Multi-functionalised graphene nanoflakes as tumour-targeting theranostic drug-delivery vehicles

Graphene nanoflakes (GNFs) consist of a graphene sheet approximately 30 nm in diameter with a pristine aromatic system and an edge terminated with carboxylic acid groups. Their high water solubility and relative ease of functionalisation using carboxylate chemistry means that GNFs are potential scaffolds for the synthesis of theranostic agents. In this work, GNFs were multi-functionalised with derivatives of (i) a peptide-based Glu-NH-C(O)-NH-Lys ligand that binds prostate-specific membrane antigen (PSMA), (ii) a potent anti-mitotic drug (R)-ispinesib, (iii) the chelate desferrioxamine B (DFO), and (iv) an albumin-binding tag reported to extend pharmacokinetic half-life in vivo. Subsequent 68Ga radiochemistry and experiments in vitro and in vivo were used to evaluate the performance of GNFs in theranostic drug design. Efficient 68Ga-radiolabelling was achieved and the particle-loading of (R)-ispinesib and Glu-NH-C(O)-NH-Lys was confirmed using cellular assays. Using dose–response curves and FACS analysis it was shown that GNFs loaded with (R)-ispinesib inhibited the kinesin spindle protein (KSP) and induced G2/M-phase cell cycle arrest. Cellular uptake and blocking experiments demonstrated that GNFs functionalised with the Glu-NH-C(O)-NH-Lys ligand showed specificity toward PSMA expressing cells (LNCaP). The distribution profile and excretion rates of 68Ga-radiolabelled GNFs in athymic nude mice was evaluated using time–activity curves derived from dynamic positron-emission tomography (PET). Image analysis indicated that GNFs have low accumulation and retention in background tissue, with rapid renal clearance. In summary, our study shows that GNFs are suitable candidates for use in theranostic drug design

In-flight calibration of STEREO-B/WAVES antenna system

The STEREO/WAVES (SWAVES) experiment on board the two STEREO spacecraft (Solar Terrestrial Relations Observatory) launched on 25 October 2006 is dedicated to the measurement of the radio spectrum at frequencies between a few kilohertz and 16 MHz. The SWAVES antenna system consists of 6 m long orthogonal monopoles designed to measure the electric component of the radio waves. With this configuration direction finding of radio sources and polarimetry (analysis of the polarization state) of incident radio waves is possible. For the evaluation of the SWAVES data the receiving properties of the antennas, distorted by the radiation coupling with the spacecraft body and other onboard devices, have to be known accurately. In the present context, these properties are described by the antenna effective length vectors. We present the results of an in-flight calibration of the SWAVES antennas using the observations of the nonthermal terrestrial auroral kilometric radiation (AKR) during STEREO roll maneuvers in an early stage of the mission. A least squares method combined with a genetic algorithm was applied to find the effective length vectors of the STEREO Behind (STEREO-B)/WAVES antennas in a quasi-static frequency range ($L_{antenna} \ll \lambda_{wave}$) which fit best to the model and observed AKR intensity profiles. The obtained results confirm the former SWAVES antenna analysis by rheometry and numerical simulations. A final set of antenna parameters is recommended as a basis for evaluations of the SWAVES data

A mesocosm experiment investigating the effects of substratum quality and wave exposure on the survival of fish eggs

In a mesocosm experiment, the attachment of bream (Abramis brama) eggs to spawning substrata with and without periphytic biofilm coverage and their subsequent survival with and without low-intensity wave exposure were investigated. Egg attachment was reduced by 73% on spawning substrata with a natural periphytic biofilm, compared to clean substrata. Overall, this initial difference in egg numbers persisted until hatching. The difference in egg numbers was even increased in the wave treatment, while it was reduced in the no-wave control treatment. Exposure to a low-intensity wave regime affected egg development between the two biofilm treatments differently. Waves enhanced egg survival on substrata without a biofilm but reduced the survival of eggs on substrata with biofilm coverage. In the treatment combining biofilm-covered substrata and waves, no attached eggs survived until hatching. In all treatments, more than 75% of the eggs became detached from the spawning substrata during the egg incubation period, an

On the Nature of the Phase Transition in SU(N), Sp(2) and E(7) Yang-Mills theory

We study the nature of the confinement phase transition in d=3+1 dimensions in various non-abelian gauge theories with the approach put forward in [1]. We compute an order-parameter potential associated with the Polyakov loop from the knowledge of full 2-point correlation functions. For SU(N) with N=3,...,12 and Sp(2) we find a first-order phase transition in agreement with general expectations. Moreover our study suggests that the phase transition in E(7) Yang-Mills theory also is of first order. We find that it is weaker than for SU(N). We show that this can be understood in terms of the eigenvalue distribution of the order parameter potential close to the phase transition.Comment: 15 page

