The PMIP4 contribution to CMIP6 – Part 2: two interglacials, scientific objective and experimental design for Holocene and last interglacial simulations

Two interglacial epochs are included in the suite of Paleoclimate Modeling Intercomparison Project (PMIP4) simulations in the Coupled Model Intercomparison Project (CMIP6). The experimental protocols for Tier 1 simulations of the mid-Holocene (midHolocene, 6000 years before present) and the Last Interglacial (lig127k, 127,000 years before present) are described here. These equilibrium simulations are designed to examine the impact of changes in orbital forcing at times when atmospheric greenhouse gas levels were similar to those of the preindustrial period and the continental configurations were almost identical to modern. These simulations test our understanding of the interplay between radiative forcing and atmospheric circulation, and the connections among large-scale and regional climate changes giving rise to phenomena such as land-sea contrast and high-latitude amplification in temperature changes, and responses of the monsoons, as compared to today. They also provide an opportunity, through carefully designed additional CMIP6 Tier 2 and Tier 3 sensitivity experiments of PMIP4, to quantify the strength of atmosphere, ocean, cryosphere, and land-surface feedbacks. Sensitivity experiments are proposed to investigate the role of freshwater forcing in triggering abrupt climate changes within interglacial epochs. These feedback experiments naturally lead to a focus on climate evolution during interglacial periods, which will be examined through transient experiments. Analyses of the sensitivity simulations will also focus on interactions between extratropical and tropical circulation, and the relationship between changes in mean climate state and climate variability on annual to multi-decadal timescales. The comparative abundance of paleoenvironmental data and of quantitative climate reconstructions for the Holocene and Last Interglacial make these two epochs ideal candidates for systematic evaluation of model performance, and such comparisons will shed new light on the importance of external feedbacks (e.g., vegetation, dust) and the ability of state-of-the-art models to simulate climate changes realistically

PMIP4-CMIP6: the contribution of the Paleoclimate Modelling Intercomparison Project to CMIP6

The goal of the Palaeoclimate Modelling Intercomparison Project (PMIP) is to understand the response of the climate system to changes in different climate forcings and to feedbacks. Through comparison with observations of the environmental impacts of these climate changes, or with climate reconstructions based on physical, chemical or biological records, PMIP also addresses the issue of how well state-of-the-art models simulate climate changes. Palaeoclimate states are radically different from those of the recent past documented by the instrumental record and thus provide an out-of-sample test of the models used for future climate projections and a way to assess whether they have the correct sensitivity to forcings and feedbacks. Five distinctly different periods have been selected as focus for the core palaeoclimate experiments that are designed to contribute to the objectives of the sixth phase of the Coupled Model Intercomparison Project (CMIP6). This manuscript describes the motivation for the choice of these periods and the design of the numerical experiments, with a focus upon their novel features compared to the experiments performed in previous phases of PMIP and CMIP as well as the benefits of common analyses of the models across multiple climate states. It also describes the information needed to document each experiment and the model outputs required for analysis and benchmarking

Hypertrophic cardiomyopathy mutations in the calponin-homology domain of ACTN2 affect actin binding and cardiomyocyte Z-disc incorporation

α-Actinin-2 (ACTN2) is the only muscle isoform of α-actinin expressed in cardiac muscle. Mutations in this protein have been implicated in mild to moderate forms of hypertrophic cardiomyopathy (HCM). We have investigated the effects of two mutations identified from HCM patients, A119T and G111V, on the secondary and tertiary structure of a purified actin binding domain (ABD) of ACTN2 by circular dichroism and X-ray crystallography, and show small but distinct changes for both mutations. We also find that both mutants have reduced F-actin binding affinity, although the differences are not significant. The full length mEos2 tagged protein expressed in adult cardiomyocytes shows that both mutations additionally affect Z-disc localization and dynamic behaviour. Overall, these two mutations have small effects on structure, function and behaviour, which may contribute to a mild phenotype for this disease

Two interglacials: scientific objectives and experimental designs for CMIP6 and PMIP4 Holocene and last interglacial simulations

