Strain accommodation through facet matching in La1.85_\text{1.85}Sr0.15_\text{0.15}CuO4_\text{4}/Nd1.85_\text{1.85}Ce0.15_\text{0.15}CuO4_\text{4} ramp-edge junctions

Scanning nano-focused X-ray diffraction (nXRD) and high-angle annular dark-field scanning transmission electron microscopy (HAADF-STEM) are used to investigate the crystal structure of ramp-edge junctions between superconducting electron-doped Nd$_\text{1.85}$Ce$_\text{0.15}$CuO$_\text{4}$ and superconducting hole-doped La$_\text{1.85}$Sr$_\text{0.15}$CuO$_\text{4}$ thin films, the latter being the top layer. On the ramp, a new growth mode of La$_\text{1.85}$Sr$_\text{0.15}$CuO$_\text{4}$ with a 3.3 degree tilt of the c-axis is found. We explain the tilt by developing a strain accommodation model that relies on facet matching, dictated by the ramp angle, indicating that a coherent domain boundary is formed at the interface. The possible implications of this growth mode for the creation of artificial domains in morphotropic materials are discussed.Comment: 5 pages, 4 figures & 3 pages supplemental information with 2 figures. Copyright (2015) American Institute of Physics. This article may be downloaded for personal use only. Any other use requires prior permission of the author and the American Institute of Physics. The following article appeared in APL Mat. 3, 086101 (2015) and may be found at http://dx.doi.org/10.1063/1.492779

Real world experience of response to pirfenidone in patients with idiopathic pulmonary fibrosis: a two centre retrospective study.

Introduction: Pirfenidone has been shown to reduce the decline in forced vital capacity (FVC) compared to placebo in patients with idiopathic pulmonary fibrosis (IPF). Previous studies have suggested that patients with a more rapid decline in FVC during the period before starting pirfenidone experience the greatest benefit from treatment. The purpose of this retrospective observational study was to investigate the response to pirfenidone in IPF patients, comparing two groups stratified by the annual rate of decline in FVC % predicted prior to treatment. Methods: Using the rate of decline in FVC % predicted in the 12 months prior to pirfenidone, patients were stratified into slow (<5%) or rapid (≥5%) decliner groups. Comparisons in the lung function response to pirfenidone in these two groups were performed. Results: Pirfenidone resulted in no statistically significant reduction in the median annual rate of decline in FVC or FVC % predicted. In the rapid decliners, pirfenidone significantly reduced the median (IQR) annual rate of decline in FVC % predicted (-8.7 (-14.2 - -7.0) %/yr vs 2.0 (-7.1 - 6.0) %/yr; n=17; p<0.01). In the slow decliners, pirfenidone did not reduce the median (IQR) annual rate of decline in FVC % predicted (-1.3 (-3.2 - 1.3) %/yr vs -5.0 (-8.3 - -0.35) %/yr; n=17; p=0.028). Conclusions: We demonstrate the greater net effect of pirfenidone in IPF patients declining rapidly. We suggest that using an annual rate of decline in FVC of <5% and ≥5% may be useful in counselling patients with regard to pirfenidone treatment

Macrophage transplantation rescues RNASET2-deficientleukodystrophy by replacing deficient microglia in a zebrafish model

RNASET2-deficient leukodystrophy is a rare infantile white matter disorder mimicking a viral infection and resulting in severe psychomotor impairments. Despite its severity, there is little understanding of cellular mechanisms of pathogenesis and no treatments. Recent research using the rnaset2 mutant zebrafish model has suggested that microglia may be the drivers of the neuropathology, due to their failure to digest apoptotic debris during neurodevelopment. Therefore, we developed a strategy for microglial replace- ment through transplantation of adult whole kidney marrow–derived macrophages into embryonic hosts. Using live imaging, we revealed that transplant-derived macrophages can engraft within host brains and express microglia-specific markers, suggesting the adoption of a microglial phenotype. Tissue-clearing strategies revealed the persistence of transplanted cells in host brains beyond embryonic stages. We demonstrated that transplanted cells clear apoptotic cells within the brain, as well as rescue overactivation of the antiviral response otherwise seen in mutant larvae. RNA sequencing at the point of peak transplant-derived cell engraftment confirms that transplantation can reduce the brain-wide immune response and particularly, the antiviral response, in rnaset2-deficient brains. Crucially, this reduction in neuroinflammation resulted in behavioral rescue— restoring rnaset2 mutant motor activity to wild-type (WT) levels in embryonic and juvenile stages. Together, these findings demonstrate the role of microglia as the cellular drivers of neuropathology in rnaset2 mutants and that macrophage transplantation is a viable strategy for microglial replacement in the zebrafish. Therefore, microglia-targeted interventions may have therapeutic benefits in RNASET2-deficient leukodystrophy