New Debris Disks Around Nearby Main Sequence Stars: Impact on The Direct Detection of Planets

Using the MIPS instrument on the Spitzer telescope, we have searched for infrared excesses around a sample of 82 stars, mostly F, G, and K main-sequence field stars, along with a small number of nearby M stars. These stars were selected for their suitability for future observations by a variety of planet-finding techniques. These observations provide information on the asteroidal and cometary material orbiting these stars - data that can be correlated with any planets that may eventually be found. We have found significant excess 70um emission toward 12 stars. Combined with an earlier study, we find an overall 70um excess detection rate of $13 \pm 3$% for mature cool stars. Unlike the trend for planets to be found preferentially toward stars with high metallicity, the incidence of debris disks is uncorrelated with metallicity. By newly identifying 4 of these stars as having weak 24um excesses (fluxes $\sim$10% above the stellar photosphere), we confirm a trend found in earlier studies wherein a weak 24um excess is associated with a strong 70um excess. Interestingly, we find no evidence for debris disks around 23 stars cooler than K1, a result that is bolstered by a lack of excess around any of the 38 K1-M6 stars in 2 companion surveys. One motivation for this study is the fact that strong zodiacal emission can make it hard or impossible to detect planets directly with future observatories like the {\it Terrestrial Planet Finder (TPF)}. The observations reported here exclude a few stars with very high levels of emission, $>$1,000 times the emission of our zodiacal cloud, from direct planet searches. For the remainder of the sample, we set relatively high limits on dust emission from asteroid belt counterparts

Rationale, design and conduct of a randomised controlled trial evaluating a primary care-based complex intervention to improve the quality of life of heart failure patients: HICMan (Heidelberg Integrated Case Management) : study protocol

Background: Chronic congestive heart failure (CHF) is a complex disease with rising prevalence, compromised quality of life (QoL), unplanned hospital admissions, high mortality and therefore high burden of illness. The delivery of care for these patients has been criticized and new strategies addressing crucial domains of care have been shown to be effective on patients' health outcomes, although these trials were conducted in secondary care or in highly organised Health Maintenance Organisations. It remains unclear whether a comprehensive primary care-based case management for the treating general practitioner (GP) can improve patients' QoL. Methods/Design: HICMan is a randomised controlled trial with patients as the unit of randomisation. Aim is to evaluate a structured, standardized and comprehensive complex intervention for patients with CHF in a 12-months follow-up trial. Patients from intervention group receive specific patient leaflets and documentation booklets as well as regular monitoring and screening by a prior trained practice nurse, who gives feedback to the GP upon urgency. Monitoring and screening address aspects of disease-specific selfmanagement, (non)pharmacological adherence and psychosomatic and geriatric comorbidity. GPs are invited to provide a tailored structured counselling 4 times during the trial and receive an additional feedback on pharmacotherapy relevant to prognosis (data of baseline documentation). Patients from control group receive usual care by their GPs, who were introduced to guidelineoriented management and a tailored health counselling concept. Main outcome measurement for patients' QoL is the scale physical functioning of the SF-36 health questionnaire in a 12-month follow-up. Secondary outcomes are the disease specific QoL measured by the Kansas City Cardiomyopathy questionnaire (KCCQ), depression and anxiety disorders (PHQ-9, GAD-7), adherence (EHFScBS and SANA), quality of care measured by an adapted version of the Patient Chronic Illness Assessment of Care questionnaire (PACIC) and NTproBNP. In addition, comprehensive clinical data are collected about health status, comorbidity, medication and health care utilisation. Discussion: As the targeted patient group is mostly cared for and treated by GPs, a comprehensive primary care-based guideline implementation including somatic, psychosomatic and organisational aspects of the delivery of care (HICMAn) is a promising intervention applying proven strategies for optimal care. Trial registration: Current Controlled Trials ISRCTN30822978

Sustaining entrepreneurial business: a complexity perspective on processes that produce emergent practice

This article examines the management practices in an entrepreneurial small firm which sustain the business. Using a longitudinal qualitative case study, four general processes are identified (experimentation, reflexivity, organising and sensing), that together provide a mechanism to sustain the enterprise. The analysis draws on concepts from entrepreneurship and complexity science. We suggest that an entrepreneur’s awareness of the role of these parallel processes will facilitate their approaches to sustaining and developing enterprises. We also suggest that these processes operate in parallel at multiple levels, including the self, the business and inter-firm networks. This finding contributes to a general theory of entrepreneurship. A number of areas for further research are discussed arising from this result

