Antibody mediated neutralization of myelin associated EphrinB3 accelerates CNS remyelination

This is the final version of the article. It was first available from Springer via http://dx.doi.org/10.1007/s00401-015-1521-1Remyelination in multiple sclerosis (MS) lesions often remains incomplete despite the presence of oligodendrocyte progenitor cells (OPCs). Amongst other factors, successful remyelination depends on the phagocytic clearance of myelin debris. However, the proteins in myelin debris that act as potent and selective inhibitors on OPC differentiation and inhibit CNS remyelination remain unknown. Here, we identify the transmembrane signalling protein EphrinB3 as important mediator of this inhibition, using a protein analytical approach in combination with a primary rodent OPC assay. In the presence of EphrinB3, OPCs fail to differentiate. In a rat model of remyelination, infusion of EphrinB3 inhibits remyelination. In contrast, masking EphrinB3 epitopes using antibodies promotes remyelination. Finally, we identify EphrinB3 in MS lesions and demonstrate that MS lesion extracts inhibit OPC differentiation while antibody-mediated masking of EphrinB3 epitopes promotes it. Our findings suggest that EphrinB3 could be a target for therapies aiming at promoting remyelination in demyelinating disease.This work was supported by the UK MS Society Grant ref: 941/11. MRNK held a NIHR Clinical Lectureship. KAN was supported by an ERC advanced award

Experiencias y comprensiones sobre violencias contra mujeres jóvenes : relatos de mujeres entre 18 y 29 años en la ciudad de Bogotá

La violencia contra mujeres jóvenes es una problemática social que ha incrementado en los últimos años, ya que las mujeres entre los 18 y 29 años son las víctimas más frecuentes de violencia basada en género. Para el año 2013, en Colombia el más alto número de mujeres asesinadas se encontraban entre los 15 y 29 años. Sin embargo, es notable el bajo índice de denuncia de hechos de violencia contra mujeres en esta etapa del ciclo vital. Por tanto, esta investigación indaga sobre experiencias y comprensiones relativas a las violencias contra las mujeres relatadas por mujeres jóvenes entre 18 y 29 años en la ciudad de Bogotá. Para el análisis de los relatos se acude a la perspectiva de género y a categorías como subjetividad femenina, violencia contra mujeres y ámbito público-privado. Se utiliza una metodología con enfoque cualitativo y se diseña un cuestionario con 24 preguntas que fue aplicado a 40 mujeres de todos los estratos socioeconómicos, divididas en dos rangos de edades: entre 18 y 23 años, y entre 24 y 29 años, posteriormente, se realizó un grupo focal con seis mujeres. Se identifica que los tipos de violencia psicológica, sexual y física son las que más afectan a las mujeres jóvenes. Igualmente se hace evidente que, si bien las jóvenes reconocen y son conscientes sobre situaciones y tipos de violencias en lugares públicos y privados en los que se sienten o están efectivamente en riesgo, la persistencia de roles estereotipados de género coexisten con discursos contradictorios de contenido relativamente emancipatorio respecto a condiciones históricas y culturales que configuran sus subjetividades, lo cual incide de manera negativa respecto a prácticas de autoprotección y de denuncia.Violence against young women is a social issue that has increased in the last few years, women between the ages of 18 and 29 are the most frequent victims of gender-based violence. In 2013, the highest number of murdered women in Colombia was between the ages of 15 and 29. However the report rate of these violent crimes against women at this stage of their life cycle is notably low. Therefore, this investigation is about experiences related to violence against women, described by young women between the ages of 18 and 29 in the city of Bogota. For the analysis of the stories, we resort to gender perspective and categories like feminine subjectivity, violence against women, and the public-private sector. We opted for a method with a qualitative focus and designed a questionnaire with 24 questions that was presented to 40 women of all the socioeconomic levels, divided in two age groups: between 18 and 23, and between 24 and 29, afterwards we formed a focal group of six women. We identified that the types of violence that most affects young women are psychological, sexual, and physical. Likewise, it s evident that if young women recognize and are conscious about situations and types of violence in public and private places in which they feel or are in fact at risk, the persistence of stereotypical gender roles coexist with contradictory speeches of relatively emancipatory content regarding historical and cultural conditions that configure their subjectivity, which influences them in a negative way regarding practices of autoprotection and reporting of crimes.Psicólogo (a)Pregrad

VEGF/VEGFR2 signaling regulates hippocampal axon branching during development.

