Design and Synthesis of CNS-targeted Flavones and Analogues with Neuroprotective Potential Against H2O2- and Aβ1-42-Induced Toxicity in SH-SY5Y Human Neuroblastoma Cells

With the lack of available drugs able to prevent the progression of Alzheimer’s disease (AD), the discovery of new neuroprotective treatments able to rescue neurons from cell injury is presently a matter of extreme importance and urgency. Here, we were inspired by the widely reported potential of natural flavonoids to build a library of novel flavones, chromen-4-ones and their C-glucosyl derivatives, and to explore their ability as neuroprotective agents with suitable pharmacokinetic profiles. All compounds were firstly evaluated in a parallel artificial membrane permeability assay (PAMPA) to assess their effective permeability across biological membranes, namely the blood-brain barrier (BBB). With this test, we aimed not only at assessing if our candidates would be well-distributed, but also at rationalizing the influence of the sugar moiety on the physicochemical properties. To complement our analysis, logD7.4 was determined. From all screened compounds, the p-morpholinyl flavones stood out for their ability to fully rescue SH-SY5Y human neuroblastoma cells against both H2O2- and Aβ1-42-induced cell death. Cholinesterase inhibition was also evaluated, and modest inhibitory activities were found. This work highlights the potential of C-glucosylflavones as neuroprotective agents, and presents the p-morpholinyl C-glucosylflavone 37, which did not show any cytotoxicity towards HepG2 and Caco-2 cells at 100 μM, as a new lead structure for further development against AD.Fundação para a Ciência e a Tecnologia-UID/Multi/0612/2019Unión Europea-D3i4AD), FP7-PEOPLE-2013-IAPP, GA 61234

Simulating chemistry using quantum computers

The difficulty of simulating quantum systems, well-known to quantum chemists, prompted the idea of quantum computation. One can avoid the steep scaling associated with the exact simulation of increasingly large quantum systems on conventional computers, by mapping the quantum system to another, more controllable one. In this review, we discuss to what extent the ideas in quantum computation, now a well-established field, have been applied to chemical problems. We describe algorithms that achieve significant advantages for the electronic-structure problem, the simulation of chemical dynamics, protein folding, and other tasks. Although theory is still ahead of experiment, we outline recent advances that have led to the first chemical calculations on small quantum information processors.Comment: 27 pages. Submitted to Ann. Rev. Phys. Che

The Critical Behaviour of the Spin-3/2 Blume-Capel Model in Two Dimensions

The phase diagram of the spin-3/2 Blume-Capel model in two dimensions is explored by conventional finite-size scaling, conformal invariance and Monte Carlo simulations. The model in its $\tau$-continuum Hamiltonian version is also considered and compared with others spin-3/2 quantum chains. Our results indicate that differently from the standard spin-1 Blume-Capel model there is no multicritical point along the order-disorder transition line. This is in qualitative agreement with mean field prediction but in disagreement with previous approximate renormalization group calculations. We also presented new results for the spin-1 Blume-Capel model.Comment: latex 18 pages, 4 figure

In vitro and in vivo performance of methacrylated gellan gum hydrogel formulations for cartilage repair

Methacrylated gellan gum (GGMA) formulation is proposed as a second-generation hydrogel for controlled delivery of cartilage-forming cells into focal chondral lesions, allowing immediate in situ retention of cells and 3D filling of lesion volume, such approach deemed compatible with an arthroscopic procedure. Formulation optimization was carried out in vitro using chondrocytes and adipose mesenchymal stromal/stem cells (ASCs). A proof-of-concept in vivo study was conducted using a rabbit model with induced chondral lesions. Outcomes were compared with microfracture or non-treated control. Three grading scores were used to evaluate tissue repair after 8 weeks by macroscopic, histological and immunohistochemical analysis. Intense collagen type II and low collagen type I gene and protein expression were achieved in vitro by the ASC + GGMA formulation, in light with development of healthy chondral tissue. In vivo, this formulation promoted significantly superior de novo cartilage formation compared with the non-treated group. Maintenance of chondral height and integration with native tissue was further accomplished. The physicochemical properties of the proposed GGMA hydrogel exhibited highly favorable characteristics and biological performance both in vitro and in vivo, positioning itself as an attractive xeno-free biomaterial to be used with chondrogenic cells for a cost-effective treatment of focal chondral lesions. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1987-1996, 2018.Contract grant sponsor: Portuguese National Innovation Agency; contract grant number: QREN-13/SI/2011-23189info:eu-repo/semantics/publishedVersio

Effect of laser irradiation on failure mechanism of TiCp reinforcedtitanium composite coating produced by laser cladding