A method for transplantation of human HSCs into zebrafish, to replace humanised murine transplantation models

Haematopoietic stem cell (HSC) transplantation is a critical therapy for haematopoietic malignancies and immune disorders. Incomplete or delayed engraftment of HSCs in the host results in increased risk of infection and morbidity. The mechanisms of HSC engraftment are poorly understood and understanding these processes will increase transplantation success on many levels. Current animal models are immunocompromised 'humanised' mice transplanted with human HSCs. Harmful procedures include genetic manipulations and irradiation to ablate the mouse immune system, and opaque mouse tissues make visualisation of the early steps of HSC engraftment impossible. There is a need for new models to offer alternatives to humanised mice in the study of HSC transplantation. Here we described a detailed method for transplantation of human HSCs into zebrafish, before the onset of adaptive immunity. Human HSCs were purified from whole blood by enrichment of the CD34 cell population using a positive magnetic selection and further purified using an anti-CD34 antibody and cell sorting. Sorted CD34 cells were transplanted into the blood stream of 52 hour old zebrafish larvae. Human HSCs home into the zebrafish haematopoietic niche, where they engage with endothelial cells and undergo cell division. Our model offers the opportunities to image in vivo human HSC engraftment in a transparent organism, without the myeloablative strategies used in mice, and provides a unique system to understand the dynamic process of engraftment and replace current murine models. This technique can be applied to current engraftment protocols to validate the viability and efficiency of cryofrozen HSC grafts. This humanised zebrafish model will be instrumental to develop the 3Rs values in stem cell transplantation research and our detailed protocol will increase the chances of uptake of this zebrafish model by the mouse community

Ventilatory and chronotropic incompetence during incremental and constant load exercise in end-stage renal disease:a comparative physiology study

Maximal O(2) uptake is impaired in end-stage renal disease (ESRD), reducing quality of life and longevity. While determinants of maximal exercise intolerance are well defined, little is known of limitation during submaximal constant load exercise. By comparing individuals with ESRD and healthy controls, the aim of this exploratory study was to characterize mechanisms of exercise intolerance in participants with ESRD by assessing cardiopulmonary physiology at rest and during exercise. Resting spirometry and echocardiography were performed in 20 dialysis-dependent participants with ESRD (age: 59 ± 12 yr, 14 men and 6 women) and 20 healthy age- and sex-matched controls. Exercise tolerance was assessed with ventilatory gas exchange and central hemodynamics during a maximal cardiopulmonary exercise test and 30 min of submaximal constant load exercise. Left ventricular mass (292 ± 102 vs. 185 ± 83 g, P = 0.01) and filling pressure (E/e′: 6.48 ± 3.57 vs. 12.09 ± 6.50 m/s, P = 0.02) were higher in participants with ESRD; forced vital capacity (3.44 ± 1 vs. 4.29 ± 0.95 L/min, P = 0.03) and peak O(2) uptake (13.3 ± 2.7 vs. 24.6 ± 7.3 mL·kg(−1)·min(−1), P < 0.001) were lower. During constant load exercise, the relative increase in the arterial-venous O(2) difference (13 ± 18% vs. 74 ± 18%) and heart rate (32 ± 18 vs. 75 ± 29%) were less in participants with ESRD despite exercise being performed at a higher percentage of maximum minute ventilation (48 ± 3% vs. 39 ± 3%) and heart rate (82 ± 2 vs. 64 ± 2%). Ventilatory and chronotropic incompetence contribute to exercise intolerance in individuals with ESRD. Both are potential targets for medical and lifestyle interventions

