Understanding the mechanisms that determine an individual's sex remains a primary challenge for evolutionary biology. Chromosome-based systems (genotypic sex determination) that generate roughly ...equal numbers of sons and daughters accord with theory, but the adaptive significance of environmental sex determination (that is, when embryonic environmental conditions determine offspring sex, ESD) is a major unsolved problem. Theoretical models predict that selection should favour ESD over genotypic sex determination when the developmental environment differentially influences male versus female fitness (that is, the Charnov-Bull model), but empirical evidence for this hypothesis remains elusive in amniote vertebrates-the clade in which ESD is most prevalent. Here we provide the first substantial empirical support for this model by showing that incubation temperatures influence reproductive success of males differently than that of females in a short-lived lizard (Amphibolurus muricatus, Agamidae) with temperature-dependent sex determination. We incubated eggs at a variety of temperatures, and de-confounded sex and incubation temperature by using hormonal manipulations to embryos. We then raised lizards in field enclosures and quantified their lifetime reproductive success. Incubation temperature affected reproductive success differently in males versus females in exactly the way predicted by theory: the fitness of each sex was maximized by the incubation temperature that produces that sex. Our results provide unequivocal empirical support for the Charnov-Bull model for the adaptive significance of temperature-dependent sex determination in amniote vertebrates.
I entered the field of risk analysis forty years ago from a background in physics followed by doctoral training and experience in decision analysis. I came into the Society for Risk Analysis (SRA) ...after participating as a committee member in the 1983 National Academies report, Risk Assessment in the Federal Government: Managing the Process. The insights and recommendations from this report, and successor reports from 1996 and 2008, merit revisiting on this 40th anniversary. Risk analysis includes risk assessment, a process of summarizing applicable science to inform decisions; and risk management, a process of making informed choices, usually involving multiple stakeholders. Inherent in both is the need to deal with complexity, uncertainty, and differing perspectives and goals. The lessons I have learned include the need for a conceptual separation of risk management from risk assessment, the benefit of an iterative dialogue between these activities, and the wisdom of articulating and assessing what we know, what we want, and what we can do as we seek to understand and manage risks affecting ourselves and those we advise.
We examined the risk for postoperative delirium (POD) in patients with mild cognitive impairment (MCI) or dementia, and the association between POD and subsequent development of MCI or dementia in ...cognitively normal elderly patients.
Patients ≥65 yr of age enrolled in the Mayo Clinic Study of Aging who were exposed to any type of anaesthesia from 2004 to 2014 were included. Cognitive status was evaluated before and after surgery by neuropsychological testing and clinical assessment, and was defined as normal or MCI/dementia. Postoperative delirium was detected with the Confusion Assessment Method for the intensive care unit. Logistic regression analyses were performed.
Among 2014 surgical patients, 74 (3.7%) developed POD. Before surgery, 1667 participants were cognitively normal, and 347 met MCI/dementia criteria. The frequency of POD was higher in patients with pre-existing MCI/dementia compared with no MCI/dementia {8.7 vs 2.6%; odds ratio (OR) 2.53, 95% confidence interval (CI) 1.52–4.21; P<0.001}. Postoperative delirium was associated with lower education OR, 3.40 (95% CI, 1.60–7.40); P=0.002 for those with <12 vs ≥16 yr of schooling. Of the 1667 patients cognitively normal at their most recent assessment, 1152 returned for postoperative evaluation, and 109 (9.5%) met MCI/dementia criteria. The frequency of MCI/dementia at the first postoperative evaluation was higher in patients who experienced POD compared with those who did not 33.3 vs 9.0%; adjusted OR, 3.00 (95% CI, 1.12–8.05); P=0.029.
Mild cognitive impairment or dementia is a risk for POD. Elderly patients who have not been diagnosed with MCI or dementia but experience POD are more likely to be diagnosed subsequently with MCI or dementia.
Heat stress is one of the most stressful events in the life of livestock with harmful consequences for animal health, productivity and product quality. Ruminants, pigs and poultry are susceptible to ...heat stress due to their rapid metabolic rate and growth, high level of production, and species-specific characteristics such as rumen fermentation, sweating impairment, and skin insulation. Acute heat stress immediately before slaughter stimulates muscle glycogenolysis and can result in pale, soft and exudative (PSE) meat characterized by low water holding capacity (WHC). By contrast, animals subjected to chronic heat stress, have reduced muscle glycogen stores resulting in dark, firm and dry (DFD) meat with high ultimate pH and high WHC. Furthermore, heat stress leads to oxidative stress, lipid and protein oxidation, and reduced shelf life and food safety due to bacterial growth and shedding. This review discusses the scientific evidence regarding the effects of heat stress on livestock physiology and metabolism, and their consequences for meat quality and safety.
