Analysis of the Rheological Properties of Natural Hydraulic Lime-Based Suspensions for Sustainable Construction and Heritage Conservation.

Natural hydraulic lime (NHL)-based binders play a crucial role in preserving cultural heritage structures, ensuring integrity and longevity. Beyond traditional uses, these binders exhibit potential for integration into both non-structural and structural components, being compatible with innovative manufacturing processes such as digital fabrication. Meticulously designed grouts, with applicability in their fresh and hardened states, are essential for heritage stability. This study explores the relationships between mineral additions, chemical admixtures, and lime for grout formulations, aiming to advance our understanding and inform the optimization of materials for heritage restoration. Key questions include the influence of natural volcanic pozzolan (NVP) and metakaolin (MK) on rheology and the impact of varying ratios of superplasticizer on NHL-based grout's rheological behavior. This systematic evaluation of rheological parameters aims to innovate mix designs, expanding NHL-based binders' applicability in construction and science. Our hypotheses suggest that well-designed lime grout formulations, incorporating NVP and MK, can enhance rheological properties, addressing challenges in sustainable construction and heritage conservation. This research provides valuable insights for optimizing lime-based materials, fostering advancements in heritage restoration, and promoting wider NHL-based binder adoption in diverse construction applications.

Probabilistic Assessment of the Dynamic Viscosity of Self-Compacting Steel-Fiber Reinforced Concrete through a Micromechanical Model.

This article develops a probabilistic approach to a micromechanical model to calculate the dynamic viscosity in self-compacting steel-fiber reinforced concrete (SCSFRC), which implies a paradigm shift in the approach of the deterministic models used. It builds on a previous work by the authors in which Bayesian analysis is applied to rheological micromechanical models in cement paste, self-compacting mortar, and self-compacting concrete. As a consequence of the varied characteristics of the particles in these suspensions (in terms of materials, shapes, size distributions, etc.), as well as their random nature, it seems appropriate to study these systems with probabilistic models. The Bayesian analysis, thorough Markov Chain Monte Carlo and Gibbs Sampling methods, allows the conversion of parametric-deterministic models into parametric-probabilistic models, which results in enrichment in engineering and science. The incorporation of steel fibers requires a new term in the model to account for their effect on the dynamic viscosity of SCSFRC, and this new term is also treated here with the Bayesian approach. The paper uses an extensive collection of experimental data to obtain the probability density functions of the parameters for assessing the dynamic viscosity in SCSFRC. The results obtained with these parameters' distributions are much better than those calculated with the theoretical values of the parameters, which indicates that Bayesian methods are appropriated to respond to questions in complex systems with complex models.

Calculation of Dynamic Viscosity in Concentrated Cementitious Suspensions: Probabilistic Approximation and Bayesian Analysis.

We present a new focus for the Krieger-Dougherty equation from a probabilistic point of view. This equation allows the calculation of dynamic viscosity in suspensions of various types, like cement paste and self-compacting mortar/concrete. The physical meaning of the parameters that intervene in the equation (maximum packing fraction of particles and intrinsic viscosity), together with the random nature associated with these systems, make the application of the Bayesian analysis desirable. This analysis permits the transformation of parametric-deterministic models into parametric-probabilistic models, which improves and enriches their results. The initial limitations of the Bayesian methods, due to their complexity, have been overcome by numerical methods (Markov Chain Monte Carlo and Gibbs Sampling) and the development of specific software (OpenBUGS). Here we use it to compute the probability density functions that intervene in the Krieger-Dougherty equation applied to the calculation of viscosity in several cement pastes, self-compacting mortars, and self-compacting concretes. The dynamic viscosity calculations made with the Bayesian distributions are significantly better than those made with the theoretical values.

