Inhibition of the multidrug resistance P-glycoprotein: Time for a change of strategy?

P-glycoprotein (P-gp) is a key player in the multidrug-resistant phenotype in cancer. The protein confers resistance by mediating the ATP-dependent efflux of an astonishing array of anticancer drugs. Its broad specificity has been the subject of numerous attempts to inhibit the protein and restore the efficacy of anticancer drugs. The general strategy has been to develop compounds that either compete with anticancer drugs for transport or act as direct inhibitors of P-gp. Despite considerable in vitro success, there are no compounds currently available to "block" P-gp-mediated resistance in the clinic. The failure may be attributed to toxicity, adverse drug interaction, and numerous pharmacokinetic issues. This review provides a description of several alternative approaches to overcome the activity of P-gp in drug-resistant cells. These include 1) drugs that specifically target resistant cells, 2) novel nanotechnologies to provide high-dose, targeted delivery of anticancer drugs, 3) compounds that interfere with nongenomic transfer of resistance, and 4) approaches to reduce the expression of P-gp within tumors. Such approaches have been developed through the pursuit of greater understanding of resistance mediators such as P-gp, and they show considerable potential for further application. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics

Field dependence of the vortex core size in a multi-band superconductor

The magnetic field dependence of the vortex core size in the multi-band superconductor NbSe2 has been determined from muon spin rotation measurements. The spatially extended nature of the quasiparticle core states associated with the smaller gap leads to a rapid field-induced shrinkage of the core size at low fields, while the more tightly bound nature of the states associated with the larger gap leads to a field-independent core size for fields greater than 4 kOe. A simple model is proposed for the density of delocalized core states that establishes a direct relationship between the field-induced reduction of the vortex core size and the corresponding enhancement of the electronic thermal conductivity. We show that this model accurately describes both NbSe2 and the single-band superconductor V3Si.Comment: 4 pages, 4 figures. Version accepted for publication in Physical Review Letter

Structural properties of crumpled cream layers

The cream layer is a complex heterogeneous material of biological origin which forms spontaneously at the air-milk interface. Here, it is studied the crumpling of a single cream layer packing under its own weight at room temperature in three-dimensional space. The structure obtained in these circumstances has low volume fraction and anomalous fractal dimensions. Direct means and noninvasive NMR imaging technique are used to investigate the internal and external structure of these systems.Comment: 9 pages, 4 figures, accepted in J. Phys. D: Appl. Phy

Electromyography‐related pain: Muscle selection is the key modifiable study characteristic

Introduction : The aim of this study was to estimate the effects of patient, provider, and study characteristics on electromyography (EMG)‐related pain. Methods : Patients undergoing EMG rated their EMG‐related pain after each muscle was studied on a 100‐point visual analog scale (VAS). Investigators recorded the order in which the muscles were sampled, the total time spent with the needle in each muscle, and whether electrical endplate noise was noted. Results : A total of 1781 muscles were studied in 304 patients. Eleven muscles were associated with significantly more or less pain than the others. Endplate noise was associated with more pain (5.4 mm, 95% CI 2.8–7.0). There was a small, but significant effect from needling time (0.02 mm, 95% CI 0.00–0.04). Conclusions : Among factors that electromyographers can control, muscle selection has the greatest impact on pain. Our data include an extensive list of muscle‐specific EMG‐related pain scores. Provider and other study characteristics have little or no impact on EMG‐related pain. Muscle Nerve 49:570–574, 2014Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/106736/1/mus23974.pd

Spin-glass state of vortices in YBa2Cu3Oy and La2-xSrxCuO4 below the metal-to-insulator crossover

Highly disordered magnetism confined to individual weakly interacting vortices is detected by muon spin rotation in two different families of high-transition-temperature superconductors, but only in samples on the low-doping side of the low-temperature normal state metal-to-insulator crossover (MIC). The results support an extended quantum phase transition (QPT) theory of competing magnetic and superconducting orders that incorporates the coupling between CuO2 planes. Contrary to what has been inferred from previous experiments, the static magnetism that coexists with superconductivity near the field-induced QPT is not ordered. Our findings unravel the mystery of the MIC and establish that the normal state of high-temperature superconductors is ubiquitously governed by a magnetic quantum critical point in the superconducting phase.Comment: 9 pages, 9 figure

The role of cell-cell adhesion in wound healing

We present a stochastic model which describes fronts of cells invading a wound. In the model cells can move, proliferate, and experience cell-cell adhesion. We find several qualitatively different regimes of front motion and analyze the transitions between them. Above a critical value of adhesion and for small proliferation large isolated clusters are formed ahead of the front. This is mapped onto the well-known ferromagnetic phase transition in the Ising model. For large adhesion, and larger proliferation the clusters become connected (at some fixed time). For adhesion below the critical value the results are similar to our previous work which neglected adhesion. The results are compared with experiments, and possible directions of future work are proposed.Comment: to appear in Journal of Statistical Physic

Climate action for health and wellbeing in cities: a protocol for the systematic development of a database of peer-reviewed studies using machine learning methods [version 1; peer review: awaiting peer review]

