Microstructural characterization of alumina-zirconia layered ceramics using positron annihilation spectroscopy

Positron annihilation spectroscopy (PAS), indentation, nanoindentation experiments and scanning electron microscopy (SEM) observations were performed on Al₂O₃-ZrO₂ laminates samples to assess the effect of residual stresses on their mechanical and microstructural properties. Layered samples were implemented by slip-casting, constituted by two thin Al₂O₃ external layers and an intermediate thick one, consisting of a mixture of Al₂O₃ and monoclinic ZrO₂ in the range 0-30 vol.%. In these systems residual tensile stresses fields were generated inside the external layers during cooling from the sintering temperature, by the expansion of the adjacent ZrO₂-containing layer. SEM observations showed the microstructural effects due to the level of tension related to the zirconia content. A correlation between the PAS parameters and the microstructural changes caused by the presence of residual stresses was found. Nanoindentation measurements were used to trace the sign and magnitude of the residual stress gradient across the interface between the layers.This work was supported by Spanish Government under Contract MAT2006-01038. The authors gratefully acknowledge the financial support from the Comunidad de Madrid and the Ministry of Education and Science of Spain, through the ESTRUMAT-CM (MAT/77) programs.Publicad

Effect of highly dispersed yttria addition on thermal stability of hydroxyapatite

The capability of the colloidal method to produce yttria (Y₂O₃) dispersed hydroxyapatite (HA) has been investigated as an alternative method to the conventional method of mechanical mixing and sintering for developing HA-based materials that could exhibit controllable and enhanced functional properties. A water based colloidal route to produce HA materials with highly dispersed Y₂O₃ has been applied, and the effect of 10 wt.% Y₂O₃ addition to HA investigated by thermal analysis, X-ray diffraction and Fourier transform infrared spectroscopy. These measurements evidence a remarkable effect of this Y₂O₃ addition on decomposition mechanisms of synthetic HA. Results show that incorporation of Y₂O₃ as dispersed second phase is beneficial because it hinders the decomposition mechanisms of HA into calcium phosphates. This retardation will allow the control of the sintering conditions for developing HA implants with improved properties. Besides, substitution of Ca⁻2+ with Y⁻3+ ions appears to promote the formation of OH- vacancies, which could improve the conductive properties of HA favorable to osseointegration.This work has been supported by the Ministry of Science and Innova tion of Spain (MICINN) under contracts MAT2009 14448 C02 01 and IPT 310000 2010 12, and Regional Government of Madrid through the ESTRUMAT CM program (MAT 1585).Publicad

Apoptotic microtubules delimit an active caspase free area in the cellular cortex during the execution phase of apoptosis

Apoptotic microtubule network (AMN) is organized during apoptosis, forming a cortical structure beneath plasma membrane, which has an important role in preserving cell morphology and plasma membrane permeability. The aim of this study was to examine the role of AMN in maintaining plasma membrane integrity during the execution phase of apoptosis. We demonstrated in camptothecin-induced apoptosis in H460 cells that AMN delimits an active caspase free area beneath plasma membrane that permits the preservation of cellular cortex and transmembrane proteins. AMN depolymerization in apoptotic cells by a short exposure to colchicine allowed active caspases to reach the cellular cortex and cleave many key proteins involved in plasma membrane structural support, cell adhesion and ionic homeostasis. Cleavage of cellular cortex and plasma membrane proteins, such as a-spectrin, paxilin, focal adhesion kinase (FAK), E-cadherin and integrin subunit b4 was associated with cell collapse and cell detachment. Otherwise, cleavage-mediated inactivation of calcium ATPase pump (PMCA-4) and Naþ/Ca2þ exchanger (NCX) involved in cell calcium extrusion resulted in calcium overload. Furthermore, cleavage of Naþ/Kþ pump subunit b was associated with altered sodium homeostasis. Cleavage of cell cortex and plasma membrane proteins in apoptotic cells after AMN depolymerization increased plasma permeability, ionic imbalance and bioenergetic collapse, leading apoptotic cells to secondary necrosis. The essential role of caspase-mediated cleavage in this process was demonstrated because the concomitant addition of colchicine that induces AMN depolymerization and the pan-caspase inhibitor z-VAD avoided the cleavage of cortical and plasma membrane proteins and prevented apoptotic cells to undergo secondary necrosis. Furthermore, the presence of AMN was also critical for proper phosphatidylserine externalization and apoptotic cell clearance by macrophages. These results indicate that AMN is essential to preserve an active caspase free area in the cellular cortex of apoptotic cells that allows plasma membrane integrity during the execution phase of apoptosis

Cimetidine disrupts the renewal of testicular cells and the steroidogenesis in a hermaphrodite fish

The importance of histamine in the physiology of the testis in mammals and reptiles has been recently shown. Histamine receptors (Hrs) are well conserved in fish and are functional in several fish species. We report here for the first time that histamine and the mRNA of Hrh1, Hrh2 and Hrh3 are all present in the gonad of the hermaphrodite teleost fish gilthead seabream. Moreover, cimetidine, which acts in vitro as an agonist of Hrh1 and Hrh2 on this species, was intraperitoneally injected in one and two years old gilthead seabream males. After three and five days of cimetidine injection, we found that this compound differently modified the gonadal hrs transcript levels and affects the testicular cell renewal and the gene expression of steroidogenesis-related molecules as well as the serum steroid levels. Our data point to cimetidine as a reproductive disruptor and elucidate a role for histamine in the gonad of this hermaphrodite fish species through Hr signalling.Postprint2,616