Valoración de la condición física mediante el senior fitness test y el índice de masa corporal en una muestra española de personas mayores de 80 años / Evaluation of physical fitness in spanish people over 80 years of age using the senior fitness test and the body mass index

La esperanza de vida se ha incrementado notablemente en las sociedades occidentales. El ejercicio físico adaptado a personas mayores es clave para conseguir un envejecimiento activo. Objetivos: El objetivo principal fue determinar los niveles de condición física con el Senior Fitness Test (SFT) en sujetos españoles, mayores de 80 años, activos e independientes, adscritos a un programa de Condición Física de Mayores (CFM) y compararlos con los valores estadounidenses de referencia del SFT. El objetivo secundario fue analizar los resultados de nuestra población distribuidos por sexo y edad. Material y método: Se realizó un estudio transversal en 162 participantes, (142 mujeres, 87%), a los que se les aplicó el SFT para evaluar su condición física y se les midió el Índice de Masa Corporal (IMC) para valorar su influencia sobre la condición física. Resultados: En el SFT, la muestra española presentó mejor desempeño en fuerza y agilidad y niveles más bajos en flexibilidad y resistencia que la población estadounidense de referencia. No se encontraron diferencias significativas entre sexos en la población española, excepto en la prueba de resistencia a favor de los hombres (p = 0,006). El grupo mayor de 85 años presentó resultados inferiores del IMC (p = 0,007), de la fuerza del tren superior (p = 0,01) y de la flexibilidad del tren inferior (p = 0,02). La media del IMC de la muestra estudiada fue superior a la media de la población estadounidense. Conclusiones: La muestra española es más fuerte y ágil, pero menos flexible y resistente que la población estadounidense de referencia. La capacidad funcional en nuestra población mayor de 80, es similar en ambos sexos

Life expectancy has increased significantly in western societies. Physical exercise adapted to the elderly is a key factor in achieving active ageing. Objectives: Main objective was to assess the functional fitness of active, independent, over 80 years of age, Spanish subjects enrolled in a Senior Physical Fitness program using the Senior Fitness Test (SFT), and to compare the results with the SFT reference intervals. The secondary objective was to analyse the sample’s results when distributed according to age and sex. Material and method: A transversal study was conducted in 162 participants (142 women, 87%). They were administered the SFT to determine their physical abilities and their BMI was calculated in order to find out its influence on their physical condition. Results: Our Spanish sample performed better in strength and agility but presented lower outcomes in endurance and flexibility when compared to the US target population. In the Spanish sample significant differences between the two sexes were only found in the resistance score, where men performed better than women, (p = 0.006). Participants over 85 presented lower results in BMI (p = 0,007), upper body strength (p = 0.01) and lower body flexibility (p = 0.02). The mean BMI of our sample was higher than that of the American population. Conclusions: The Spanish population is stronger and has more agility, but it’s also less flexible and has lower endurance when compared to the American population. The Fitness condition in our population > 80 is similar in men and women

Molecular characterization of autophagic and apoptotic signaling induced by sorafenib in liver cancer cells.

Sorafenib is the unique accepted molecular targeted drug for the treatment of patients in advanced stage of hepatocellular carcinoma. The current study evaluated cell signaling regulation of endoplasmic reticulum (ER) stress, c-Jun-N-terminal kinase (JNK), Akt, and 5'AMP-activated protein kinase (AMPK) leading to autophagy and apoptosis induced by sorafenib. Sorafenib induced early (3-12 hr) ER stress characterized by an increase of Ser51 P-eIF2α/eIF2α, C/EBP homologous protein (CHOP), IRE1α, and sXBP1, but a decrease of activating transcription factor 6 expression, overall temporally associated with the increase of Thr183,Tyr185 P-JNK1/2/JNK1/2, Thr172 P-AMPKα, Ser413 P-Foxo3a, Thr308 P-AKt/AKt and Thr32 P-Foxo3a/Foxo3a ratios, and reduction of Ser2481 P-mammalian target of rapamycin (mTOR)/mTOR and protein translation. This pattern was related to a transient increase of tBid, Bim EL , Beclin-1, Bcl-xL, Bcl-2, autophagy markers, and reduction of myeloid cell leukemia-1 (Mcl-1) expression. The progressive increase of CHOP expression, and reduction of Thr308 P-AKt/AKt and Ser473 P-AKt/AKt ratios were associated with the reduction of autophagic flux and an additional upregulation of Bim EL expression and caspase-3 activity (24 hr). Small interfering-RNA (si-RNA) assays showed that Bim, but not Bak and Bax, was involved in the induction of caspase-3 in sorafenib-treated HepG2 cells. Sorafenib increased autophagic and apoptotic markers in tumor-derived xenograft model. In conclusion, the early sorafenib-induced ER stress and regulation of JNK and AMPK-dependent signaling were related to the induction of survival autophagic process. The sustained drug treatment induced a progressive increase of ER stress and PERK-CHOP-dependent rise of Bim EL , which was associated with the shift from autophagy to apoptosis. The kinetic of Bim EL expression profile might also be related to the tight balance between AKt- and AMPK-related signaling leading to Foxo3a-dependent BIM EL upregulation.