Spiral Structure when Setting up Pericentre Glow: Possible Giant Planets at Hundreds of AU in the HD141569 Disk

This paper discusses the impact of introducing a planet on an eccentric orbit into a planetesimal disk. That planet's secular perturbations cause the orbits of the planetesimals to evolve in such a way that at any one time planetesimals at the same distance from the star have common pericentres and eccentricities. This causes the surface density distribution of an extended planetesimal disk to exhibit two spirals, one exterior the other interior to the planet's orbit. These two spirals unwind in different directions and their structure is described by two parameters: the time since the planet was introduced and the planet's eccentricity. At late times the spirals become tightly wound and the offset centre of symmetry of the pericentre glow approximation is recovered. Comparison with spiral structure seen in the HD141569 disk shows that its spiral at 325 AU is similar to that caused by introducing a planet 5 Myr ago with a mass 0.2-2M_Jup orbiting at 235-250 AU with an eccentricity of 0.05-0.2; likewise a Saturn mass planet at 150 AU would cause structure like that seen at 200 AU. More definitive statements about any planets orbiting HD141569 from this model could be made once the effect of the binary companion on the disk is known, and once the disk's structure has been better characterised down to 100 AU, including the location of the star within the disk. The relatively young age of this system (~5 Myr) means that if giant planets really do exist at hundreds of AU from HD141569, this provides a unique opportunity to set constraints on the mechanism by which those planets came to be at such large distances.Comment: 13 pages, accepted by A&

Explosive Dome Eruptions Modulated by Periodic Gas-Driven Inflation

Volcan Santiaguito (Guatemala) “breathes” with extraordinary regularity as the edifice\u27s conduit system accumulates free gas, which periodically vents to the atmosphere. Periodic pressurization controls explosion timing, which nearly always occurs at peak inflation, as detected with tiltmeters. Tilt cycles in January 2012 reveal regular 26 ± 6 min inflation/deflation cycles corresponding to at least ~101 kg/s of gas fluxing the system. Very long period (VLP) earthquakes presage explosions and occur during cycles when inflation rates are most rapid. VLPs locate ~300 m below the vent and indicate mobilization of volatiles, which ascend at ~50 m/s. Rapid gas ascent feeds pyroclast-laden eruptions lasting several minutes and rising to ~1 km. VLPs are not observed during less rapid inflation episodes; instead, gas vents passively through the conduit producing no infrasound and no explosion. These observations intimate that steady gas exsolution and accumulation in shallow reservoirs may drive inflation cycles at open-vent silicic volcanoes

Impact of different infliximab dose regimens on treatment response and drug survival in 462 patients with psoriatic arthritis: results from the nationwide registries DANBIO and ICEBIO.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access.The aim of this study was to describe dose regimens, dose escalation and clinical outcomes in TNF-α inhibitor (TNFi)-naive patients with PsA treated with infliximab in routine rheumatology care.We conducted an observational cohort study based on the nationwide Danish Rheumatologic Database (DANBIO) and Center for Rheumatology Research (ICEBIO) registries. Stratified by country, characteristics of patients treated with ≤3 mg infliximab/kg body weight, 3-5 mg/kg or ≥5 mg/kg every 8 weeks were described. Outcomes were evaluated by ACR 20%, 50% and 70% (ACR20/50/70) responses and European League Against Rheumatism good response after 6 months, disease activity after 12 months, Kaplan-Meier plots and regression analyses.Four hundred and sixty-two patients (376 Danish, 86 Icelandic) received treatment with infliximab. In Danish patients, the starting dose was ≤3 mg/kg in 110 patients (29%), 3-5 mg/kg in 157 (42%), ≥5 mg/kg in 38 (10%) and unregistered in 71 (19%). In Icelandic patients, corresponding numbers were 64 (74%), 17 (27%), 0 (0%) and 5 (6%). Patients with a higher body weight received lower doses per kilogram. Danish patients received higher doses than Icelandic patients at baseline [median 3.1 (interquartile range 3.0-3.8) vs 2.3 (2.1-2.9) mg/kg, P 70% of Icelandic and Danish PsA patients treated with infliximab received sustained doses below the 5 mg/kg every 8 weeks recommended in international guidelines. Lower starting doses did not affect drug survival or response