| 1. |
- Brierley, Chris M., et al.
(författare)
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Large-scale features and evaluation of the PMIP4-CMIP6 midHolocene simulations
- 2020
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Ingår i: Climate of the Past. - : Copernicus GmbH. - 1814-9324 .- 1814-9332. ; 16:5, s. 1847-1872
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Tidskriftsartikel (refereegranskat)abstract
- The mid-Holocene (6000 years ago) is a standard time period for the evaluation of the simulated response of global climate models using palaeoclimate reconstructions. The latest mid-Holocene simulations are a palaeoclimate entry card for the Palaeoclimate Model Intercomparison Project (PMIP4) component of the current phase of the Coupled Model Intercomparison Project (CMIP6) - hereafter referred to as PMIP4-CMIP6. Here we provide an initial analysis and evaluation of the results of the experiment for the mid-Holocene. We show that state-of-the-art models produce climate changes that are broadly consistent with theory and observations, including increased summer warming of the Northern Hemisphere and associated shifts in tropical rainfall. Many features of the PMIP4-CMIP6 simulations were present in the previous generation (PMIP3-CMIP5) of simulations. The PMIP4-CMIP6 ensemble for the mid-Holocene has a global mean temperature change of -0.3 K, which is -0.2K cooler than the PMIP3-CMIP5 simulations predominantly as a result of the prescription of realistic greenhouse gas concentrations in PMIP4-CMIP6. Biases in the magnitude and the sign of regional responses identified in PMIP3-CMIP5, such as the amplification of the northern African monsoon, precipitation changes over Europe, and simulated aridity in mid-Eurasia, are still present in the PMIP4-CMIP6 simulations. Despite these issues, PMIP4-CMIP6 and the mid-Holocene provide an opportunity both for quantitative evaluation and derivation of emergent constraints on the hydrological cycle, feedback strength, and potentially climate sensitivity.
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| 2. |
- Döscher, Ralf, et al.
(författare)
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The EC-Earth3 Earth system model for the Coupled Model Intercomparison Project 6
- 2022
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Ingår i: Geoscientific Model Development. - : Copernicus GmbH. - 1991-959X .- 1991-9603. ; 15:7, s. 2973-3020
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Tidskriftsartikel (refereegranskat)abstract
- The Earth system model EC-Earth3 for contributions to CMIP6 is documented here, with its flexible coupling framework, major model configurations, a methodology for ensuring the simulations are comparable across different high-performance computing (HPC) systems, and with the physical performance of base configurations over the historical period. The variety of possible configurations and sub-models reflects the broad interests in the EC-Earth community. EC-Earth3 key performance metrics demonstrate physical behavior and biases well within the frame known from recent CMIP models. With improved physical and dynamic features, new Earth system model (ESM) components, community tools, and largely improved physical performance compared to the CMIP5 version, EC-Earth3 represents a clear step forward for the only European community ESM. We demonstrate here that EC-Earth3 is suited for a range of tasks in CMIP6 and beyond.
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| 3. |
- Gorski, Mathias, et al.
(författare)
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Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies
- 2022
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Ingår i: Kidney International. - : Elsevier. - 0085-2538 .- 1523-1755. ; 102:3, s. 624-639
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Tidskriftsartikel (refereegranskat)abstract
- Estimated glomerular filtration rate (eGFR) reflects kidney function. Progressive eGFR-decline can lead to kidney failure, necessitating dialysis or transplantation. Hundreds of loci from genome-wide association studies (GWAS) for eGFR help explain population cross section variability. Since the contribution of these or other loci to eGFR-decline remains largely unknown, we derived GWAS for annual eGFR-decline and meta-analyzed 62 longitudinal studies with eGFR assessed twice over time in all 343,339 individuals and in high-risk groups. We also explored different covariate adjustment. Twelve genomewide significant independent variants for eGFR-decline unadjusted or adjusted for eGFR- baseline (11 novel, one known for this phenotype), including nine variants robustly associated across models were identified. All loci for eGFR-decline were known for cross-sectional eGFR and thus distinguished a subgroup of eGFR loci. Seven of the nine variants showed variant- by-age interaction on eGFR cross section (further about 350,000 individuals), which linked genetic associations for eGFR-decline with agedependency of genetic cross- section associations. Clinically important were two to four-fold greater genetic effects on eGFR-decline in high-risk subgroups. Five variants associated also with chronic kidney disease progression mapped to genes with functional in- silico evidence (UMOD, SPATA7, GALNTL5, TPPP). An unfavorable versus favorable nine-variant genetic profile showed increased risk odds ratios of 1.35 for kidney failure (95% confidence intervals 1.03- 1.77) and 1.27 for acute kidney injury (95% confidence intervals 1.08-1.50) in over 2000 cases each, with matched controls). Thus, we provide a large data resource, genetic loci, and prioritized genes for kidney function decline, which help inform drug development pipelines revealing important insights into the age-dependency of kidney function genetics.