Home Browse Climate action for health and wellbeing in cities: a protocol for... ALL METRICS 99 VIEWS 11 DOWNLOADS Get PDF Get XML Cite Export Track Email Share ▬ STUDY PROTOCOL Climate action for health and wellbeing in cities: a protocol for the systematic development of a database of peer-reviewed studies using machine learning methods [version 1; peer review: awaiting peer review] Kristine Belesova https://orcid.org/0000-0002-6160-50411, Max Callaghan https://orcid.org/0000-0001-8292-87582, Jan C Minx https://orcid.org/0000-0002-2862-01782, Felix Creutzig2, Catalina Turcu https://orcid.org/0000-0003-2663-25863, Emma Hutchinson1, James Milner1, Melanie Crane https://orcid.org/0000-0002-3058-22114, Andy Haines https://orcid.org/0000-0002-8053-46051, Michael Davies5, Paul Wilkinson1 Author details 1 Department of Public Health, Environments and Society and Centre on Climate Change and Planetary Health, London School of Hygiene and Tropical Medicine, London, WC1H 9SH, UK 2 Mercator Research Institute on Global Commons and Climate Change, Berlin, 10829, Germany 3 Bartlett School of Planning, University College London, London, WC1H 0QB, UK 4 Charles Perkins Centre, Sydney School of Public Health, University of Sydney, Sydney, Australia 5 Bartlett School Environment, Energy & Resources, University College London, London, WC1H 0QB, UK Kristine Belesova Roles: Conceptualization, Data Curation, Investigation, Methodology, Supervision, Writing – Original Draft Preparation, Writing – Review & Editing Max Callaghan Roles: Data Curation, Investigation, Methodology, Software, Writing – Review & Editing Jan C Minx Roles: Conceptualization, Investigation, Methodology, Software, Writing – Review & Editing Felix Creutzig Roles: Conceptualization, Investigation, Methodology, Software, Writing – Review & Editing Catalina Turcu Roles: Investigation, Methodology, Writing – Review & Editing Emma Hutchinson Roles: Investigation, Methodology, Writing – Review & Editing James Milner Roles: Methodology, Writing – Review & Editing Melanie Crane Roles: Methodology, Writing – Review & Editing Andy Haines Roles: Conceptualization, Funding Acquisition, Methodology, Supervision, Writing – Review & Editing Michael Davies Roles: Conceptualization, Funding Acquisition, Methodology, Writing – Review & Editing Paul Wilkinson Roles: Conceptualization, Funding Acquisition, Methodology, Supervision, Writing – Review & Editing Abstract Cities produce more than 70% of global greenhouse gas emissions. Action by cities is therefore crucial for climate change mitigation as well as for safeguarding the health and wellbeing of their populations under climate change. Many city governments have made ambitious commitments to climate change mitigation and adaptation and implemented a range of actions to address them. However, a systematic record and synthesis of the findings of evaluations of the effect of such actions on human health and wellbeing is currently lacking. This, in turn, impedes the development of robust knowledge on what constitutes high-impact climate actions of benefit to human health and wellbeing, which can inform future action plans, their implementation and scale-up. The development of a systematic record of studies reporting climate and health actions in cities is made challenging by the broad landscape of relevant literature scattered across many disciplines and sectors, which is challenging to effectively consolidate using traditional literature review methods. This protocol reports an innovative approach for the systematic development of a database of studies of climate change mitigation and adaptation actions implemented in cities, and their benefits (or disbenefits) for human health and wellbeing, derived from peer-reviewed academic literature. Our approach draws on extensive tailored search strategies and machine learning methods for article classification and tagging to generate a database for subsequent systematic reviews addressing questions of importance to urban decision-makers on climate actions in cities for human health and wellbeing

Penetration depth, multiband superconductivity, and absence of muon-induced perturbation in superconducting PrOs4_{4}Sb12_{12}

Transverse-field muon spin rotation ($\mu$SR) experiments in the heavy-fermion superconductor PrOs$_{4}$Sb$_{12}$ ($T_{c}=1.85$ K) suggest that the superconducting penetration depth $\lambda(T)$ is temperature-independent at low temperatures, consistent with a gapped quasiparticle excitation spectrum. In contrast, radiofrequency (rf) inductive measurements yield a stronger temperature dependence of $\lambda(T)$, indicative of point nodes in the gap. This discrepancy appears to be related to the multiband structure of PrOs$_{4}$Sb$_{12}$. Muon Knight shift measurements in PrOs$_{4}$Sb$_{12}$ suggest that the perturbing effect of the muon charge on the neighboring Pr$^{3+}$ crystalline electric field is negligibly small, and therefore is unlikely to cause the difference between the $\mu$SR and rf results.Comment: 10 pages, 7 figure

Diffusion NMR characterization of catalytic silica supports:a tortuous path

Mesoporous silicas have found widespread application within the field of heterogeneous catalysis. Acid functionalization of such materials, through one-pot or postsynthetic grafting of sulfonic acid groups, imparts activity for fatty acid esterification, with the studious choice of pore geometry facilitating significant rate enhancements. Diffusion NMR has been utilized for the first time to characterize the structure of mesoporous silicas through the transport behavior of systematically related carboxylic acids confined within their mesopore networks. A reduced diffusion coefficient is obtained for species constrained within the 3-dimensional interconnected pores of KIT-6 relative to the 2-dimensional noninterconnected pore channels of SBA-15. The effective tortuosity of both porous silicas increases with the acid chain length, with the diffusion behavior of long-chain acids dominated by the alkyl chain and silica architecture. Carboxylic acid diffusion within these two pore networks is unlikely to be rate-limiting in catalytic esterification over sulfonic acid silica analogues. Physicochemical insights from diffusion NMR will aid the future design of optimal silica architectures for catalytic applications