The intramitochondrial dynamin-related GTPase, Mgm1p, is a component of a protein complex that mediates mitochondrial fusion

Abalance between fission and fusion events determines the morphology of mitochondria. In yeast, mitochondrial fission is regulated by the outer membrane–associated dynamin-related GTPase, Dnm1p. Mitochondrial fusion requires two integral outer membrane components, Fzo1p and Ugo1p. Interestingly, mutations in a second mitochondrial-associated dynamin-related GTPase, Mgm1p, produce similar phenotypes to fzo1 and ugo cells. Specifically, mutations in MGM1 cause mitochondrial fragmentation and a loss of mitochondrial DNA that are suppressed by abolishing DNM1-dependent fission. In contrast to fzo1ts mutants, blocking DNM1-dependent fission restores mitochondrial fusion in mgm1ts cells during mating. Here we show that blocking DNM1-dependent fission in Δmgm1 cells fails to restore mitochondrial fusion during mating. To examine the role of Mgm1p in mitochondrial fusion, we looked for molecular interactions with known fusion components. Immunoprecipitation experiments revealed that Mgm1p is associated with both Ugo1p and Fzo1p in mitochondria, and that Ugo1p and Fzo1p also are associated with each other. In addition, genetic analysis of specific mgm1 alleles indicates that Mgm1p's GTPase and GTPase effector domains are required for its ability to promote mitochondrial fusion and that Mgm1p self-interacts, suggesting that it functions in fusion as a self-assembling GTPase. Mgm1p's localization within mitochondria has been controversial. Using protease protection and immuno-EM, we have shown previously that Mgm1p localizes to the intermembrane space, associated with the inner membrane. To further test our conclusions, we have used a novel method using the tobacco etch virus protease and confirm that Mgm1p is present in the intermembrane space compartment in vivo. Taken together, these data suggest a model where Mgm1p functions in fusion to remodel the inner membrane and to connect the inner membrane to the outer membrane via its interactions with Ugo1p and Fzo1p, thereby helping to coordinate the behavior of the four mitochondrial membranes during fusion

Sectoral specialisation in the EU a macroeconomic perspective

This paper analyses trends in sectoral specialisation in the EU and concludes the following: 1) The European production structure appears more homogenous than that of the US. 2) While sectoral specialisation has shown a slight increase in some smaller euro area countries towards the end-1990s, it is too early to detect any potential impact of EMU. 3) Despite some changes in sectoral composition, the business cycles of euro area countries became more synchronised over the 1990s, which may be seen as reassuring from the point of view of the single monetary policy. 4) Sectoral re-allocation accounts for as much as 50% of the increase in labour productivity growth in business sector services in the euro area. 5) The slowdown of European labour productivity growth relative to the US since the mid-1990s is explained by a stronger performance in the US wholesale and retail trade, financial intermediation and high-tech manufacturing sectors.

Three-phase traffic theory and two-phase models with a fundamental diagram in the light of empirical stylized facts

Despite the availability of large empirical data sets and the long history of traffic modeling, the theory of traffic congestion on freeways is still highly controversial. In this contribution, we compare Kerner's three-phase traffic theory with the phase diagram approach for traffic models with a fundamental diagram. We discuss the inconsistent use of the term "traffic phase" and show that patterns demanded by three-phase traffic theory can be reproduced with simple two-phase models, if the model parameters are suitably specified and factors characteristic for real traffic flows are considered, such as effects of noise or heterogeneity or the actual freeway design (e.g. combinations of off- and on-ramps). Conversely, we demonstrate that models created to reproduce three-phase traffic theory create similar spatiotemporal traffic states and associated phase diagrams, no matter whether the parameters imply a fundamental diagram in equilibrium or non-unique flow- density relationships. In conclusion, there are different ways of reproducing the empirical stylized facts of spatiotemporal congestion patterns summarized in this contribution, and it appears possible to overcome the controversy by a more precise definition of the scientific terms and a more careful comparison of models and data, considering effects of the measurement process and the right level of detail in the traffic model used.Comment: 18 pages in the published article, 13 figures, 2 table

Competitiveness and the export performance of the euro area

Chapter 1 provides an overview and assessment of the price competitiveness and export performance of the euro area and the larger euro area countries, as well as an evaluation of how standard equations have been able to explain actual export developments. Chapter 2 carries out a constant market share analysis for the euro area and thereby sheds light on the reasons for movements in aggregate export market shares by looking at the sectoral and geographical composition of euro area exports. Chapter 3 looks at the evolution of the technological competitiveness of the euro area and major competitors – proxied by patenting activity and R&D expenditure – and analyses some structural indicators of competitiveness using survey data. Chapter 4 then looks at the impact of FDI on competitiveness and export performance. Finally, Chapter 5 summarises the main findings of the report, but also critically evaluates their importance and implications.

gaBERT — an Irish Language model

The BERT family of neural language models have become highly popular due to their ability to provide sequences of text with rich context-sensitive token encodings which are able to generalise well to many NLP tasks. We introduce gaBERT, a monolingual BERT model for the Irish language. We compare our gaBERT model to multilingual BERT and the monolingual Irish WikiBERT, and we show that gaBERT provides better representations for a downstream parsing task. We also show how different filtering criteria, vocabulary size and the choice of subword tokenisation model affect downstream performance. We compare the results of fine-tuning a gaBERT model with an mBERT model for the task of identifying verbal multiword expressions, and show that the fine-tuned gaBERT model also performs better at this task. We release gaBERT and related code to the community

Interventions for preventing oral mucositis for patients with cancer receiving treatment

