Metabolic changes upon GLS inhibition by CB-839 in glioma cell lines

Many tumors use Gln for both energy generation and as a biosynthetic precursor. Glutaminases (GAs) catalyze the first step of glutaminolysis by converting glutamine (Gln) into glutamate and ammonia in the mitochondria. In humans, two genes encode for glutaminases: GLS and GLS2. We examined the metabolic consequences of inhibiting GLS activity in glioma cells by using the clinically relevant inhibitor CB-839. We treated three glioblastoma (GBM) cell lines with CB-839 and performed untargeted metabolomics and isotope tracing experiments using U-13C-labeled Gln and 15N-labeled Gln in the amido group to ascertain the metabolic fates of Gln carbon and nitrogen. Untargeted metabolomics results showed that CB-839 treatment significantly depleted tricarboxylic acid cycle (TCAC) intermediates and related metabolites in the three human glioblastoma cell lines assayed. This result was also confirmed by a lower labeling from U-13C- Gln in these metabolites. U-13C- Gln tracing also revealed reductive carboxylation-related labeling in these cell lines, and this pathways was also suppressed by CB-839. Metabolomics results showed an accumulation of the de novo purine biosynthesis intermediates inosine monophosphate and/or AICAR, and a decrease in uridine monophosphate, while 15N-Gln tracing results showed a decreased labeling from Gln amido group in AMP, GMP, UMP and CTP in T98G cell line when treated with CB-839. Finally, metabolomics showed higher levels of trimethyllysine and, in T98G cells, a 22-fold increase in 5-methyl-cytosine.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Antioxidant responses related to temozolomide resistance in glioblastoma

Ministerio de Ciencia, Innovación y Universidades; Universidad de Málaga CBUA.Glioblastoma remains one of the most challenging and devastating cancers, with only a very small proportion of patients achieving 5-year survival. The current standard of care consists of surgery, followed by radiation therapy with concurrent and maintenance chemotherapy with the alkylating agent temozolomide. To date, this drug is the only one that provides a significant survival benefit, albeit modest, as patients end up acquiring resistance to this drug. As a result, tumor progression and recurrence inevitably occur, leading to death. Several factors have been proposed to explain this resistance, including an upregulated antioxidant system to keep the elevated intracellular ROS levels, a hallmark of cancer cells, under control. In this review, we discuss the mechanisms of chemoresistance -including the important role of glioblastoma stem cells-with emphasis on antioxidant defenses and how agents that impair redox balance (i.e.: sulfasalazine, erastin, CB-839, withaferin, resveratrol, curcumin, chloroquine, and hydroxychloroquine) might be advantageous in combined therapies against this type of cancer.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Rapid decrease in titer and breadth of neutralizing anti-HCV antibodies in HIV/HCV-coinfected patients who achieved SVR

The main targets for neutralizing anti-hepatitis C virus (HCV) antibodies (HCV-nAbs) are the E1 and E2 envelope glycoproteins. We have studied the characteristics of HCV-nAbs through a retrospective study involving 29 HIV/HCV-coinfected patients who achieved sustained virological response (SVR) with pegIFNα+ribavirin anti-HCV therapy. Plasma samples at baseline and week 24 after SVR were used to perform neutralization assays against fve JFH1-based HCV recombinant viruses coding for E1 and E2 from genotypes 1a (H77), 1b (J4), 2a (JFH1), 3a (S52) and 4a (ED43). At baseline, the majority of plasma samples neutralized 1a, 1b, 2a, and 4a, but not 3a, genotypes. Twenty-four weeks following SVR, most neutralizing titers declined substantially. Furthermore, titers against 3a and 2a were not detected in many patients. Plasma samples with high HCV-nAb titers neutralized all genotypes, and the highest titers at the starting point correlated with the highest titers at week 24 after SVR. In conclusion, high titers of broad-spectrum HCV-nAbs were detected in HIV/HCV-coinfected individuals, however, those titers declined soon after SVRThis study was supported by grants from Instituto de Salud Carlos III (ISCIII; grant numbers PI14/01094 and PI17/00657 to JB, PI17/00903 to JGG, PI14CIII/00011 and PI17CIII/00003 to SR) and Ministerio de Sanidad, Servicios Sociales e Igualdad (grant number EC11-241). Te study was also funded by the RD16CIII/0002/0002, RD16/0025/0018, and RD16/0025/0017 projects as part of the Plan Nacional R+D+I and co-funded by ISCIII- Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER

Metabolic Adjustments following Glutaminase Inhibition by CB-839 in Glioblastoma Cell Lines