Polyoxometalates as potential next‐generation metallodrugs in the combat against cancer

Polyoxometalates (POMs) are an emerging class of inorganic metal oxides, which over the last decades demonstrated promising biological activities by the virtue of their great diversity in structures and properties. They possess high potential for the inhibition of various tumor types; however, their unspecific interactions with biomolecules and toxicity impede their clinical usage. The current focus of the field of biologically active POMs lies on organically functionalized and POM-based nanocomposite structures as these hybrids show enhanced anticancer activity and significantly reduced toxicity towards normal cells in comparison to unmodified POMs. Although the antitumor activity of POMs is well documented, their mechanisms of action are still not well understood. In this Review, an overview is given of the cytotoxic effects of POMs with a special focus on POM-based hybrid and nanocomposite structures. Furthermore, we aim to provide proposed mode of actions and to identify molecular targets. POMs are expected to develop into the next generation of anticancer drugs that selectively target cancer cells while sparing healthy cells.FCT - SFRH/BSAB/129821/2017info:eu-repo/semantics/publishedVersio

Pantothenate Rescues Iron Accumulation in Pantothenate Kinase-Associated Neurodegeneration Depending on the Type of Mutation

Neurodegeneration with brain iron accumulation (NBIA) is a group of inherited neurologic disorders in which iron accumulates in the basal ganglia resulting in progressive dystonia, spasticity, parkinsonism, neuropsychiatric abnormalities, and optic atrophy or retinal degeneration. The most prevalent form of NBIA is pantothenate kinase-associated neurodegeneration (PKAN) associated with mutations in the gene of pantothenate kinase 2 (PANK2), which is essential for coenzyme A (CoA) synthesis. There is no cure for NBIA nor is there a standard course of treatment. In the current work, we describe that fibroblasts derived from patients harbouring PANK2 mutations can reproduce many of the cellular pathological alterations found in the disease, such as intracellular iron and lipofuscin accumulation, increased oxidative stress, and mitochondrial dysfunction. Furthermore, mutant fibroblasts showed a characteristic senescent morphology. Treatment with pantothenate, the PANK2 enzyme substrate, was able to correct all pathological alterations in responder mutant fibroblasts with residual PANK2 enzyme expression. However, pantothenate had no effect on mutant fibroblasts with truncated/incomplete protein expression. The positive effect of pantothenate in particular mutations was also confirmed in induced neurons obtained by direct reprograming of mutant fibroblasts. Our results suggest that pantothenate treatment can stabilize the expression levels of PANK2 in selected mutations. These results encourage us to propose our screening model as a quick and easy way to detect pantothenate-responder patients with PANK2 mutations. The existence of residual enzyme expression in some affected individuals raises the possibility of treatment using high dose of pantothenate.Instituto de Salud Carlos III FIS PI16/00786Junta de Andalucía CTS-5725, BIO-122Dirección General de Investigación Científica y Técnica BFU2015-64536-

Clinical Symptoms in Fibromyalgia Are Better Associated to Lipid Peroxidation Levels in Blood Mononuclear Cells Rather than in Plasma

This is an open-access article distributed under the terms of the Creative Commons Attribution License.[Background] We examined lipid peroxidation (LPO) in blood mononuclear cells (BMCs) and plasma, as a marker of oxidative damage, and its association to clinical symptoms in Fibromyalgia (FM) patients. [Methods]: We conducted a case–control and correlational study comparing 65 patients and 45 healthy controls. Clinical parameters were evaluated using the Fibromyalgia Impact Questionnaire (FIQ), visual analogues scales (VAS), and the Beck Depression Inventory (BDI). Oxidative stress was determined by measuring LPO in BMCs and plasma. [Results]: We found increased LPO levels in BMCs and plasma from FM patients as compared to normal control (P<0.001). A significant correlation between LPO in BMCs and clinical parameters was observed (r = 0.584, P<0.001 for VAS; r = 0.823, P<0.001 for FIQ total score; and r = 0.875, P<0.01 for depression in the BDI). We also found a positive correlation between LPO in plasma and clinical symptoms (r = 0.452, P<0.001 for VAS; r = 0.578, P<0.001 for FIQ total score; and r = 0.579, P<0.001 for depression in the BDI). Partial correlation analysis controlling for age and BMI, and sex, showed that both LPO in cells and plasma were independently associated to clinical symptoms. However, LPO in cells, but not LPO in plasma, was independently associated to clinical symptoms when controlling for depression (BDI scores). [Discussion]: The results of this study suggest a role for oxidative stress in the pathophysiology of fibromyalgia and that LPO in BMCs rather than LPO in plasma is better associated to clinical symptoms in FM.This work was supported by Spanish FIS PI080500 grant, and FIS EC08/00076 grant, Ministerio de Sanidad, Spain, and Federación Andaluza de Fibromialgia y Fatiga Crónica (ALBA Andalucía). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewe

