165 research outputs found
Data integration with the Climate Science Modelling Language
The Climate Science Modelling Language (CSML) has been developed by the NERC DataGrid (NDG) project as a standards-based data model and XML markup for describing and constructing climate science datasets. It uses conceptual models from emerging standards in GIS to define a number of feature types, and adopts schemas of the Geography Markup Language (GML) where possible for encoding.
A prototype deployment of CSML is being trialled across
the curated archives of the British Atmospheric and Oceanographic Data Centres. These data include a wide range of data types â both observational and model â and heterogeneous file-based storage systems. CSML provides a semantic abstraction layer for data files, and is exposed through higher level data delivery services. In NDG these will include file instantiation services (for formats of choice) and the web services of the Open Geospatial
Consortium (OGC)
Screening of DUB activity and specificity by MALDI-TOF mass spectrometry
Deubiquitylases (DUBs) are key regulators of the ubiquitin system which cleave ubiquitin moieties from proteins and polyubiquitin chains. Several DUBs have been implicated in various diseases and are attractive drug targets. We have developed a sensitive and fast assay to quantify in vitro DUB enzyme activity using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry. Unlike other current assays, this method uses unmodified substrates, such as diubiquitin topoisomers. By analyzing 42 human DUBs against all diubiquitin topoisomers we provide an extensive characterization of DUB activity and specificity. Our results confirm the high specificity of many members of the OTU and JAMM DUB families and highlight that all USPs tested display low linkage selectivity. We also demonstrate that this assay can be deployed to assess the potency and specificity of DUB inhibitors by profiling 11 compounds against a panel of 32 DUBs
The pharmacological regulation of cellular mitophagy
Small molecules are pharmacological tools of considerable value for dissecting complex biological processes and identifying potential therapeutic interventions. Recently, the cellular quality-control process of mitophagy has attracted considerable research interest; however, the limited availability of suitable chemical probes has restricted our understanding of the molecular mechanisms involved. Current approaches to initiate mitophagy include acute dissipation of the mitochondrial membrane potential (ÎΚm) by mitochondrial uncouplers (for example, FCCP/CCCP) and the use of antimycin A and oligomycin to impair respiration. Both approaches impair mitochondrial homeostasis and therefore limit the scope for dissection of subtle, bioenergy-related regulatory phenomena. Recently, novel mitophagy activators acting independently of the respiration collapse have been reported, offering new opportunities to understand the process and potential for therapeutic exploitation. We have summarized the current status of mitophagy modulators and analyzed the available chemical tools, commenting on their advantages, limitations and current applications
Effects of cumulus cell removal time during in vitro fertilization on embryo quality and pregnancy outcomes: a prospective randomized sibling-oocyte study
RBR ligaseâmediated ubiquitin transfer: a tale with many twists and turns
RBR ligases are an enigmatic class of E3 ubiquitin ligases that combine properties of RING and HECT-type E3s and undergo multilevel regulation through autoinhibition, post-translational modifications, multimerization and interaction with binding partners. Here, we summarize recent progress in RBR structures and function, which has uncovered commonalities in the mechanisms by which different family members transfer ubiquitin through a multistep process. However, these studies have also highlighted clear differences in the activity of different family members, suggesting that each RBR ligase has evolved specific properties to fit the biological process it regulates
Overexpression of Human and Fly Frataxins in Drosophila Provokes Deleterious Effects at Biochemical, Physiological and Developmental Levels
10 pages, 5 figures. 21779322[PubMed] PMCID: PMC3136927BACKGROUND: Friedreich's ataxia (FA), the most frequent form of inherited ataxias in the Caucasian population, is caused by a reduced expression of frataxin, a highly conserved protein. Model organisms have contributed greatly in the efforts to decipher the function of frataxin; however, the precise function of this protein remains elusive. Overexpression studies are a useful approach to investigate the mechanistic actions of frataxin; however, the existing literature reports contradictory results. To further investigate the effect of frataxin overexpression, we analyzed the consequences of overexpressing human (FXN) and fly (FH) frataxins in Drosophila.
METHODOLOGY/PRINCIPAL FINDINGS: We obtained transgenic flies that overexpressed human or fly frataxins in a general pattern and in different tissues using the UAS-GAL4 system. For both frataxins, we observed deleterious effects at the biochemical, histological and behavioral levels. Oxidative stress is a relevant factor in the frataxin overexpression phenotypes. Systemic frataxin overexpression reduces Drosophila viability and impairs the normal embryonic development of muscle and the peripheral nervous system. A reduction in the level of aconitase activity and a decrease in the level of NDUF3 were also observed in the transgenic flies that overexpressed frataxin. Frataxin overexpression in the nervous system reduces life span, impairs locomotor ability and causes brain degeneration. Frataxin aggregation and a misfolding of this protein have been shown not to be the mechanism that is responsible for the phenotypes that have been observed. Nevertheless, the expression of human frataxin rescues the aconitase activity in the fh knockdown mutant.