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| 4. |
- Gorski, Mathias, et al.
(författare)
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Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline
- 2021
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Ingår i: Kidney International. - : Elsevier. - 0085-2538 .- 1523-1755. ; 99:4, s. 926-939
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Tidskriftsartikel (refereegranskat)abstract
- Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m2/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m2 at follow-up among those with eGFRcrea 60 mL/min/1.73m2 or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.
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| 5. |
- Gravgaard Askjær, Thomas, et al.
(författare)
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Multi-centennial Holocene climate variability in proxy records and transient model simulations
- 2022
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Ingår i: Quaternary Science Reviews. - : Elsevier BV. - 0277-3791 .- 1873-457X. ; 296
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Tidskriftsartikel (refereegranskat)abstract
- Variability on centennial to multi-centennial timescales is mentioned as a feature in reconstructions of the Holocene climate. As more long transient model simulations with complex climate models become available and efforts have been made to compile large proxy databases, there is now a unique opportunity to study multi-centennial variability with greater detail and a large amount of data than earlier. This paper presents a spectral analysis of transient Holocene simulations from 9 models and 120 proxy records to find the common signals related to oscillation periods and geographic dependencies and discuss the implications for the potential driving mechanisms. Multi-centennial variability is significant in most proxy records, with the dominant oscillation periods around 120–130 years and an average of 240 years. Spectra of model-based global mean temperature (GMT) agree well with proxy evidence with significant multi-centennial variability in all simulations with the dominant oscillation periods around 120–150 years. It indicates a comparatively good agreement between model and proxy data. A lack of latitudinal dependencies in terms of oscillation period is found in both the model and proxy data. However, all model simulations have the highest spectral density distributed over the Northern hemisphere high latitudes, which could indicate a particular variability sensitivity or potential driving mechanisms in this region. Five models also have differentiated forcings simulations with various combinations of forcing agents. Significant multi-centennial variability with oscillation periods between 100 and 200 years is found in all forcing scenarios, including those with only orbital forcing. The different forcings induce some variability in the system. Yet, none appear to be the predominant driver based on the spectral analysis. Solar irradiance has long been hypothesized to be a primary driver of multi-centennial variability. However, all the simulations without this forcing have shown significant multi-centennial variability. The results then indicate that internal mechanisms operate on multi-centennial timescales, and the North Atlantic-Arctic is a region of interest for this aspect.
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| 6. |
- Kang, Nai-xin, et al.
