Direct Binding of a Hepatitis C Virus Inhibitor to the Viral Capsid Protein

Over 130 million people are infected chronically with hepatitis C virus (HCV), which, together with HBV, is the leading cause of liver disease. Novel small molecule inhibitors of Hepatitis C virus (HCV) are needed to complement or replace current treatments based on pegylated interferon and ribavirin, which are only partially successful and plagued with side-effects. Assembly of the virion is initiated by the oligomerization of core, the capsid protein, followed by the interaction with NS5A and other HCV proteins. By screening for inhibitors of core dimerization, we previously discovered peptides and drug-like compounds that disrupt interactions between core and other HCV proteins, NS3 and NS5A, and block HCV production. Here we report that a biotinylated derivative of SL209, a prototype small molecule inhibitor of core dimerization (IC50 of 2.80 µM) that inhibits HCV production with an EC50 of 3.20 µM, is capable of penetrating HCV-infected cells and tracking with core. Interaction between the inhibitors, core and other viral proteins was demonstrated by SL209–mediated affinity-isolation of HCV proteins from lysates of infected cells, or of the corresponding recombinant HCV proteins. SL209-like inhibitors of HCV core may form the basis of novel treatments of Hepatitis C in combination with other target-specific HCV drugs such as inhibitors of the NS3 protease, the NS5B polymerase, or the NS5A regulatory protein. More generally, our work supports the hypothesis that inhibitors of viral capsid formation might constitute a new class of potent antiviral agents, as was recently also shown for HIV capsid inhibitors

Scenario-Based Design Theorizing:The Case of a Digital Idea Screening Cockpit

As ever more companies encourage employees to innovate, a surplus of ideas has become reality in many organizations – often exceeding the available resources to execute them. Building on insights from a literature review and a 3-year collaboration with a banking software provider, the paper suggests a Digital Idea Screening Cockpit (DISC) to address this challenge. Following a design science research approach, it suggests a prescriptive design theory that provides practitioner-oriented guidance for implementing a DISC. The study shows that, in order to facilitate the assessment, selection, and tracking of ideas for different stakeholders, such a system needs to play a dual role: It needs to structure decision criteria and at the same be flexible to allow for creative expression. Moreover, the paper makes a case for scenario-based design theorizing by developing design knowledge via scenarios

Nasal continuous positive airway pressure improves myocardial perfusion reserve and endothelial-dependent vasodilation in patients with obstructive sleep apnea

<p>Abstract</p> <p>Background</p> <p>Obstructive sleep apnea (OSA) has been associated with cardiovascular disease (CVD), but whether OSA is an independent risk factor for CVD is controversial. The purpose of this study is to determine if patients with OSA have subclinical cardiovascular disease that is detectable by multi-modality cardiovascular imaging and whether these abnormalities improve after nasal continuous positive airway pressure (nCPAP).</p> <p>Results</p> <p>Of the 35 consecutive subjects with newly diagnosed moderate to severe OSA recruited from the Stanford Sleep Disorders Clinic, 20 patients were randomized to active vs. sham nCPAP. Active nCPAP was titrated to pressures that would prevent sleep disordered breathing based on inpatient polysomnography. OSA patients had baseline vascular function abnormalities including decreased myocardial perfusion reserve (MPR), brachial flow mediated dilation (FMD) and nitroglycerin-induced coronary vasodilation. Patients randomized to active nCPAP had improvement of MPR (1.5 ± 0.5 vs. 3.0 ± 1.3, p = 0.02) and brachial FMD (2.5% ± 5.7% vs. 9.0% ± 6.5%, p = 0.03) after treatment, but those randomized to sham nCPAP showed no significant improvement. There were no significant changes seen in chamber sizes, systolic and diastolic function, valvular function and coronary vasodilation to nitroglycerin.</p> <p>Conclusions</p> <p>Patients with moderate to severe OSA had decreased MPR and brachial FMD that improved after 3 months of nCPAP. These findings suggest that relief of apnea in OSA may improve microvascular disease and endothelial dysfunction, which may prevent the development of overt cardiovascular disease. Further study in a larger patient population may be warranted.</p

An enterprise engineering approach for the alignment of business and information technology strategy

Information systems and information technology (IS/IT, hereafter just IT) strategies usually depend on a business strategy. The alignment of both strategies improves their strategic plans. From an external perspective, business and IT alignment is the extent to which the IT strategy enables and drives the business strategy. This article reviews strategic alignment between business and IT, and proposes the use of enterprise engineering (EE) to achieve this alignment. The EE approach facilitates the definition of a formal dialog in the alignment design. In relation to this, new building blocks and life-cycle phases have been defined for their use in an enterprise architecture context. This proposal has been adopted in a critical process of a ceramic tile company for the purpose of aligning a strategic business plan and IT strategy, which are essential to support this process. © 2011 Taylor & Francis.Cuenca, L.; Boza, A.; Ortiz, A. (2011). 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Review: Information Technology and Organizational Performance: An Integrative Model of IT Business Value. MIS Quarterly, 28(2), 283. doi:10.2307/25148636Newkirk, H. E., & Lederer, A. L. (2006). Incremental and Comprehensive Strategic Information Systems Planning in an Uncertain Environment. IEEE Transactions on Engineering Management, 53(3), 380-394. doi:10.1109/tem.2006.877446Noran, O. (2003). An analysis of the Zachman framework for enterprise architecture from the GERAM perspective. Annual Reviews in Control, 27(2), 163-183. doi:10.1016/j.arcontrol.2003.09.002Noran, O. (2005). A systematic evaluation of the C4ISR AF using ISO15704 Annex A (GERAM). Computers in Industry, 56(5), 407-427. doi:10.1016/j.compind.2004.12.005Ortiz, A., Lario, F., & Ros, L. (1999). Enterprise Integration—Business Processes Integrated Management: a proposal for a methodology to develop Enterprise Integration Programs. 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Ecosystem Services in the Service-Dominant Logic Framework.

Peer reviewe

Sleep-spindle detection: crowdsourcing and evaluating performance of experts, non-experts and automated methods

Sleep spindles are discrete, intermittent patterns of brain activity observed in human electroencephalographic data. Increasingly, these oscillations are of biological and clinical interest because of their role in development, learning and neurological disorders. We used an Internet interface to crowdsource spindle identification by human experts and non-experts, and we compared their performance with that of automated detection algorithms in data from middle- to older-aged subjects from the general population. We also refined methods for forming group consensus and evaluating the performance of event detectors in physiological data such as electroencephalographic recordings from polysomnography. Compared to the expert group consensus gold standard, the highest performance was by individual experts and the non-expert group consensus, followed by automated spindle detectors. This analysis showed that crowdsourcing the scoring of sleep data is an efficient method to collect large data sets, even for difficult tasks such as spindle identification. Further refinements to spindle detection algorithms are needed for middle- to older-aged subjects