Emerging priorities for HIV service delivery

Nathan Ford and co-authors discuss global priorities in the provision of HIV prevention and treatment services

Logarithmic rate dependence in deforming granular materials

Rate-independence for stresses within a granular material is a basic tenet of many models for slow dense granular flows. By contrast, logarithmic rate dependence of stresses is found in solid-on-solid friction, in geological settings, and elsewhere. In this work, we show that logarithmic rate-dependence occurs in granular materials for plastic (irreversible) deformations that occur during shearing but not for elastic (reversible) deformations, such as those that occur under moderate repetitive compression. Increasing the shearing rate, \Omega, leads to an increase in the stress and the stress fluctuations that at least qualitatively resemble what occurs due to an increase in the density. Increases in \Omega also lead to qualitative changes in the distributions of stress build-up and relaxation events. If shearing is stopped at t=0, stress relaxations occur with \sigma(t)/ \sigma(t=0) \simeq A \log(t/t_0). This collective relaxation of the stress network over logarithmically long times provides a mechanism for rate-dependent strengthening.Comment: 4 pages, 5 figures. RevTeX

Insight into mechanics of AFM tip-based nanomachining: bending of cantilevers and machined grooves

Atomic force microscope (AFM) tip-based nanomachining is currently the object of intense research investigations. Values of the load applied to the tip at the free end of the AFM cantilever probe used for nanomachining are always large enough to induce plastic deformation on the specimen surface contrary to the small load values used for the conventional contact mode AFM imaging. This study describes an important phenomenon specific for AFM nanomachining in the forward direction: under certain processing conditions, the deformed shape of the cantilever probe may change from a convex to a concave orientation. The phenomenon can principally change the depth and width of grooves machined, e.g. the grooves machined on a single crystal copper specimen may increase by 50% on average following such a change in the deformed shape of the cantilever. It is argued that this phenomenon can take place even when the AFM-based tool is operated in the so-called force-controlled mode. The study involves the refined theoretical analysis of cantilever probe bending, the analysis of experimental signals monitored during the backward and forward AFM tip-based machining and the inspection of the topography of produced grooves

The lncRNA HOTAIR transcription is controlled by HNF4α-induced chromatin topology modulation

The expression of the long noncoding RNA HOTAIR (HOX Transcript Antisense Intergenic RNA) is largely deregulated in epithelial cancers and positively correlates with poor prognosis and progression of hepatocellular carcinoma and gastrointestinal cancers. Furthermore, functional studies revealed a pivotal role for HOTAIR in the epithelial-to-mesenchymal transition, as this RNA is causal for the repressive activity of the master factor SNAIL on epithelial genes. Despite the proven oncogenic role of HOTAIR, its transcriptional regulation is still poorly understood. Here hepatocyte nuclear factor 4-α (HNF4α), as inducer of epithelial differentiation, was demonstrated to directly repress HOTAIR transcription in the mesenchymal-to epithelial transition. Mechanistically, HNF4α was found to cause the release of a chromatin loop on HOTAIR regulatory elements thus exerting an enhancer-blocking activity

SAHA-induced TRAIL-sensitisation of Multiple Myeloma cells is enhanced in 3D cell culture

Multiple Myeloma (MM) is currently incurable despite many novel therapies. Tumour Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) is a potential anti-tumour agent although effects as a single agent are limited. In this study, we investigated whether the Histone Deacetylase (HDAC) inhibitor SAHA can enhance TRAIL-induced apoptosis and target TRAIL resistance in both suspension culture, and 3D cell culture as a model of disseminated MM lesions that form in bone. The effects of SAHA and/or TRAIL in 6 Multiple Myeloma cell lines were assessed in both suspension cultures and in an Alginate-based 3D cell culture model. The effect of SAHA and/or TRAIL was assessed on apoptosis by assessment of nuclear morphology using Hoechst 33342/Propidium Iodide staining. Viable cell number was assessed by CellTiter-Glo luminescence assay, Caspase-8 and -9 activities were measured by Caspase-Glo™ assay kit. TRAIL-resistant cells were generated by culture of RPMI 8226 and NCI-H929 by acute exposure to TRAIL followed by selection of TRAIL-resistant cells. TRAIL significantly induced apoptosis in a dose-dependent manner in OPM-2, RPMI 8226, NCI-H929, U266, JJN-3 MM cell lines and ADC-1 plasma cell leukaemia cells. SAHA amplified TRAIL responses in all lines except OPM-2, and enhanced TRAIL responses were both via Caspase-8 and -9. SAHA treatment induced growth inhibition that further increased in the combination treatment with TRAIL in MM cells. The co-treatment of TRAIL and SAHA reduced viable cell numbers all cell lines. TRAIL responses were further potentiated by SAHA in 3D cell culture in NCI-H929, RPMI 8226 and U266 at lower TRAIL + SAHA doses than in suspension culture. However TRAIL responses in cells that had been selected for TRAIL resistance were not further enhanced by SAHA treatment. SAHA is a potent sensitizer of TRAIL responses in both TRAIL sensitive and resistant cell lines, in both suspension and 3D culture, however SAHA did not sensitise TRAIL-sensitive cell populations that had been selected for TRAIL-resistance from initially TRAIL-sensitive populations. SAHA may increase TRAIL sensitivity in insensitive cells, but not in cells that have specifically been selected for acquired TRAIL-resistance. [Abstract copyright: Copyright © 2017 Elsevier Inc. All rights reserved.

