Robust skill of decadal climate predictions Smith, D. M.; Eade, R.; Scaife, A. A. ...
NPJ climate and atmospheric science,
05/2019, Letnik:
2, Številka:
1
Journal Article, Publication
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Abstract
There is a growing need for skilful predictions of climate up to a decade ahead. Decadal climate predictions show high skill for surface temperature, but confidence in forecasts of ...precipitation and atmospheric circulation is much lower. Recent advances in seasonal and annual prediction show that the signal-to-noise ratio can be too small in climate models, requiring a very large ensemble to extract the predictable signal. Here, we reassess decadal prediction skill using a much larger ensemble than previously available, and reveal significant skill for precipitation over land and atmospheric circulation, in addition to surface temperature. We further propose a more powerful approach than used previously to evaluate the benefit of initialisation with observations, improving our understanding of the sources of skill. Our results show that decadal climate is more predictable than previously thought and will aid society to prepare for, and adapt to, ongoing climate variability and change.
It has been observed in the literature that measurements of low-mass Drell–Yan (DY) transverse momentum spectra at low center-of-mass energies
s
are not well described by perturbative QCD ...calculations in collinear factorization in the region where transverse momenta are comparable with the DY mass. We examine this issue from the standpoint of the Parton Branching (PB) method, combining next-to-leading-order (NLO) calculations of the hard process with the evolution of transverse momentum dependent (TMD) parton distributions. We compare our predictions with experimental measurements at low DY mass, and find very good agreement. In addition we use the low mass DY measurements at low
s
to determine the width
q
s
of the intrinsic Gauss distribution of the PB-TMDs at low evolution scales. We find values close to what has earlier been used in applications of PB-TMDs to high-energy processes at the Large Hadron Collider (LHC) and HERA. We find that at low DY mass and low
s
even in the region of
p
T
/
m
DY
∼
1
the contribution of multiple soft gluon emissions (included in the PB-TMDs) is essential to describe the measurements, while at larger masses (
m
DY
∼
m
Z
) and LHC energies the contribution from soft gluons in the region of
p
T
/
m
DY
∼
1
is small.
Peer-to-peer (P2P) energy trading is one of the promising approaches for implementing decentralized electricity market paradigms. In the P2P trading, each actor negotiates directly with a set of ...trading partners. Since the physical network or grid is used for energy transfer, power losses are inevitable, and grid-related costs always occur during the P2P trading. A proper market clearing mechanism is required for the P2P energy trading between different producers and consumers. This paper proposes a decentralized market clearing mechanism for the P2P energy trading considering the privacy of the agents, power losses as well as the utilization fees for using the third party owned network. Grid-related costs in the P2P energy trading are considered by calculating the network utilization fees using an electrical distance approach. The simulation results are presented to verify the effectiveness of the proposed decentralized approach for market clearing in P2P energy trading.
Summary
To explore the radiosensitivity of andrographolide on esophageal cancer cell line ECA109. The inhibition effects of andrographolide were measured using ...3‐(4,5‐dimethyl‐2‐thiazolyl)‐2,5‐diphenyl‐2H‐tetrazolium (MTT) assay. Clonogenic survival assay was used to evaluate the effects of andrographolide on the radiosensitivity of esophageal cancer cells. Immunofluorescence was employed to examine Bax expression. The changes in cell cycle distribution and apoptosis were assayed using flow cytometry. The expression of NF‐κb/Cleaved‐Caspase3/Bax/Bcl‐2 was measured using Western blot analysis. DNA damage was detected via γ‐H2AX foci counting. With a clear dose and time effects, andrographolide was found to inhibit the proliferation of esophageal cell line ECA109. The results of the clonogenic survival assay show that andrographolide could markedly enhance radiosensitivity (P < 0.05) with a sensitizing enhancement ratio of 1.28. Andrographolide caused a dose‐dependent increase in Cleaved‐Caspase3/Bax protein expression and a decrease in Bcl‐2/NF‐κb expression. Apoptosis in andrographolide‐treated ECA‐109 increased significantly compared with the apoptosis in the simple drug and radiation combined with drug groups (P < 0.001; P < 0.05). Moreover, compared with the independent radiation group, the andrographolide combined with radiation group increased the number of DNA double chain breaks. Andrographolide can increase the radiosensitivity of esophageal cell line ECA109. This result may be associated with the decrease in the NF‐κb level and the induced apoptosis of esophageal cancer cells.
