Development of doped-KMgF3 fluoro-perovskite nanoparticles with upconversion properties for potential biomedical application

Upconverting nanoparticles (UCNps) possess the ability to convert light from low to high energy. In particular, the absorption of radiation by these nanomaterials in the near-infrared region of the spectrum, and their subsequent emission in the visible region, is of great interest for biomedical applications. Conventional antitumor therapies often produce a high degree of side effects. Consequently, it is proposed to investigate the development of less invasive alternative therapies as photothermal therapy, using UCNps. The upconversion property could be achieved by incorporating dopants (rare earths and transition metals) in fluorine-based crystalline environments. On the other hand, it is important to control the size of the nanoparticles for their use in biomedical applications, for that reason we plan to obtain nanoparticles with an approximate size less than 50 nm. In the present work, the development of KMgF3 fluoroperovskite nanoparticles by solvothermal synthesis is presented, applying a factorial experimental design which consists of four factors (temperature, time and two limiting reagents) at two levels and choosing the average particle size as a variable response. The samples were characterized by powder X-ray diffraction and Transmission Electron Microscopy, in order to know the crystalline phase and particle size. As a result, KMgF3 nanoparticles with an average size between 13 and 31 nm were obtained. In addition, data obtained were statistically processed by Analysis of Variance, to determine the significant factors and their interactions, achieving the optimal synthesis conditions. From these results, a series of samples doped with Mn2+ and/or Nd3+ were obtained in order to find the optimal dopant concentrations for efficient upconversion properties. Our work is the starting point for the development of UCNps allowing them to be applied in future antitumor therapies.Agencia Nacional de investigación e InnovaciónPEDECIBAComisión Académica de Postgrad

Fluoro-perovskite nanomaterials for photodynamic cancer treatment”

Upconverting nanoparticles (UCNps) possess the ability to convert light from low to high energy. In particular, the absorption of radiation by these nanomaterials in the near-infrared region of the spectrum, and their subsequent emission in the visible region, is of great interest for biomedical applications. Conventional antitumor therapies often produce a high degree of side effects. Consequently, it is proposed to investigate the development of less invasive alternative therapies as photothermal therapy, using UCNps. The upconversion property could be achieved by incorporating dopants (rare earths and transition metals) in fluorine-based crystalline environments. On the other hand, it is important to control the size of the nanoparticles for their use in biomedical applications, for that reason we plan to obtain nanoparticles with an approximate size less than 50 nm. In the present work, the development of KMgF3 fluoroperovskite nanoparticles by solvothermal synthesis is presented, applying a factorial experimental design which consists of four factors (temperature, time and two limiting reagents) at two levels and choosing the average particle size as a variable response. The samples were characterized by powder X-ray diffraction and Transmission Electron Microscopy, in order to know the crystalline phase and particle size. As a result, KMgF3 nanoparticles with an average size between 13 and 31 nm were obtained. In addition, data obtained were statistically processed by Analysis of Variance, to determine the significant factors and their interactions, achieving the optimal synthesis conditions. From these results, a series of samples doped with Mn2+ and/or Nd3+ were obtained in order to find the optimal dopant concentrations for efficient upconversion properties. Our work is the starting point for the development of UCNps allowing them to be applied in future antitumor therapies.Agencia Nacional de investigación e InnovaciónPrograma de Desarrollo de las Ciencias BásicasComisión Académica de Postgrad

Targeted metabolomic profiling in rat tissues reveals sex differences

Sex differences affect several diseases and are organ-and parameter-specific. In humans and animals, sex differences also influence the metabolism and homeostasis of amino acids and fatty acids, which are linked to the onset of diseases. Thus, the use of targeted metabolite profiles in tissues represents a powerful approach to examine the intermediary metabolism and evidence for any sex differences. To clarify the sex-specific activities of liver, heart and kidney tissues, we used targeted metabolomics, linear discriminant analysis (LDA), principal component analysis (PCA), cluster analysis and linear correlation models to evaluate sex and organ-specific differences in amino acids, free carnitine and acylcarnitine levels in male and female Sprague-Dawley rats. Several intra-sex differences affect tissues, indicating that metabolite profiles in rat hearts, livers and kidneys are organ-dependent. Amino acids and carnitine levels in rat hearts, livers and kidneys are affected by sex: male and female hearts show the greatest sexual dimorphism, both qualitatively and quantitatively. Finally, multivariate analysis confirmed the influence of sex on the metabolomics profiling. Our data demonstrate that the metabolomics approach together with a multivariate approach can capture the dynamics of physiological and pathological states, which are essential for explaining the basis of the sex differences observed in physiological and pathological conditions

