Epoxide based inhibitors of the hepatitis C virus non-structural 2 autoprotease

Hepatitis C virus (HCV) non-structural 2 (NS2) encodes an essential protease activity responsible for processing at the NS2-NS3 junction which represents an attractive antiviral target. Attempts to inhibit the NS2 autoprotease with mechanism-based protease inhibitors and substrate peptides have had limited success. We report a series of epoxide-containing small molecules capable of blocking NS2-NS3 proteolysis in vitro and demonstrate the potential for selectivity towards the NS2 autoprotease. A compound within this series was able to perturb HCV genome replication in a subgenomic replicon system only when polyprotein processing was dependent on NS2 autoprotease activity, in addition it inhibited replication of full length HCV. These findings suggest blocking HCV polyprotein processing through inhibition of the NS2 autoprotease represents a viable route to exert an antiviral effect

Reuse of Steel in the Construction Industry: Challenges and Opportunities

The construction industry plays a critical role in tackling the challenges of climate change, carbon emissions, and resource consumption. To achieve a low-emission built environment, urgent action is required to reduce the carbon emissions associated with steel production and construction processes. Reusing structural steel elements could make a significant impact in this direction, but there are five key challenges to overcome: limited material availability, maximizing different reusable materials from demolition, lack of adequate design rules and standards, high upfront costs and overlooked carbon impact of the demolition prior to construction, and the need to engage and coordinate the complete construction ecosystem. This article described these barriers and proposed solutions to them by leveraging the digital technologies and artificial intelligence. The proposed solutions aim to promote reuse practices, facilitate the development of certification and regulation for reuse, and minimize the environmental impact of steel construction. The solutions explored here can also be extended to other construction materials

Protoptype integrated design (Pride) system reference manual. Volume 2: Schema definition

An initial description of an evolving relational database schema is presented for the management of finite element model design and analysis data. The report presents a description of each relation including attribute names, data types, and definitions. The format of this report is such that future modifications and enhancements may be easily incorporated

Identification of a small molecule inhibitor of Ebolavirus genome replication and transcription using in silico screening.

Ebola virus (EBOV) causes a severe haemorrhagic fever in humans and has a mortality rate over 50%. With no licensed drug treatments available, EBOV poses a significant threat. Investigations into possible therapeutics have been severely hampered by the classification of EBOV as a BSL4 pathogen. Here, we describe a drug discovery pathway combining in silico screening of compounds predicted to bind to a hydrophobic pocket on the nucleoprotein (NP); with a robust and rapid EBOV minigenome assay for inhibitor validation at BSL2. One compound (MCCB4) was efficacious (EC50 4.8 μM), exhibited low cytotoxicity (CC50 > 100 μM) and was specific, with no effect on either a T7 RNA polymerase driven firefly luciferase or a Bunyamwera virus minigenome. Further investigations revealed that this small molecule inhibitor was able to outcompete established replication complexes, an essential aspect for a potential EBOV treatment

Consideration of Shared Decision Making in Nursing: A Review of Clinicians’ Perceptions and Interventions

As the number of individuals with chronic illness increases so has the need for strategies to enable nurses to engage them effectively in daily management of their conditions. Shared decision making between patients and nurses is one approach frequently discussed in the literature. This paper reviews recent studies of shared decision making and the meaning of findings for the nurse-patient relationship. Patients likely to prefer to engage in shared decision making are younger and have higher levels of education. However, there is a lack of evidence for the effect of shared decision making on patient outcomes. Further, studies are needed to examine shared decision making when the patient is a child. Nurses are professionally suited to engage their patients fully in treatment plans. More evidence for how shared decision making affects outcomes and how nurses can successfully achieve such engagement is needed

The Growing Role of Electron Microscopy in Anti-parasitic Drug Discovery

Parasitic diseases are a huge burden on human health causing significant morbidity and mortality. However, parasitic structure based drug discovery programmes have been hindered by a lack of high resolution structural information from parasitic derived proteins and have largely relied upon homology models from mammalian systems. The recent renaissance in electron microscopy (EM) has caused a dramatic rise in the number of structures being determined at high resolution and subsequently enabled it to be thought of as a tool in drug discovery. In this review, we discuss the challenges associated with the structural determination of parasitic proteins. We then discuss the reasons behind the resurgence in EM, how it may overcome some of these challenges and provide examples of EM derived parasitic protein structures. Finally, we discuss the challenges which EM needs to overcome before it is used as a mainstream technique in parasitic drug discovery