Anti-HIV-1 activity of cellulose acetate phthalate: Synergy with soluble CD4 and induction of "dead-end" gp41 six-helix bundles

BACKGROUND: Cellulose acetate phthalate (CAP), a promising candidate microbicide for prevention of sexual transmission of the human immunodeficiency virus type 1 (HIV-1) and other sexually transmitted disease (STD) pathogens, was shown to inactivate HIV-1 and to block the coreceptor binding site on the virus envelope glycoprotein gp120. It did not interfere with virus binding to CD4. Since CD4 is the primary cellular receptor for HIV-1, it was of interest to study CAP binding to HIV-1 complexes with soluble CD4 (sCD4) and its consequences, including changes in the conformation of the envelope glycoprotein gp41 within virus particles. METHODS: Enzyme-linked immunosorbent assays (ELISA) were used to study CAP binding to HIV-1-sCD4 complexes and to detect gp41 six-helix bundles accessible on virus particles using antibodies specific for the α-helical core domain of gp41. RESULTS: 1) Pretreatment of HIV-1 with sCD4 augments subsequent binding of CAP; 2) there is synergism between CAP and sCD4 for inhibition of HIV-1 infection; 3) treatment of HIV-1 with CAP induced the formation of gp41 six-helix bundles. CONCLUSIONS: CAP and sCD4 bind to distinct sites on HIV-1 IIIB and BaL virions and their simultaneous binding has profound effects on virus structure and infectivity. The formation of gp41 six-helical bundles, induced by CAP, is known to render the virus incompetent for fusion with target cells thus preventing infection

Thin Current Sheet Behind the Dipolarization Front

We report a unique conjugate observation of fast flows and associated current sheet disturbances in the near-Earth magnetotail by MMS (Magnetospheric Multiscale) and Cluster preceding a positive bay onset of a small substorm at ∼14:10 UT, September 8, 2018. MMS and Cluster were located both at X ∼ −14 RE. A dipolarization front (DF) of a localized fast flow was detected by Cluster and MMS, separated in the dawn-dusk direction by ∼4 RE, almost simultaneously. Adiabatic electron acceleration signatures revealed from the comparison of the energy spectra confirm that both spacecraft encounter the same DF. We analyzed the change in the current sheet structure based on multi-scale multi-point data analysis. The current sheet thickened during the passage of DF, yet, temporally thinned subsequently associated with another flow enhancement centered more on the dawnward side of the initial flow. MMS and Cluster observed intense perpendicular and parallel current in the off-equatorial region mainly during this interval of the current sheet thinning. Maximum field-aligned currents both at MMS and Cluster are directed tailward. Detailed analysis of MMS data showed that the intense field-aligned currents consisted of multiple small-scale intense current layers accompanied by enhanced Hall-currents in the dawn-dusk flow-shear region. We suggest that the current sheet thinning is related to the flow bouncing process and/or to the expansion/activation of reconnection. Based on these mesoscale and small-scale multipoint observations, 3D evolution of the flow and current-sheet disturbances was inferred preceding the development of a substorm current wedge

The challenges of communicating research evidence in practice: perspectives from UK health visitors and practice nurses

<p>Background: Health practitioners play a pivotal role in providing patients with up-to-date evidence and health information. Evidence-based practice and patient-centred care are transforming the delivery of healthcare in the UK. Health practitioners are increasingly balancing the need to provide evidence-based information against that of facilitating patient choice, which may not always concur with the evidence base. There is limited research exploring how health practitioners working in the UK, and particularly those more autonomous practitioners such as health visitors and practice nurses working in community practice settings, negotiate this challenge. This research provides a descriptive account of how health visitors and practice nurses negotiate the challenges of communicating health information and research evidence in practice.</p> <p>Methods: A total of eighteen in-depth telephone interviews were conducted in the UK between September 2008 and May 2009. The participants comprised nine health visitors and nine practice nurses, recruited via adverts on a nursing website, posters at a practitioner conference and through recommendation. Thematic analysis, with a focus on constant comparative method, was used to analyse the data.</p> <p>Results: The data were grouped into three main themes: communicating evidence to the critically-minded patient; confidence in communicating evidence; and maintaining the integrity of the patient-practitioner relationship. These findings highlight some of the daily challenges that health visitors and practice nurses face with regard to the complex and dynamic nature of evidence and the changing attitudes and expectations of patients. The findings also highlight the tensions that exist between differing philosophies of evidence-based practice and patient-centred care, which can make communicating about evidence a daunting task.</p> <p>Conclusions: If health practitioners are to be effective at communicating research evidence, we suggest that more research and resources need to be focused on contextual factors, such as how research evidence is negotiated, appraised and communicated within the dynamic patient-practitioner relationship.</p&gt

Theorems on existence and global dynamics for the Einstein equations

This article is a guide to theorems on existence and global dynamics of solutions of the Einstein equations. It draws attention to open questions in the field. The local-in-time Cauchy problem, which is relatively well understood, is surveyed. Global results for solutions with various types of symmetry are discussed. A selection of results from Newtonian theory and special relativity that offer useful comparisons is presented. Treatments of global results in the case of small data and results on constructing spacetimes with prescribed singularity structure or late-time asymptotics are given. A conjectural picture of the asymptotic behaviour of general cosmological solutions of the Einstein equations is built up. Some miscellaneous topics connected with the main theme are collected in a separate section.Comment: Submitted to Living Reviews in Relativity, major update of Living Rev. Rel. 5 (2002)

A fast and low-power microelectromechanical system-based non-volatile memory device

Several new generation memory devices have been developed to overcome the low performance of conventional silicon-based flash memory. In this study, we demonstrate a novel non-volatile memory design based on the electromechanical motion of a cantilever to provide fast charging and discharging of a floating-gate electrode. The operation is demonstrated by using an electromechanical metal cantilever to charge a floating gate that controls the charge transport through a carbon nanotube field-effect transistor. The set and reset currents are unchanged after more than 11 h constant operation. Over 500 repeated programming and erasing cycles were demonstrated under atmospheric conditions at room temperature without degradation. Multinary bit programming can be achieved by varying the voltage on the cantilever. The operation speed of the device is faster than a conventional flash memory and the power consumption is lower than other memory devices

Targeted antitumour therapy – future perspectives

The advent of targeted therapy presents an unprecedented opportunity for advances in the treatment of cancer. A key challenge will be to translate the undoubted promise of targeted agents into tangible clinical benefits. Achieving this goal is likely to be dependent upon a number of factors. These include continued research to improve our understanding of the heterogeneity and complexity of the tumour microenvironment; refinement of clinical trial design to incorporate nontraditional end points such as the optimum biological dose and health-related quality of life; and the use of technological advancements in proteomics, genomics and biomarker development to better predict tumour types and patient subsets that may be particularly responsive to treatment, as well as enable a more accurate assessment of drug effect at the molecular level. In summary, the future success of targeted agents will require an integrated multidisciplinary approach involving all stakeholders