Glioblastoma multiforme is the most common primary brain tumor. Unfortunately, it is also one of the cancer types that has the worst morbidity and mortality ratios, so new targets and treatments need to be found. The metabolism of glutamine is fundamental for the proliferation of many tumor cells, including glioblastomas. Glutaminase isoenzyme GLS is one of the responsible enzymes for the pro-oncogenic pathways that induce metabolic reprogramming and leads to altered levels of some amino acids and other key intermediary metabolites in glioblastoma. Using the clinically approved GLS inhibitor CB-839 (Telaglenastat), we found significant changes in glutamine metabolism, including both the oxidative and reductive fates of Gln-derived alpha-ketoglutarate in the tricarboxylic acid cycle, in three glioblastoma cell lines. One of them, the T98G glioblastoma cell line, showed the greatest modification of metabolite levels involved in the de novo biosynthetic pathways for nucleotides, as well as a higher content of methylated and acetylated metabolites.This research was funded by Ministerio de Ciencia y Tecnología of Spain, grant number RTI2018-096866-B-I00 (to J.M.M. and J.M.) and Junta de Andalucía, Grant UMA18-FEDERJA-082 (to J.M.). R.J.D. is supported by the Howard Hughes Medical Institute, the National Cancer Institute (R35CA220444901), the Cancer Prevention and Research Institute of Texas, and the Moody Foundation. J.D.l.S.-J. is granted by FPU17/04084, Ministerio de Ciencia, Innovación y Universidades. Partial funding for open access charge: Universidad de Málag

Relación altura-diámetro para Abies religiosa Kunth Schltdl. & Cham. en el centro y sur de México

La altura total de los árboles es una variable importante en silvicultura y manejo forestal; sin embargo, su medición en campo es relativamente difícil y costosa. El objetivo de la presente investigación fue desarrollar una ecuación altura-diámetro que permita estimar de forma precisa la altura de árboles de Abies religiosa en el centro y sur de México. Para el ajuste de ecuaciones locales se utilizó un tamaño de muestra de 2 747 datos, que son suficientes para describir el comportamiento de las curvas sobre la variabilidad natural de la altura total de los individuos. Para la selección del mejor modelo se fijaron los siguientes criterios: coeficiente de determinación ajustada, sesgo, error medio; así como, el análisis gráfico y numérico de los residuales. La explicación de las variables independientes de cada modelo fue altamente aceptable, ya que todos fueron superiores (R2adj=0.96), además de presentar errores (REMC) por debajo de 0.44 metros y con sesgos cercanos a cero. Aunado a lo anterior, el modelo de Bates y Watts fue seleccionado mediante el análisis gráfico. Este tipo de ecuación es aplicable en las diferentes unidades de manejo forestal del país para trabajos de inventarios forestales; ya que reduce el tiempo, costo y, a su vez, minimizan los errores de campo

The morphometric acclimation to depth explains the long-term resilience of the seagrass Cymodocea nodosa in a shallow tidal lagoon

Cadiz Bay is a shallow mesotidal lagoon with extensive populations of the seagrass Cymodocea nodosa at intertidal and shallow subtidal elevations. This work aims to understand the mechanisms behind the resilience of this species to gradual sea level rise by studying its acclimation capacity to depth along the shallow littoral, and therefore, to gradual variations in the light environment. To address this objective, these populations have been monitored seasonally over a 10 year period, representing the longest seasonal database available in the literature for this species. The monitoring included populations at 0.4, -0.08 and -0.5 m LAT. The results show that C. nodosa has a strong seasonality for demographic and shoot dynamic properties - with longer shoots and larger growth in summer (high temperature) than in winter (low temperature), but also some losses. Moreover, shoots have different leaf morphometry depending on depth, with small and dense shoots in the intertidal areas (0.4 m) and sparse large shoots in the subtidal ones (-0.08 and 0.5 m). These differences in morphometry and shoot dynamic properties, combined with the differences in shoot density, explain the lack of differences in meadow production balance (i.e. meadow growth - meadow losses) between the intertidal (0.4 m) and the deepest population (-0.5 m), supporting the long term resilience of Cymodocea nodosa in Cadiz Bay. This study contributes to the understanding of the mechanisms behind seagrass stability and resilience, which is particularly important towards predicting the effects of climate change on these key coastal ecosystems, and also highlights the value of continuous long-term monitoring efforts to evaluate seagrass trajectories

