Topical application of entry inhibitors as "virustats" to prevent sexual transmission of HIV infection

With the continuing march of the AIDS epidemic and little hope for an effective vaccine in the near future, work to develop a topical strategy to prevent HIV infection is increasingly important. This stated, the track record of large scale "microbicide" trials has been disappointing with nonspecific inhibitors either failing to protect women from infection or even increasing HIV acquisition. Newer strategies that target directly the elements needed for viral entry into cells have shown promise in non-human primate models of HIV transmission and as these agents have not yet been broadly introduced in regions of highest HIV prevalence, they are particularly attractive for prophylaxis. We review here the agents that can block HIV cellular entry and that show promise as topical strategies or "virustats" to prevent mucosal transmission of HIV infectio

Caveolins/caveolae protect adipocytes from fatty acid-mediated lipotoxicity

Mice and humans lacking functional caveolae are dyslipidemic and have reduced fat stores and smaller fat cells. To test the role of caveolins/caveolae in maintaining lipid stores and adipocyte integrity, we compared lipolysis in caveolin-1 (Cav1)-null fat cells to that in cells reconstituted for caveolae by caveolin-1 re-expression. We find that the Cav1-null cells have a modestly enhanced rate of lipolysis and reduced cellular integrity compared with reconstituted cells as determined by the release of lipid metabolites and lactic dehydrogenase, respectively, into the media. There are no apparent differences in the levels of lipolytic enzymes or hormonally stimulated phosphorylation events in the two cell lines. In addition, acute fasting, which dramatically raises circulating fatty acid levels in vivo, causes a significant upregulation of caveolar protein constituents. These results are consistent with the hypothesis that caveolae protect fat cells from the lipotoxic effects of elevated levels fatty acids, which are weak detergents at physiological pH, by virtue of the property of caveolae to form detergentresistant membrane domains

Exact half-BPS Type IIB interface solutions I: Local solution and supersymmetric Janus

The complete Type IIB supergravity solutions with 16 supersymmetries are obtained on the manifold $AdS_4 \times S^2 \times S^2 \times \Sigma$ with $SO(2,3) \times SO(3) \times SO(3)$ symmetry in terms of two holomorphic functions on a Riemann surface $\Sigma$, which generally has a boundary. This is achieved by reducing the BPS equations using the above symmetry requirements, proving that all solutions of the BPS equations solve the full Type IIB supergravity field equations, mapping the BPS equations onto a new integrable system akin to the Liouville and Sine-Gordon theories, and mapping this integrable system to a linear equation which can be solved exactly. Amongst the infinite class of solutions, a non-singular Janus solution is identified which provides the AdS/CFT dual of the maximally supersymmetric Yang-Mills interface theory discovered recently. The construction of general classes of globally non-singular solutions, including fully back-reacted $AdS_5 \times S^5$ and supersymmetric Janus doped with D5 and/or NS5 branes, is deferred to a companion paper.Comment: LaTeX, 69 pages, 3 figures, v2: references adde

Designing an e-learning tool to support health practitioners caring for patients taking multiple medications

Background: Population ageing and improvements in healthcare mean the number of people living with two or more chronic conditions, or ‘multimorbidity’, is rapidly increasing. This presents a challenge to current disease-specific care delivery models. Adherence to prescribed medications appears particularly challenging for individuals living with multimorbidity, given the often-complex drug regimens required to treat multiple conditions. Poor adherence is associated with increased mortality, as well as wasted healthcare resources. Supporting medication adherence is a key priority for general practitioners (GPs) and practice nurses as they are responsible for much of the disease counselling and medication prescribing associated with chronic illnesses. Despite this, practical resources and training for health practitioners on how to promote adherence in practice is currently lacking. Informed by the principles of patient and public involvement (PPI), the aim of this research was to develop a patient informed e-learning resource to help GPs and nurses support medication adherence. Method: Utilising collective intelligence (CI) and scenario-based design (SBD) methodology, input was gathered from key stakeholders in medication adherence to gain insights into barriers to supporting people with multimorbidity who are receiving polypharmacy, strategies for overcoming these barriers, and user needs and requirements to inform the design of the e-learning tool. Results: In total, 67 barriers to supporting people who are taking multiple medications were identified across 8 barrier categories. 162 options for overcoming the identified barriers were then generated. This data was used in the design of a flexible e-learning tool for continuous professional development, that has been integrated into general practice and clinical education programmes as a supportive tool. Conclusions: Using CI and SBD methodology was an effective way of facilitating collaboration, idea-generation, and the co-creation of design solutions amongst a diverse group of stakeholders. This approach could be usefully applied to address other complex healthcare-related challenges

Dynamics of Immune Reconstitution and Activation Markers in HIV+ Treatment-Naïve Patients Treated with Raltegravir, Tenofovir Disoproxil Fumarate and Emtricitabine

Background: The dynamics of CD4+ T cell reconstitution and changes in immune activation and inflammation in HIV-1 disease following initiation of antiretroviral therapy (ART) are incompletely defined and their underlying mechanisms poorly understood. Methods: Thirty-nine treatment-naïve patients were treated with raltegravir, tenofovir DF and emtricitabine. Immunologic and inflammatory indices were examined in persons with sustained virologic control during 48 weeks of therapy. Results: Initiation of ART increased CD4+ T cell numbers and decreased activation and cell cycle entry among CD4+ and CD8+ T cell subsets, and attenuated markers of coagulation (D-dimer levels) and inflammation (IL-6 and TNFr1). These indices decayed at different rates and almost all remained elevated above levels measured in HIV-seronegatives through 48 weeks of viral control. Greater first and second phase CD4+ T cell restoration was related to lower T cell activation and cell cycling at baseline, to their decay with treatment, and to baseline levels of selected inflammatory indices, but less so to their changes on therapy. Conclusions: ART initiation results in dynamic changes in viral replication, T cell restoration, and indices of immune activation, inflammation, and coagulation. These findings suggest that determinants of T cell activation/cycling and inflammation/coagulation may have distinguishable impact on immune homeostasis. Trial Registration Clinicaltrials.gov NCT0066097

