Potentiation of Synaptic GluN2B NMDAR Currents by Fyn Kinase Is Gated through BDNF-Mediated Disinhibition in Spinal Pain Processing

In chronic pain states, the neurotrophin brain-derived neurotrophic factor (BDNF) transforms the output of lamina I spinal neurons by decreasing synaptic inhibition. Pain hypersensitivity also depends on N-methyl-D-aspartate receptors (NMDARs) and Src-family kinases, but the locus of NMDAR dysregulation remains unknown. Here, we show that NMDAR-mediated currents at lamina I synapses are potentiated in a peripheral nerve injury model of neuropathic pain. We find that BDNF mediates NMDAR potentiation through activation of TrkB and phosphorylation of the GluN2B subunit by the Src-family kinase Fyn. Surprisingly, we find that Cl−-dependent disinhibition is necessary and sufficient to prime potentiation of synaptic NMDARs by BDNF. Thus, we propose that spinal pain amplification is mediated by a feedforward mechanism whereby loss of inhibition gates the increase in synaptic excitation within individual lamina I neurons. Given that neither disinhibition alone nor BDNF-TrkB signaling is sufficient to potentiate NMDARs, we have discovered a form of molecular coincidence detection in lamina I neurons

Revising the hygroscopicity of inorganic sea salt particles

This is the final version of the article. Available from Springer Nature via the DOI in this record.Sea spray is one of the largest natural aerosol sources and plays an important role in the Earth's radiative budget. These particles are inherently hygroscopic, that is, they take-up moisture from the air, which affects the extent to which they interact with solar radiation. We demonstrate that the hygroscopic growth of inorganic sea salt is 8-15% lower than pure sodium chloride, most likely due to the presence of hydrates. We observe an increase in hygroscopic growth with decreasing particle size (for particle diameters <150 nm) that is independent of the particle generation method. We vary the hygroscopic growth of the inorganic sea salt within a general circulation model and show that a reduced hygroscopicity leads to a reduction in aerosol-radiation interactions, manifested by a latitudinal-dependent reduction of the aerosol optical depth by up to 15%, while cloud-related parameters are unaffected. We propose that a value of κs=1.1 (at RH=90%) is used to represent the hygroscopicity of inorganic sea salt particles in numerical models.P.Z. was partially financed by an Advanced Postdoc.Mobility fellowship of the Swiss National Science Foundation (grant no. P300P2_147776). M.E.S., C.L. and I.R. were financed by the Nordic Center of Excellence on Cryosphere-Atmosphere-Cloud-Climate-Interactions (NCoE CRAICC) and the Swedish Research Council (Vetenskapsradet). O.V. and A.V. were supported by the Academy of Finland Centre of Excellence (grant no. 272041) and The Doctoral School of the University of Eastern Finland. J.C.C. and M.G. received financial support from the European Research Commission via the ERC grant ERC-CoG 615922-BLACARAT. A.N. acknowledges support from a Georgia Power Scholar chair and a Cullen-Peck faculty fellowship. S.B. and M.M.-F. acknowledge funding by the Swiss National Science Foundation (grant no. 200020_146760/1). I. Tegen (TROPOS, Germany) is acknowledged for providing help with the sea spray source functions. We thank D. Eklöf and Z. Bacsik from the Department of Materials and Environmental Chemistry at Stockholm University for their assistance in the pycnometre and Fourier transform infrared spectrometer measurements. The ECHAM-HAMMOZ model is developed by a consortium composed of ETH Zurich, Max Planck Institut für Meteorologie, Forschungszentrum Jülich, University of Oxford, the Finnish Meteorological Institute and the Leibniz Institute for Tropospheric Research, and managed by the Center for Climate Systems Modeling (C2SM) at ETH Zurich

The development of a miniaturised balloon-borne cloud water sampler and its first deployment in the high Arctic

The chemical composition of cloud water can be used to infer the sources of particles upon which cloud droplets and ice crystals have formed. In order to obtain cloud water for analysis of chemical composition for elevated clouds in the pristine high Arctic, balloon-borne active cloud water sampling systems are the optimal approach. However, such systems have not been feasible to deploy previously due to their weight and the challenging environmental conditions. We have taken advantage of recent developments in battery technology to develop a miniaturised cloud water sampler for balloon-borne collection of cloud water. Our sampler is a bulk sampler with a cloud drop cutoff diameter of approximately 8 µm and an estimated collection efficiency of 70%. The sampler was heated to prevent excessive ice accumulation and was able to operate for several hours under the extreme conditions encountered in the high Arctic. We have tested and deployed the new sampler on a tethered balloon during the Microbiology-Ocean-Cloud-Coupling in the High Arctic (MOCCHA) campaign in August and September 2018 close to the North pole. The sampler was able to successfully retrieve cloud water samples that were analysed to determine their chemical composition as well as their ice-nucleating activity. Given the pristine conditions found in the high Arctic we have placed significant emphasis on the development of a suitable cleaning procedure to minimise background contamination by the sampler itself

