The CORDEX-CORE initiative was developed with the aim of producing homogeneous regional climate model (RCM) projections over domains world wide. In its first phase, two RCMs were run at 0.22° ...resolution downscaling 3 global climate models (GCMs) from the CMIP5 program for 9 CORDEX domains and two climate scenarios, the RCP2.6 and RCP8.5. The CORDEX-CORE simulations along with the CMIP5 GCM ensemble and the most recently produced CMIP6 GCM ensemble are analyzed, with focus on several temperature, heat, wet and dry hazard indicators for present day and mid-century and far future time slices. The CORDEX-CORE ensemble shows a better performance than the driving GCMs for several hazard indices due to its higher spatial resolution. For the far future time slice the 3 ensembles project an increase in all temperature and heat indices analyzed under the RCP8.5 scenario. The largest increases are always shown by the CMIP6 ensemble, except for Tx > 35 °C, for which the CORDEX-CORE projects higher warming. Extreme wet and flood prone maxima are projected to increase by the RCM ensemble over the la Plata basin in South America, the Congo basin in Africa, east North America, north east Europe, India and Indochina, regions where a better performance is obtained, whereas the GCM ensembles show small or negligible signals. Compound hazard hotspots based on heat, drought and wet indicators are detected in each continent worldwide in region like Central America, the Amazon, the Mediterranean, South Africa and Australia, where a linear relation is shown between the heatwave and drought change signal, and region like Arabian peninsula, the central and south east Africa region (SEAF), the north west America (NWN), south east Asia, India, China and central and northern European regions (WCE, NEU) where the same linear relation is found for extreme precipitation and HW increases. Although still limited, the CORDEX-CORE initiative was able to produce high resolution climate projections with almost global coverage and can provide an important resource for impact assessment and climate service activities.
The new Coordinated Output for Regional Evaluations (CORDEX-CORE) ensemble provides high-resolution, consistent regional climate change projections for the major inhabited areas of the world. It ...serves as a solid scientific basis for further research related to vulnerability, impact, adaptation and climate services in addition to existing CORDEX simulations. The aim of this study is to investigate and document the climate change information provided by the CORDEX-CORE simulation ensemble, as a part of the World Climate Research Programme (WCRP) CORDEX community. An overview of the annual and monthly mean climate change information in selected regions in different CORDEX domains is presented for temperature and precipitation, providing the foundation for detailed follow-up studies and applications. Initially, two regional climate models (RCMs), REMO and RegCM were used to downscale global climate model output. The driving simulations by AR5 global climate models (AR5-GCMs) were selected to cover the spread of high, medium, and low equilibrium climate sensitivity at a global scale. The CORDEX-CORE ensemble has doubled the spatial resolution compared to the previously existing CORDEX simulations in most of the regions (25
km
(0.22
∘
) versus 50
km
(0.44
∘
)) leading to a potentially improved representation of, e.g., physical processes in the RCMs. The analysis focuses on changes in the IPCC physical climate reference regions. The results show a general reasonable representation of the spread of the temperature and precipitation climate change signals of the AR5-GCMs by the CORDEX-CORE simulations in the investigated regions in all CORDEX domains by mostly covering the AR5 interquartile range of climate change signals. The simulated CORDEX-CORE monthly climate change signals mostly follow the AR5-GCMs, although for specific regions they show a different change in the course of the year compared to the AR5-GCMs, especially for RCP8.5, which needs to be investigated further in region specific process studies.
The added value of using regional climate models (RCMs) to downscale data from general circulation models (GCMs) has often been questioned and researched. Although several studies have used different ...methods to identify (and in some cases quantify) the added value, there is still a need to find a general metric that quantifies the added value of any variable. This paper builds on past studies to propose a new metric of added value in the simulation of present-day climate which measures the difference in the probability density functions (PDFs) at each grid-cell between a model and an observation source, and then compares the results of the RCM and GCM in order to spatially compute the added value index. The same method is also adapted to quantify the climate change downscaling signal in a way that is consistent with the present-day metric. These new metrics are tested on the daily precipitation output from the EURO-CORDEX and CORDEX-CORE projection ensembles and reveal an overall positive added value of RCMs, especially at the tail-end of the distribution. Higher added value is obtained in areas of complex topography and coast-lines, as well as in tropical regions. Areas with large added value in present-day climate are consistent with areas of significant climate change downscaling signal in the RCP 8.5 far future simulations, and when the analysis is repeated at a low-resolution. The use of different resolution observations shows that the added value tends to decrease when models are compared to low-resolution observation datasets.
