The role of CO2 decline for the onset of Northern Hemisphere glaciation

The Pliocene–Pleistocene Transition (PPT), from around 3.2 to 2.5 million years ago (Ma), represented a major shift in the climate system and was characterized by a gradual cooling trend and the appearance of large continental ice sheets over northern Eurasia and North America. Paleo evidence indicates that the PPT was accompanied and possibly caused by a decrease in atmospheric CO2, but the temporal resolution of CO2 reconstructions is low for this period of time and uncertainties remain large. Therefore, instead of applying existent CO2 reconstructions we solved an ‘inverse’ problem by finding a schematic CO2 concentration scenario that allows us to simulate the temporal evolution of key climate characteristics in agreement with paleoclimate records. To this end, we performed an ensemble of transient simulations with an Earth system model of intermediate complexity from which we derived a best guess transient CO2 scenario for the interval from 3.2 to 2.4 Ma that gives the best fit between the simulated and reconstructed benthic δ18O and global sea surface temperature evolution. Our data-constrained CO2 scenarios are consistent with recent CO2 reconstructions and suggest a gradual CO2 decline from 375–425 to 275–300 ppm, between 3.2 and 2.4 Ma. In addition to a gradual decline, the best fit to paleoclimate data requires the existence of pronounced CO2 variability coherent with the 41-kyr (1 kyr = 1000 years) obliquity cycle. In our simulations the long-term CO2 decline is accompanied by a relatively abrupt intensification of Northern Hemisphere glaciation at around 2.7 Ma. This is the result of a threshold behaviour of the ice sheets response to gradual CO2 decrease and orbital forcing. The simulated Northern Hemisphere ice sheets during the early Pleistocene glacial cycles reach a maximum volume equivalent to a sea level drop of about 40 m. Both ice volume and benthic δ18O are dominated by 41-kyr cyclicity. Our simulations suggest that before 2.7 Ma Greenland was ice free during summer insolation maxima and only partly ice covered during periods of minimum summer insolation. A fully glaciated Greenland comparable to its present-day ice volume is modelled only during glacial maxima after 2.7 Ma and more continuously after 2.5 Ma

Natriuretic peptides and integrated risk assessment for cardiovascular disease. an individual-participant-data meta-analysis

BACKGROUND: Guidelines for primary prevention of cardiovascular diseases focus on prediction of coronary heart disease and stroke. We assessed whether or not measurement of N-terminal-pro-B-type natriuretic peptide (NT-proBNP) concentration could enable a more integrated approach than at present by predicting heart failure and enhancing coronary heart disease and stroke risk assessment. METHODS: In this individual-participant-data meta-analysis, we generated and harmonised individual-participant data from relevant prospective studies via both de-novo NT-proBNP concentration measurement of stored samples and collection of data from studies identified through a systematic search of the literature (PubMed, Scientific Citation Index Expanded, and Embase) for articles published up to Sept 4, 2014, using search terms related to natriuretic peptide family members and the primary outcomes, with no language restrictions. We calculated risk ratios and measures of risk discrimination and reclassification across predicted 10 year risk categories (ie, <5%, 5% to <7·5%, and ≥7·5%), adding assessment of NT-proBNP concentration to that of conventional risk factors (ie, age, sex, smoking status, systolic blood pressure, history of diabetes, and total and HDL cholesterol concentrations). Primary outcomes were the combination of coronary heart disease and stroke, and the combination of coronary heart disease, stroke, and heart failure. FINDINGS: We recorded 5500 coronary heart disease, 4002 stroke, and 2212 heart failure outcomes among 95 617 participants without a history of cardiovascular disease in 40 prospective studies. Risk ratios (for a comparison of the top third vs bottom third of NT-proBNP concentrations, adjusted for conventional risk factors) were 1·76 (95% CI 1·56-1·98) for the combination of coronary heart disease and stroke and 2·00 (1·77-2·26) for the combination of coronary heart disease, stroke, and heart failure. Addition of information about NT-proBNP concentration to a model containing conventional risk factors was associated with a C-index increase of 0·012 (0·010-0·014) and a net reclassification improvement of 0·027 (0·019-0·036) for the combination of coronary heart disease and stroke and a C-index increase of 0·019 (0·016-0·022) and a net reclassification improvement of 0·028 (0·019-0·038) for the combination of coronary heart disease, stroke, and heart failure. INTERPRETATION: In people without baseline cardiovascular disease, NT-proBNP concentration assessment strongly predicted first-onset heart failure and augmented coronary heart disease and stroke prediction, suggesting that NT-proBNP concentration assessment could be used to integrate heart failure into cardiovascular disease primary prevention

Asymmetry and uncertainties in biogeophysical climate-vegetation feedback over a range of CO2 forcings

