Using alignment with corporate strategy for the selection of a project portfolio based on ANP

Trabajo presentado al 14th International Symposium on the Analytic Hierarchy Process celebrado en Washington (US) del 29 de junio al 2 de julio de 2014.In this paper a new approach to prioritize project portfolio in an efficient and reliable way is presented. The research methodology is based on a combination of a synthesis of the literature across the diverse fields of project management, project alignment, multicriteria decision methods and a parallel analysis of an industrial case study. The paper introduces a rigorous methodology with acceptable complexity which seeks to assist managers of the National Electricity Corporation of Venezuela (Corpoelec) in their yearly resources' assignment on their projects portfolio. The aim being to determine the degree of alignment of each project to corporate strategy based on the judgments of a group of experts on the expected contribution of the projects to the business strategic objectives. The model presented can be used both as a descriptive and a prescriptive model. The approach presented uses project prioritization based on the multi-criteria decisionmaking technique called Analytic Network Process. Thus the corporate strategic objectives will be used as prioritization criteria to obtain the Relative Alignment Index (RAI).Peer Reviewe

A Bacterial Shortcut to Amyloidosis

21 p.-10 fig.The synthetic bacterial prionoid RepA-WH1 causes a vertically transmissible amyloid proteinopathy in Escherichia coli that inhibits growth and eventually kills the cells. Recent in vitro studies show that RepA-WH1 builds pores through model lipid membranes, suggesting a possible mechanism for bacterial cell death. By comparing acutely (A31V) and mildly (ΔN37) cytotoxic mutant variants of the protein, we report here that RepA-WH1(A31V) expression decreases the intracellular osmotic pressure and compromise bacterial viability under either aerobic or anaerobic conditions. Both are effects expected from threatening membrane integrity and are in agreement with findings on the impairment by RepA-WH1(A31V) of the proton motive force (PMF)-dependent transport of ions (Fe3+) and ATP1 synthesis. Systems approaches reveal that, in aerobiosis, the PMF-independent respiratory dehydrogenase NdhII is induced in response to the reduction in intracellular levels of iron. While NdhII is known to generate H2O2 as a by-product of the autoxidation of its FAD cofactor, key proteins in the defense against oxidative stress (OxyR, KatE), together with other stress-resistance factors, are sequestered by co-aggregation with the RepA-WH1(A31V) amyloid. Our findings suggest a route for RepA-WH1 toxicity in bacteria: a primary hit of damage to the membrane, compromising bionergetics, triggers a stroke of oxidative stress, which is exacerbated due to the aggregation-dependent inactivation of enzymes and transcription factors that enable the cellular response to such injury. The proteinopathy caused by the prion-like protein RepA-WH1 in bacteria recapitulates some of the core hallmarks of human amyloid diseases.This work has been supported by grants from Spanish AEI / EU-FEDER (BIO2012-30852, BIO2015- 68730-R and CSD2009-00088) and CSIC (i-LINK0889) to R.G. We acknowledge support of the publication fee by the CSIC Open Access Support Initiative through its Unit of Information Resources for Research (URICI).Peer reviewe

Misfolded α-Synuclein in Autosomal Dominant Alzheimer's Disease.

We analyzed Lewy body (LB) pathology in 18 autosomal dominant Alzheimer's disease (ADAD) brains via immunohistochemistry. Real-time quaking induced conversion was used to detect misfolded α-synuclein (α-syn) in 18 living ADAD cerebrospinal fluid (CSF) samples. Concomitant LB pathology was present in 44% ADAD brains. Only 6% CSF samples were positive for misfolded α-syn. In an additional AD sample, all patients with confirmed LB presented misfolded α-syn in postmortem CSF regardless of the LB staging. In conclusion, misfolded α-syn in CSF was scarce in symptomatic living ADAD individuals, in contrast to postmortem brain tissue. These results suggest late appearance of LB pathology in ADAD

LPA1 receptor and chronic stress: Effects on behaviour and the genes involved in the hippocampal excitatory/inhibitory balance.