Abstract We describe the first effort within the Coordinated Regional Climate Downscaling Experiment–Coordinated Output for Regional Evaluation, or CORDEX-CORE EXP-I. It consists of a set of ...twenty-first-century projections with two regional climate models (RCMs) downscaling three global climate model (GCM) simulations from the CMIP5 program, for two greenhouse gas concentration pathways (RCP8.5 and RCP2.6), over nine CORDEX domains at ∼25-km grid spacing. Illustrative examples from the initial analysis of this ensemble are presented, covering a wide range of topics, such as added value of RCM nesting, extreme indices, tropical and extratropical storms, monsoons, ENSO, severe storm environments, emergence of change signals, and energy production. They show that the CORDEX-CORE EXP-I ensemble can provide downscaled information of unprecedented comprehensiveness to increase understanding of processes relevant for regional climate change and impacts, and to assess the added value of RCMs. The CORDEX-CORE EXP-I dataset, which will be incrementally augmented with new simulations, is intended to be a public resource available to the scientific and end-user communities for application to process studies, impacts on different socioeconomic sectors, and climate service activities. The future of the CORDEX-CORE initiative is also discussed.
The added value of using regional climate models (RCMs) to downscale data from general circulation models (GCMs) has often been questioned and researched. Although several studies have used different ...methods to identify (and in some cases quantify) the added value, there is still a need to find a general metric that quantifies the added value of any variable. This paper builds on past studies to propose a new metric of added value in the simulation of present-day climate which measures the difference in the probability density functions (PDFs) at each grid-cell between a model and an observation source, and then compares the results of the RCM and GCM in order to spatially compute the added value index. The same method is also adapted to quantify the climate change downscaling signal in a way that is consistent with the present-day metric. These new metrics are tested on the daily precipitation output from the EURO-CORDEX and CORDEX-CORE projection ensembles and reveal an overall positive added value of RCMs, especially at the tail-end of the distribution. Higher added value is obtained in areas of complex topography and coast-lines, as well as in tropical regions. Areas with large added value in present-day climate are consistent with areas of significant climate change downscaling signal in the RCP 8.5 far future simulations, and when the analysis is repeated at a low-resolution. The use of different resolution observations shows that the added value tends to decrease when models are compared to low-resolution observation datasets.
Pathological growth of cardiomyocytes (hypertrophy) is a major determinant for the development of heart failure, one of the leading medical causes of mortality worldwide. Here we show that the ...microRNA (miRNA)-212/132 family regulates cardiac hypertrophy and autophagy in cardiomyocytes. Hypertrophic stimuli upregulate cardiomyocyte expression of miR-212 and miR-132, which are both necessary and sufficient to drive the hypertrophic growth of cardiomyocytes. MiR-212/132 null mice are protected from pressure-overload-induced heart failure, whereas cardiomyocyte-specific overexpression of the miR-212/132 family leads to pathological cardiac hypertrophy, heart failure and death in mice. Both miR-212 and miR-132 directly target the anti-hypertrophic and pro-autophagic FoxO3 transcription factor and overexpression of these miRNAs leads to hyperactivation of pro-hypertrophic calcineurin/NFAT signalling and an impaired autophagic response upon starvation. Pharmacological inhibition of miR-132 by antagomir injection rescues cardiac hypertrophy and heart failure in mice, offering a possible therapeutic approach for cardiac failure.
Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive Schwann cell (SC)-lineage-derived sarcomas. Molecular events driving SC-to-MPNST transformation are incompletely understood. ...Here, we show that human MPNSTs exhibit elevated HIPPO-TAZ/YAP expression, and that TAZ/YAP hyperactivity in SCs caused by Lats1/2 loss potently induces high-grade nerve-associated tumors with full penetrance. Lats1/2 deficiency reprograms SCs to a cancerous, progenitor-like phenotype and promotes hyperproliferation. Conversely, disruption of TAZ/YAP activity alleviates tumor burden in Lats1/2-deficient mice and inhibits human MPNST cell proliferation. Moreover, genome-wide profiling reveals that TAZ/YAP-TEAD1 directly activates oncogenic programs, including platelet-derived growth factor receptor (PDGFR) signaling. Co-targeting TAZ/YAP and PDGFR pathways inhibits tumor growth. Thus, our findings establish a previously unrecognized convergence between Lats1/2-TAZ/YAP signaling and MPNST pathogenesis, revealing potential therapeutic targets in these untreatable tumors.