Abstract
The GLASS-JWST Early Release Science (hereafter GLASS-JWST-ERS) Program will obtain and make publicly available the deepest extragalactic data of the ERS campaign. It is primarily designed ...to address two key science questions, namely, “what sources ionized the universe and when?” and “how do baryons cycle through galaxies?”, while also enabling a broad variety of first look scientific investigations. In primary mode, it will obtain NIRISS and NIRSpec spectroscopy of galaxies lensed by the foreground Hubble Frontier Field cluster, Abell 2744. In parallel, it will use NIRCam to observe two fields that are offset from the cluster center, where lensing magnification is negligible, and which can thus be effectively considered blank fields. In order to prepare the community for access to this unprecedented data, we describe the scientific rationale, the survey design (including target selection and observational setups), and present pre-commissioning estimates of the expected sensitivity. In addition, we describe the planned public releases of high-level data products, for use by the wider astronomical community.
Cytochrome P450 2C9 (CYP2C9) is one of the most abundant CYP enzymes in the human liver. CYP2C9 metabolizes more than 100 therapeutic drugs, including tolbutamide, glyburide, diclofenac, celecoxib, ...torasemide, phenytoin losartan, and S-warfarin). Some natural and herbal compounds are also metabolized by CYP2C9, probably leading to the formation of toxic metabolites. CYP2C9 also plays a role in the metabolism of several endogenous compounds such as steroids, melatonin, retinoids and arachidonic acid. Many CYP2C9 substrates are weak acids, but CYP2C9 also has the capacity to metabolise neutral, highly lipophilic compounds. A number of ligand-based and homology models of CYP2C9 have been reported and this has provided insights into the binding of ligands to the active site of CYP2C9. Data from the site-directed mutagenesis studies have revealed that a number of residues (e.g. Arg97, Phe110, Val113, Phe114, Arg144, Ser286, Asn289, Asp293 and Phe476) play an important role in ligand binding and determination of substrate specificity. The resolved crystal structures of CYP2C9 have confirmed the importance of these residues in substrate recognition and ligand orientation. CYP2C9 is activated by dapsone and its analogues and R-lansoprazole in a stereo-specific and substrate-dependent manner, probably through binding to the active site and inducing positive cooperativity. CYP2C9 is subject to induction by rifampin, phenobarbital, and dexamethasone, indicating the involvement of pregnane X receptor, constitutive androstane receptor and glucocorticoid receptor in the regulation of CYP2C9. A number of compounds have been found to inhibit CYP2C9 and this may provide an explanation for some clinically important drug interactions. Tienilic acid, suprofen and silybin are mechanism-based inhibitors of CYP2C9. Given the critical role of CYP2C9 in drug metabolism and the presence of polymorphisms, it is important to identify drug candidates as potential substrates, inducer or inhibitors of CYP2C9 in drug development and drug discovery scientists should develop drugs with minimal interactions with this enzyme. Further studies are warranted to explore the molecular determinants for ligand-CYP2C9 binding and the structure-activity relationships.
We recently derived mouse expanded potential stem cells (EPSCs) from individual blastomeres by inhibiting the critical molecular pathways that predispose their differentiation. EPSCs had enriched ...molecular signatures of blastomeres and possessed developmental potency for all embryonic and extra-embryonic cell lineages. Here, we report the derivation of porcine EPSCs, which express key pluripotency genes, are genetically stable, permit genome editing, differentiate to derivatives of the three germ layers in chimeras and produce primordial germ cell-like cells in vitro. Under similar conditions, human embryonic stem cells and induced pluripotent stem cells can be converted, or somatic cells directly reprogrammed, to EPSCs that display the molecular and functional attributes reminiscent of porcine EPSCs. Importantly, trophoblast stem-cell-like cells can be generated from both human and porcine EPSCs. Our pathway-inhibition paradigm thus opens an avenue for generating mammalian pluripotent stem cells, and EPSCs present a unique cellular platform for translational research in biotechnology and regenerative medicine.