Two interglacial epochs are included in the suite of paleoclimate simulations in the present phase of the Coupled Model Intercomparison Project (CMIP6). Equilibrium simulations of the mid-50 Holocene (midHolocene, 6000 years before present) and the Last Interglacial (lig127k, 127,000 years before present) are designed to examine the impact of changes in orbital forcing at times when atmospheric greenhouse gas levels were similar to those of the preindustrial period and the continental configurations were almost identical to modern. These simulations test our understanding of the interplay between radiative forcing and atmospheric circulation, and the connections among large-scale and regional climate changes giving rise to phenomena such as land-sea contrast and high-latitude amplification in temperature changes, and responses of the monsoons, as compared to today. They also provide an opportunity, through carefully designed additional sensitivity experiments as part of the Paleoclimate Modeling Intercomparison Project (PMIP4), to quantify the strength of atmosphere, ocean, cryosphere, and land-surface feedbacks. Sensitivity experiments are proposed to investigate the role of freshwater forcing in triggering abrupt climate changes within interglacial epochs. These feedback experiments naturally lead to a focus on climate evolution during interglacial periods, which will be examined through transient experiments. Analyses of the sensitivity simulations will also focus on interactions between extratropical and tropical circulation, and the relationship between changes in mean climate state and climate variability on annual to multi-decadal timescales. The comparative abundance of paleoenvironmental data and of quantitative climate reconstructions for the Holocene and Last Interglacial make these two epochs ideal candidates for systematic evaluation of model performance, and such comparisons will shed new light on the importance of external feedbacks (e.g., vegetation, dust) and the ability of state-of-the-art models to simulate climate changes realistically

The PMIP4 contribution to CMIP6 – Part 4: scientific objectives and experimental design of the PMIP4-CMIP6 Last Glacial Maximum experiments and PMIP4 sensitivity experiments

The Last Glacial Maximum (LGM, 21 000 years ago) is one of the suite of paleoclimate simulations included in the current phase of the Coupled Model Intercomparison Project (CMIP6). It is an interval when insolation was similar to the present, but global ice volume was at a maximum, eustatic sea level was at or close to a minimum, greenhouse gas concentrations were lower, atmospheric aerosol loadings were higher than today, and vegetation and land-surface characteristics were different from today. The LGM has been a focus for the Paleoclimate Modelling Intercomparison Project (PMIP) since its inception, and thus many of the problems that might be associated with simulating such a radically different climate are well documented. The LGM state provides an ideal case study for evaluating climate model performance because the changes in forcing and temperature between the LGM and pre-industrial are of the same order of magnitude as those projected for the end of the 21st century. Thus, the CMIP6 LGM experiment could provide additional information that can be used to constrain estimates of climate sensitivity. The design of the Tier 1 LGM experiment (lgm) includes an assessment of uncertainties in boundary conditions, in particular through the use of different reconstructions of the ice sheets and of the change in dust forcing. Additional (Tier 2) sensitivity experiments have been designed to quantify feedbacks associated with land-surface changes and aerosol loadings, and to isolate the role of individual forcings. Model analysis and evaluation will capitalize on the relative abundance of paleoenvironmental observations and quantitative climate reconstructions already available for the LGM

Insulinlike Growth Factor-Binding Protein-1 Improves Vascular Endothelial Repair in Male Mice in the Setting of Insulin Resistance

Insulin resistance is associated with impaired endothelial regeneration in response to mechanical injury. We recently demonstrated that insulinlike growth factor–binding protein-1 (IGFBP1) ameliorated insulin resistance and increased nitric oxide generation in the endothelium. In this study, we hypothesized that IGFBP1 would improve endothelial regeneration and restore endothelial reparative functions in the setting of insulin resistance. In male mice heterozygous for deletion of insulin receptors, endothelial regeneration after femoral artery wire injury was enhanced by transgenic expression of human IGFBP1 (hIGFBP1). This was not explained by altered abundance of circulating myeloid angiogenic cells. Incubation of human endothelial cells with hIGFBP1 increased integrin expression and enhanced their ability to adhere to and repopulate denuded human saphenous vein ex vivo. In vitro, induction of insulin resistance by tumor necrosis factor α (TNFα) significantly inhibited endothelial cell migration and proliferation. Coincubation with hIGFBP1 restored endothelial migratory and proliferative capacity. At the molecular level, hIGFBP1 induced phosphorylation of focal adhesion kinase, activated RhoA and modulated TNFα-induced actin fiber anisotropy. Collectively, the effects of hIGFBP1 on endothelial cell responses and acceleration of endothelial regeneration in mice indicate that manipulating IGFBP1 could be exploited as a putative strategy to improve endothelial repair in the setting of insulin resistance

