Autophagy is required for normal skin homeostasis and its disordered regulation is implicated in a range of cutaneous diseases. Several well-characterized biomarkers of autophagy are used experimentally to quantify autophagic activity or clinically to correlate autophagy with disease progression. This article discusses the advantages and limitations of different approaches for measuring autophagy as well as the techniques for modulating autophagy. These include analysis of endogenous LC3, a central autophagy regulatory protein, and measurement of LC3 flux using a dual-fluorescent reporter, which provides a quantitative readout of autophagy in cell culture systems in vitro and animal models in vivo. Degradation of SQSTM1/p62 during autophagy is proposed as an alternative biomarker allowing the analysis of autophagy both experimentally and clinically. However, the complex regulation of individual autophagy proteins and their involvement in multiple pathways means that several proteins must be analyzed together, preferably over a time course to accurately interpret changes in autophagic activity. Genetic modification of autophagy proteins can be used to better understand basic autophagic mechanisms contributing to health and disease, whereas small molecule inhibitors of autophagy regulatory proteins, lysosomal inhibitors, or activators of cytotoxic autophagy have been explored as potential treatments for skin disorders where autophagy is defective.

In 2017, 34.8% of total electricity consumption in Northern Ireland was generated from renewable sources located in Northern Ireland. Alongside other significant changes to the electricity sector this leads to an increasing need for reactive power. This paper provides an overview of NIE Networks' nodal controller project which aims to deliver reactive power support to the wider system through the utilisation of Distributed Energy Resources (DERs). The requirements and implementation of the nodal controller are outlined with future work proposed to provide additional reactive power support to the system.

This study presents the methodology, experience and practical outcomes of the risk assessment-based revision of loss-of-mains (LOM) protection settings in the NIE Networks' distribution system. An investigative project has been undertaken by the authors to revise the current LOM practice as recommended by the G59/1/NI regulation and to propose the settings which would meet the all-Ireland transmission system stability criteria. It is also important to ensure that any increased personal risk is realistically quantified and satisfies the health and safety requirements. Both aspects (i.e. LOM protection stability and sensitivity) are covered in the study. The results and observations included in the study aim to provide the means and supporting evidence for achieving the best compromise in the revision of LOM protection settings.

Cancer metastasis is the most important prognostic factor determining patient survival, but currently there are very few drugs or therapies that specifically inhibit the invasion and metastasis of cancer cells. Currently, human cancer metastasis is largely studied using transgenic and immunocompromised mouse xenograft models, which are useful for analysing end-point tumour growth but are unable to accurately and reliably monitor in vivo invasion, intravasation, extravasation or secondary tumour formation of human cancer cells. Furthermore, limits in our ability to accurately monitor early stages of tumour growth and detect micro-metastases likely results in pain and suffering to the mice used for cancer xenograft experiments. Zebrafish (Danio rerio) embryos, however, offer many advantages as a model system for studying the complex, multi-step processes involved during cancer metastasis. This article describes a detailed method for the analysis of human cancer cell invasion and metastasis in zebrafish embryos before they reach protected status at 5 days post fertilisation. Results demonstrate that human cancer cells actively invade within a zebrafish microenvironment, and form metastatic tumours at secondary tissue sites, suggesting that the mechanisms involved during the different stages of metastasis are conserved between humans and zebrafish, supporting the use of zebrafish embryos as a viable model of human cancer metastasis. We suggest that the embryonic zebrafish xenograft model of human cancer is a tractable laboratory model that can be used to understand cancer biology, and as a direct replacement of mice for the analysis of drugs that target cancer invasion and metastasis.