(författare)
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Anemoside B4 inhibits enterovirus 71 propagation in mice through upregulating 14-3-3 expression and type I interferon responses
- 2022
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Ingår i: Acta Pharmacologica Sinica. - : Springer Nature. - 1671-4083 .- 1745-7254. ; 43, s. 977-991
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Tidskriftsartikel (refereegranskat)abstract
- Enterovirus 71 (EV71) is the major pathogens of human hand, foot, and mouth disease (HFMD). EV71 efficiently escapes innate immunity responses of the host to cause infection. At present, no effective antiviral drugs for EV71 are available. Anemoside B4 (B4) is a natural saponin isolated from the roots of Pulsatilla chinensis (Bunge) Regel. P. chinensis extracts that shows a wide variety of biological activities. In this study, we investigated the antiviral activities of B4 against EV71 both in cell culture and in suckling mice. We showed that B4 (12.5-200 mu M) dose dependently increased the viability of EV71-infected RD cells with an IC50 value of 24.95 +/- 0.05 mu M against EV71. The antiviral activity of B4 was associated with enhanced interferon (IFN)-beta response, since knockdown of IFN-beta abolished its antiviral activity. We also confirmed that the enhanced IFN response was mediated via activation of retinoic acid-inducible gene I (RIG-I) like receptors (RLRs) pathway, and it was executed by upregulation of 14-3-3 protein, which disrupted the interaction between yes-associated protein (YAP) and interferon regulatory factor 3 (IRF3). By using amino acids in cell culture (SILAC)-based proteomics profiling, we identified the Hippo pathway as the top-ranking functional cluster in B4-treated EV71-infected cells. In vivo experiments were conducted in suckling mice (2-day-old) infected with EV71 and subsequently B4 (200 mg center dot kg(-1) center dot d(-1), i.p.) was administered for 16 days. We showed that B4 administration effectively suppressed EV71 replication and improved muscle inflammation and limb activity. Meanwhile, B4 administration regulated the expressions of HFMD biomarkers IL-10 and IFN-gamma, attenuating complications of EV71 infection. Collectively, our results suggest that B4 could enhance the antiviral effect of IFN-beta by orchestrating Hippo and RLRs pathway, and B4 would be a potential lead compound for developing an anti-EV71 drug.
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| 7. |
- Ngo, Debby, et al.
(författare)
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Circulating testican-2 is a podocyte-derived marker of kidney health
- 2020
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 117:40, s. 25026-25035
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Tidskriftsartikel (refereegranskat)abstract
- In addition to their fundamental role in clearance, the kidneys release select molecules into the circulation, but whether any of these anabolic functions provides insight on kidney health is unknown. Using aptamer-based proteomics, we characterized arterial (A)-to-renal venous (V) gradients for >1,300 proteins in 22 individuals who underwent invasive sampling. Although most of the proteins that changed significantly decreased from A to V, consistent with renal clearance, several were found to increase, the most significant of which was testican-2. To assess the clinical implications of these physiologic findings, we examined proteomic data in the Jackson Heart Study (JHS), an African-American cohort (n = 1,928), with replication in the Framingham Heart Study (FHS), a White cohort (n = 1,621). In both populations, testican-2 had a strong, positive correlation with estimated glomerular filtration rate (eGFR). In addition, higher baseline testican-2 levels were associated with a lower rate of eGFR decline in models adjusted for age, gender, hypertension, type 2 diabetes, body mass index, baseline eGFR, and albuminuria. Glomerular expression of testican-2 in human kidneys was demonstrated by immunohistochemistry, immunofluorescence, and electron microscopy, while single-cell RNA sequencing of human kidneys showed expression of the cognate gene, SPOCK2, exclusively in podocytes. In vitro, testican-2 increased glomerular endothelial tube formation and motility, raising the possibility that its secretion has a functional role within the glomerulus. Taken together, our findings identify testican-2 as a podocyte-derived biomarker of kidney health and prognosis.
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| 8. |
- Ngo, Debby, et al.
(författare)
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Proteomic profiling reveals novel biomarkers and pathways in yype 2 diabetes risk
- 2021
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Ingår i: JCI Insight. - : American Society for Clinical Investigation. - 2379-3708. ; 6:5
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Tidskriftsartikel (refereegranskat)abstract
- Recent advances in proteomic technologies have made high throughput profiling of low abundance proteins in large epidemiological cohorts increasingly feasible. We investigated whether aptamer-based proteomic profiling could identify biomarkers associated with future development of type 2 diabetes (T2DM) beyond known risk factors. We identified dozens of markers with highly significant associations with future T2DM across two large longitudinal cohorts (n=2,839) followed for up to 16 years. We leveraged proteomic, metabolomic, genetic and clinical data from humans to nominate one specific candidate to test for potential causal relationships in model systems. Our studies identified functional effects of aminoacylase 1 (ACY1), a top protein association with future T2DM risk, on amino acid metabolism and insulin homeostasis in vitro and in vivo. Further, a loss-of-function variant associated with circulating levels of the biomarker WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing protein 2 (WFIKKN2) was in turn associated with fasting glucose, hemoglobin A1c and HOMA-IR measurements in humans. In addition to identifying novel disease markers and potential pathways in T2DM, we provide publicly available data to be leveraged for new insights about gene function and disease pathogenesis in the context of human metabolism. .
