A Pan-African Convection-Permitting Regional Climate Simulation with the Met Office Unified Model: CP4-Africa

This is the final version. Available on open access from the American Meteorological Society via the DOI in this recordA convection-permitting multiyear regional climate simulation using the Met Office Unified Model has been run for the first time on an Africa-wide domain. The model has been run as part of the Future Climate for Africa (FCFA) Improving Model Processes for African Climate (IMPALA) project, and its configuration, domain, and forcing data are described here in detail. The model [Pan-African Convection-Permitting Regional Climate Simulation with the Met Office UM (CP4-Africa)] uses a 4.5-km horizontal grid spacing at the equator and is run without a convection parameterization, nested within a global atmospheric model driven by observations at the sea surface, which does include a convection scheme. An additional regional simulation, with identical resolution and physical parameterizations to the global model, but with the domain, land surface, and aerosol climatologies of CP4-Africa, has been run to aid in the understanding of the differences between the CP4-Africa and global model, in particular to isolate the impact of the convection parameterization and resolution. The effect of enforcing moisture conservation in CP4-Africa is described and its impact on reducing extreme precipitation values is assessed. Preliminary results from the first five years of the CP4-Africa simulation show substantial improvements in JJA average rainfall compared to the parameterized convection models, with most notably a reduction in the persistent dry bias in West Africa, giving an indication of the benefits to be gained from running a convection-permitting simulation over the whole African continent.Natural Environment Research Council (NERC

Identifying networks in social media: The case of #Grexit

We examine the intensity of ‘#Grexit’ usage in Twitter during a period of economic and financial turbulence. Using a frequency-analysis technique, we illustrate that we can extract detailed information from social media data. This allows us to map the networks of interest as it is reflected in Twitter. Our findings identify high-interest in Grexit from Twitter users in key peripheral countries, core Eurozone members as well as core EU member states outside the Eurozone. Overall, our study presents a useful tool for identifying clusters. This is part of a new research agenda utilising the information extracted from big data available via social media channels

A qualitative study of nursing student experiences of clinical practice

BACKGROUND: Nursing student's experiences of their clinical practice provide greater insight to develop an effective clinical teaching strategy in nursing education. The main objective of this study was to investigate student nurses' experience about their clinical practice. METHODS: Focus groups were used to obtain students' opinion and experiences about their clinical practice. 90 baccalaureate nursing students at Shiraz University of Medical Sciences (Faculty of Nursing and Midwifery) were selected randomly from two hundred students and were arranged in 9 groups of ten students. To analyze the data the method used to code and categories focus group data were adapted from approaches to qualitative data analysis. RESULTS: Four themes emerged from the focus group data. From the students' point of view," initial clinical anxiety", "theory-practice gap"," clinical supervision", professional role", were considered as important factors in clinical experience. CONCLUSION: The result of this study showed that nursing students were not satisfied with the clinical component of their education. They experienced anxiety as a result of feeling incompetent and lack of professional nursing skills and knowledge to take care of various patients in the clinical setting

Preferential Fas-mediated apoptotic execution at G1 phase: the resistance of mitotic cells to the cell death

Apoptosis is induced by various stresses generated from the extracellular and intracellular environments. The fidelity of the cell cycle is monitored by surveillance mechanisms that arrest its further progression if any crucial process has not been completed or damages are sustained, and then the cells with problems undergo apoptosis. Although the molecular mechanisms involved in the regulation of the cell cycle and that of apoptosis have been elucidated, the links between them are not clear, especially that between cell cycle and death receptor-mediated apoptosis. By using the HeLa.S-Fucci (fluorescent ubiquitination-based cell cycle indicator) cells, we investigated the relationship between the cell cycle progression and apoptotic execution. To monitor apoptotic execution during cell cycle progression, we observed the cells after induction of apoptosis with time-lapse fluorescent microscopy. About 70% of Fas-mediated apoptotic cells were present at G1 phase and about 20% of cells died immediately after cytokinesis, whereas more than 60% of etoposide-induced apoptotic cells were at S/G2 phases in random culture of the cells. These results were confirmed by using synchronized culture of the cells. Furthermore, mitotic cells showed the resistance to Fas-mediated apoptosis. In conclusion, these findings suggest that apoptotic execution is dependent on cell cycle phase and Fas-mediated apoptosis preferentially occurs at G1 phase

A Whole Cell Assay to Measure Caspase-6 Activity by Detecting Cleavage of Lamin A/C

Caspase-6 is a cysteinyl protease implicated in neurodegenerative conditions including Alzheimer's and Huntington's disease making it an attractive target for therapeutic intervention. A greater understanding of the role of caspase-6 in disease has been hampered by a lack of suitable cellular assays capable of specifically detecting caspase-6 activity in an intact cell environment. This is mainly due to the use of commercially available peptide substrates and inhibitors which lack the required specificity to facilitate development of this type of assay. We report here a 384-well whole-cell chemiluminescent ELISA assay that monitors the proteolytic degradation of endogenously expressed lamin A/C during the early stages of caspase-dependent apoptosis. The specificity of lamin A/C proteolysis by caspase-6 was demonstrated against recombinant caspase family members and further confirmed in genetic deletion studies. In the assay, plasma membrane integrity remained intact as assessed by release of lactate dehydrogenase from the intracellular environment and the exclusion of cell impermeable peptide inhibitors, despite the induction of an apoptotic state. The method described here is a robust tool to support drug discovery efforts targeting caspase-6 and is the first reported to specifically monitor endogenous caspase-6 activity in a cellular context

Open Source Brain: A Collaborative Resource for Visualizing, Analyzing, Simulating, and Developing Standardized Models of Neurons and Circuits

