Combined therapies of antithrombotics and antioxidants delay in silico brain tumor progression

Glioblastoma multiforme, the most frequent type of primary brain tumor, is a rapidly evolving and spatially heterogeneous high-grade astrocytoma that presents areas of necrosis, hypercellularity and microvascular hyperplasia. The aberrant vasculature leads to hypoxic areas and results in an increase of the oxidative stress selecting for more invasive tumor cell phenotypes. In our study we assay in silico different therapeutic approaches which combine antithrombotics, antioxidants and standard radiotherapy. To do so, we have developed a biocomputational model of glioblastoma multiforme that incorporates the spatio-temporal interplay among two glioma cell phenotypes corresponding to oxygenated and hypoxic cells, a necrotic core and the local vasculature whose response evolves with tumor progression. Our numerical simulations predict that suitable combinations of antithrombotics and antioxidants may diminish, in a synergetic way, oxidative stress and the subsequent hypoxic response. This novel therapeutical strategy, with potentially low or no toxicity, might reduce tumor invasion and further sensitize glioblastoma multiforme to conventional radiotherapy or other cytotoxic agents, hopefully increasing median patient overall survival time.Comment: 8 figure

Easy and Versatile Synthesis of Bulk Quantities of Highly Enriched 13C-Graphene Materials for Biological and Safety Applications

The preparation of bulk quantities of 13C-labeled graphene materials is relevant for basic investigations and for practical applications. In addition, 13C-labeled graphene materials can be very useful in biological and environmental studies, as they may allow the detection of graphene or its derivatives in cells or organs. In this paper, we describe the synthesis of 13C-labeled graphene materials (few-layer graphene, FLG, and graphene oxide, GO) on a tens of mg scale, starting from 13C-labeled methane to afford carbon fibers, followed by liquid-phase exfoliation (FLG) or oxidation (GO). The materials have been characterized by several analytical and microscopic techniques, including Raman and nuclear magnetic resonance spectroscopies, thermogravimetric analysis, X-ray photoelectron spectroscopy, and X-ray powder diffraction. As a proof of concept, the distribution of the title compounds in cells has been investigated. In fact, the analysis of the 13C/12C ratio with isotope ratio mass spectrometry (IRMS) allows the detection and quantification of very small amounts of material in cells or biological compartments with high selectivity, even when the material has been degraded. During the treatment of 13C-labeled FLG with HepG2 cells, 4.1% of the applied dose was found in the mitochondrial fraction, while 4.9% ended up in the nuclear fraction. The rest of the dose did not enter into the cell and remained in the plasma membrane or in the culture media.La preparación de cantidades a granel de materiales de grafeno marcados con 13C es relevante para investigaciones básicas y para aplicaciones prácticas. Además, los materiales de grafeno marcados con 13C pueden ser muy útiles en estudios biológicos y medioambientales, ya que pueden permitir la detección de grafeno o sus derivados en células u órganos. En este trabajo describimos la síntesis de materiales de grafeno marcados con 13C (grafeno de pocas capas, FLG, y óxido de grafeno, GO) a escala de decenas de mg, partiendo de metano marcado con 13C para obtener fibras de carbono, seguidas de exfoliación en fase líquida (FLG) u oxidación (GO). Los materiales se han caracterizado mediante varias técnicas analíticas y microscópicas, como las espectroscopias Raman y de resonancia magnética nuclear, el análisis termogravimétrico, la espectroscopia de fotoelectrones de rayos X y la difracción de rayos X en polvo. Como prueba de concepto, se ha investigado la distribución de los compuestos del título en las células. De hecho, el análisis de la relación 13C/12C con espectrometría de masas de relación isotópica (IRMS) permite la detección y cuantificación de cantidades muy pequeñas de material en células o compartimentos biológicos con alta selectividad, incluso cuando el material se ha degradado. Durante el tratamiento de FLG marcado con 13C con células HepG2, el 4,1% de la dosis aplicada se encontró en la fracción mitocondrial, mientras que el 4,9% acabó en la fracción nuclear. El resto de la dosis no entró en la célula y permaneció en la membrana plasmática o en el medio de cultivo

Composición nutricional de nuevas variedades de cacahuate (Arachis Hypogaea L.)

