Assessing biological and methodological aspects of brain volume loss in multiple sclerosis

Importance: Before using brain volume loss (BVL) as a marker of therapeutic response in multiple sclerosis (MS), certain biological and methodological issues must be clarified. Objectives: To assess the dynamics of BVL as MS progresses and to evaluate the repeatability and exchangeability of BVL estimates with Jacobian Integration (JI) and Functional Magnetic Resonance Imaging of the Brain (FMRIB) Software Library (FSL) (specifically, the Structural Image Evaluation, Using Normalisation, of Atrophy-Cross-Sectional [SIENA-X] tool or FMRIB's Integrated Registration and Segmentation Tool [FIRST]). Design, Setting, and Participants: A cohort of patients who had either clinically isolated syndrome or MS was enrolled from February 2011 through October 2015. All underwent a series of annual magnetic resonance imaging (MRI) scans. Images from 2 cohorts of healthy volunteers were used to evaluate short-term repeatability of the MRI measurements (n = 34) and annual BVL (n = 20). Data analysis occurred from January to May 2017. Main Outcomes and Measures: The goodness of fit of different models to the dynamics of BVL throughout the MS disease course was assessed. The short-term test-retest error was used as a measure of JI and FSL repeatability. The correlations (R2) of the changes quantified in the brain using JI and FSL, together with the accuracy of the annual BVL cutoffs to discriminate patients with MS from healthy volunteers, were used to measure compatibility of imaging methods. Results: A total of 140 patients with clinically isolated syndrome or MS were enrolled, including 95 women (67.9%); the group had a median (interquartile range) age of 40.7 (33.6-48.1) years. Patients underwent 4 MRI scans with a median (interquartile range) interscan period of 364 (351-379) days. The 34 healthy volunteers (of whom 18 [53%] were women; median [IQR] age, 33.5 [26.2-42.5] years) and 20 healthy volunteers (of whom 10 [50%] were women; median [IQR] age, 33.0 [28.7-39.2] years) underwent 2 MRI scans within a median (IQR) of 24.5 (0.0-74.5) days and 384.5 (366.3-407.8) days for the short-term and long-term MRI follow-up, respectively. The BVL rates were higher in the first 5 years after MS onset (R2 = 0.65 for whole-brain volume change and R2 = 0.52 for gray matter volume change) with a direct association with steroids (β = 0.280; P = .02) and an inverse association with age at MS onset, particularly in the first 5 years (β = 0.015; P = .047). The reproducibility of FSL (SIENA) and JI was similar for whole-brain volume loss, while JI gave more precise, less biased estimates for specific brain regions than FSL (SIENA-X and FIRST). The correlation between whole-brain volume loss using JI and FSL was high (R2 = 0.92), but the same correlations were poor for specific brain regions. The area under curve of the whole-brain volume change to discriminate between patients with MS and healthy volunteers was similar, although the thresholds and accuracy index were distinct for JI and FSL. Conclusions and Relevance: The proposed BVL threshold of less than 0.4% per year as a marker of therapeutic efficiency should be reconsidered because of the different dynamics of BVL as MS progresses and because of the limited reproducibility and variability of estimates using different imaging methods

Protocolo de implementación del LMyS : implementación del laboratorio de modelamiento y simulación

La creación del Laboratorio de Modelamiento y Simulación (LMyS) se lleva a cabo con el objeto de adelantar investigación original y apoyar los proyectos en desarrollo dentro de la Facultad de Administración, mediante el modelamiento desde las ciencias de la complejidad y la matemática no clásica. Este desarrollo obedece a la necesidad de dar respuestas a la realidad cambiante y dinámica en la que los modelos tradicionales no han dado una respuesta satisfactoria o suficiente. Gracias al LMyS se materializan los avances y desarrollos de los grupos de investigación de la Facultad a través del modelamiento y simulación con lógicas no-clásicas (modal, difusa, paraconsistente y lógica cuántica, entre otras), que permitan posteriormente producir a nivel computacional implementaciones de estos modelos. De este modo, mediante las contribuciones del LMyS se busca que, por un lado, exista innovación en el conocimiento con el rigor apropiado y a niveles mundiales en el estudio de los sistemas dinámicos modelados a partir de las organizaciones, y, por otro, se erija como una herramienta para el sector empresarial y productivo en los procesos de toma de decisión. Al mismo tiempo que adelanta investigaciones que conducen a, y se condensan en, registros y patentes, el LMyS quiere contribuir al apoyo a la investigación en la disciplina de la administración. Así, el LMyS hace parte del gran proyecto de la Facultad de Administración de la Universidad del Rosario que le permitirá abordar problemáticas actuales y futuras, en torno a la dinámica económica y social, pero con enfoques igualmente políticos, financieros y otros en el marco de un mundo caracterizado por una enorme complejidad (creciente). El desarrollo de la investigación de la Facultad de Administración tiene como una gran influencia las ciencias de la complejidad, tratando de entregar a la comunidad empresarial herramientas, modelos o perspectivas diferentes que le permitan enfrentar la incertidumbre y disminuir los niveles de riesgo

Predictors of vision impairment in Multiple Sclerosis.