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| 9. |
- Shi, Xiaoxu, et al.
(författare)
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Calendar effects on surface air temperature and precipitation based on model-ensemble equilibrium and transient simulations from PMIP4 and PACMEDY
- 2022
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Ingår i: Climate of the Past. - : Copernicus GmbH. - 1814-9324 .- 1814-9332. ; 18:5, s. 1047-1070
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Tidskriftsartikel (refereegranskat)abstract
- Numerical modeling enables a comprehensive understanding not only of the Earth's system today, but also of the past. To date, a significant amount of time and effort has been devoted to paleoclimate modeling and analysis, which involves the latest and most advanced Paleoclimate Modelling Intercomparison Project phase 4 (PMIP4). The definition of seasonality, which is influenced by slow variations in the Earth's orbital parameters, plays a key role in determining the calculated seasonal cycle of the climate. In contrast to the classical calendar used today, where the lengths of the months and seasons are fixed, the angular calendar calculates the lengths of the months and seasons according to a fixed number of degrees along the Earth's orbit. When comparing simulation results for different time intervals, it is essential to account for the angular calendar to ensure that the data for comparison are from the same position along the Earth's orbit. Most models use the classical calendar, which can lead to strong distortions of the monthly and seasonal values, especially for the climate of the past. Here, by analyzing daily outputs from multiple PMIP4 model simulations, we examine calendar effects on surface air temperature and precipitation under mid-Holocene, Last Interglacial, and pre-industrial climate conditions. We came to the following conclusions. (a) The largest cooling bias occurs in boreal autumn when the classical calendar is applied for the mid-Holocene and Last Interglacial, due to the fact that the vernal equinox is fixed on 21 March. (b) The sign of the temperature anomalies between the Last Interglacial and pre-industrial in boreal autumn can be reversed after the switch from the classical to angular calendar, particularly over the Northern Hemisphere continents. (c) Precipitation over West Africa is overestimated in boreal summer and underestimated in boreal autumn when the classical seasonal cycle is applied. (d) Finally, month-length adjusted values for surface air temperature and precipitation are very similar to the day-length adjusted values, and therefore correcting the calendar based on the monthly model results can largely reduce the artificial bias. In addition, we examine the calendar effects in three transient simulations for 6-0 ka by AWIESM, MPI-ESM, and IPSL-CM. We find significant discrepancies between adjusted and unadjusted temperature values over continents for both hemispheres in boreal autumn, while for other seasons the deviations are relatively small. A drying bias can be found in the summer monsoon precipitation in Africa (in the classical calendar), whereby the magnitude of bias becomes smaller over time. Overall, our study underlines the importance of the application of calendar transformation in the analysis of climate simulations. Neglecting the calendar effects could lead to a profound artificial distortion of the calculated seasonal cycle of surface air temperature and precipitation.
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| 10. |
- Wang, Hui, et al.
(författare)
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Endoplasmic reticulum-targeted fluorogenic probe based on pyrimidine derivative for visualizing exogenous/endogenous H2S in living cells
- 2020
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Ingår i: Dyes and pigments. - : ELSEVIER SCI LTD. - 0143-7208 .- 1873-3743. ; 179
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Tidskriftsartikel (refereegranskat)abstract
- Developing new probes for visualizing H2S in the endoplasmic reticulum (ER) is of great significance in physiological and pathological fields in that the probe can antagonise ER stress. Herein, we try to explore efficient reporting fluorophores based on three pyrimidine derivatives (L1, L2 and L3), and eventually, a novel probe WH2S was fabricated by using emissive pyrimidine derivative (L1) as the reporting fluomphore. Upon the addition of H2S, the probe processed a thiolytic cleavage to regenerate L1, delivering a remarkable fluorescence enhancement. Probe WH2S presents a perfect selectivity, high sensitivity and low detection limit (3.81 mu M) towards H2S in the buffer media. Most importantly, fluorescence microscopy experiments demonstrate that WH2S can precisely accumulate in ER and detect exogenous/endogenous H2S at cellular level. These results imply that probe WH2S possesses great potentiality in tracking target H2S in complicated and changeable living systems.
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