Role of p63 and p73 isoforms on the cell death in patients with hepatocellular carcinoma submitted to orthotopic liver transplantation.

BACKGROUND & AIMS: Patients with hepatocellular carcinoma (HCC) submitted to orthotopic liver transplantation (OLT) have a variable 5-year survival rate limited mostly by tumor recurrence. The etiology, age, sex, alcohol, Child-Pugh, and the immunesuppressor have been associated with tumour recurrence. The expression of ΔNp73 is related to the reduced survival of patients with HCC. The study evaluated the expression of p63 and p73 isoforms and cell death receptors, and their relation to tumour recurrence and survival. The results were in vitro validated in HCC cell lines. METHODS: HCC sections from patients submitted to OLT were used. The in vitro study was done in differentiated hepatitis B virus (HBV)-expressing Hep3B and control HepG2 cells. The expression of cell death receptors and cFLIPS/L, caspase-8 and -3 activities, and cell proliferation were determined in control and p63 and p73 overexpressing HCC cells. RESULTS: The reduced tumor expression of cell death receptors and TAp63 and TAp73, and increased ΔNp63 and ΔNp73 expression were associated with tumor recurrence and reduced survival. The in vitro study demonstrated that HBV-expressing Hep3B vs HepG2 cells showed reduced expression of p63 and p73, cell death receptors and caspase activation, and increased cFLIPL/cFLIPS ratio. The overexpression of TAp63 and TAp73 exerted a more potent pro-apoptotic and anti-proliferative effects in Hep3B than HepG2-transfected cells which was related to cFLIPL upregulation. CONCLUSIONS: The reduction of TAp63 and TAp73 isoforms, rather than alteration of ΔN isoform expression, exerted a significant functional repercussion on cell death and proliferation in HBV-expressing HepB cells.

Nitric Oxide Synthase Type III Overexpression By Gene Therapy Exerts Antitumoral Activity In Mouse Hepatocellular Carcinoma.

Hepatocellular carcinoma develops in cirrhotic liver. The nitric oxide (NO) synthase type III (NOS-3) overexpression induces cell death in hepatoma cells. The study developed gene therapy designed to specifically overexpress NOS-3 in cultured hepatoma cells, and in tumors derived from orthotopically implanted tumor cells in fibrotic livers. Liver fibrosis was induced by CCl4 administration in mice. Hepa 1-6 cells were used for in vitro and in vivo experiments. The first generation adenovirus was designed to overexpress NOS-3 (or GFP) and luciferase cDNA under the regulation of murine alpha-fetoprotein (AFP) and Rous Sarcoma Virus (RSV) promoters, respectively. Both adenoviruses were administered through the tail vein two weeks after orthotopic tumor cell implantation. AFP-NOS-3/RSV-Luciferase increased oxidative-related DNA damage, p53, CD95/CD95L expression and caspase-8 activity in cultured Hepa 1-6 cells. The increased expression of CD95/CD95L and caspase-8 activity was abolished by l-NAME or p53 siRNA. The tail vein infusion of AFP-NOS- 3/RSV-Luciferase adenovirus increased cell death markers, and reduced cell proliferation of established tumors in fibrotic livers. The increase of oxidative/nitrosative stress induced by NOS-3 overexpression induced DNA damage, p53, CD95/CD95L expression and cell death in hepatocellular carcinoma cells. The effectiveness of the gene therapy has been demonstrated in vitro and in vivo.

CD95 signaling in cancer treatment.