Aim: To determine Canadian GPs view on which COPD patients: a) are not optimally treated b) should be treated with LABA/LAMA FDC. Methods: 45 1-hour, 1-on-1 interviews were conducted in Montreal, Toronto and Vancouver. GPs discussed their treatment algorithm for COPD, reviewed how they perceived the importance of ICS in COPD, and which patients would benefit from a LABA/LAMA FDC. Results: GPs suspect COPD in smokers and ex-smokers and classify based on patient symptoms and progression over ensuing visits. They ideally confirm with a spirometer test, especially to differentiate from asthma. This is often omitted by Toronto MDs, citing recent removal of government remuneration cf. Vancouver MDs. Overall a very symptomatic patient or one with frequent exacerbations is considered severe and a patient with no symptoms is mild. Mild patients are often not treated. The most common first line maintenance therapy prescribed is a LAMA. Patients with persistent complaints will receive a LABA/ICS FDC, even if they do not exacerbate. GPs consider the ideal candidate for a LABA/LAMA FDC to be a symptomatic COPD patient despite maintenance therapies, either LAMA or LABA ICS FDC. They expect that this treatment will reduce exacerbations. This could be an opportune time to reconsider the patients on a LABA/ICS FDC, recognizing that many patients may not actually need an ICS. They estimate ∼65%-70% of their patients are on triple therapy (LAMA+LABA/ICS) regardless of exacerbation status. ∼50% of the physicians mention risk of pneumonia with ICS. Mention was also made that a patient with osteoporosis, glaucoma and diabetes could benefit from an ICS-free treatment such as LAMA/LABA FDC.

SummaryBackgroundSocio‐demographic predictors for the development of clinically observed, infantile eczema have not been formally examined in a large population‐based study. Few studies of eczema risk factors have included current, objective eczema outcomes as well as parent‐reported history.ObjectivesWe aimed to measure the population prevalence of infantile eczema using novel sampling methodology, and identify socio‐demographic risk factors for eczema in the first year of life.MethodsA population‐based cross‐sectional study of infantile allergy (the HealthNuts study, n = 4972, response rate 74.1%) was conducted from 2008‐2011 in Melbourne, Australia. Infants were examined for current eczema at age 12 months (mean 12.7, SD 0.7). Parents provided information about the infants’ history of eczema and demographic factors. Factors associated with eczema were modelled using multinomial logistic regression.ResultsThe population prevalence of observed eczema at 12 months was 20.3% (95% CI 19.0, 21.5), while cumulative prevalence for parent‐reported eczema was 28.0% (95% CI 26.7, 29.4). The strongest predictors of eczema were maternal eczema and asthma (multinomial (M)‐OR 1.7, P < 0.001, and M‐OR 1.4, P = 0.007), male sex (M‐OR 1.4, P < 0.001), and East Asian ethnicity (M‐OR 1.6, P < 0.001) with over 80% of infants with all risk factors exhibiting eczema. East Asian parents, particularly recent migrants, reported fewer allergies than other parents.Conclusions and Clinical RelevanceApproximately, one in three infants developed eczema by 12 months of age. East Asian infants are at increased risk of eczema despite their parents having lower rates of allergy than non‐Asian parents. Gene‐environment interactions may explain the differential effect seen in this minority group.

BACKGROUND:Few studies have focused on pollen exposure and asthma in children. None have examined associations between persistent exposure to pollen in infancy and aeroallergen sensitisation and asthma in childhood.OBJECTIVES:To examine the association between higher ambient levels of pollen in the first 3-6 months of life and risk of eczema, sensitization to food and aeroallergens at 2 years and asthma or hayfever at age 6-7 years combined.METHODS:Using a birth cohort of 620 infants with a family history of allergic disease born between 1990 and 1994, we examined risk of eczema or allergic sensitization (SPT > 3 mm to at least one of cow's milk, egg white, peanut, house dust-mite, rye grass, and cat dander) by age 2 and asthma or hayfever at age 6-7. Daily ambient levels of pollen were measured during this period.RESULTS:Cumulative exposure to pollen concentrations up to 6 months was associated with aeroallergen sensitization with the highest risk occurring at 3 months (aOR = 1.34, 95% CI 1.06-1.72). Cumulative exposure to pollen up to 3 months was also associated with hayfever (aOR = 1.14, 95% CI 1.009-1.29) and between 4 and 6 months exposure with asthma only (aOR=1.35, 95% CI 1.07-1.72).CONCLUSION:Persistent pollen exposure in infancy appears to increase the risk of asthma and hayfever in children. These results support the hypothesis that there is a critical window of opportunity in early development which may be important for modification of allergic outcomes.