Computational models are powerful tools for exploring the properties of complex biological systems. In neuroscience, data-driven models of neural circuits that span multiple scales are increasingly being used to understand brain function in health and disease. But their adoption and reuse has been limited by the specialist knowledge required to evaluate and use them. To address this, we have developed Open Source Brain, a platform for sharing, viewing, analyzing, and simulating standardized models from different brain regions and species. Model structure and parameters can be automatically visualized and their dynamical properties explored through browser-based simulations. Infrastructure and tools for collaborative interaction, development, and testing are also provided. We demonstrate how existing components can be reused by constructing new models of inhibition-stabilized cortical networks that match recent experimental results. These features of Open Source Brain improve the accessibility, transparency, and reproducibility of models and facilitate their reuse by the wider community

Clioquinol and pyrrolidine dithiocarbamate complex with copper to form proteasome inhibitors and apoptosis inducers in human breast cancer cells

INTRODUCTION: A physiological feature of many tumor tissues and cells is the tendency to accumulate high concentrations of copper. While the precise role of copper in tumors is cryptic, copper, but not other trace metals, is required for angiogenesis. We have recently reported that organic copper-containing compounds, including 8-hydroxyquinoline-copper(II) and 5,7-dichloro-8-hydroxyquinoline-copper(II), comprise a novel class of proteasome inhibitors and tumor cell apoptosis inducers. In the current study, we investigate whether clioquinol (CQ), an analog of 8-hydroxyquinoline and an Alzheimer's disease drug, and pyrrolidine dithiocarbamate (PDTC), a known copper-binding compound and antioxidant, can interact with copper to form cancer-specific proteasome inhibitors and apoptosis inducers in human breast cancer cells. Tetrathiomolybdate (TM), a strong copper chelator currently being tested in clinical trials, is used as a comparison. METHODS: Breast cell lines, normal, immortalized MCF-10A, premalignant MCF10AT1K.cl2, and malignant MCF10DCIS.com and MDA-MB-231, were treated with CQ or PDTC with or without prior interaction with copper, followed by measurement of proteasome inhibition and cell death. Inhibition of the proteasome was determined by levels of the proteasomal chymotrypsin-like activity and ubiquitinated proteins in protein extracts of the treated cells. Apoptotic cell death was measured by morphological changes, Hoechst staining, and poly(ADP-ribose) polymerase cleavage. RESULTS: When in complex with copper, both CQ and PDTC, but not TM, can inhibit the proteasome chymotrypsin-like activity, block proliferation, and induce apoptotic cell death preferentially in breast cancer cells, less in premalignant breast cells, but are non-toxic to normal/non-transformed breast cells at the concentrations tested. In contrast, CQ, PDTC, TM or copper alone had no effects on any of the cells. Breast premalignant or cancer cells that contain copper at concentrations similar to those found in patients, when treated with just CQ or PDTC alone, but not TM, undergo proteasome inhibition and apoptosis. CONCLUSION: The feature of breast cancer cells and tissues to accumulate copper can be used as a targeting method for anticancer therapy through treatment with novel compounds such as CQ and PDTC that become active proteasome inhibitors and breast cancer cell killers in the presence of copper

Modulating RNA structure and catalysis: lessons from small cleaving ribozymes

RNA is a key molecule in life, and comprehending its structure/function relationships is a crucial step towards a more complete understanding of molecular biology. Even though most of the information required for their correct folding is contained in their primary sequences, we are as yet unable to accurately predict both the folding pathways and active tertiary structures of RNA species. Ribozymes are interesting molecules to study when addressing these questions because any modifications in their structures are often reflected in their catalytic properties. The recent progress in the study of the structures, the folding pathways and the modulation of the small ribozymes derived from natural, self-cleaving, RNA motifs have significantly contributed to today’s knowledge in the field

Over-elongation of centrioles in cancer promotes centriole amplification and chromosome missegregation

G.M. and A.G. were funded by the FCT-Harvard Medical School Program Portugal grant (HMSP-CT/SAU-ICT/0075/2009) and individual FCT post-doctoral fellowships (SFRH/BPD/98439/2013 and SFRH/BPD/82420/2011, respectively). The M.B-D. laboratory is supported by IGC, an EMBO installation grant, ERC grant ERC-2010-StG-261344, FCT grants (FCT Investigator to M.B-D., POCI-01-0145-FEDER-016390 and PTDC/BIM-ONC/6858/2014) and a FCT-Harvard Medical School Program Portugal grant (HMSP-CT/SAU-ICT/0075/2009)

Combination of searches for heavy spin-1 resonances using 139 fb−1 of proton-proton collision data at s = 13 TeV with the ATLAS detector

A combination of searches for new heavy spin-1 resonances decaying into different pairings of W, Z, or Higgs bosons, as well as directly into leptons or quarks, is presented. The data sample used corresponds to 139 fb−1 of proton-proton collisions at = 13 TeV collected during 2015–2018 with the ATLAS detector at the CERN Large Hadron Collider. Analyses selecting quark pairs (qq, bb, , and tb) or third-generation leptons (τν and ττ) are included in this kind of combination for the first time. A simplified model predicting a spin-1 heavy vector-boson triplet is used. Cross-section limits are set at the 95% confidence level and are compared with predictions for the benchmark model. These limits are also expressed in terms of constraints on couplings of the heavy vector-boson triplet to quarks, leptons, and the Higgs boson. The complementarity of the various analyses increases the sensitivity to new physics, and the resulting constraints are stronger than those from any individual analysis considered. The data exclude a heavy vector-boson triplet with mass below 5.8 TeV in a weakly coupled scenario, below 4.4 TeV in a strongly coupled scenario, and up to 1.5 TeV in the case of production via vector-boson fusion