CONCLUSION/SIGNIFICANCE: Our results provide in vivo evidence of a functional equivalence for human and fly frataxins and indicate that the control of frataxin expression is important for treatments that aim to increase frataxin levels.This work was supported by grants from Fondo Investigaciones Sanitarias (ISCIII06- PI0677) and La FundaciĂł la MaratĂł TV3 (exp 101932) of Spain. JVL is supported by the European Friedreich's Ataxia Consortium for Translational Studies. SS is a recipient of a fellowship from Ministerio de Ciencia e InnovaciĂłn of Spain.Peer reviewe
Structural insights into the catalysis and regulation of E3 ubiquitin ligases
Covalent attachment (conjugation) of one or more ubiquitin molecules to protein substrates governs numerous eukaryotic cellular processes, including apoptosis, cell division and immune responses. Ubiquitylation was originally associated with protein degradation, but it is now clear that ubiquitylation also mediates processes such as proteinâprotein interactions and cell signalling depending on the type of ubiquitin conjugation. Ubiquitin ligases (E3s) catalyse the final step of ubiquitin conjugation by transferring ubiquitin from ubiquitin-conjugating enzymes (E2s) to substrates. In humans, more than 600 E3s contribute to determining the fates of thousands of substrates; hence, E3s need to be tightly regulated to ensure accurate substrate ubiquitylation. Recent findings illustrate how E3s function on a structural level and how they coordinate with E2s and substrates to meticulously conjugate ubiquitin. Insights regarding the mechanisms of E3 regulation, including structural aspects of their autoinhibition and activation are also emerging
Potassium and Sodium Transport in Yeast
[EN] As the proper maintenance of intracellular potassium and sodium concentrations
is vital for cell growth, all living organisms have developed a cohort
of strategies to maintain proper monovalent cation homeostasis. In the model yeast
Saccharomyces cerevisiae, potassium is accumulated to relatively high concentrations
and is required for many aspects of cellular function, whereas high intracellular
sodium/potassium ratios are detrimental to cell growth and survival. The fact that
S. cerevisiae cells can grow in the presence of a broad range of concentrations of
external potassium (10 Mâ2.5 M) and sodium (up to 1.5 M) indicates the existence
of robust mechanisms that have evolved to maintain intracellular concentrations of
these cations within appropriate limits. In this review, current knowledge regarding
potassium and sodium transporters and their regulation will be summarized. The
cellular responses to high sodium and potassium and potassium starvation will also
be discussed, as well as applications of this knowledge to diverse fields, including
antifungal treatments, bioethanol production and human disease.L.Y. is funded by grant BFU2011-30197-C03-03 from the Spanish Ministry of Science and Innovation (Madrid, Spain) and EUI2009-04147 [Systems Biology of Microorganisms (SysMo2) European Research Area-Network (ERA-NET)].Yenush, L. (2016). Potassium and Sodium Transport in Yeast. Advances in Experimental Medicine and Biology. 892:187-228. https://doi.org/10.1007/978-3-319-25304-6_8S187228892Ahmed A, Sesti F, Ilan N, Shih TM, Sturley SL et al (1999) A molecular target for viral killer toxin: TOK1 potassium channels. Cell 99:283â291Albert A, Yenush L, Gil-Mascarell MR, Rodriguez PL, Patel S et al (2000) X-ray structure of yeast Hal2p, a major target of lithium and sodium toxicity, and identification of framework interactions determining cation sensitivity. 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COVID-19 Severity and Cardiovascular Outcomes in SARS-CoV-2-Infected Patients With Cancer and Cardiovascular Disease
BACKGROUND: Data regarding outcomes among patients with cancer and co-morbid cardiovascular disease (CVD)/cardiovascular risk factors (CVRF) after SARS-CoV-2 infection are limited.
OBJECTIVES: To compare Coronavirus disease 2019 (COVID-19) related complications among cancer patients with and without co-morbid CVD/CVRF.
METHODS: Retrospective cohort study of patients with cancer and laboratory-confirmed SARS-CoV-2, reported to the COVID-19 and Cancer Consortium (CCC19) registry from 03/17/2020 to 12/31/2021. CVD/CVRF was defined as established CVD
RESULTS: Among 10,876 SARS-CoV-2 infected patients with cancer (median age 65 [IQR 54-74] years, 53% female, 52% White), 6253 patients (57%) had co-morbid CVD/CVRF. Co-morbid CVD/CVRF was associated with higher COVID-19 severity (adjusted OR: 1.25 [95% CI 1.11-1.40]). Adverse CV events were significantly higher in patients with CVD/CVRF (all
CONCLUSIONS: Co-morbid CVD/CVRF is associated with higher COVID-19 severity among patients with cancer, particularly those not receiving active cancer therapy. While infrequent, COVID-19 related CV complications were higher in patients with comorbid CVD/CVRF. (COVID-19 and Cancer Consortium Registry [CCC19]; NCT04354701)
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