Pricing reverse mortgages in Spain

[EN] In Spain, as in other European countries, the continuous ageing of the population creates a need for long-term care services and their financing. However, in Spain the development of this kind of services is still embryonic. The aim of this article is to obtain a calculation method for reverse mortgages in Spain based on the fit and projection of dynamic tables for Spanish mortality, using the Lee and Carter model. Mortality and life expectancy for the next 20 years are predicted using the fitted model, and confidence intervals are obtained from the prediction errors of parameters for the mortality index of the model. The last part of the article illustrates an application of the results to calculate the reverse mortgage model promoted by the Spanish Instituto de Crédito Oficial (Spanish State Financial Agency), for which the authors have developed a computer application.The authors are indebted to Jose Garrido, whose suggestions improved the original manuscript, and to the anonymous referee for his/her valuable comments. This work was partially supported by grants from the MEyC (Ministerio de Educacio´n y Ciencia, Spain), projects MTM2010- 14961 and MTM2008-05152.Debón Aucejo, AM.; Montes, F.; Sala, R. (2013). Pricing reverse mortgages in Spain. European Actuarial Journal. 3:23-43. https://doi.org/10.1007/s13385-013-0071-yS23433Blay-Berrueta D (2007) Sistemas de cofinaciaciación de la dependencia: seguro privado frente a hipoteca inversa. Cuadernos de la Fundación, Fundación Mapfre Estudios, Madrid.Booth H (2006) Demographic forecasting: 1980 to 2005 in review. 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Mpidr wp 2001–2007, Center for Demography and Ecology Information, University of Wisconsin-Madison.Chinloy P, Megbolugbe I (1994) Reverse mortgages: contracting and crossover. J Am Real Estate Urban Econ Assoc 22(2):367–386Coale A, Guo G (1989) Revisited regional model life tables at very low levels of mortality. Popul Index 55:613–643Coale A, Kisker E (1990) Defects in data old age mortality in the United States: New procedures for calculating approximately accurate mortality schedules and lifes tables at the highest ages. Asian Pac Popul Forum 4:1–31Cossette H, Delwarde A, Denuit M, Guillot F, Étienne M (2007) Pension plan valuation and mortality projection: a case study with mortality data. N Am Actuar J 11(2):1–34.Costa-Font J (2009) Ageing in place? exploring elderly people’s housing preferences in Spain. Urban Stud 46(2):295–316Costa-Font J (2013) Housing-related well-being in older people: the impact of environmental and financial influences. Urban Stud 50(4):657–673Currie I, Kirkby J, Durban M, Eilers P (2004) Smooth Lee–Carter models and beyond. In: Workshop on Lee–Carter Methods, http://www.ma.hw.ac.uk/~iain/workshop/workshop.html . Accessed 4 Mar 2005Czado C, Delwarde A, Denuit M (2005) Bayesian Poisson log-bilinear mortality projections. Insur Math Econ 36(3):260–284D’Amato V, Haberman S, Piscopo G, Russolillo M (2012) Modelling dependent data for longevity projections. Insur Math Econ 51(3):694–701Davidoff T (2012) Can ‘high costs’ justify weak demand for the home equity conversion mortgage? Technical report, available at SSRNDavidoff T, Welke G (2007) Selection and moral hazard in the reverse mortgage market. Technical report, Haas School of Business, UC BerkeleyDebón A, Montes F, Mateu J, Porcu E, Bevilacqua M (2008) Modelling residuals dependence in dymanic life tables. Comput Stat Data Anal 52(3):3128–3147Debón A, Montes F, Puig F (2008) Modelling and forecasting mortality in Spain. Eur J Oper Res 189(3):624–637Debón A, Montes F, Sala R (2009) Tablas de mortalidad dinámicas. Una aplicación a la hipoteca inversa en España. Fundación ICO. Publicaciones de la Universitat de Valéncia, ValenciaDebón A, Montes F, Martínez-Ruiz F (2011) Statistical methods to compare mortality for a group with non-divergent populations: an application to Spanish regions. Eur Actuar J 1:291–308Delwarde A, Denuit M, Eilers P (2007) Smoothing the Lee–Carter and poisson log-bilinear models for mortality forecasting: a penalized log-likelihood approach. Stat Modell 7(1):29–48Denuit M (2007) Distribution of the random future life expectancies in log-bilinear mortality projections models. Lifetime Data Anal 13(3):381–397Denuit M, Goderniaux A (2004) Closing and projecting lifetables using log-linear models. Mitteilungen. der Schweizerischen Aktuarvereingung 1:29–49Felipe A, Guillén M, Pérez-Marín A (2002) Recent mortality trends in the Spanish population. 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Fibroblast Growth Factor 23 (FGF23) and Alpha-Klotho Stimulate Osteoblastic MC3T3.E1 Cell Proliferation and Inhibit Mineralization