The LPA1 receptor, one of the six characterized G protein-coupled receptors (LPA1-6) through which lysophosphatidic acid acts, is likely involved in promoting normal emotional behaviours. Current data suggest that the LPA-LPA1-receptor pathway may be involved in mediating the negative consequences of stress on hippocampal function. However, to date, there is no available information regarding the mechanisms whereby the LPA1 receptor mediates this adaptation. To gain further insight into how the LPA-LPA1 pathway may prevent the negative consequences of chronic stress, we assessed the effects of the continuous delivery of LPA on depressive-like behaviours induced by a chronic restraint stress protocol. Because a proper excitatory/inhibitory balance seems to be key for controlling the stress response system, the gene expression of molecular markers of excitatory and inhibitory neurotransmission was also determined. In addition, the hippocampal expression of mineralocorticoid receptor genes and glucocorticoid receptor genes and proteins as well as plasma corticosterone levels were determined. Contrary to our expectations, the continuous delivery of LPA in chronically stressed animals potentiated rather than inhibited some (e.g., anhedonia, reduced latency to the first immobility period), though not all, behavioural effects of stress. Furthermore, this treatment led to an alteration in the genes coding for proteins involved in the excitatory/inhibitory balance in the ventral hippocampus and to changes in corticosterone levels. In conclusion, the results of this study reinforce the assumption that LPA is involved in emotional regulation, mainly through the LPA1 receptor, and regulates the effects of stress on hippocampal gene expression and hippocampus-dependent behaviour.This study was supported by FEDER/Ministerio de Ciencia, Innovación y Universidades – Agencia Estatal de Investigación/__(PSI2017-83408-P) to C.P., Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía (SEJ1863 to C.P. and CTS-643 to G.E.-T), Consejería de Salud, Junta de Andalucía, (NICOLÁS MONARDE to G.E-T). Ministerio de Educación, Cultura y Deporte (FPU14/01610 to R.D.M.-F. and intramural funding from the EPFL to C.S

Systems biology of antioxidants

Understanding the role of oxidative injury will allow for therapy with agents that scavenge ROS (reactive oxygen species) and antioxidants in the management of several diseases related to free radical damage. The majority of free radicals are generated by mitochondria as a consequence of the mitochondrial cycle, whereas free radical accumulation is limited by the action of a variety of antioxidant processes that reside in every cell. In the present review, we provide an overview of the mitochondrial generation of ROS and discuss the role of ROS in the regulation of endothelial and adipocyte function. Moreover, we also discuss recent findings on the role of ROS in sepsis, cerebral ataxia and stroke. These results provide avenues for the therapeutic potential of antioxidants in a variety of diseases

Angiosarcoma of the nasal cavity: a case report

Angiosarcomas are malignant neoplasias of rapid growth that develop from endothelial cells. They represent 2% of all sarcomas and only 1–4% are located in the aerodigestive tract. Since 1977, only 16 cases have been reported

Evolución paleoambiental de la mitad sur de la Península Ibérica. Aplicación a la evaluación del comportamiento de los repositorios de residuos radiactivos

Esta publicación refleja los resultados obtenidos de la realización de los proyectos "EQUIP: Evidency from Quaternary Infills Palaeohydrogeology" (F 14W/ CT96/0031), financiado por la UE, "Evolución Paleoclimática de [a Mitad Sur de [a Península Ibérica" financiado por ENRESA y "Paleoclima" financiado por el Consejo de Seguridad Nuclear y ENRESA. La cuenca de Guadix-Baza, sector oriental, es una de las escasas zonas europeas donde se ha conservado un registro razonablemente completo del Pleistoceno. La cuenca de Guadix Baza, en régimen continental desde el Plioceno, funcionó bajo un régimen centrípeto, con abanicos aluviales en los bordes y una zona compleja lacustre en mosaico en su centro. Se ha podido establecer la existencia de una amplia variedad de facies aluviales y fluviales y sus interrelaciones. La sedimentación en el margen lacustre estaba constituida por arenas bioclásticas y lutitas con fósiles, mientras que en zonas más centrales predominaron lutitas yesíferas, lutitas con yeso intrasedimentario, arenas yesíferas yesos y, ocasionalmente, carbonatos que durante un período concreto depositaron los materiales que configuran el "Nivel Calcáreo de Orce", calizas y dolomías con cantidades variables de yeso y terrígenos cerca de los bordes. El trabajo de campo permitió el establecimiento de una serie estratigráfica tipo compuesta, que refleja los principales acontecimiento paleoambientales que tuvieron lugar durante el Pleistoceno. Con el fin de evitar la yesificación de la calcita y aragonito, propia del ambiente lacustre, la serie tipo de ha establecido en el registro del margen lacustre. Con ayuda del análisis paleomagnético y el análisis de la racemización de aminoácidos en conchas de moluscos y ostrácodos se ha establecido la cronología numérica de la sección estratigráfica tipo que cubre desde el límite Plioceno-Pleistoceno hasta unos 250 ka BP, cuando la erosión de la cabecera del río Fardes alcanza la cuenca abriéndola hacia el valle del Guadalquivir y cesando [a sedimentación lacustre. También se ha datado un depósito de terraza fluvial. Se han obtenido datos paleoambientales "instantáneos" mediante el estudio palinológico, el análisis paleobotánico de material silicificado (madera opalizada) o carbonizado (análisis paleoantracológico), el análisis geoquímico orgánico de algunos niveles especialmente favorables. La geoquímica orgánica de biomarcadores de algunos niveles concretos proporcionó datos sobre su origen (plantas terrestres o acuáticas) y confirmó que un conspicuo nivel carbonoso tuvo su origen en un incendio forestal. El análisis paleobiológico basado en la distribución de especies de ostrácodos, gasterópodos y pelecípodos ha permitido una primera aproximación paleoambiental, pese al evidente sesgo introducido por la presencia de fuentes salinas y materiales yesíferos en el área fuente de los abanicos aluviales del límite oriental de la cuenca. Esta interpretación se ha depurado mediante el estudio geoquímico inorgánico, isótopos estables y elementos traza de las conchas calcíticas de ostrácodos. Ello ha permitido el establecimiento de una alternancia de períodos "fríos y húmedos" y "cálidos y áridos" que permiten reconocer de las clases climáticas "mediterráneo seco" y "mediterráneo húmedo" sensu Horowitz (1989), que tienen sus correlatos en el registro paleoclimático de los grandes lagos del rift del Mar Muerto, el Mar Caspio y lagos pluviales de Norte América. La correlación de los datos isotópicos con las paleosalinidades deducidas del estudio de las inclusiones fluidas en yeso intrasedimentario ha permitido corroborar estas interpretaciones. Esto plantea un nuevo enfoque en el análisis del comportamiento de los repositorios de residuos radiactivos de alta