Don't lose sight of the importance of the individual in effective falls prevention interventions

Falls remain a major public health problem, despite strong growth in the research evidence of effective single and multifactorial interventions, particularly in the community setting. A number of aspects of falls prevention require individual tailoring, despite limitations being reported regarding some of these, including questions being raised regarding the role of falls risk screening and falls risk assessment. Being able to personalise an individual's specific risk and risk factors, increase their understanding of what interventions are likely to be effective, and exploring options of choice and preference, can all impact upon whether or not an individual undertakes and sustains participation in one or more recommendations, which will ultimately influence outcomes. On all of these fronts, the individual patient receiving appropriate and targeted interventions that are meaningful, feasible and that they are motivated to implement, remains central to effective translation of falls prevention research evidence into practice

The ice-nucleating activity of Arctic sea surface microlayer samples and marine algal cultures

In recent years, sea spray as well as the biological material it contains has received increased attention as a source of ice-nucleating particles (INPs). Such INPs may play a role in remote marine regions, where other sources of INPs are scarce or absent. In the Arctic, these INPs can influence water–ice partitioning in low-level clouds and thereby the cloud lifetime, with consequences for the surface energy budget, sea ice formation and melt, and climate. Marine aerosol is of a diverse nature, so identifying sources of INPs is challenging. One fraction of marine bioaerosol (phytoplankton and their exudates) has been a particular focus of marine INP research. In our study we attempt to address three main questions. Firstly, we compare the ice-nucleating ability of two common phytoplankton species with Arctic seawater microlayer samples using the same instrumentation to see if these phytoplankton species produce ice-nucleating material with sufficient activity to account for the ice nucleation observed in Arctic microlayer samples. We present the first measurements of the ice-nucleating ability of two predominant phytoplankton species: Melosira arctica, a common Arctic diatom species, and Skeletonema marinoi, a ubiquitous diatom species across oceans worldwide. To determine the potential effect of nutrient conditions and characteristics of the algal culture, such as the amount of organic carbon associated with algal cells, on the ice nucleation activity, Skeletonema marinoi was grown under different nutrient regimes. From comparison of the ice nucleation data of the algal cultures to those obtained from a range of sea surface microlayer (SML) samples obtained during three different field expeditions to the Arctic (ACCACIA, NETCARE, and ASCOS), we found that they were not as ice active as the investigated microlayer samples, although these diatoms do produce ice-nucleating material. Secondly, to improve our understanding of local Arctic marine sources as atmospheric INPs we applied two aerosolization techniques to analyse the ice-nucleating ability of aerosolized microlayer and algal samples. The aerosols were generated either by direct nebulization of the undiluted bulk solutions or by the addition of the samples to a sea spray simulation chamber filled with artificial seawater. The latter method generates aerosol particles using a plunging jet to mimic the process of oceanic wave breaking. We observed that the aerosols produced using this approach can be ice active, indicating that the ice-nucleating material in seawater can indeed transfer to the aerosol phase. Thirdly, we attempted to measure ice nucleation activity across the entire temperature range relevant for mixed-phase clouds using a suite of ice nucleation measurement techniques – an expansion cloud chamber, a continuous-flow diffusion chamber, and a cold stage. In order to compare the measurements made using the different instruments, we have normalized the data in relation to the mass of salt present in the nascent sea spray aerosol. At temperatures above 248 K some of the SML samples were very effective at nucleating ice, but there was substantial variability between the different samples. In contrast, there was much less variability between samples below 248 K. We discuss our results in the context of aerosol–cloud interactions in the Arctic with a focus on furthering our understanding of which INP types may be important in the Arctic atmosphere

ER and HER2 expression are positively correlated in HER2 non-overexpressing breast cancer

PMCID: PMC3446380This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

Managerial Work in a Practice-Embodying Institution - The role of calling, the virtue of constancy

What can be learned from a small scale study of managerial work in a highly marginal and under-researched working community? This paper uses the ‘goods-virtues-practices-institutions’ framework to examine the managerial work of owner-directors of traditional circuses. Inspired by MacIntyre’s arguments for the necessity of a narrative understanding of the virtues, interviews explored how British and Irish circus directors accounted for their working lives. A purposive sample was used to select subjects who had owned and managed traditional touring circuses for at least 15 years, a period in which the economic and reputational fortunes of traditional circuses have suffered badly. This sample enabled the research to examine the self-understanding of people who had, at least on the face of it, exhibited the virtue of constancy. The research contributes to our understanding of the role of the virtues in organizations by presenting evidence of an intimate relationship between the virtue of constancy and a ‘calling’ work orientation. This enhances our understanding of the virtues that are required if management is exercised as a domain-related practice

Biomechanics of bone-fracture fixation by stiffness-graded plates in comparison with stainless-steel plates