Different HCV Exposure Drives Specific miRNA Profile in PBMCs of HIV Patients

Micro RNAs (miRNAs) are essential players in HIV and HCV infections, as both viruses modulate cellular miRNAs and interact with the miRNA-mediated host response. We aim to analyze the miRNA profile of HIV patients with different exposure to HCV to explore specific signatures in the miRNA profile of PBMCs for each type of infection. We massively sequenced small RNAs of PBMCs from 117 HIV+ infected patients: 45 HIV+ patients chronically infected with HCV (HIV/HCV+), 36 HIV+ that spontaneously clarified HCV after acute infection (HIV/HCV-) and 36 HIV+ patients without previous HCV infection (HIV). Thirty-two healthy patients were used as healthy controls (HC). Differential expression analysis showed significantly differentially expressed (SDE) miRNAs in HIV/HCV+ (n = 153), HIV/HCV- (n = 169) and HIV (n = 153) patients. We found putative dysregulated pathways, such as infectious-related and PI3K signaling pathways, common in all contrasts. Specifically, putatively targeted genes involved in antifolate resistance (HIV/HV+), cancer-related pathways (HIV/HCV-) and HIF-signaling (HIV) were identified, among others. Our findings revealed that HCV strongly influences the expression profile of PBMCs from HIV patients through the disruption of its miRNome. Thus, different HCV exposure can be identified by specific miRNA signatures in PBMCs.This work has been supported by grants from Institute of Health Carlos III, [PI15CIII/00031 and PI18CIII/00020/ to AFR and VB] and the Foundation Universidad Alfonso X el Sabio-Santander [grant number 1.010.932 to AFR] and the Spanish AIDS Research Network (RD16CIII/0002/0002), and Centro de Investigación Biomédica en Red (CIBER) en Enfermedades Infecciosas (CB21/13/00044). AFR is supported by the Miguel Servet programme from Fondo de Investigación Sanitaria (ISCIII) [CP14/CIII/00010 and CPII20CIII/0001].info:eu-repo/semantics/publishedVersio

The MEDESS-GIB database: Tracking the Atlantic water inflow

On 9 September 2014, an intensive drifter deployment was carried out in the Strait of Gibraltar. In the frame of the MEDESS-4MS Project (EU MED Program), the MEDESS-GIB experiment consisted of the deployment of 35 satellite tracked drifters, mostly of CODE-type, equipped with temperature sensor sampling at a rate of 30min. Drifters were distributed along and on both sides of the Strait of Gibraltar. The MEDESS-GIB deployment plan was designed as to ensure quasi-synoptic spatial coverage. To this end, four boats covering an area of about 680NM2 in 6h were coordinated. As far as these authors know, this experiment is the most important exercise in the area in terms of number of drifters released. Collected satellite-tracked data along drifter trajectories have been quality controlled and processed to build the presented MEDESS-GIB database. This paper reports the MEDESS-GIB data set that comprises drifter trajectories, derived surface currents and in situ SST measurements collected along the buoys tracks. This series of data is available through the PANGAEA (Data Publisher for Earth and Environmental Science) repository, with the following doi:10.1594/PANGAEA.853701. Likewise, the MEDESS-GIB data will be incorporated as part of the Copernicus Marine historical products. The MEDESS-GIB data set provides a complete Lagrangian view of the surface inflow of Atlantic waters through the Strait of Gibraltar and thus, very useful data for further studies on the surface circulation patterns in the Alboran Sea, and their links with one of the most energetic Mediterranean Sea flows: the Algerian Current

HCV eradication with DAAs differently affects HIV males and females: A whole miRNA sequencing characterization

Gender-specific consequences after HCV eradication are unexplored. MicroRNAs (miRNAs) play a crucial role in the immune response against viral infections. However, few have highlighted miRNA role in sex-biased disease or therapy response. We aim to assess gender differences reflected in the miRNA expression of HIV/HCV-coinfected patients who achieve sustained virological response (SVR) with direct acting antivirals (DAAs). We conducted a prospective study of miRNA expression in PBMCs from 28 chronic HIV/HCV-coinfected patients (HIV/HCV) at baseline and after achieving SVR with DAAs. Sixteen HIV-monoinfected patients (HIV) and 36 healthy controls (HC) were used as controls. Identification of significant differentially expressed (SDE) miRNAs was performed with generalized linear model and mixed GLMs. We also explored putative dysregulated biological pathways. At baseline, the HIV/HCV patients showed differences in the miRNA profile concerning the HIV group (165 and 102 SDE miRNAs for males and females, respectively). Gender-stratified analysis of HIV/HCV group at baseline versus at SVR achievement showed higher differences in males (80 SDE miRNAs) than in females (55 SDE miRNAs). After SVR, HIV/HCV group showed similar values to HIV individuals, especially in females (1 SDE miRNA). However, ten miRNAs in males remained dysregulated, which were mainly involved in cancer, fatty acid, and inflammatory pathways. Taken together, our results show gender-biased dysregulation in the miRNA expression profile of PBMCs after HCV eradication with DAAs. These differences were normalized in females, while miRNA profile and their target-related pathways in males lack of normalization, which may be related to a high-risk of developing liver-related complications

Cultural Heritage in Europe: A commitment for socioeconomic change from managing our past II