Visual impairment significantly alters the quality of life of people with Multiple Sclerosis (MS). The objective of this study was to identify predictors (independent variables) of visual outcomes, and to define their relationship with neurological disability and retinal atrophy when assessed by optical coherence tomography (OCT). We performed a cross-sectional analysis of 119 consecutive patients with MS, assessing vision using high contrast visual acuity (LogMar), 2.5% and 1.25% low contrast visual acuity (Sloan charts), and color vision (Hardy-Rand-Rittler plates). Quality of vision is a patient reported outcome based on an individual's unique perception of his or her vision and was assessed with the Visual Functioning Questionnaire-25 (VFQ-25) with the 10 neuro-ophthalmologic items. MS disability was assessed using the expanded disability status scale (EDSS), the MS functional composite (MSFC) and the brief repetitive battery-neuropsychology (BRB-N). Retinal atrophy was assessed using spectral domain OCT, measuring the thickness of the peripapillar retinal nerve fiber layer (pRNFL) and the volume of the ganglion cell plus inner plexiform layer (GCIPL). The vision of patients with MS was impaired, particularly in eyes with prior optic neuritis. Retinal atrophy (pRNFL and GCIPL) was closely associated with impaired low contrast vision and color vision, whereas the volume of the GCIPL showed a trend (p = 0.092) to be associated with quality of vision. Multiple regression analysis revealed that EDSS was an explanatory variable for high contrast vision after stepwise analysis, GCIPL volume for low contrast vision, and GCIPL volume and EDSS for color vision. The explanatory variables for quality of vision were high contrast vision and color vision. In summary, quality of vision in MS depends on the impairment of high contrast visual acuity and color vision due to the disease

Dissecting the long-term emission behaviour of the BL Lac object Mrk 421

We report on long-term multiwavelengthmonitoring of blazar Mrk 421 by the GLAST-AGILE Support Program of the Whole Earth Blazar Telescope (GASP-WEBT) collaboration and Steward Observatory, and by the Swift and Fermi satellites. We study the source behaviour in the period 2007–2015, characterized by several extreme flares. The ratio between the optical, X-ray and γ -ray fluxes is very variable. The γ -ray flux variations show a fair correlation with the optical ones starting from 2012.We analyse spectropolarimetric data and find wavelengthdependence of the polarization degree (P), which is compatible with the presence of the host galaxy, and no wavelength dependence of the electric vector polarization angle (EVPA). Optical polarimetry shows a lack of simple correlation between P and flux and wide rotations of the EVPA.We build broad-band spectral energy distributions with simultaneous near-infrared and optical data from the GASP-WEBT and ultraviolet and X-ray data from the Swift satellite. They show strong variability in both flux and X-ray spectral shape and suggest a shift of the synchrotron peak up to a factor of ∼50 in frequency. The interpretation of the flux and spectral variability is compatible with jet models including at least two emitting regions that can change their orientation with respect to the line of sight.http://10.0.4.69/mnras/stx2185Accepted manuscrip

Balancing groundwater conservation and rural livelihoods under water and climate uncertainties: An integrated hydro-economic modeling framework

In arid countries worldwide, social conflicts between irrigation-based human development and the conservation of aquatic ecosystems are widespread and attract many public debates. This research focuses on the analysis of water and agricultural policies aimed at conserving groundwater resources and maintaining rurallivelihoods in a basin in Spain's central arid region. Intensive groundwater mining for irrigation has caused overexploitation of the basin's large aquifer, the degradation of reputed wetlands and has given rise to notable social conflicts over the years. With the aim of tackling the multifaceted socio-ecological interactions of complex water systems, the methodology used in this study consists in a novel integration into a common platform of an economic optimization model and a hydrology model WEAP (Water Evaluation And Planning system). This robust tool is used to analyze the spatial and temporal effects of different water and agricultural policies under different climate scenarios. It permits the prediction of different climate and policy outcomes across farm types (water stress impacts and adaptation), at basin's level (aquifer recovery), and along the policies’ implementation horizon (short and long run). Results show that the region's current quota-based water policies may contribute to reduce water consumption in the farms but will not be able to recover the aquifer and will inflict income losses to the rural communities. This situation would worsen in case of drought. Economies of scale and technology are evidenced as larger farms with cropping diversification and those equipped with modern irrigation will better adapt to water stress conditions. However, the long-term sustainability of the aquifer and the maintenance of rurallivelihoods will be attained only if additional policy measures are put in place such as the control of illegal abstractions and the establishing of a water bank. Within the policy domain, the research contributes to the new sustainable development strategy of the EU by concluding that, in water-scarce regions, effective integration of water and agricultural policies is essential for achieving the water protection objectives of the EU policies. Therefore, the design and enforcement of well-balanced region-specific polices is a major task faced by policy makers for achieving successful water management that will ensure nature protection and human development at tolerable social costs. From a methodological perspective, this research initiative contributes to better address hydrological questions as well as economic and social issues in complex water and human systems. Its integrated vision provides a valuable illustration to inform water policy and management decisions within contexts of water-related conflicts worldwide

