Emb-LPD adult offspring maintain the increase in neuron proportion in the cortex, display increased cortex thickness, and exhibit short-term memory deficit analyzed by the novel-object recognition assay. Last, we identify altered expression of fragile X family genes as a potential molecular mechanism for adverse programming of brain development. Collectively, these data demonstrate that poor maternal nutrition from conception is sufficient to cause abnormal brain development and adult memory loss.