Interventions for preventing oral mucositis for patients with cancer receiving treatmentTreatment for cancer (including bone marrow transplant) can cause oral mucositis (severe ulcers in the mouth). This painful condition can cause difficulties in eating, drinking and swallowing, and may also be associated with infections which may require the patient to stay longer in hospital. Different strategies are used to try and prevent this condition, and the review of trials found that some of these are effective. Two interventions, cryotherapy (ice chips) and keratinocyte growth factor (palifermin®) showed some benefit in preventing mucositis. Sucralfate is effective in reducing the severity of mucositis, and a further seven interventions, aloe vera, amifostine, intravenous glutamine, granulocyte‐colony stimulating factor (G‐CSF), honey, laser and antibiotic lozenges containing polymixin/tobramycin/amphotericin (PTA) showed weaker evidence of benefit. These were evaluated in patients with different types of cancer, undergoing different types of cancer treatment. Benefits may be restricted to the disease and treatment combinations evaluated

Purification of Reversibly Oxidized Proteins (PROP) Reveals a Redox Switch Controlling p38 MAP Kinase Activity

Oxidation of cysteine residues of proteins is emerging as an important means of regulation of signal transduction, particularly of protein kinase function. Tools to detect and quantify cysteine oxidation of proteins have been a limiting factor in understanding the role of cysteine oxidation in signal transduction. As an example, the p38 MAP kinase is activated by several stress-related stimuli that are often accompanied by in vitro generation of hydrogen peroxide. We noted that hydrogen peroxide inhibited p38 activity despite paradoxically increasing the activating phosphorylation of p38. To address the possibility that cysteine oxidation may provide a negative regulatory effect on p38 activity, we developed a biochemical assay to detect reversible cysteine oxidation in intact cells. This procedure, PROP, demonstrated in vivo oxidation of p38 in response to hydrogen peroxide and also to the natural inflammatory lipid prostaglandin J2. Mutagenesis of the potential target cysteines showed that oxidation occurred preferentially on residues near the surface of the p38 molecule. Cysteine oxidation thus controls a functional redox switch regulating the intensity or duration of p38 activity that would not be revealed by immunodetection of phosphoprotein commonly interpreted as reflective of p38 activity

Cell-type specific RNA-Seq reveals novel roles and regulatory programs for terminally differentiated Dictyostelium cells

Abstract Background A major hallmark of multicellular evolution is increasing complexity by the evolution of new specialized cell types. During Dictyostelid evolution novel specialization occurred within taxon group 4. We here aim to retrace the nature and ancestry of the novel “cup” cells by comparing their transcriptome to that of other cell types. Results RNA-Seq was performed on purified mature spore, stalk and cup cells and on vegetative amoebas. Clustering and phylogenetic analyses showed that cup cells were most similar to stalk cells, suggesting that they share a common ancestor. The affinity between cup and stalk cells was also evident from promoter-reporter studies of newly identified cell-type genes, which revealed late expression in cups of many stalk genes. However, GO enrichment analysis reveal the unexpected prominence of GTPase mediated signalling in cup cells, in contrast to enrichment of autophagy and cell wall synthesis related transcripts in stalk cells. Combining the cell type RNA-Seq data with developmental expression profiles revealed complex expression dynamics in each cell type as well as genes exclusively expressed during terminal differentiation. Most notable were nine related hssA-like genes that were highly and exclusively expressed in cup cells. Conclusions This study reveals the unique transcriptomes of the mature cup, stalk and spore cells of D. discoideum and provides insight into the ancestry of cup cells and roles in signalling that were not previously realized. The data presented in this study will serve as an important resource for future studies into the regulation and evolution of cell type specialization

The Lung Screen Uptake Trial (LSUT): protocol for a randomised controlled demonstration lung cancer screening pilot testing a targeted invitation strategy for high risk and ‘hard-to-reach’ patients

Background Participation in low-dose CT (LDCT) lung cancer screening offered in the trial context has been poor, especially among smokers from socioeconomically deprived backgrounds; a group for whom the risk-benefit ratio is improved due to their high risk of lung cancer. Attracting high risk participants is essential to the success and equity of any future screening programme. This study will investigate whether the observed low and biased uptake of screening can be improved using a targeted invitation strategy. Methods/design A randomised controlled trial design will be used to test whether targeted invitation materials are effective at improving engagement with an offer of lung cancer screening for high risk candidates. Two thousand patients aged 60–75 and recorded as a smoker within the last five years by their GP, will be identified from primary care records and individually randomised to receive either intervention invitation materials (which take a targeted, stepped and low burden approach to information provision prior to the appointment) or control invitation materials. The primary outcome is uptake of a nurse-led ‘lung health check’ hospital appointment, during which patients will be offered a spirometry test, an exhaled carbon monoxide (CO) reading, and an LDCT if eligible. Initial data on demographics (i.e. age, sex, ethnicity, deprivation score) and smoking status will be collected in primary care and analysed to explore differences between attenders and non-attenders with respect to invitation group. Those who attend the lung health check will have further data on smoking collected during their appointment (including pack-year history, nicotine dependence and confidence to quit). Secondary outcomes will include willingness to be screened, uptake of LDCT and measures of informed decision-making to ensure the latter is not compromised by either invitation strategy. Discussion If effective at improving informed uptake of screening and reducing bias in participation, this invitation strategy could be adopted by local screening pilots or a national programme. Trial registration This study was registered with the ISRCTN (International Standard Registered Clinical/soCial sTudy Number : ISRCTN21774741) on the 23rd September 2015 and the NIH ClinicalTrials.gov database (NCT0255810) on the 22nd September 2015