Laser cladding is an effective technique to coat a metallic substrate with a layer of a different nature.It has been widely reported that the most important combined parameters controlling the quality ofthe coating are the specific energy (E) and the powder density ( ). In the present work, clad depositsof Ti6Al4V + 60 wt.% TiC were prepared on a Ti6Al4V substrate using an optimum combination of Ec= 24 J/mm2 and c= 3 mg/mm2. These experiments were performed using a laser power of 400 and600 W, in order to study the effect of laser power on the properties of the clad. The microstructure, phasecomposition and nanohardness of the coatings were investigated by optical microscopy, scanning elec-tron microscopy and X-ray diffraction. During laser processing, TiC can be partially converted to TiCX(X = 0.5) due mainly to the TiC dissolution into the laser-generated melting pool and subsequent precipi-tation during cooling. It was observed that the lower laser power limit reduces primary TiC dissolution butit also promotes secondary carbide alignment at the interface. On the other hand, the damage mechanisminduced by high laser power is dominated by primary TiC particle cracking by the high stress concentra-tion at the particle matrix interface followed by ductile failure of the matrix. It is also remarkable thatirradiance affects the TiC/TiCxratio despite Ecand care fixed and it determines hardness distributioninside the coating.Authors thank MINECO funding in special the Training of Research Staff programme with the help BES-2009-013589 and the support of the Comision Interministerial de Ciencia y Tecnologia (CICYT), Spain, under Grant MAT2012-39124. This work was developed at the Materials Technology Unit of the Polytechnic University of Valencia associated to CSIC through the National Centre for Metallurgical Research (CENIM). Finally, thank the EU for the funding received through the FEDER help in the project UPOV08-3E-005 for the purchase of equipment and the Generalitat Valenciana for the help ACOMP/2012/094.Candel Bou, JJ.; Jiménez, J.; Franconetti Rodríguez, P.; Amigó Borrás, V. (2014). Effect of laser irradiation on failure mechanism of TiCp reinforcedtitanium composite coating produced by laser cladding. Journal of Materials Processing Technology. 214(11):2325-2332. https://doi.org/10.1016/j.jmatprotec.2014.04.035S232523322141

Validation and optimization of AFP-based biomarker panels for early HCC detection in Latin America and Europe

Background: HCC is a major cause of cancer death worldwide. Serum biomarkers such as alpha-fetoprotein (AFP), protein induced by vitamin K absence-II, and the Gender, Age, AFP-L3, AFP, Des-gamma-carboxy prothrombin (GALAD) score have been recommended for HCC surveillance. However, inconsistent recommendations in international guidelines limit their clinical utility.Methods: In this multicenter study, over 2000 patient samples were collected in 6 Latin American and 2 European countries. The performance of the GALAD score was validated in cirrhotic cases, and optimized versions were tested for early-stage HCC and prediagnostic HCC detection.Results: The GALAD score could distinguish between HCC and cirrhosis in Latin American patients with an AUC of 0.76, sensitivity of 70%, and specificity of 83% at the conventional cutoff value of −0.63. In a European cohort, GALAD had an AUC of 0.69, sensitivity of 66%, and specificity of 72%. Optimizing the score in the 2 large multicenter cohorts revealed that AFP-L3 contributed minimally to early-stage HCC detection. Thus, we developed a modified GALAD score without AFP-L3, the ASAP (age, sex, AFP, and protein induced by vitamin K absence-II), which showed promise for early-stage HCC detection upon validation. The ASAP score also identified patients with cirrhosis at high risk for advanced-stage HCC up to 15 months before diagnosis (p < 0.0001) and differentiated HCC from hemangiomas, with a specificity of 100% at 71% sensitivity.Conclusion: Our comprehensive analysis of large sample cohorts validates the GALAD score’s utility in Latin American, Spanish, and Dutch patients for early-stage HCC detection. The optimized GALAD without AFP-L3, the ASAP score, is a good alternative and shows greater promise for HCC prediction

A városi tipizálás, a gazdasági növekedés és a járműipar főbb összefüggései Kelet-Közép-Európában = Main Correlation of the City Structures, Economic Growth and Automotive Industry in Central and Eastern Europe

Napjainkban a városkutatások reneszánszát tapasztalhatjuk, a városok a regionális és országos gazdasági növekedés, a fejlődés és a versenyképesség gócpontjai, amelyben igen koncentráltan zajlanak a térbeli folyamatok. Ezen kijelentést alapul véve, a dolgozat célja összetettnek tekinthető. Egyrészt röviden be kívánja mutatni a napjainkban is átalakulóként jellemezhető kelet-közép-európai térség speciális területi egyenlőtlenségeit, a városokat és városias térségeket. További célként a különböző városias térségtípusok, a járműipari központok és a gazdasági növekedés összefüggéseinek kimutatását határoztuk meg. Konvergencia vizsgálatunk világosan bebizonyította, hogy az autóipari központok városai hozzájárulnak Kelet-Közép-Európa térségi gazdasági- és térségi dinamikáihoz