Evaluating the large-scale hydrological cycle response within the Pliocene Model Intercomparison Project Phase 2 (PlioMIP2) ensemble

The mid-Pliocene (∼3 Ma) is one of the most recent warm periods with high CO2 concentrations in the atmosphere and resulting high temperatures, and it is often cited as an analog for near-term future climate change. Here, we apply a moisture budget analysis to investigate the response of the large-scale hydrological cycle at low latitudes within a 13-model ensemble from the Pliocene Model Intercomparison Project Phase 2 (PlioMIP2). The results show that increased atmospheric moisture content within the mid-Pliocene ensemble (due to the thermodynamic effect) results in wetter conditions over the deep tropics, i.e., the Pacific intertropical convergence zone (ITCZ) and the Maritime Continent, and drier conditions over the subtropics. Note that the dynamic effect plays a more important role than the thermodynamic effect in regional precipitation minus evaporation (PmE) changes (i.e., northward ITCZ shift and wetter northern Indian Ocean). The thermodynamic effect is offset to some extent by a dynamic effect involving a northward shift of the Hadley circulation that dries the deep tropics and moistens the subtropics in the Northern Hemisphere (i.e., the subtropical Pacific). From the perspective of Earth's energy budget, the enhanced southward cross-equatorial atmospheric transport (0.22 PW), induced by the hemispheric asymmetries of the atmospheric energy, favors an approximately 1∘ northward shift of the ITCZ. The shift of the ITCZ reorganizes atmospheric circulation, favoring a northward shift of the Hadley circulation. In addition, the Walker circulation consistently shifts westward within PlioMIP2 models, leading to wetter conditions over the northern Indian Ocean. The PlioMIP2 ensemble highlights that an imbalance of interhemispheric atmospheric energy during the mid-Pliocene could have led to changes in the dynamic effect, offsetting the thermodynamic effect and, hence, altering mid-Pliocene hydroclimate

The impact of immediate breast reconstruction on the time to delivery of adjuvant therapy: the iBRA-2 study

Background: Immediate breast reconstruction (IBR) is routinely offered to improve quality-of-life for women requiring mastectomy, but there are concerns that more complex surgery may delay adjuvant oncological treatments and compromise long-term outcomes. High-quality evidence is lacking. The iBRA-2 study aimed to investigate the impact of IBR on time to adjuvant therapy. Methods: Consecutive women undergoing mastectomy ± IBR for breast cancer July–December, 2016 were included. Patient demographics, operative, oncological and complication data were collected. Time from last definitive cancer surgery to first adjuvant treatment for patients undergoing mastectomy ± IBR were compared and risk factors associated with delays explored. Results: A total of 2540 patients were recruited from 76 centres; 1008 (39.7%) underwent IBR (implant-only [n = 675, 26.6%]; pedicled flaps [n = 105,4.1%] and free-flaps [n = 228, 8.9%]). Complications requiring re-admission or re-operation were significantly more common in patients undergoing IBR than those receiving mastectomy. Adjuvant chemotherapy or radiotherapy was required by 1235 (48.6%) patients. No clinically significant differences were seen in time to adjuvant therapy between patient groups but major complications irrespective of surgery received were significantly associated with treatment delays. Conclusions: IBR does not result in clinically significant delays to adjuvant therapy, but post-operative complications are associated with treatment delays. Strategies to minimise complications, including careful patient selection, are required to improve outcomes for patients