Climate–vegetation feedback has the potential to significantly contribute to climate change, but little is known about its range of uncertainties. Here, using an Earth system model of intermediate complexity we address possible uncertainties in the strength of the biogeophysical climate–vegetation feedback using a single-model multi-physics ensemble. Equilibrium experiments with halving (140 ppm) and doubling (560 ppm) of CO2 give a contribution of the vegetation–climate feedback to global temperature change in the range −0.3 to −0.1 °C and −0.1 to 0.2 °C, respectively. There is an asymmetry between warming and cooling, with a larger, positive vegetation–climate feedback in the lower CO2 climate. Hotspots of climate–vegetation feedback are the boreal zone, the Amazon rainforest and the Sahara. Albedo parameterization is the dominant source of uncertainty in the subtropics and at high northern latitudes, while uncertainties in evapotranspiration are more relevant in the tropics. We analyse the separate impact of changes in stomatal conductance, leaf area index and vegetation dynamics on climate and we find that different processes are dominant in lower and higher CO2 worlds. The reduction in stomatal conductance gives the main contribution to temperature increase for a doubling of CO2, while dynamic vegetation is the dominant process in the CO2 halving experiments. Globally the climate–vegetation feedback is rather small compared to the sum of the fast climate feedbacks. However, it is comparable to the amplitude of the fast feedbacks at high northern latitudes where it can contribute considerably to polar amplification. The uncertainties in the climate–vegetation feedback are comparable to the multi-model spread of the fast climate feedbacks

Bistable systems with stochastic noise: Virtues and limits of effective one-dimensional Langevin equations

The understanding of the statistical properties and of the dynamics of multistable systems is gaining more and more importance in a vast variety of scientific fields. This is especially relevant for the investigation of the tipping points of complex systems. Sometimes, in order to understand the time series of given observables exhibiting bimodal distributions, simple one-dimensional Langevin models are fitted to reproduce the observed statistical properties, and used to investing-ate the projected dynamics of the observable. This is of great relevance for studying potential catastrophic changes in the properties of the underlying system or resonant behaviours like those related to stochastic resonance-like mechanisms. In this paper, we propose a framework for encasing this kind of studies, using simple box models of the oceanic circulation and choosing as observable the strength of the thermohaline circulation. We study the statistical properties of the transitions between the two modes of operation of the thermohaline circulation under symmetric boundary forcings and test their agreement with simplified one-dimensional phenomenological theories. We extend our analysis to include stochastic resonance-like amplification processes. We conclude that fitted one-dimensional Langevin models, when closely scrutinised, may result to be more ad-hoc than they seem, lacking robustness and/or well-posedness. They should be treated with care, more as an empiric descriptive tool than as methodology with predictive power

Mid-Pleistocene transition in glacial cycles explained by declining CO2 and regolith removal

Variations in Earth's orbit pace the glacial-interglacial cycles of the Quaternary, but the mechanisms that transform regional and seasonal variations in solar insolation into glacial-interglacial cycles are still elusive. Here, we present transient simulations of coevolution of climate, ice sheets, and carbon cycle over the past 3 million years. We show that a gradual lowering of atmospheric CO2 and regolith removal are essential to reproduce the evolution of climate variability over the Quaternary. The long-term CO2 decrease leads to the initiation of Northern Hemisphere glaciation and an increase in the amplitude of glacial-interglacial variations, while the combined effect of CO2 decline and regolith removal controls the timing of the transition from a 41,000- to 100,000-year world. Our results suggest that the current CO2 concentration is unprecedented over the past 3 million years and that global temperature never exceeded the preindustrial value by more than 2°C during the Quaternary

Mid-Pleistocene transition in glacial cycles explained by declining CO2and regolith removal

Variations in Earth’s orbit pace the glacial-interglacial cycles of the Quaternary, but the mechanisms that transform regional and seasonal variations in solar insolation into glacial-interglacial cycles are still elusive. Here, we present transient simulations of coevolution of climate, ice sheets, and carbon cycle over the past 3 million years. We show that a gradual lowering of atmospheric CO2 and regolith removal are essential to reproduce the evolution of climate variability over the Quaternary. The long-term CO2 decrease leads to the initiation of Northern Hemisphere glaciation and an increase in the amplitude of glacial-interglacial variations, while the combined effect of CO2 decline and regolith removal controls the timing of the transition from a 41,000- to 100,000-year world. Our results suggest that the current CO2 concentration is unprecedented over the past 3 million years and that global temperature never exceeded the preindustrial value by more than 2°C during the Quaternary

Aberrant regulation of RANKL/OPG in women at high risk of developing breast cancer