BACKGROUND:The literature is contradictory concerning pet exposure and risk of allergic disease in childhood especially among those with a family history of allergy.OBJECTIVE:To investigate the relationship between cat and dog exposure at birth and allergic outcomes over the first 12 years in a birth cohort selected for familial allergy.METHODS:A prospective birth cohort of 620 infants with a family history of allergic diseases was recruited. Data on pet keeping, family demographics and cord blood samples were collected at birth. Information on childhood wheeze, eczema and hay fever was collected 18 times in the first 2 years, at 7 years and at 12 years. Skin prick tests were conducted at 2, 7 and 12 years, and in parents. Regression analyses were used to investigate the relevant associations while adjusting for potential confounders.RESULTS:Exposure to cats or dogs at birth showed a moderate reduction in risk of wheeze (aOR = 0.76; 95% CI 0.53, 1.09) and hay fever (aOR = 0.71; 0.49, 1.02) after 7 years of age. Protective effects were stronger in children of non-sensitized fathers (aOR wheeze 0.55; 0.31, 0.98; aOR hay fever 0.33; 0.15, 0.77 on exposure to cats alone, or cats or dogs at birth). Pet keeping was not related to cord blood IgE or sensitization from 2 to 12 years.CONCLUSIONS AND CLINICAL RELEVANCE:Pets at birth either decreased or had no effect on allergic disease up to age 12. We found no evidence that exposure to cats or dogs at birth increases the risk of allergic disease in high-risk children.

The study of cylindrical and spherical converging shock waves propagating in solid materials is relevant to the production of high temperatures and pressures in condensed matter with applications to inertial confinement fusion [1]. However, experimental studies conducted in the area are prone to complications derived from the measurement techniques available and the difficulty of producing a quasi-radially symmetric flow.

504 Background: KRAS mutations (MUT), present in ~40% of CRC, predict benefit from EGFR MAb treatment. The effect of mutation status on benefit from chemotherapy alone is less clear. Methods: Following ethics approval, 223 CRC patients with known KRAS status treated at a single institution were retrospectively analyzed for response to chemotherapy prior to initiation of EGFR MAb therapy. Tumour response rate and progression-free survival (PFS) were determined retrospectively. Given chemotherapy sequencing variability, a measure of the time to chemotherapy-refractory state (TTCR) was defined as time from start of first line therapy to progression on all drugs; ie fluoropyrimidines (F), irinotecan (I), and oxaliplatin (O), +/- bevacizumab (B). Results: Patients were median age 60 years (25-86), 58/42% male/female, 38% rectal or rectosigmoid, 18% liver-only metastases, 45.6% stage I-III and 54.4% stage IV at initial diagnosis, 43% prior adjuvant chemotherapy, 43/57% KRAS MUT/wild-type(WT) status. With a median follow-up of 27 months, 64 (29%) are alive. TTCR did not vary by KRAS status, with median 16.7 vs 14.8 months in WT vs MUT status patients, respectively, HR 0.85 [0.65-1.12], p=0.26. Overall survival (which now includes influence of any subsequent EGFR MAb therapy, received by 76/126 (60%) of KRAS WT status patients) did not differ significantly by KRAS status, with median survival 34.3 vs 29.2 months for WT vs MUT status, respectively, 0.79 [0.58-1.08], p=0.14. Conclusions: For most treatment strategies KRAS status did not affect 1st line PFS or time to chemotherapy-refractory state. However, for patients who received triple combination therapy, MUT status was associated with early progression. Small sample size, chance or some yet-to-be-elucidated molecular interaction may account for this finding. [Table: see text]