The CD95/CD95 ligand (CD95L) system regulates cell death, which plays a relevant role in cancer. The impairment of the CD95/CD95L system in cancer cells may lead to apoptosis resistance and contributes to tumor progression. However, a complete loss of CD95 is rarely seen in human cancers, and many cancer cells express large quantities of CD95. Furthermore, cancer patients frequently have elevated levels of the CD95L, which raise the possibility that CD95 could also participate in tumor growth through its non-apoptotic activities depending of cell lineages or tumor stage. For this reason, CD95 signaling has to be taken into account in tumor biology, and the multiple regulatory targets of CD95/CD95L suggest that they may be used as a potential therapeutic strategy to treat cancer. The present review is an update of anti-CD95-related cancer therapies such as anti-CD95 antibodies, CD95L fusion proteins, CD95 pro-drugs, as well as the new genetic CD95-based therapies.

Functional suppression of Kcnq1 leads to early sodium channel remodelling and cardiac conduction system dysmorphogenesis.

AIMS: Ion channel remodelling and ventricular conduction system (VCS) alterations play relevant roles in the generation of cardiac arrhythmias, but the interaction between ion channel remodelling and cardiac conduction system dysfunctions in an arrhythmogenic context remain unexplored. METHODS AND RESULTS: We have used a transgenic mouse line previously characterized as an animal model of Long QT Syndrome (LQTS) to analyse ion channel remodelling and VCS configuration. Reverse transcriptase-PCR and immunohistochemistry analysis showed early cardiac sodium channel upregulation at embryonic stages prior to the onset of Kv potassium channel remodelling, and cardiac hypertrophy at foetal stages. In line with these findings, patch-clamp assays demonstrated changes in sodium current density and a slowing of recovery from inactivation. Functional analysis by optical mapping revealed an immature ventricular activation pattern as well as an increase in the total left ventricle activation time in foetal transgenic hearts. Morphological analysis of LQTS transgenic mice in a Cx40(GFP/+)background demonstrated VCS dysmorphogenesis during heart development. CONCLUSIONS: Our data demonstrate early sodium channel remodelling secondary to IKs blockage in a mouse model of LQTS leading to morphological and functional anomalies in the developing VCS and cardiac hypertrophy. These results provide new insights into the mechanisms underlying foetal and neonatal cardiac electrophysiological disorders, which might help understand how molecular, functional, and morphological alterations are linked to clinical pathologies such as cardiac congenital anomalies, arrhythmias, and perinatal sudden death.

Nitric oxide and cell death in liver cancer cells.

Nitric oxide (NO) is a lipophillic, highly diffusible, and short-lived physiological messenger which regulates a variety of physiopathological responses. NO may exert its cellular action through cGMP-dependent and cGMP-independent pathways which includes different postranslational modifications. The effect of NO in cancer depends on the activity and localization of NOS isoforms, concentration and duration of NO exposure, cellular sensitivity, and hypoxia/re-oxygenation process. NO regulates critical factors such as the hypoxia inducible factor-1 (HIF-1) and p53 generally leading to growth arrest, apoptosis or adaptation. NO sensitizes hepatoma cells to chemotherapeutic compounds probably through increased p53 and cell death receptor expressions.

Targeting tyrosine kinase receptors in hepatocellular carcinoma.

The recent discoveries of genomic and molecular markers in hepatocellular carcinoma (HCC) have improved the understanding about the complexity of the signal transduction pathways as well as their relevance in normal and liver cancer cells. The identification of the functional repercussions of punctual mutations and crosstalk among cell signaling will promote the identification of specific combinatorial targeted molecular therapies to specific subsets of patients which will allow the development of personalized-based therapy and increase the survival of patients. Numerous molecular targets are in the cross-road between oncogenic and anti-apoptotic programs, genetic or epigenetic alterations, which overall may have a similar cellular phenotype. The standard antineoplastic chemotherapeutic regimes based on cytotoxic agents leads to significant side effect and modest response rates, marginal changes in natural history, and toxicities that may impact the quality of life of patients. Different strategies involving gene therapy, targeted antibodies or small molecules have been used to regulate cell death/proliferation signals, as well as angiogenesis in liver tumors. In this sense, Sorafenib recently approved for renal cell carcinoma, represents the first tyrosine kinase inhibitor (TKI) licensed for the treatment of patients with advanced HCC. This review summarizes the current status of molecular receptor TKI-based targeted therapy in HCC driving different pathways involved in cell survival, proliferation, migration, angiogenesis and metastasis, which include the regulation of Raf/MEK/ERK, PI3K/Akt/mTOR, and Jak/STAT cell signaling. The study also provides information about cell signaling crosstalk relevant in tyrosine kinase receptors (TKR)-based systemic therapy in HCC.