Procjena cito-/genotoksičnosti irinotekana u V79-stanicama primjenom komet-testa, mikronukleus-testa i testa kromosomskih aberacija

Irinotecan is a topoisomerase I interactive agent, widely used in the treatment of metastatic colorectal cancer. The genotoxic effects of the maximum single dose (18 μg mL-1), recommended monotherapy dose (9 μg mL-1), and recommended combined therapy dose (4.5 μg mL-1) of irinotecan were studied on V79 cells using the comet assay, chromosome aberration assay, and micronucleus test. The cells were treated with irinotecan for 2 h or 24 h. The statistical signifi cance of the results was determined using the one-way ANOVA test and a nonparametric Mann Whitney U test. The comet assay did not show dose-dependent or time-dependent effects. The chromosome aberration analysis showed large DNA rearrangements, i.e., chromosome exchanges. Although the exposed cultures showed a signifi cant increase in micronucleated cells in respect to control, no dose-dependent relation was established among the treated cultures. Timedependent effect was also not observed.Irinotekan je citotoksični lijek koji inhibira enzim DNA-topoizomerazu I. U širokoj je primjeni u terapiji metastatskog karcinoma kolona i rektuma. U uvjetima in vitro primjenom komet-testa, analize kromosomskih aberacija i mikronukleus-testa na V79-stanicama istražili smo genotoksični učinak maksimalne pojedinačne doze (18 μg mL-1), preporučene monoterapijske doze (9 μg mL-1) i preporučene doze irinotekana za kombiniranu terapiju (4,5 μg mL-1). Kulture stanica bile su tretirane irinotekanom 2 h i 24 h. Statistička značajnost određivana je jednosmjernim ANOVA-testom i neparametrijskim Mann Whitneyevim U-testom. Komet-testom nije utvrđen učinak koncentracije i/ili vremena izloženosti. Analiza kromosomskih aberacija pokazala je prisutnost izmjena kromatida, tj. porast broja triradijusa i tetraradijusa. Iako je u kulturama stanica izloženi irinotekanu opažen značajan porast broja mikronukleusa u odnosu na kontrolu, nije uočena ovisnost o dozi lijeka ni o vremenu izloženosti u opisanim eksperimentalnim uvjetima. Dobiveni rezultati upućuju na genotoksičnost irinotekana za V79-stanice. Nijednom od primijenjenih metoda nije utvrđena ovisnost učinka irinotekana o vremenu ili dozi

Measurement of the Bottom-Strange Meson Mixing Phase in the Full CDF Data Set

We report a measurement of the bottom-strange meson mixing phase \beta_s using the time evolution of B0_s -> J/\psi (->\mu+\mu-) \phi (-> K+ K-) decays in which the quark-flavor content of the bottom-strange meson is identified at production. This measurement uses the full data set of proton-antiproton collisions at sqrt(s)= 1.96 TeV collected by the Collider Detector experiment at the Fermilab Tevatron, corresponding to 9.6 fb-1 of integrated luminosity. We report confidence regions in the two-dimensional space of \beta_s and the B0_s decay-width difference \Delta\Gamma_s, and measure \beta_s in [-\pi/2, -1.51] U [-0.06, 0.30] U [1.26, \pi/2] at the 68% confidence level, in agreement with the standard model expectation. Assuming the standard model value of \beta_s, we also determine \Delta\Gamma_s = 0.068 +- 0.026 (stat) +- 0.009 (syst) ps-1 and the mean B0_s lifetime, \tau_s = 1.528 +- 0.019 (stat) +- 0.009 (syst) ps, which are consistent and competitive with determinations by other experiments.Comment: 8 pages, 2 figures, Phys. Rev. Lett 109, 171802 (2012

Vitamin E prevents lipid peroxidation and iron accumulation in PLA2G6-Associated Neurodegeneration

23 Páginas.-- 17 FigurasPLA2G6-Associated Neurodegeneration (PLAN) is a rare neurodegenerative disease with autosomal recessive inheritance, which belongs to the NBIA (Neurodegeneration with Brain Iron Accumulation) group. Although the pathogenesis of the disease remains largely unclear, lipid peroxidation seems to play a central role in the pathogenesis. Currently, there is no cure for the disease.This work was supported by FIS PI16/00786 and PI19/00377 grants, Instituto de Salud Carlos III, Spain and Fondo Europeo de Desarrollo Regional (FEDR-Unión Europea), Proyectos de Investigación de Excelencia de la Junta de Andalucía CTS-5725 and PY18-850 and by AIDNAI (Association Internationale de Dystrophie Neuro Axonale Infantile), ENACH (Asociación de Enfermos de Neurodegeneración con Acumulación Cerebral de Hierro), AEPMI (Asociación de Enfermos de Patología Mitocondrial), FEDER (Federación Española de Enfermedades Raras) and Fundación MERK Salud. S. Povea-Cabello is a recipient of Ayudas para la Formación del Profesorado Universitario (FPU) from Ministerio de Universidades de España.Peer reviewe