We present an approximate description of the behavior of an elastic-plastic material processed by a cylindrically or spherically symmetric converging shock, following Whitham's shock dynamics theory. Originally applied with success to various gas dynamics problems, this theory is presently derived for solid media, in both elastic and plastic regimes. The exact solutions of the shock dynamics equations obtained reproduce well the results obtained by high-resolution numerical simulations. The examined constitutive laws share a compressible neo-Hookean structure for the internal energy e=e(s)(I(1))+e(h)(ρ,ς), where e(s) accounts for shear through the first invariant of the Cauchy-Green tensor, and e(h) represents the hydrostatic contribution as a function of the density ρ and entropy ς. In the strong-shock limit, reached as the shock approaches the axis or origin r=0, we show that compression effects are dominant over shear deformations. For an isothermal constitutive law, i.e., e(h)=e(h)(ρ), with a power-law dependence e(h) is proportional to ρ(α), shock dynamics predicts that for a converging shock located at r=R(t) at time t, the Mach number increases as M is proportional to [log(1/R)](α), independently of the space index s, where s=2 in cylindrical geometry and 3 in spherical geometry. An alternative isothermal constitutive law with p(ρ) of the arctanh type, which enforces a finite density in the strong-shock limit, leads to M is proportional to R(-(s-1)) for strong shocks. A nonisothermal constitutive law, whose hydrostatic part e(h) is that of an ideal gas, is also tested, recovering the strong-shock limit M is proportional to R(-(s-1)/n(γ)) originally derived by Whitham for perfect gases, where γ is inherently related to the maximum compression ratio that the material can reach, (γ+1)/(γ-1). From these strong-shock limits, we also estimate analytically the density, radial velocity, pressure, and sound speed immediately behind the shock. While the hydrostatic part of the energy essentially commands the strong-shock behavior, the shear modulus and yield stress modify the compression ratio and velocity of the shock far from the axis or origin. A characterization of the elastic-plastic transition in converging shocks, which involves an elastic precursor and a plastic compression region, is finally exposed.

We study the shock-driven turbulent mixing that occurs when a perturbed planar density interface is impacted by a planar shock wave of moderate strength and subsequently reshocked. The present work is a systematic study of the influence of the relative molecular weights of the gases in the form of the initial Atwood ratio A. We investigate the cases A = ± 0.21, ±0.67 and ±0.87 that correspond to the realistic gas combinations air–CO2, air–SF6 and H2–air. A canonical, three-dimensional numerical experiment, using the large-eddy simulation technique with an explicit subgrid model, reproduces the interaction within a shock tube with an endwall where the incident shock Mach number is ~1.5 and the initial interface perturbation has a fixed dominant wavelength and a fixed amplitude-to-wavelength ratio ~0.1. For positive Atwood configurations, the reshock is followed by secondary waves in the form of alternate expansion and compression waves travelling between the endwall and the mixing zone. These reverberations are shown to intensify turbulent kinetic energy and dissipation across the mixing zone. In contrast, negative Atwood number configurations produce multiple secondary reshocks following the primary reshock, and their effect on the mixing region is less pronounced. As the magnitude of A is increased, the mixing zone tends to evolve less symmetrically. The mixing zone growth rate following the primary reshock approaches a linear evolution prior to the secondary wave interactions. When considering the full range of examined Atwood numbers, measurements of this growth rate do not agree well with predictions of existing analytic reshock models such as the model by Mikaelian (Physica D, vol. 36, 1989, p. 343). Accordingly, we propose an empirical formula and also a semi-analytical, impulsive model based on a diffuse-interface approach to describe the A-dependence of the post-reshock growth rate.

We present a finite-difference based solver for hyper-elastic and viscoplastic systems using a hybrid of the weighted essentially non-oscillatory (WENO) schemes combined with explicit centered difference to solve the equations of motion expressed in an Eulerian formulation. By construction our approach minimizes both numerical dissipation errors and the creation of curl-constraint violating errors away from discontinuities while avoiding the calculation of hyperbolic characteristics often needed in general finite-volume schemes. As a result of the latter feature, the formulation allows for a wide range of constitutive relations and only an upper-bound on the speed of sound at each time is required to ensure a stable timestep is chosen. Several one- and two-dimensional examples are presented using a range of constitutive laws with and without additional plastic modeling. In addition we extend the reflection technique combined with ghost-cells to enforce fixed boundaries with a zero tangential stress condition (i.e. free-slip).

We present an analytical study of the linearized impulsive Richtmyer-Meshkov flow for incompressible elastic solids. Seminumerical prior investigations of a related shock-driven compressible elastic problem suggest that the interface amplitude remains bounded in time, in contrast to the unstable behavior found for gases. Our approach considers a base unperturbed flow and a linearization of the conservation equations around the base solution. The resulting initial and boundary value problem is solved using Laplace transform techniques. Analysis of the singularities of the resultant function in the Laplace domain allows us to perform a parametric study of the behavior of the interface in time. We identify two differentiated long-term patterns for the interface, which depends on the material properties: standing wave and oscillating decay. Finally, we present results for the vorticity distribution, which show that the shear stiffness of the solids is responsible both for the stabilization of the interface, and also for the period of the interface oscillations. Comparisons with previous results are discussed.