Diseño web, apoyo RRSS: Empresa Jansá Cultura y Tecnología https://appcultura.comEl proyecto formará en el Patrimonio Cultural existente en la Unión Europea desde su gestión. Supone actividades como: 1. Conocer los bienes culturales desde la visión crítica de los procesos de patrimonialización hasta la catalogación e inventario. 2 Planificar su financiación, legislación o la ordenación urbanística y territorial. 3. Controlar las acciones ilícitas que pueden deteriorarlos, así como la venta o la transmisión de estos bienes. 4. Plantear su socialización desde la interpretación y la difusión en ámbitos formales e informales, desde estrategias de turismo, tecnológicas o de redes sociales, así como realizar procesos participativos, de implicación de la sociedad civil y organizaciones interesadas en la toma de decisiones sobre su tratamiento. 5. Ser capaces de evaluar a corto, largo y medio plazo y desde múltiples perspectivas, incluida la del impacto socioeconómico. De la importancia del tema habla por si sola la declaración del Parlamento Europeo para la celebración del Año 2018 y que reproducimos (http://www.consilium.europa.eu/es/press/press-releases/2017/02/09-cultural-heritage/): " Año Europeo del Patrimonio Cultural en 2018: celebración de la diversidad y la riqueza de nuestro patrimonio europeo, cuyos objetivos son: - Promover la diversidad cultural, el diálogo intercultural y la cohesión social; - Poner de relieve la contribución económica del patrimonio cultural a los sectores cultural y de la creación, en particular a las pequeñas y medianas empresas, y al desarrollo local y regional; - Hacer hincapié en el papel del patrimonio cultural en las relaciones exteriores de la UE, por ejemplo, en la prevención de conflictos, la reconciliación tras estos y la reconstrucción del patrimonio cultural destruido " Abordar estos temas requiere una formación transdisciplinar, que aporta el equipo de docentes de la Universidad Complutense de Madrid y de la Universidad Politécnica de Madrid pertenecientes a las siguientes áreas de conocimiento: historia, historia del arte, geografía, arqueología, economía, sociología, psicología, derecho, arquitectura, ingeniería de las telecomunicaciones y de caminos, canales y puertos. A ellos se le suma una trayectoria de cerca de 30 años en los temas referidos, siendo nuestros centros pioneros en España para impartir esa formación y sin lugar a dudas innovadores en la transversalidad con la que las hemos impulsado en nuestras distintas facultades y escuelas, donde no existe el área de conocimiento como tal. Participamos miembros de varios grupos de investigación, como el de Gestión del Patrimonio Cultural, Patrimonio Turismo y Desarrollo o Paisajes Culturales. Destacan responsabilidades y docencias en Másteres como el de Conservación y Restauración en Patrimonio Arquitectónico, de la UPM o el de Museos y Patrimonio Histórico Artístico de la UCM, lineas de doctorado en Turismo y Desarrollo, asignaturas de grado y posgrados como Patrimonio Urbano, Paisaje Cultural y Ordenación Territorial o la gestión del patrimonio arqueológico. Así mismo la mayoría de nosotros hemos sido evaluados positivamente por el programa Docentia, y hemos participado y dirigido otros proyectos de innovación como el que se encuentra en los antecedentes a este sobre Patrimonio Cultural en CIU y el del decanato de la Fac. Geografía e Historia de Living Unilab sobre APs y ecosistemas de aprendizaje. Iniciativas con las que continuaremos participando. Pero, sin lugar a dudas, ha sido el Máster Interuniversitario Patrimonio Cultural en el S.XXI: Gestión e investigación, un motor de arranque para iniciativas conjuntas entre este equipo, a través del Campus de Excelencia Internacional, y es justo este año cuando se pone en marcha y podremos allí explorar gran parte de nuestras innovaciones recogidas en este proyecto. A estos esfuerzos se suma el alumnado: 13 estudiantes de grados y posgrados comprometidxs con la oportunidad que nos ofrece el pasado. No hay mejor aval para nuestra propuesta.The Educational Innovation Project “Cultural Heritage in Europe: a commitment for socioeconomic change from managing our past” of the Complutense University of Madrid together with the Technical University of Madrid, took advantage of the celebration of the European Year of Cultural Heritage 2018 to open new paths of transversal and multidisciplinary knowledge in the field of Cultural Heritage by applying a type of classroom teaching that would allow students to offer projects that could have an impact on society and contribute to meeting the objectives set by the European Commission for this year's celebration. From a European perspective, the project has completed a triple aspect: researcher, education and public service when working and disseminating Cultural Heritage among the population of Madrid and Europe. The work has been done on disciplines as diverse as Architecture, History, Civil Engineering, Geography, Tourism, etc. to compose from the different subjects involved a speech that will contribute to this field.Depto. de Prehistoria, Historia Antigua y ArqueologíaFac. de Geografía e HistoriaFALSEAyuntamiento de Madrid/Foro de Empresas por Madridsubmitte