Global assessment of biomass suitability for ironmaking — opportunities for co-location of sustainable biomass, iron and steel production and supportive policies

Iron and steel production processes are amongst the biggest industrial contributors to the global carbon emissions, and national as well as international obligations are set to drive their significant emission reductions. One of the possible strategies is to partially substitute fossil fuels used during the iron ore reduction process by sustainably-sourced biomass. The extent of the opportunities for such fuel switching, however, varies for each country. Theoretically, biomass into ironmaking should be only supported for countries which present co-location of sustainably domestically sourced biomass in sufficient quantity, a substantial iron and steel industry and supportive national policies. Using a multi-criteria global suitability assessment approach developed in this research, the status of countries’ steel industry, sustainable biomass resources and supportive policies were examined for top 40 steel production countries via the blast furnace ironmaking route. The results highlight those countries with significant potential to use domestically sourced biomass for such application and advance the efficient use of the limited biomass resources from the global perspective. Specifically countries such as Canada, Sweden, China, USA and France were identified as the most suitable, but other countries present opportunities that could be overcome if the corresponding barriers are identified

Generation and characterisation of Friedreich ataxia YG8R mouse fibroblast and neural stem cell models

This article has been made available through the Brunel Open Access Publishing Fund.Background: Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disease caused by GAA repeat expansion in the first intron of the FXN gene, which encodes frataxin, an essential mitochondrial protein. To further characterise the molecular abnormalities associated with FRDA pathogenesis and to hasten drug screening, the development and use of animal and cellular models is considered essential. Studies of lower organisms have already contributed to understanding FRDA disease pathology, but mammalian cells are more related to FRDA patient cells in physiological terms. Methodology/Principal Findings: We have generated fibroblast cells and neural stem cells (NSCs) from control Y47R mice (9 GAA repeats) and GAA repeat expansion YG8R mice (190+120 GAA repeats). We then differentiated the NSCs in to neurons, oligodendrocytes and astrocytes as confirmed by immunocytochemical analysis of cell specific markers. The three YG8R mouse cell types (fibroblasts, NSCs and differentiated NSCs) exhibit GAA repeat stability, together with reduced expression of frataxin and reduced aconitase activity compared to control Y47R cells. Furthermore, YG8R cells also show increased sensitivity to oxidative stress and downregulation of Pgc-1α and antioxidant gene expression levels, especially Sod2. We also analysed various DNA mismatch repair (MMR) gene expression levels and found that YG8R cells displayed significant reduction in expression of several MMR genes, which may contribute to the GAA repeat stability. Conclusions/Significance: We describe the first fibroblast and NSC models from YG8R FRDA mice and we confirm that the NSCs can be differentiated into neurons and glia. These novel FRDA mouse cell models, which exhibit a FRDA-like cellular and molecular phenotype, will be valuable resources to further study FRDA molecular pathogenesis. They will also provide very useful tools for preclinical testing of frataxin-increasing compounds for FRDA drug therapy, for gene therapy, and as a source of cells for cell therapy testing in FRDA mice. © 2014 Sandi et al

Bioavailability in soils

The consumption of locally-produced vegetables by humans may be an important exposure pathway for soil contaminants in many urban settings and for agricultural land use. Hence, prediction of metal and metalloid uptake by vegetables from contaminated soils is an important part of the Human Health Risk Assessment procedure. The behaviour of metals (cadmium, chromium, cobalt, copper, mercury, molybdenum, nickel, lead and zinc) and metalloids (arsenic, boron and selenium) in contaminated soils depends to a large extent on the intrinsic charge, valence and speciation of the contaminant ion, and soil properties such as pH, redox status and contents of clay and/or organic matter. However, chemistry and behaviour of the contaminant in soil alone cannot predict soil-to-plant transfer. Root uptake, root selectivity, ion interactions, rhizosphere processes, leaf uptake from the atmosphere, and plant partitioning are important processes that ultimately govern the accumulation ofmetals and metalloids in edible vegetable tissues. Mechanistic models to accurately describe all these processes have not yet been developed, let alone validated under field conditions. Hence, to estimate risks by vegetable consumption, empirical models have been used to correlate concentrations of metals and metalloids in contaminated soils, soil physico-chemical characteristics, and concentrations of elements in vegetable tissues. These models should only be used within the bounds of their calibration, and often need to be re-calibrated or validated using local soil and environmental conditions on a regional or site-specific basis.Mike J. McLaughlin, Erik Smolders, Fien Degryse, and Rene Rietr

WNT signalling in prostate cancer

Genome sequencing and gene expression analyses of prostate tumours have highlighted the potential importance of genetic and epigenetic changes observed in WNT signalling pathway components in prostate tumours-particularly in the development of castration-resistant prostate cancer. WNT signalling is also important in the prostate tumour microenvironment, in which WNT proteins secreted by the tumour stroma promote resistance to therapy, and in prostate cancer stem or progenitor cells, in which WNT-β-catenin signals promote self-renewal or expansion. Preclinical studies have demonstrated the potential of inhibitors that target WNT receptor complexes at the cell membrane or that block the interaction of β-catenin with lymphoid enhancer-binding factor 1 and the androgen receptor, in preventing prostate cancer progression. Some WNT signalling inhibitors are in phase I trials, but they have yet to be tested in patients with prostate cancer