BACKGROUND: In the internal fixation of fractured bone by means of bone-plates fastened to the bone on its tensile surface, an on-going concern has been the excessive stress-shielding of the bone by the excessively-stiff stainless-steel plate. The compressive stress-shielding at the fracture-interface immediately after fracture-fixation delays callus formation and bone healing. Likewise, the tensile stress-shielding of the layer of the bone underneath the plate can cause osteoporosis and decrease in tensile strength of this layer. METHOD: In order to address this problem, we propose to use stiffness-graded plates. Accordingly, we have computed (by finite-element analysis) the stress distribution in the fractured bone fixed by composite plates, whose stiffness is graded both longitudinally and transversely. RESULTS: It can be seen that the stiffness-graded composite-plates cause less stress-shielding (as an example: at 50% of the healing stage, stress at the fracture interface is compressive in nature i.e. 0.002 GPa for stainless steel plate whereas stiffness graded plates provides tensile stress of 0.002 GPa. This means that stiffness graded plate is allowing the 50% healed bone to participate in loadings). Stiffness-graded plates are more flexible, and hence permit more bending of the fractured bone. This results in higher compressive stresses induced at the fractured faces accelerate bone-healing. On the other hand, away from the fracture interface the reduced stiffness and elastic modulus of the plate causes the neutral axis of the composite structure to be lowered into the bone resulting in the higher tensile stress in the bone-layer underneath the plate, wherein is conducive to the bone preserving its tensile strength. CONCLUSION: Stiffness graded plates (with in-built variable stiffness) are deemed to offer less stress-shielding to the bone, providing higher compressive stress at the fractured interface (to induce accelerated healing) as well as higher tensile stress in the intact portion of the bone (to prevent bone remodeling and osteoporosis)

Fluticasone furoate: once-daily evening treatment versus twice-daily treatment in moderate asthma

<p>Abstract</p> <p>Background</p> <p>Inhaled corticosteroids are the recommended first-line treatment for asthma but adherence to therapy is suboptimal. The objectives of this study were to compare the efficacy and safety of once-daily (OD) evening and twice-daily (BD) regimens of the novel inhaled corticosteroid fluticasone furoate (FF) in asthma patients.</p> <p>Methods</p> <p>Patients with moderate asthma (age ≥ 12 years; pre-bronchodilator forced expiratory volume in 1 second (FEV₁) 40-85% predicted; FEV₁reversibility of ≥ 12% and ≥ 200 ml) were randomized to FF or fluticasone propionate (FP) regimens in a double-blind, crossover study. Patients were not permitted to have used any ICS for ≥ 8 weeks prior to enrolment and subsequently received doses of FF or FP 200 μg OD, FF or FP 100 μg BD and matching placebo by inhalation for 28 days each. Primary endpoint was Day 28 evening pre-dose (trough) FEV₁; non-inferiority of FF 200 μg OD and FF 100 μg BD was assessed, as was superiority of all active treatment relative to placebo. Adverse events (AEs) and 24-hour urinary cortisol excretion were assessed.</p> <p>Results</p> <p>The intent-to-treat population comprised 147 (FF) and 43 (FP) patients. On Day 28, pre-dose FEV₁showed FF 200 μg OD to be non-inferior (pre-defined limit -110 ml) to FF 100 μg BD (mean treatment difference 11 ml; 95% CI: -35 to +56 ml); all FF and FP regimens were significantly superior to placebo (p ≤ 0.02). AEs were similar to placebo; no serious AEs were reported. Urinary cortisol excretion at Day 28 for FF was lower than placebo (ratios: 200 μg OD, 0.75; 100 μg BD, 0.84; p ≤ 0.02).</p> <p>Conclusions</p> <p>FF 200 μg OD in the evening is an efficacious and well tolerated treatment for asthma patients and is not inferior to the same total BD dose.</p> <p>Trial registration</p> <p>Clinicaltrials.gov; <a href="http://www.clinicaltrials.gov/ct2/show/NCT00766090">NCT00766090</a>.</p

Men's Experiences of the UK Criminal Justice System Following Female-Perpetrated Intimate Partner Violence

© 2015 Springer Science+Business Media New York The current study aimed to explore men’s experience of the UK Criminal Justice System (CJS) following female-perpetrated intimate partner violence (IPV). Unstructured face-to-face and Skype interviews were conducted with six men aged between 40–65 years. Interviews were transcribed and analysed using interpretative phenomenological analysis (IPA). Due to the method of analysis and the sensitive nature of the research, the researcher engaged in a process of reflexivity. Four main themes were identified, including ‘Guilty until Proven Innocent: Victim Cast as Perpetrator;’ ‘Masculine Identity;’ ‘Psychological Impact’ and ‘Light at the End of the Tunnel.’ Themes were discussed and illustrated with direct quotes drawn from the transcripts. Directions for future research, criminal justice interventions, and therapeutic interventions were discussed