Stromboli: a natural laboratory of environmental science

The science of environment is per se multi- and inter-disciplinary. It is not possible to separate the role of the physical, chemical, biological, and anthropic factors, respectively. Research must therefore rely on suitable natural laboratories, where all different effects can be simultaneously monitored and investigated. Stromboli is a volcanic island slightly North of Sicily, within a tectonic setting characterised by a Benioff zone, curved like a Greek theatre, opened towards the Tyrrhenian Sea, with deep earthquakes. Moreover, it is a unique volcano in the world in that since at least ~ 3000 years ago, it has exploded very regularly, about every 15^20 min. Hence, it is possible to monitor statistically phenomena occurring prior, during, and after every explosion. The Istituto Nazionale di Geofisica e Vulcanologia (INGV) has recently established a permanent Laboratory and an extensive interdisciplinary programme is being planned. A few main classes of items are to be considered including: (1) matter exchange (solid, liquid, gas, chemistry); (2) thermal and/or radiative coupling; (3) electromagnetic coupling; (4) deformation; (5) biospheric implications; and (6) anthropic relations since either the times of the Neolithic Revolution. Such an entire multidisciplinary perspective is discussed, being much beyond a mere volcanological concern. We present here the great heuristic potential of such a unique facility, much like a natural laboratory devoted to the investigation of the environment and climate.Published429-442JCR Journalreserve

“Diseño experimental aplicado al desarrollo de nanopartículas de fluoro-perovskitas KMgF3 con propiedades de conversión ascendente con potencial aplicación biomédica”

Las nanopartículas de conversión ascendente (UCNps) poseen la capacidad de convertir la luz de baja a alta energía. En particular, la absorción de radiación de estos nanomateriales en la región infrarroja cercana (NIR) del espectro, y su posterior emisión en la región visible, resulta de gran interés para aplicaciones biomédicas. Las terapias anti-tumorales convencionales frecuentemente producen un alto grado de efectos colaterales. En consecuencia, se plantea investigar el desarrollo de terapias alternativas menos invasivas, empleando las UCNps. La propiedad de conversión ascendente se logra incorporando dopantes (tierras raras y metales de transición) en entornos cristalinos a base de flúor. En este trabajo se presenta el desarrollo de nanopartículas de fluoro-perovskita de KMgF3 mediante síntesis solvotérmica, aplicando el diseño experimental factorial, con el fin de conocer las condiciones óptimas de síntesis. Este diseño comprende cuatro factores (temperatura, tiempo y dos reactivos limitantes) a dos niveles y eligiéndose como variable de respuesta el tamaño de partícula. Las muestras fueron caracterizadas mediante difracción de rayos X de polvo y Microscopía Electrónica de Transmisión, con el fin de conocer la fase, cristalinidad y tamaño de partícula. Se obtuvieron nanopartículas de KMgF3 de tamaño promedio entre 13 y 31 nm. Los datos obtenidos fueron procesados estadísticamente mediante análisis de varianza, determinando así los factores significativos y sus interacciones, permitiendo conocer las condiciones óptimas de síntesis. Este trabajo es el punto de partida para la posterior incorporación de dopantes a las nanopartículas permitiendo en el futuro ser aplicadas en terapias anti-tumorales.Agencia Nacional de investigación e InnovaciónPrograma de Desarrollo de las Ciencias BásicasComisión Académica de Postgrad

Regional and local environmental conditions do not shape the response to warming of a marine habitat-forming species

The differential response of marine populations to climate change remains poorly understood. Here, we combine common garden thermotolerance experiments in aquaria and population genetics to disentangle the factors driving the population response to thermal stress in a temperate habitatforming species: the octocoral Paramuricea clavata. Using eight populations separated from tens of meters to hundreds of kilometers, which were differentially impacted by recent mortality events, we identify 25 degrees C as a critical thermal threshold. After one week of exposure at this temperature, seven of the eight populations were affected by tissue necrosis and after 30 days of exposure at this temperature, the mean % of affected colonies increased gradually from 3 to 97%. We then demonstrate the weak relation between the observed differential phenotypic responses and the local temperature regimes experienced by each population. A significant correlation was observed between these responses and the extent of genetic drift impacting each population. Local adaptation may thus be hindered by genetic drift, which seems to be the main driver of the differential response. Accordingly, conservation measures should promote connectivity and control density erosion in order to limit the impact of genetic drift on marine populations facing climate change