Cholesterol Depletion in Adipocytes Causes Caveolae Collapse Concomitant with Proteosomal Degradation of Cavin-2 in a Switch-Like Fashion

Caveolae, little caves of cell surfaces, are enriched in cholesterol, a certain level of which is required for their structural integrity. Here we show in adipocytes that cavin-2, a peripheral membrane protein and one of 3 cavin isoforms present in caveolae from non-muscle tissue, is degraded upon cholesterol depletion in a rapid fashion resulting in collapse of caveolae. We exposed 3T3-L1 adipocytes to the cholesterol depleting agent methyl-β-cyclodextrin, which results in a sudden and extensive degradation of cavin-2 by the proteasome and a concomitant movement of cavin-1 from the plasma membrane to the cytosol along with loss of caveolae. The recovery of cavin-2 at the plasma membrane is cholesterol-dependent and is required for the return of cavin-1 from the cytosol to the cell surface and caveolae restoration. Expression of shRNA directed against cavin-2 also results in a cytosolic distribution of cavin-1 and loss of caveolae. Taken together, these data demonstrate that cavin-2 functions as a cholesterol responsive component of caveolae that is required for cavin-1 localization to the plasma membrane, and caveolae structural integrity

Entanglement entropy of Wilson surfaces from bubbling geometries in M-theory

We consider solutions of eleven-dimensional supergravity constructed in [1,2] that are half-BPS, locally asymptotic to $AdS_7\times S^4$ and are the holographic dual of heavy Wilson surfaces in the six-dimensional $(2,0)$ theory. Using these bubbling solutions we calculate the holographic entanglement entropy for a spherical entangling surface in the presence of a planar Wilson surface. In addition, we calculate the holographic stress tensor and, by evaluating the on-shell supergravity action, the expectation value of the Wilson surface operator.Comment: 42 pages, 4 figures, v2: minor modification

MURC/Cavin-4 and cavin family members form tissue-specific caveolar complexes

Polymerase I and transcript release factor (PTRF)/Cavin is a cytoplasmic protein whose expression is obligatory for caveola formation. Using biochemistry and fluorescence resonance energy transfer–based approaches, we now show that a family of related proteins, PTRF/Cavin-1, serum deprivation response (SDR)/Cavin-2, SDR-related gene product that binds to C kinase (SRBC)/Cavin-3, and muscle-restricted coiled-coil protein (MURC)/Cavin-4, forms a multiprotein complex that associates with caveolae. This complex can constitutively assemble in the cytosol and associate with caveolin at plasma membrane caveolae. Cavin-1, but not other cavins, can induce caveola formation in a heterologous system and is required for the recruitment of the cavin complex to caveolae. The tissue-restricted expression of cavins suggests that caveolae may perform tissue-specific functions regulated by the composition of the cavin complex. Cavin-4 is expressed predominantly in muscle, and its distribution is perturbed in human muscle disease associated with Caveolin-3 dysfunction, identifying Cavin-4 as a novel muscle disease candidate caveolar protein

Complexity in the binding of minor groove agents: netropsin has two thermodynamically different DNA binding modes at a single site

Structural results with minor groove binding agents, such as netropsin, have provided detailed, atomic level views of DNA molecular recognition. Solution studies, however, indicate that there is complexity in the binding of minor groove agents to a single site. Netropsin, for example, has two DNA binding enthalpies in isothermal titration calorimetry (ITC) experiments that indicate the compound simultaneously forms two thermodynamically different complexes at a single AATT site. Two proposals for the origin of this unusual observation have been developed: (i) two different bound species of netropsin at single binding sites and (ii) a netropsin induced DNA hairpin to duplex transition. To develop a better understanding of DNA recognition complexity, the two proposals have been tested with several DNAs and the methods of mass spectrometry (MS), polyacrylamide gel electrophoresis (PAGE) and nuclear magnetic resonance spectroscopy in addition to ITC. All of the methods with all of the DNAs investigated clearly shows that netropsin forms two different complexes at AATT sites, and that the proposal for an induced hairpin to duplex transition in this system is incorrect

Case study for model validation : assessing a model for thermal decomposition of polyurethane foam.

A case study is reported to document the details of a validation process to assess the accuracy of a mathematical model to represent experiments involving thermal decomposition of polyurethane foam. The focus of the report is to work through a validation process. The process addresses the following activities. The intended application of mathematical model is discussed to better understand the pertinent parameter space. The parameter space of the validation experiments is mapped to the application parameter space. The mathematical models, computer code to solve the models and its (code) verification are presented. Experimental data from two activities are used to validate mathematical models. The first experiment assesses the chemistry model alone and the second experiment assesses the model of coupled chemistry, conduction, and enclosure radiation. The model results of both experimental activities are summarized and uncertainty of the model to represent each experimental activity is estimated. The comparison between the experiment data and model results is quantified with various metrics. After addressing these activities, an assessment of the process for the case study is given. Weaknesses in the process are discussed and lessons learned are summarized