Six peanut (Arachis hypogaea L.) cultivars (Col-24-Gro, Col-61-Gto, VA-81-B, Ranferi Díaz, NC-2 and Florunner) were studied for agricultural yield, chemical composition (protein, fat, carbohydrates, fiber and ash), amino acid profile, digestibility, fatty acid profile, tocopherol and sterol contents. Results indicated that Ranferi Díaz and Col-61-Gto presented the highest yield (6.3 Ton/ha). Protein content was from 23.5 to 26.6% and fat content ranged from 49.8-53.4%. Mean digestibility was 86%. Lysine and threonine levels in all cultivars were sufficient to meet human requirements. Total saturated fatty acids ranged from 15-18%. The oleic/linoleic ratio was estimated 1.3-1.4. Tocopherol levels varied from 390 to 706 ppm. The highest tocopherol levels corresponded to the cultivars with the lowest yield. The alpha tocopherol content was estimated at 90-150 ppm, while gamma tocopherol was 270-570 ppm.The main sterol present was βsitosterol (approx. 65%). Ranferi Diaz variety presented the highest agronomic yield and the highest protein content but low oleic acid, low sterols and low total tocopherols. The differences among cultivars suggest differences in their applications.Se estudio el rendimiento agrícola y composición química (proteína, grasa, carbohidratos, fibra y cenizas), perfil de amino ácidos, digestibilidad, perfil de ácidos grasos, contenido de tocoferol y de esteroles de seis variedades de cacahuate (Arachis hypogaea L.) Col-24-Gro, Col-61-Gto, VA-81B, Ranferi Díaz, NC-2 y Florunner. Los resultados mostraron que el mayor rendimiento se logró en las variedades Ranferi Díaz y Col-61-Gto (6.3 Ton/ha). El contenido de proteína fue de 23.5 a 26.6% y el contenido de grasa en un intervalo de 49.8 a 53.4%. La digestibilidad promedio de las seis variedades fue de 86%. El contenido de lisina y treonina en la proteína de todas las variedades fue suficiente para satisfacer los requerimientos del humano. La composición del aceite de las diferentes variedades de cacahuate se caracterizó por contener de 15-18% de ácidos grasos saturados. La relación oleico/linoleico fue de 1.3-1.4. El contenido de tocoferoles totales fue entre 390 a 706 ppm. El mayor contenido de tocoferol correspondió a las variedades con los rendimientos más bajos. Con respecto al contenido de alfa tocoferol se encontró entre 90-150 ppm y el gamma tocoferol fue entre 270570 ppm. El contenido de beta-sitosterol fue similar en las seis variedades (aprox. 65%). La variedad Ranferi Diaz presentó el más alto rendimiento agronómico y el más alto contenido de proteína. Sin embargo, esta variedad presento el más bajo contenido de ácido oleico, bajo contenido de esteroles y bajo contenido de tocoferoles totales. Estas diferencias entre las variedades de cacahuate sugieren que cada una de ellas deberá tener diferente uso como alimento

Calibration of the Logarithmic-Periodic Dipole Antenna (LPDA) Radio Stations at the Pierre Auger Observatory using an Octocopter

An in-situ calibration of a logarithmic periodic dipole antenna with a frequency coverage of 30 MHz to 80 MHz is performed. Such antennas are part of a radio station system used for detection of cosmic ray induced air showers at the Engineering Radio Array of the Pierre Auger Observatory, the so-called Auger Engineering Radio Array (AERA). The directional and frequency characteristics of the broadband antenna are investigated using a remotely piloted aircraft (RPA) carrying a small transmitting antenna. The antenna sensitivity is described by the vector effective length relating the measured voltage with the electric-field components perpendicular to the incoming signal direction. The horizontal and meridional components are determined with an overall uncertainty of 7.4^{+0.9}_{-0.3} % and 10.3^{+2.8}_{-1.7} % respectively. The measurement is used to correct a simulated response of the frequency and directional response of the antenna. In addition, the influence of the ground conductivity and permittivity on the antenna response is simulated. Both have a negligible influence given the ground conditions measured at the detector site. The overall uncertainties of the vector effective length components result in an uncertainty of 8.8^{+2.1}_{-1.3} % in the square root of the energy fluence for incoming signal directions with zenith angles smaller than 60{\deg}.Comment: Published version. Updated online abstract only. Manuscript is unchanged with respect to v2. 39 pages, 15 figures, 2 table

Multi-resolution anisotropy studies of ultrahigh-energy cosmic rays detected at the Pierre Auger Observatory

We report a multi-resolution search for anisotropies in the arrival directions of cosmic rays detected at the Pierre Auger Observatory with local zenith angles up to $80^\circ$ and energies in excess of 4 EeV ($4 \times 10^{18}$ eV). This search is conducted by measuring the angular power spectrum and performing a needlet wavelet analysis in two independent energy ranges. Both analyses are complementary since the angular power spectrum achieves a better performance in identifying large-scale patterns while the needlet wavelet analysis, considering the parameters used in this work, presents a higher efficiency in detecting smaller-scale anisotropies, potentially providing directional information on any observed anisotropies. No deviation from isotropy is observed on any angular scale in the energy range between 4 and 8 EeV. Above 8 EeV, an indication for a dipole moment is captured; while no other deviation from isotropy is observed for moments beyond the dipole one. The corresponding $p$-values obtained after accounting for searches blindly performed at several angular scales, are $1.3 \times 10^{-5}$ in the case of the angular power spectrum, and $2.5 \times 10^{-3}$ in the case of the needlet analysis. While these results are consistent with previous reports making use of the same data set, they provide extensions of the previous works through the thorough scans of the angular scales.Comment: Published version. Added journal reference and DOI. Added Report Numbe