Display omitted
•Human MPNSTs exhibit elevated HIPPO-TAZ/YAP expression•TAZ/YAP hyperactivity in Schwann cells potently induces high-grade nerve tumors•Lats1/2 dysregulation activates oncogenic programs, including PDGFR signaling•Co-targeting TAZ/YAP and PDGFR pathways inhibits MPNST tumor growth
Wu et al. find that HIPPO-TAZ/YAP expression is elevated in malignant peripheral nerve sheath tumors (MPNST). Lats1/2 deficiency in Schwann cells induces hyperactivation of TAZ/YAP and increased PDGFR signaling, leading to the development of MPNST in mice. Inhibition of TAZ/YAP and PDGFR reduces MPNST growth.
Cardiac fibroblasts (CFs) drive extracellular matrix remodeling after pressure overload, leading to fibrosis and diastolic dysfunction. Recent studies described the role of long noncoding RNAs ...(lncRNAs) in cardiac pathologies. Nevertheless, detailed reports on lncRNAs regulating CF biology and describing their implication in cardiac remodeling are still missing.
Here, we aimed at characterizing lncRNA expression in murine CFs after chronic pressure overload to identify CF-enriched lncRNAs and investigate their function and contribution to cardiac fibrosis and diastolic dysfunction.
Global lncRNA profiling identified several dysregulated transcripts. Among them, the lncRNA maternally expressed gene 3 (
) was found to be mostly expressed by CFs and to undergo transcriptional downregulation during late cardiac remodeling. In vitro,
regulated the production of matrix metalloproteinase-2 (MMP-2). GapmeR-mediated silencing of
in CFs resulted in the downregulation of
-2 transcription, which, in turn, was dependent on P53 activity both in the absence and in the presence of transforming growth factor-β I. Chromatin immunoprecipitation showed that further induction of
-2 expression by transforming growth factor-β I was blocked by
silencing through the inhibition of P53 binding on the
promoter. Consistently, inhibition of
in vivo after transverse aortic constriction prevented cardiac MMP-2 induction, leading to decreased cardiac fibrosis and improved diastolic performance.
Collectively, our findings uncover a critical role for
in the regulation of MMP-2 production by CFs in vitro and in vivo, identifying a new player in the development of cardiac fibrosis and potential new target for the prevention of cardiac remodeling.
Recent studies highlighted long noncoding RNAs (lncRNAs) to play an important role in cardiac development. However, understanding of lncRNAs in cardiac diseases is still limited. Global lncRNA ...expression profiling indicated that several lncRNA transcripts are deregulated during pressure overload-induced cardiac hypertrophy in mice. Using stringent selection criteria, we identified Chast (cardiac hypertrophy-associated transcript) as a potential lncRNA candidate that influences cardiomyocyte hypertrophy. Cell fractionation experiments indicated that Chast is specifically up-regulated in cardiomyocytes in vivo in transverse aortic constriction (TAC)-operated mice. In accordance, CHAST homolog in humans was significantly up-regulated in hypertrophic heart tissue from aortic stenosis patients and in human embryonic stem cell-derived cardiomyocytes upon hypertrophic stimuli. Viral-based overexpression of Chast was sufficient to induce cardiomyocyte hypertrophy in vitro and in vivo. GapmeR-mediated silencing of Chast both prevented and attenuated TAC-induced pathological cardiac remodeling with no early signs on toxicological side effects. Mechanistically, Chast negatively regulated Pleckstrin homology domain-containing protein family M member 1 (opposite strand of Chast), impeding cardiomyocyte autophagy and driving hypertrophy. These results indicate that Chast can be a potential target to prevent cardiac remodeling and highlight a general role of lncRNAs in heart diseases.
Energetic stress compels cells to evolve adaptive mechanisms to adjust their metabolism. Inhibition of mTOR kinase complex 1 (mTORC1) is essential for cell survival during glucose starvation. How ...mTORC1 controls cell viability during glucose starvation is not well understood. Here we show that the mTORC1 effectors eukaryotic initiation factor 4E binding proteins 1/2 (4EBP1/2) confer protection to mammalian cells and budding yeast under glucose starvation. Mechanistically, 4EBP1/2 promote NADPH homeostasis by preventing NADPH-consuming fatty acid synthesis via translational repression of Acetyl-CoA Carboxylase 1 (ACC1), thereby mitigating oxidative stress. This has important relevance for cancer, as oncogene-transformed cells and glioma cells exploit the 4EBP1/2 regulation of ACC1 expression and redox balance to combat energetic stress, thereby supporting transformation and tumorigenicity in vitro and in vivo. Clinically, high EIF4EBP1 expression is associated with poor outcomes in several cancer types. Our data reveal that the mTORC1-4EBP1/2 axis provokes a metabolic switch essential for survival during glucose starvation which is exploited by transformed and tumor cells.
PDF