Multi-wavelength landscape of the young galaxy cluster RX J1257.2+4738 at z = 0.866 I. The infrared view

Context. Many studies have shown how galaxy properties (e.g. colours, morphology, star-forming (SF) activity, active galactic nuclei population) change not only with redshift, but also with local galaxy density, revealing the important effect of the stellar/halo mass and the environment in the evolution of galaxies. A detailed analysis of the star formation activity in a representative sample of clusters will help us to understand the physical processes that cause the observed changes. Aims. We performed a thorough analysis of the star formation activity in the young massive galaxy cluster RX J1257+4738 at z = 0.866, with emphasis on the relationship between the local environment of the cluster galaxies and their star formation activity. We present an optical and infrared (IR) study that benefited from the large amount of data available for this cluster, including new OSIRIS/GTC and Herschel imaging observations. Methods. Using a multi-wavelength catalogue from the optical to the near-infrared, we measured photometric redshifts through a χ2 spectral energy distribution fitting procedure. We implemented a reliable and carefully chosen cluster membership selection criterion including Monte Carlo simulations and derived a sample of 292 reliable cluster member galaxies for which we measured the following properties: optical colours, stellar masses, ages, ultraviolet luminosities and local densities. Using the MIPS 24 μm and Herschel data, we measured total IR luminosities and star formation rates (SFRs). Results. Of the sample of 292 cluster galaxies, 38 show far-infrared (FIR) emission with an SFR between 0.5 and 45 M⊙ yr-1. The spatial distribution of the FIR emitters within the cluster density map and the filament-like overdensities observed suggest that RX J1257 is not virialised, but is in the process of assembly. The average star formation as a function of the cluster environment parametrised by the local density of galaxies does not show any clear trend. However, the fraction of SF galaxies unveils that the cluster intermediate-density regions is preferred for the SF activity to enhance, since we observe a significant increase of the FIR-emitter fraction in this environment. The analysis of the extinction distributions of the optically red and blue SF galaxies supports the assumption of the red SF galaxies as a dusty population

Ablation of Dido3 compromises lineage commitment of stem cells in vitro and during early embryonic development

The death inducer obliterator (Dido) locus encodes three protein isoforms, of which Dido3 is the largest and most broadly expressed. Dido3 is a nuclear protein that forms part of the spindle assembly checkpoint (SAC) and is necessary for correct chromosome segregation in somatic and germ cells. Here we report that specific ablation of Dido3 function in mice causes lethal developmental defects at the onset of gastrulation. Although these defects are associated with centrosome amplification, spindle malformation and a DNA damage response, we provide evidence that embryonic lethality of the Dido3 mutation cannot be explained by its impact on chromosome segregation alone. We show that loss of Dido3 expression compromises differentiation of embryonic stem cells in vitro and of epiblast cells in vivo, resulting in early embryonic death at around day 8.5 of gestation. Close analysis of Dido3 mutant embryoid bodies indicates that ablation of Dido3, rather than producing a generalized differentiation blockade, delays the onset of lineage commitment at the primitive endoderm specification stage. The dual role of Dido3 in chromosome segregation and stem cell differentiation supports the implication of SAC components in stem cell fate decisions

Rab18 Dynamics in Adipocytes in Relation to Lipogenesis, Lipolysis and Obesity

Lipid droplets (LDs) are organelles that coordinate lipid storage and mobilization, both processes being especially important in cells specialized in managing fat, the adipocytes. Proteomic analyses of LDs have consistently identified the small GTPase Rab18 as a component of the LD coat. However, the specific contribution of Rab18 to adipocyte function remains to be elucidated. Herein, we have analyzed Rab18 expression, intracellular localization and function in relation to the metabolic status of adipocytes. We show that Rab18 production increases during adipogenic differentiation of 3T3-L1 cells. In addition, our data show that insulin induces, via phosphatidylinositol 3-kinase (PI3K), the recruitment of Rab18 to the surface of LDs. Furthermore, Rab18 overexpression increased basal lipogenesis and Rab18 silencing impaired the lipogenic response to insulin, thereby suggesting that this GTPase promotes fat accumulation in adipocytes. On the other hand, studies of the β-adrenergic receptor agonist isoproterenol confirmed and extended previous evidence for the participation of Rab18 in lipolysis. Together, our data support the view that Rab18 is a common mediator of lipolysis and lipogenesis and suggests that the endoplasmic reticulum (ER) is the link that enables Rab18 action on these two processes. Finally, we describe, for the first time, the presence of Rab18 in human adipose tissue, wherein the expression of this GTPase exhibits sex- and depot-specific differences and is correlated to obesity. Taken together, these findings indicate that Rab18 is involved in insulin-mediated lipogenesis, as well as in β-adrenergic-induced lipolysis, likely facilitating interaction of LDs with ER membranes and the exchange of lipids between these compartments. A role for Rab18 in the regulation of adipocyte biology under both normal and pathological conditions is proposed