A comprehensive systematic review of CSF proteins and peptides that defne Alzheimer’s disease

Background: During the last two decades, over 100 proteomics studies have identifed a variety of potential bio‑ markers in CSF of Alzheimer’s (AD) patients. Although several reviews have proposed specifc biomarkers, to date, the statistical relevance of these proteins has not been investigated and no peptidomic analyses have been generated on the basis of specifc up- or down- regulation. Herein, we perform an analysis of all unbiased explorative proteom‑ ics studies of CSF biomarkers in AD to critically evaluate whether proteins and peptides identifed in each study are consistent in distribution; direction change; and signifcance, which would strengthen their potential use in studies of AD pathology and progression. Methods: We generated a database containing all CSF proteins whose levels are known to be signifcantly altered in human AD from 47 independent, validated, proteomics studies. Using this database, which contains 2022 AD and 2562 control human samples, we examined whether each protein is consistently present on the basis of reliable statistical studies; and if so, whether it is over- or under-represented in AD. Additionally, we performed a direct analysis of available mass spectrometric data of these proteins to generate an AD CSF peptide database with 3221 peptides for further analysis. Results: Of the 162 proteins that were identifed in 2 or more studies, we investigated their enrichment or depletion in AD CSF. This allowed us to identify 23 proteins which were increased and 50 proteins which were decreased in AD, some of which have never been revealed as consistent AD biomarkers (i.e. SPRC or MUC18). Regarding the analysis of the tryptic peptide database, we identifed 87 peptides corresponding to 13 proteins as the most highly consistently altered peptides in AD. Analysis of tryptic peptide fngerprinting revealed specifc peptides encoded by CH3L1, VGF, SCG2, PCSK1N, FBLN3 and APOC2 with the highest probability of detection in AD. Conclusions: Our study reveals a panel of 27 proteins and 21 peptides highly altered in AD with consistent statistical signifcance; this panel constitutes a potent tool for the classifcation and diagnosis of AD

Ultrahigh-energy neutrino follow-up of Gravitational Wave events GW150914 and GW151226 with the Pierre Auger Observatory

On September 14, 2015 the Advanced LIGO detectors observed their first gravitational-wave (GW) transient GW150914. This was followed by a second GW event observed on December 26, 2015. Both events were inferred to have arisen from the merger of black holes in binary systems. Such a system may emit neutrinos if there are magnetic fields and disk debris remaining from the formation of the two black holes. With the surface detector array of the Pierre Auger Observatory we can search for neutrinos with energy above 100 PeV from point-like sources across the sky with equatorial declination from about -65 deg. to +60 deg., and in particular from a fraction of the 90% confidence-level (CL) inferred positions in the sky of GW150914 and GW151226. A targeted search for highly-inclined extensive air showers, produced either by interactions of downward-going neutrinos of all flavors in the atmosphere or by the decays of tau leptons originating from tau-neutrino interactions in the Earth's crust (Earth-skimming neutrinos), yielded no candidates in the Auger data collected within $\pm 500$ s around or 1 day after the coordinated universal time (UTC) of GW150914 and GW151226, as well as in the same search periods relative to the UTC time of the GW candidate event LVT151012. From the non-observation we constrain the amount of energy radiated in ultrahigh-energy neutrinos from such remarkable events.Comment: Published version. Added journal reference and DOI. Added Report Numbe

Azimuthal asymmetry in the risetime of the surface detector signals of the Pierre Auger Observatory

The azimuthal asymmetry in the risetime of signals in Auger surface detector stations is a source of information on shower development. The azimuthal asymmetry is due to a combination of the longitudinal evolution of the shower and geometrical effects related to the angles of incidence of the particles into the detectors. The magnitude of the effect depends upon the zenith angle and state of development of the shower and thus provides a novel observable, $(\sec \theta)_\mathrm{max}$, sensitive to the mass composition of cosmic rays above $3 \times 10^{18}$ eV. By comparing measurements with predictions from shower simulations, we find for both of our adopted models of hadronic physics (QGSJETII-04 and EPOS-LHC) an indication that the mean cosmic-ray mass increases slowly with energy, as has been inferred from other studies. However, the mass estimates are dependent on the shower model and on the range of distance from the shower core selected. Thus the method has uncovered further deficiencies in our understanding of shower modelling that must be resolved before the mass composition can be inferred from $(\sec \theta)_\mathrm{max}$.Comment: Replaced with published version. Added journal reference and DO

The Pierre Auger Observatory: Contributions to the 34th International Cosmic Ray Conference (ICRC 2015)

Contributions of the Pierre Auger Collaboration to the 34th International Cosmic Ray Conference, 30 July - 6 August 2015, The Hague, The NetherlandsComment: 24 proceedings, the 34th International Cosmic Ray Conference, 30 July - 6 August 2015, The Hague, The Netherlands; will appear in PoS(ICRC2015