Dinosaur bonebed amber from an original swamp forest soil

Dinosaur bonebeds with amber content, yet scarce, offer a superior wealth and quality of data on ancient terrestrial ecosystems. However, the preserved palaeodiversity and/or taphonomic characteristics of these exceptional localities had hitherto limited their palaeobiological potential. Here, we describe the amber from the Lower Cretaceous dinosaur bonebed of Ariño (Teruel, Spain) using a multidisciplinary approach. Amber is found in both a root layer with amber strictly in situ and a litter layer mainly composed of aerial pieces unusually rich in bioinclusions, encompassing 11 insect orders, arachnids, and a few plant and vertebrate remains, including a feather. Additional palaeontological data¿charophytes, palynomorphs, ostracods¿ are provided. Ariño arguably represents the most prolific and palaeobiologically diverse locality in which fossiliferous amber and a dinosaur bonebed have been found in association, and the only one known where the vast majority of the palaeontological assemblage suffered no or low-grade pre-burial transport. This has unlocked unprecedentedly complete and reliable palaeoecological data out of two complementary windows of preservation¿the bonebed and the amber¿from the same site

High prognostic value of measurable residual disease detection by flow cytometry in chronic lymphocytic leukemia patients treated with front-line fludarabine, cyclophosphamide, and rituximab, followed by three years of rituximab maintenance

It has been postulated that monitoring measurable residual disease (MRD) could be used as a surrogate marker of progression-free survival (PFS) in chronic lymphocytic leukemia (CLL) patients after treatment with immunochemotherapy regimens. In this study, we analyzed the outcome of 84 patients at 3 years of follow-up after first-line treatment with fludarabine, cyclophosphamide and rituximab (FCR) induction followed by 36 months of rituximab maintenance thearpy. MRD was assessed by a quantitative four-color flow cytometry panel with a sensitivity level of 10-4. Eighty out of 84 evaluable patients (95.2%) achieved at least a partial response or better at the end of induction. After clinical evaluation, 74 patients went into rituximab maintenance and the primary endpoint was assessed in the final analysis at 3 years of follow-up. Bone marrow (BM) MRD analysis was performed after the last planned induction course and every 6 months in cases with detectable residual disease during the 36 months of maintenance therapy. Thirty-seven patients (44%) did not have detectable residual disease in the BM prior to maintenance therapy. Interestingly, 29 patients with detectable residual disease in the BM after induction no longer had detectable disease in the BM following maintenance therapy. After a median followup of 6.30 years, the median overall survival (OS) and PFS had not been reached in patients with either undetectable or detectable residual disease in the BM, who had achieved a complete response at the time of starting maintenance therapy. Interestingly, univariate analysis showed that after rituximab maintenance OS was not affected by IGHV status (mutated vs. unmutated OS: 85.7% alive at 7.2 years vs. 79.6% alive at 7.3 years, respectively). As per protocol, 15 patients (17.8%), who achieved a complete response and undetectable peripheral blood and BM residual disease after four courses of induction, were allowed to stop fludarabine and cyclophosphamide and complete two additional courses of rituximab and continue with maintenance therapy for 18 cycles. Surprisingly, the outcome in this population was similar to that observed in patients who received the full six cycles of the induction regimen. These data show that, compared to historic controls, patients treated with FCR followed by rituximab maintenance have high-quality responses with fewer relapses and improved OS. The tolerability of this regime is favorable. Furthermore, attaining an early undetectable residual disease status could shorten the duration of chemoimmunotherapy, reducing toxicities and preventing long-term side effects. The analysis of BM MRD after fludarabine-based induction could be a powerful predictor of post-maintenance outcomes in patients with CLL undergoing rituximab maintenance and could be a valuable tool to identify patients at high risk of relapse, influencing further treatment strategies