The Mcm2–7 replicative helicase is central to all steps of eukaryotic DNA replication. The hexameric ring of Mcm subunits forms six essential ATPases whose contributions to replication initiation ...remain unclear. Mcm2–7 complexes containing ATPase-motif mutations showed Mcm2–7 ATP binding and hydrolysis are required for helicase loading. Loading-defective Mcm2–7 mutant complexes were defective in initial Mcm2–7 recruitment or Cdt1 release. Comparison with Cdc6 ATPase mutants showed that Cdc6 ATP hydrolysis is not required for helicase loading but instead drives removal of Mcm2–7 complexes that cannot complete loading. A subset of Mcm2–7 ATPase-site mutants completed helicase loading but could not initiate replication. Individual mutants were defective in distinct events during helicase activation, including maintenance of DNA association, recruitment of the GINS helicase activator, and DNA unwinding. Consistent with its heterohexameric structure, our findings show that the six Mcm2–7 ATPase active sites are specialized for different functions during helicase loading and activation.
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•Mcm2–7 ATP binding and hydrolysis is required for helicase loading and activation•Mcm2–7 ATPase mutations inhibit Mcm2–7 recruitment and Cdt1 release during loading•Cdc6 ATP hydrolysis releases loading-defective Mcm2–7 but is not required for loading•Loading-competent Mcm2–7 ATPase mutants show defects in CMG formation and DNA retention
The eukaryotic replicative DNA helicase, the Mcm2–7 complex, participates in every event of chromosomal DNA replication. This ring-shaped complex includes six ATPase domains found at each subunit interface. Kang et al. demonstrate that, in addition to DNA unwinding, specific Mcm2–7 ATPases regulate distinct steps during helicase loading and activation.
Anaesthetic and sedative drugs transiently disrupt normal neural activity to facilitate healthcare procedures in children, but they can also cause long-term brain injury in experimental animal ...models. The US Food and Drug Administration (FDA) has recently advised that repeated or lengthy exposures to anaesthetic and sedative drugs prior to 3 yr of age have the potential to harm the development of children's brains and added warnings to these drug labels. Paediatric anaesthesia toxicity could represent a significant public health issue, and concern about this potential injury in children has become an important issue for families, paediatric clinicians and healthcare regulators. Since late 2015, important new data from five major clinical studies have been published. This narrative review aims to provide a brief overview of the preclinical and clinical literature, including a comprehensive review of these recent additions to the human literature. We integrate these new data with prior studies to provide further insights into how these clinical findings can be applied to children.
Soil respiration (Rs), the soil‐to‐atmosphere CO2 flux produced by microbes and plant roots, is a critical but uncertain component of the global carbon cycle. Our current understanding of the ...variability and dynamics is limited by the coarse spatial resolution of existing estimates. We predicted annual Rs and associated uncertainty across the world at 1‐km resolution using a quantile regression forest algorithm trained with observations from the global Soil Respiration Database spanning from 1961 to 2011. This model yielded a global annual Rs estimate of 87.9 Pg C/year with an associated global uncertainty of 18.6 (mean absolute error) and 40.4 (root mean square error) Pg C/year. The estimated annual heterotrophic respiration (Rh), derived from empirical relationships with Rs, was 49.7 Pg C/year over the same period. Predicted Rs rates and associated uncertainty varied widely across vegetation types, with the greatest predicted rates of Rs in evergreen broadleaf forests (accounting for 20.9% of global Rs). The greatest prediction uncertainties were in northern latitudes and arid to semiarid ecosystems, suggesting that these areas should be targeted in future measurement campaigns. This study provides predictions of Rs (and associated prediction uncertainty) at unprecedentedly high spatial resolution across the globe that could help constrain local‐to‐global process‐based models. Furthermore, it provides insights into the large variability of Rs and Rh across vegetation classes and identifies regions and vegetation types with poor model performance that should be prioritized for future data collection.
Plain Language Summary
Soils emit large amounts of carbon dioxide to the atmosphere every year via the process of soil respiration, which greatly exceeds emissions from human sources. However, rates of soil respiration are highly variable in space, which limits our ability to balance global carbon budgets and forecast climate change. We used a novel application of a machine learning approach to predict annual rates of soil respiration at high resolution (1 km) across the globe and examined spatial patterns of the associated uncertainty of these predictions. Predictions were made based on how observations of soil respiration were related to climate (annual temperature and annual and seasonal precipitation) and vegetation information. Predicted annual soil respiration and prediction uncertainty varied across ecosystem types and regions. Our predictions suggest that evergreen tropical forests dominate global annual soil respiration emissions. Dryland, wetland, and cold ecosystems had the highest associated prediction uncertainties, suggesting that future soil respiration measurements would be especially useful in these areas. The high spatial resolution of our predictions will help researchers studying the carbon cycle at local to global scales.