A 1D periodic structure of ferroelectric domains in epitaxial BiFeO3 films is created. By careful control of the growth mechanism for the SrRuO3 bottom electrode, its in‐plane lattice parameters are ...confined by the underlying DyScO3 (110)O single‐ crystal substrate, enabling the formation of an expitaxial film of (110)O SrRuO3 with a single structural domain (see figure).
•Venetoclax resistance is mediated by methylation and silencing of PUMA.•Treatment algorithms should consider the PUMA, MCL1, and BAX status.
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The BCL2 inhibitor venetoclax has been ...approved to treat different hematological malignancies. Because there is no common genetic alteration causing resistance to venetoclax in chronic lymphocytic leukemia (CLL) and B-cell lymphoma, we asked if epigenetic events might be involved in venetoclax resistance. Therefore, we employed whole-exome sequencing, methylated DNA immunoprecipitation sequencing, and genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 screening to investigate venetoclax resistance in aggressive lymphoma and high-risk CLL patients. We identified a regulatory CpG island within the PUMA promoter that is methylated upon venetoclax treatment, mediating PUMA downregulation on transcript and protein level. PUMA expression and sensitivity toward venetoclax can be restored by inhibition of methyltransferases. We can demonstrate that loss of PUMA results in metabolic reprogramming with higher oxidative phosphorylation and adenosine triphosphate production, resembling the metabolic phenotype that is seen upon venetoclax resistance. Although PUMA loss is specific for acquired venetoclax resistance but not for acquired MCL1 resistance and is not seen in CLL patients after chemotherapy-resistance, BAX is essential for sensitivity toward both venetoclax and MCL1 inhibition. As we found loss of BAX in Richter’s syndrome patients after venetoclax failure, we defined BAX-mediated apoptosis to be critical for drug resistance but not for disease progression of CLL into aggressive diffuse large B-cell lymphoma in vivo. A compound screen revealed TRAIL-mediated apoptosis as a target to overcome BAX deficiency. Furthermore, antibody or CAR T cells eliminated venetoclax resistant lymphoma cells, paving a clinically applicable way to overcome venetoclax resistance.
Two complementary articles shed new light on resistance to venetoclax in lymphoid malignancies. Thijssen et al use single-cell studies to reveal the multilayered nature of the mechanisms underpinning the recurrence of chronic lymphocytic leukemia in patients on long-term venetoclax, identifying a range of recurring genetic and epigenetic changes in apoptotic regulators. Overlying this heterogeneity, heightened expression of MCL1 driven by NF-κB is ubiquitous but reversible upon drug discontinuation. Thomalla and colleagues use B-lineage cell lines and patient samples to elegantly demonstrate how methylation and silencing of PUMA, a pro-apoptotic, causes failure of venetoclax. Both articles provide clinically applicable suggestions for circumventing emergent resistance to venetoclax.
Over the past three decades, considerable effort has been dedicated to quantifying the pace of ageing yet identifying the most essential metrics of ageing remains challenging due to lack of ...comprehensive measurements and heterogeneity of the ageing processes. Most of the previously proposed metrics of ageing have been emerged from cross‐sectional associations with chronological age and predictive accuracy of mortality, thus lacking a conceptual model of functional or phenotypic domains. Further, such models may be biased by selective attrition and are unable to address underlying biological constructs contributing to functional markers of age‐related decline. Using longitudinal data from the Baltimore Longitudinal Study of Aging (BLSA), we propose a conceptual framework to identify metrics of ageing that may capture the hierarchical and temporal relationships between functional ageing, phenotypic ageing and biological ageing based on four hypothesized domains: body composition, energy regulation, homeostatic mechanisms and neurodegeneration/neuroplasticity. We explored the longitudinal trajectories of key variables within these phenotypes using linear mixed‐effects models and more than 10 years of data. Understanding the longitudinal trajectories across these domains in the BLSA provides a reference for researchers, informs future refinement of the phenotypic ageing framework and establishes a solid foundation for future models of biological ageing.
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