Elevated serum levels of the phosphate-regulating hormone fibroblast growth factor 23 (FGF23) are found in patients with phosphate wasting diseases and chronic kidney disease-mineral and bone disorder (CKD-MBD). These diseases are associated with rickets and renal osteodystrophy, respectively. FGF23 is secreted from osteoblastic cells and signals through FGFRs, membrane coreceptor alpha-Klotho (Klotho), and, possibly, a circulating form of Klotho. Despite the absence of detectable Klotho on osteoblastic cells, studies have suggested that forced FGF23 expression in osteoblasts inhibited mineralization. Thus, we examined the effects of exogenously applied FGF23 on osteoblastic MC3T3.E1 cell proliferation and differentiation, with and without soluble Klotho. MC3T3.E1 cells were cultured in osteoblast differentiation medium, supplemented with FGF23 (0.1–1,000 ng/mL), Klotho (50 ng/mL), the combination FGF23 + Klotho, and FGF2 (100 ng/mL) as a control. Neither FGF23 nor Klotho exposure affected proliferation of day 4 growth phase cells or mineralization of day 14 cultures. In contrast, FGF23 + Klotho resulted in inhibition of mineralization and osteoblast activity markers at day 14, and a slight, reproducible induction of proliferation. Inhibition of FGFR1, but not FGFR2 or FGFR3, completely restored FGF23 + Klotho-induced inhibition of alkaline phosphatase (ALP) activity at day 7. ALP activity was partially restored by the MAPK inhibitor U0126 but not inhibitors p38 and P13K. Thus, soluble Klotho enables FGF23 signaling in MC3T3.E1 cells, likely through FGFR 1(IIIc). Elevated FGF23 actions, in part, appear to parallel FGF2 with lower potency. In addition to affecting bone via indirect phosphate wasting pathways, supraphysiological FGF23 and soluble Klotho may directly impact bone in diseases with elevated FGF23 levels

Annexin-A1 protein and its relationship to cortisol in human saliva

Salivary cortisol is commonly used as a clinical biomarker of endocrine status and also as a marker of psychosocial stress. Annexin-A1 (AnxA1) is an anti-inflammatory protein whose expression is modulated by glucocorticoids. Our principal objectives were to (i) detect the presence of and (ii) measure AnxA1 protein in whole human saliva and to (iii) investigate whether salivary cortisol and AnxA1 are correlated in healthy humans. A total of 37 healthy participants (male and female) were used in the study. Saliva was collected using salivette tubes. Salivary cortisol and AnxA1 protein were sampled at between 3 and 6 time points over 24 h and measured for cortisol and AnxA1 protein using specific ELISA's. The presence of salivary AnxA1 protein was confirmed by Western blotting. AnxA1 protein is detectable in whole human saliva, as detected by Western blot analysis and ELISA. A diurnal rhythm was evident in both salivary cortisol (P 0.05), whereas salivary cortisol was significantly elevated between time 0 and 30 min post waking (P < 0.001). AnxA1 protein correlates positively with salivary cortisol, indicating that cortisol is most likely a regulator of AnxA1 in human saliva

The failure of microglia to digest developmental apoptotic cells contributes to the pathology of RNASET2-deficient leukoencephalopathy

The contribution of microglia in neurological disorders is emerging as a leading disease driver rather than a consequence of pathology. RNAseT2‐deficient leukoencephalopathy is a severe childhood white matter disorder affecting patients in their first year of life and mimicking a cytomegalovirus brain infection. The early onset and resemblance of the symptoms to a viral infection suggest an inflammatory and embryonic origin of the pathology. There are no treatments available for this disease as our understanding of the cellular drivers of the pathology are still unknown. In this study, using a zebrafish mutant for the orthologous rnaset2 gene, we have identified an inflammatory signature in early development and an antiviral immune response in mature adult brains. Using the optical transparency and the ex utero development of the zebrafish larvae we studied immune cell behavior during brain development and identified abnormal microglia as an early marker of pathology. Live imaging and electron microscopy identified that mutant microglia displayed an engorged morphology and were filled with undigested apoptotic cells and undigested substrate. Using microglia‐specific depletion and rescue experiments, we identified microglia as drivers of this embryonic phenotype and potential key cellular player in the pathology of RNAseT2‐deficient leukoencephalopathy. Our zebrafish model also presented with reduced survival and locomotor defects, therefore recapitulating many aspects of the human disease. Our study therefore placed our rnaset2 mutant at the forefront of leukodystrophy preclinical models and highlighted tissue‐specific approaches as future therapeutic avenues