Key Points
A high spatial resolution machine learning approach was used for estimating soil respiration across the world
Predictions of soil respiration varied widely across ecosystem classes, and allowed for suitable estimates of heterotrophic respiration
Associated prediction uncertainty was highest in high latitudes and data scarce regions, which should be targets for future measurements
•Analysis of literature data provides insight into the mechanisms by which HIP improves fatigue life.•HIP improves fatigue life of PBF Ti-6Al-4V by decreasing the fraction of the defect population ...that can initiate fatigue cracks and by changing the microstructure surrounding defects.•The idea that microstructure near defects evolves differently than the microstructure away from defects during HIP treatment is supported by EBSD orientation maps.•The gained understanding provides initial guidance on HIP soak parameters (Temperature-Pressure-Time) to improve high cycle fatigue performance in PBF Ti-6Al-4V.
Hot isostatic pressing (HIP) is often needed to obtain powder bed fused (PBF) Ti-6Al-4V parts with good fatigue performance. This manuscript attempts to clarify the mechanisms through which HIP treatment acts to improve high cycle fatigue performance. Several mechanisms are considered and examined against experimental data sets available in the literature. The results suggest that HIP may act most significantly by decreasing the fraction of the defect population that can initiate fatigue cracks, both by decreasing defect sizes below a threshold and by changing the microstructure that surrounds defects. Given the novelty of the latter conclusion, an electron backscatter diffraction microscopy study was performed for validation. The gained understanding provides initial guidance on the choice of optimum HIP soak parameters (Temperature-Pressure-Time) for the high cycle fatigue performance of PBF Ti-6Al-4V.
Because metastasis is associated with the majority of cancer-related deaths, its prevention is a clinical aspiration. Prostanoids are a large family of bioactive lipids derived from the activity of ...cyclooxygenase-1 (COX-1) and COX-2. Aspirin impairs the biosynthesis of all prostanoids through the irreversible inhibition of both COX isoforms. Long-term administration of aspirin leads to reduced distant metastases in murine models and clinical trials, but the COX isoform, downstream prostanoid, and cell compartment responsible for this effect are yet to be determined. Here, we have shown that aspirin dramatically reduced lung metastasis through inhibition of COX-1 while the cancer cells remained intravascular and that inhibition of platelet COX-1 alone was sufficient to impair metastasis. Thromboxane A2 (TXA2) was the prostanoid product of COX-1 responsible for this antimetastatic effect. Inhibition of the COX-1/TXA2 pathway in platelets decreased aggregation of platelets on tumor cells, endothelial activation, tumor cell adhesion to the endothelium, and recruitment of metastasis-promoting monocytes/macrophages, and diminished the formation of a premetastatic niche. Thus, platelet-derived TXA2 orchestrates the generation of a favorable intravascular metastatic niche that promotes tumor cell seeding and identifies COX-1/TXA2 signaling as a target for the prevention of metastasis.
Foxp3+ T regulatory (Treg) cells promote immunological tumor tolerance, but how their immune-suppressive function is regulated in the tumor microenvironment (TME) remains unknown. Here, we used ...intravital microscopy to characterize the cellular interactions that provide tumor-infiltrating Treg cells with critical activation signals. We found that the polyclonal Treg cell repertoire is pre-enriched to recognize antigens presented by tumor-associated conventional dendritic cells (cDCs). Unstable cDC contacts sufficed to sustain Treg cell function, whereas T helper cells were activated during stable interactions. Contact instability resulted from CTLA-4-dependent downregulation of co-stimulatory B7-family proteins on cDCs, mediated by Treg cells themselves. CTLA-4-blockade triggered CD28-dependent Treg cell hyper-proliferation in the TME, and concomitant Treg cell inactivation was required to achieve tumor rejection. Therefore, Treg cells self-regulate through a CTLA-4- and CD28-dependent feedback loop that adjusts their population size to the amount of local co-stimulation. Its disruption through CTLA-4-blockade may off-set therapeutic benefits in cancer patients.
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•The TCR repertoire of Treg cells is enriched for reactivity to antigens in the TME•Tumor Treg cells use CTLA-4 to destabilize their own interactions with dendritic cells•CTLA-4 blockade causes the CD28-mediated expansion of tumor-associated Treg cells•Following CTLA-4 blockade, Treg cells continue to promote tumor immune tolerance
Intravital imaging studies of the tumor microenvironment provide insights into how Treg cells interact with dendritic cells and modulate their numbers through a CTLA-4- and CD28-dependent feedback loop. Disruption of this feedback loop by CTLA-4 blockade may thwart the efficacy of immune checkpoint therapy.
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