182 research outputs found
Safe Concurrency Introduction through Slicing
Traditional refactoring is about modifying the structure of existing code without changing its behaviour, but with the aim of making code easier to understand, modify, or reuse. In this paper, we introduce three novel refactorings for retrofitting concurrency to Erlang applications, and demonstrate how the use of program slicing makes the automation of these refactorings possible
Identification of fragments binding to SARS-CoV-2 nsp10 reveals ligand-binding sites in conserved interfaces between nsp10 and nsp14/nsp16
Since the emergence of SARS-CoV-2 in 2019, Covid-19 has developed into a serious threat to our health, social and economic systems. Although vaccines have been developed in a tour-de-force and are now increasingly available, repurposing of existing drugs has been less successful. There is a clear need to develop new drugs against SARS-CoV-2 that can also be used against future coronavirus infections. Non-structural protein 10 (nsp10) is a conserved stimulator of two enzymes crucial for viral replication, nsp14 and nsp16, exhibiting exoribonuclease and methyltransferase activities. Interfering with RNA proofreading or RNA cap formation represents intervention strategies to inhibit replication. We applied fragment-based screening using nano differential scanning fluorometry and X-ray crystallography to identify ligands targeting SARS-CoV-2 nsp10. We identified four fragments located in two distinct sites: one can be modelled to where it would be located in the nsp14–nsp10 complex interface and the other in the nsp16–nsp10 complex interface. Microscale thermophoresis (MST) experiments were used to quantify fragment affinities for nsp10. Additionally, we showed by MST that the interaction by nsp14 and 10 is weak and thereby that complex formation could be disrupted by small molecules. The fragments will serve as starting points for the development of more potent analogues using fragment growing techniques and structure-based drug design
Regulation of the Cardiac Na+/K+ ATPase by Phospholemman
Hansraj Dhayan, Rajender Kumar, Andreas Kukol, ‘Regulation of the Cardiac Na+/K+ ATPase by Phospholemman’, in Sajal Chakraborti, Naranjan Dhalla, eds., Regulation of Membrane Na+-K+ ATPase, (Switzerland: Springer, 2016), ISBN 978-3-319-24748-9, eISBN 978-3-319-24750-2.Peer reviewe
Testing for parameter instability in predictive regression models
We consider tests for structural change, based on the SupF and Cramer-von-Mises type statistics of Andrews (1993) and Nyblom (1989), respectively, in the slope and/or intercept parameters of a predictive regression model where the predictors display strong persistence. The SupF type tests are motivated by alternatives where the parameters display a small number of breaks at deterministic points in the sample, while the Cramer-von-Mises alternative is one where the coefficients are random and slowly evolve through time. In order to allow for an unknown degree of persistence in the predictors, and for both conditional and unconditional heteroskedasticity in the data, we implement the tests using a fixed regressor wild bootstrap procedure. The asymptotic validity of the bootstrap tests is established by showing that the asymptotic distributions of the bootstrap parameter constancy statistics, conditional on the data, coincide with those of the asymptotic null distributions of the corresponding statistics computed on the original data, conditional on the predictors. Monte Carlo simulations suggest that the bootstrap parameter stability tests work well in finite samples, with the tests based on the Cramer-von-Mises type principle seemingly the most useful in practice. An empirical application to U.S. stock returns data demonstrates the practical usefulness of these methods
Proceedings of EADPH Pre -Congress Workshop held on Wednesday, 11 September 2019 at Het Pand, University of Ghent, Belgium. Best practices in dental curricula development – a follow-up to the 2018 EADPH Pre-Congress Workshop
This document reports the proceedings of a workshop held in Ghent on 11 September 2019, the day before the annual congress of the European Association of Dental Public Health. It is taken directly from the transcription of an audio recording.
The workshop consisted of eight short presentations which described curriculum changes and examples of inter-professional education and practice involving dental public health in European countries. The presentations were followed by discussions in four small working groups and reports from each group which highlighted achievements, barriers and challenge
AMP-Activated Protein Kinase (AMPK) Mediates Nutrient Regulation of Thioredoxin-Interacting Protein (TXNIP) in Pancreatic Beta-Cells
Thioredoxin-interacting protein (TXNIP) regulates critical biological processes including inflammation, stress and apoptosis. TXNIP is upregulated by glucose and is a critical mediator of hyperglycemia-induced beta-cell apoptosis in diabetes. In contrast, the saturated long-chain fatty acid palmitate, although toxic to the beta-cell, inhibits TXNIP expression. The mechanisms involved in the opposing effects of glucose and fatty acids on TXNIP expression are unknown. We found that both palmitate and oleate inhibited TXNIP in a rat beta-cell line and islets. Palmitate inhibition of TXNIP was independent of fatty acid beta-oxidation or esterification. AMP-activated protein kinase (AMPK) has an important role in cellular energy sensing and control of metabolic homeostasis; therefore we investigated its involvement in nutrient regulation of TXNIP. As expected, glucose inhibited whereas palmitate stimulated AMPK. Pharmacologic activators of AMPK mimicked fatty acids by inhibiting TXNIP. AMPK knockdown increased TXNIP expression in presence of high glucose with and without palmitate, indicating that nutrient (glucose and fatty acids) effects on TXNIP are mediated in part via modulation of AMPK activity. TXNIP is transcriptionally regulated by carbohydrate response element-binding protein (ChREBP). Palmitate inhibited glucose-stimulated ChREBP nuclear entry and recruitment to the Txnip promoter, thereby inhibiting Txnip transcription. We conclude that AMPK is an important regulator of Txnip transcription via modulation of ChREBP activity. The divergent effects of glucose and fatty acids on TXNIP expression result in part from their opposing effects on AMPK activity. In light of the important role of TXNIP in beta-cell apoptosis, its inhibition by fatty acids can be regarded as an adaptive/protective response to glucolipotoxicity. The finding that AMPK mediates nutrient regulation of TXNIP may have important implications for the pathophysiology and treatment of diabetes
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