Breast cancer is the most common female cancer, affecting approximately one in eight women during their lifetime in North America and Europe. Receptor Activator of NF-kB Ligand (RANKL), its receptor RANK and the natural antagonist osteoprotegerin (OPG) are essential regulators of bone resorption. We have initially shown that RANKL/RANK are essential for hormone-driven mammary epithelial proliferation in pregnancy and RANKL/RANK have been implicated in mammary stem cell biology. Using genetic mouse-models, we and others identified the RANKL/RANK system as a key regulator of sex hormone, BRCA1-mutation, and oncogene-driven breast cancer and we proposed that RANKL/RANK might be involved in the initiation of breast tumors. We now report that in postmenopausal women without known genetic predisposition, high RANKL and progesterone serum levels stratify a subpopulation of women at high risk of developing breast cancer 12-24 months before diagnosis (5.33-fold risk, 95%CI 1.5-25.4; P=0.02). In women with established breast cancer, we demonstrate that RANKL/OPG ratios change dependent on the presence of circulating tumor cells (CTCs). Finally, we show in a prospective human breast cancer cohort that alterations in RANKL/OPG ratios are significantly associated with breast cancer manifestation. These data indicate that the RANKL/RANK/OPG system is deregulated in post-menopausal women at high risk for breast cancer and in women with circulating tumor cells. Thus, serum levels of RANKL/OPG are potentially indicative of predisposition and progression of breast cancer in humans. Advancement of our findings towards clinical application awaits prior validation in independent patient cohorts

Genetic evidence for a role of adiponutrin in the metabolism of apolipoprotein B-containing lipoproteins

Adiponutrin (PNPLA3) is a predominantly liver-expressed transmembrane protein with phospholipase activity that is regulated by fasting and feeding. Recent genome-wide association studies identified PNPLA3 to be associated with hepatic fat content and liver function, thus pointing to a possible involvement in the hepatic lipoprotein metabolism. The aim of this study was to examine the association between two common variants in the adiponutrin gene and parameters of lipoprotein metabolism in 23 274 participants from eight independent West-Eurasian study populations including six population-based studies [Bruneck (n = 800), KORA S3/F3 (n = 1644), KORA S4/F4 (n = 1814), CoLaus (n = 5435), SHIP (n = 4012), Rotterdam (n = 5967)], the SAPHIR Study as a healthy working population (n = 1738) and the Utah Obesity Case-Control Study including a group of 1037 severely obese individuals (average BMI 46 kg/m2) and 827 controls from the same geographical region of Utah. We observed a strong additive association of a common non-synonymous variant within adiponutrin (rs738409) with age-, gender-, and alanine-aminotransferase-adjusted lipoprotein concentrations: each copy of the minor allele decreased levels of total cholesterol on average by 2.43 mg/dl (P = 8.87 × 10−7), non-HDL cholesterol levels by 2.35 mg/dl (P = 2.27 × 10−6) and LDL cholesterol levels by 1.48 mg/dl (P = 7.99 × 10−4). These associations remained significant after correction for multiple testing. We did not observe clear evidence for associations with HDL cholesterol or triglyceride concentrations. In conclusion, our study suggests that adiponutrin is involved in the metabolism of apoB-containing lipoprotein

Use of Repeated Blood Pressure and Cholesterol Measurements to Improve Cardiovascular Disease Risk Prediction: An Individual-Participant-Data Meta-Analysis

The added value of incorporating information from repeated blood pressure and cholesterol measurements to predict cardiovascular disease (CVD) risk has not been rigorously assessed. We used data on 191,445 adults from the Emerging Risk Factors Collaboration (38 cohorts from 17 countries with data encompassing 1962-2014) with more than 1 million measurements of systolic blood pressure, total cholesterol, and high-density lipoprotein cholesterol. Over a median 12 years of follow-up, 21,170 CVD events occurred. Risk prediction models using cumulative mean values of repeated measurements and summary measures from longitudinal modeling of the repeated measurements were compared with models using measurements from a single time point. Risk discrimination (Cindex) and net reclassification were calculated, and changes in C-indices were meta-analyzed across studies. Compared with the single-time-point model, the cumulative means and longitudinal models increased the C-index by 0.0040 (95% confidence interval (CI): 0.0023, 0.0057) and 0.0023 (95% CI: 0.0005, 0.0042), respectively. Reclassification was also improved in both models; compared with the single-time-point model, overall net reclassification improvements were 0.0369 (95% CI: 0.0303, 0.0436) for the cumulative-means model and 0.0177 (95% CI: 0.0110, 0.0243) for the longitudinal model. In conclusion, incorporating repeated measurements of blood pressure and cholesterol into CVD risk prediction models slightly improves risk prediction