Human-specific histone methylation signatures at transcription start sites in prefrontal neurons

Cognitive abilities and disorders unique to humans are thought to result from adaptively driven changes in brain transcriptomes, but little is known about the role of cis-regulatory changes affecting transcription start sites (TSS). Here, we mapped in human, chimpanzee, and macaque prefrontal cortex the genome-wide distribution of histone H3 trimethylated at lysine 4 (H3K4me3), an epigenetic mark sharply regulated at TSS, and identified 471 sequences with human-specific enrichment or depletion. Among these were 33 loci selectively methylated in neuronal but not non-neuronal chromatin from children and adults, including TSS at DPP10 (2q14.1), CNTN4 and CHL1 (3p26.3), and other neuropsychiatric susceptibility genes. Regulatory sequences at DPP10 and additional loci carried a strong footprint of hominid adaptation, including elevated nucleotide substitution rates and regulatory motifs absent in other primates (including archaic hominins), with evidence for selective pressures during more recent evolution and adaptive fixations in modern populations. Chromosome conformation capture at two neurodevelopmental disease loci, 2q14.1 and 16p11.2, revealed higher order chromatin structures resulting in physical contact of multiple human-specific H3K4me3 peaks spaced 0.5-1 Mb apart, in conjunction with a novel cis-bound antisense RNA linked to Polycomb repressor proteins and downregulated DPP10 expression. Therefore, coordinated epigenetic regulation via newly derived TSS chromatin could play an important role in the emergence of human-specific gene expression networks in brain that contribute to cognitive functions and neurological disease susceptibility in modern day humans

Nitric oxide synthetic pathway in red blood cells Is impaired in coronary artery disease

Background:All the enzymatic factors/cofactors involved in nitric oxide (NO) metabolism have been recently found in red blood cells. Increased oxidative stress impairs NO bioavailability and has been described in plasma of coronary artery disease (CAD) patients. The aim of the study was to highlight a potential dysfunction of the metabolic profile of NO in red blood cells and in plasma from CAD patients compared with healthy controls.Methods:We determined L-arginine/NO pathway by liquid-chromatography tandem mass spectrometry and high performance liquid chromatography methods. The ratio of oxidized and reduced forms of glutathione, as index of oxidative stress, was measured by liquid-chromatography tandem mass spectrometry method. NO synthase expression and activity were evaluated by immunofluorescence staining and ex-vivo experiments of L-[15N2]arginine conversion to L-[15N]citrulline respectively.Results:Increased amounts of asymmetric and symmetric dimethylarginines were found both in red blood cells and in plasma of CAD patients in respect to controls. Interestingly NO synthase expression and activity were reduced in CAD red blood cells. In contrast, oxidized/reduced glutathione ratio was increased in CAD and was associated to arginase activity.Conclusion:Our study analyzed for the first time the whole metabolic pathway of L-arginine/NO, both in red blood cells and in plasma, highlighting an impairment of NO pathway in erythrocytes from CAD patients, associated with decreased NO synthase expression/activity and increased oxidative stress

Nitric oxide synthetic pathway in patients with microvascular angina and its relations with oxidative stress

A decreased nitric oxide (NO) bioavailability and an increased oxidative stress play a pivotal role in different cardiovascular pathologies. As red blood cells (RBCs) participate in NO formation in the bloodstream, the aim of this study was to outline the metabolic profile of L-arginine (Arg)/NO pathway and of oxidative stress status in RBCs and in plasma of patients with microvascular angina (MVA), investigating similarities and differences with respect to coronary artery disease (CAD) patients or healthy controls (Ctrl). Analytes involved in Arg/NO pathway and the ratio of oxidized and reduced forms of glutathione were measured by LC-MS/MS. The arginase and the NO synthase (NOS) expression were evaluated by immunofluorescence staining. RBCs from MVA patients show increased levels of NO synthesis inhibitors, parallel to that found in plasma, and a reduction of NO synthase expression. When summary scores were computed, both patient groups were associated with a positive oxidative score and a negative NO score, with the CAD group located in a more extreme position with respect to Ctrl. This finding points out to an impairment of the capacity of RBCs to produce NO in a pathological condition characterized mostly by alterations at the microvascular bed with no significant coronary stenosis