Cardiac conduction system anomalies and sudden cardiac death: insights from murine models.

The cardiac conduction system (CCS) is composed of a group of myocardial tissues that control and coordinate the heart. Alterations in the CCS - especially in the His-Purkinje system, have been identified as a major cause of lethal arrhythmias. Unstable arrhythmias secondary to channelopathies significantly increase the risk of sudden cardiac death (SCD). SCD is a major contributor to mortality in industrialized countries, and most cases of SCD in the young are related to inherited ion channel diseases. In this paper, we review a series of studies with murine transgenic models that revealed that some arrhythmias are associated with the CCS and may lead to SCD.

Tissue distribution and subcellular localization of the cardiac sodium channel during mouse heart development.

AIMS: The aim of this study was to analyse the mRNA expression levels and protein distribution of the cardiac sodium channel Scn5a/Nav1.5 during mouse cardiogenesis. METHODS AND RESULTS: Scn5a mRNA levels were determined by real-time RT-PCR using embryonic hearts ranging from E9.5 to E17.5 as well as postnatal and adult hearts. In addition, Scn5a protein (Nav1.5) distribution was analysed by immunohistochemistry and confocal microscopy. Scn5a mRNA levels displayed a peak at stage E11.5, decreased during the subsequent stages and then steadily increased from E17.5 onwards, and throughout the postnatal to the adult stages. Immunohistochemistry experiments revealed comparable distribution of Nav1.5 between the different cardiac chambers at early embryonic stages. During the foetal stages, Nav1.5 showed an enhanced expression in the trabeculated myocardium and in the bundle branches. At the subcellular level, Nav1.5 and Scn1b double-immunostaining analysis is consistent with the presence of both sodium channel subunits in the T-tubule system and the intercalated discs. CONCLUSION: Our results demonstrate that the cardiac sodium channel, Nav1.5, shows a dynamic expression pattern during mouse heart development, indicating that it could play an important role in the acquisition of a mature pattern of conduction and contraction during cardiogenesis.

Validación de la técnica para la determinación cuantitativa de cefotaxima sódica por Clar / Validation of the technique for the quantitative determination of cefotaxime sodium by high-performance liquid chromatography (HPLC)

Se realizó la validación del método de cromatografía líquida de alta resolución (CLAR) para la determinación cuantitativa de cefotaxima sódica, un compuesto de actividad antibacteriana reconocida. Teniendo en cuenta que el método se clasifica como método para la determinación cuantitativa de ingrediente activo o compuesto mayoritario en formulaciones o materia prima, se evaluaron los parámetros: especificidad, linealidad, precisión y exactitud. Los resultados obtenidos demostraron que la técnica es fiable, pues permitió la determinación del compuesto estudiado en presencia de las impurezas de la síntesis y productos de degradación. Además, el procesamiento estadístico de los resultados evidenció la linealidad, precisión y exactitud del método

Validación de la técnica para la determinación cuantitativa de cefotaxima sódica por Clar / Validation of the technique for the quantitative determination of sodium cefotaxima for Clar

Se realizó la validación del método de cromatografía líquida de alta resolución (CLAR) para la determinación cuantitativa de cefotaxima sódica, un compuesto de actividad antibacteriana reconocida. Teniendo en cuenta que el método se clasifica como método para la determinación cuantitativa de ingrediente activo o compuesto mayoritario en formulaciones o materia prima, se evaluaron los parámetros: especificidad, linealidad, precisión y exactitud. Los resultados obtenidos demostraron que la técnica es fiable, pues permitió la determinación del compuesto estudiado en presencia de las impurezas de la síntesis y productos de degradación. Además, el procesamiento estadístico de los resultados evidenció la linealidad, precisión y exactitud del método(AU)