Axon branching is crucial for proper formation of neuronal networks. Although originally identified as an angiogenic factor, VEGF also signals directly to neurons to regulate their development and function. Here we show that VEGF and its receptor VEGFR2 (also known as KDR or FLK1) are expressed in mouse hippocampal neurons during development, with VEGFR2 locally expressed in the CA3 region. Activation of VEGF/VEGFR2 signaling in isolated hippocampal neurons results in increased axon branching. Remarkably, inactivation of VEGFR2 also results in increased axon branching in vitro and in vivo. The increased CA3 axon branching is not productive as these axons are less mature and form less functional synapses with CA1 neurons. Mechanistically, while VEGF promotes the growth of formed branches without affecting filopodia formation, loss of VEGFR2 increases the number of filopodia and enhances the growth rate of new branches. Thus, a controlled VEGF/VEGFR2 signaling is required for proper CA3 hippocampal axon branching during mouse hippocampus development

Sirolimus-eluting stent fracture with thrombus, visualization by optical coherence tomography

FLRTs are broadly expressed proteins with the unique property of acting as homophilic cell adhesion molecules and as heterophilic repulsive ligands of Unc5/Netrin receptors. How these functions direct cell behavior and the molecular mechanisms involved remain largely unclear. Here we use X-ray crystallography to reveal the distinct structural bases for FLRT-mediated cell adhesion and repulsion in neurons. We apply this knowledge to elucidate FLRT functions during cortical development. We show that FLRTs regulate both the radial migration of pyramidal neurons, as well as their tangential spread. Mechanistically, radial migration is controlled by repulsive FLRT2-Unc5D interactions, while spatial organization in the tangential axis involves adhesive FLRT-FLRT interactions. Further, we show that the fundamental mechanisms of FLRT adhesion and repulsion are conserved between neurons and vascular endothelial cells. Our results reveal FLRTs as powerful guidance factors with structurally encoded repulsive and adhesive surfaces

The Planetary Nebula population of the Sagittarius Dwarf Spheroidal Galaxy

The identification of two new Planetary Nebulae in the Sagittarius Dwarf Spheroidal Galaxy (Sgr) is presented. This brings the total number to four. The first, StWr 2-21, belongs to the main body of Sgr. The second, the halo PN BoBn 1, has a location, distance and velocity in agreement with the leading tidal tail of Sgr. We estimate that 10 per cent of the Galactic halo consists of Sgr debris. The specific frequency of PNe indicates a total luminosity of Sgr, including its tidal tails, of M_V=-14.1. StWr 2-21 shows a high abundance of [O/H]=-0.23, which confirms the high-metallicity population in Sgr uncovered by Bonaficio et al. (2004). The steep metallicity--age gradient in Sgr is due to ISM removal during the Galactic plane passages, ISM reformation due to stellar mass loss, and possibly accretion of metal-enriched gas from our Galaxy. The ISM re-formation rate of Sgr, from stellar mass loss, is 5 X 10^-4 M_sun yr^-1, amounting to ~10^6 M_sun per orbital period. HST images reveal well-developed bipolar morphologies, and provide clear detections of the central stars. All three stars with deep spectra show WR-lines, suggesting that the progenitor mass and metallicity determines whether a PN central star develops a WR spectrum. One Sgr PN belongs to the class of IR-[WC] stars. Expansion velocities are determined for three nebulae. Comparison with hydrodynamical models indicates an initial density profile of rho ~ r^-3. This is evidence for increasing mass-loss rates on the AGB. Peak mass-loss rates are indicated of ~ 10^-4 M_sun yr^-1. The IR-[WC] PN, He 2-436, provides the sole direct detection of dust in a dwarf spheroidal galaxy, to date.Comment: 16 pages. MNRAS, accepted for publicatio

Enhancement of endogenous neurogenesis in ephrin-B3 deficient mice after transient focal cerebral ischemia

Cerebral ischemia stimulates endogenous neurogenesis. However, the functional relevance of this phenomenon remains unclear because of poor survival and low neuronal differentiation rates of newborn cells. Therefore, further studies on mechanisms regulating neurogenesis under ischemic conditions are required, among which ephrin-ligands and ephrin-receptors (Eph) are an interesting target. Although Eph/ephrin proteins like ephrin-B3 are known to negatively regulate neurogenesis under physiological conditions, their role in cerebral ischemia is largely unknown. We therefore studied neurogenesis, brain injury and functional outcome in ephrin-B3−/− (knockout) and ephrin-B3+/+ (wild-type) mice submitted to cerebral ischemia. Induction of stroke resulted in enhanced cell proliferation and neuronal differentiation around the lesion site of ephrin-B3−/− compared to ephrin-B3+/+ mice. However, prominent post-ischemic neurogenesis in ephrin-B3−/− mice was accompanied by significantly increased ischemic injury and motor coordination deficits that persisted up to 4 weeks. Ischemic injury in ephrin-B3−/− mice was associated with a caspase-3-dependent activation of the signal transducer and activator of transcription 1 (STAT1). Whereas inhibition of caspase-3 had no effect on brain injury in ephrin-B3+/+ animals, infarct size in ephrin-B3−/− mice was strongly reduced, suggesting that aggravated brain injury in these animals might involve a caspase-3-dependent activation of STAT1. In conclusion, post-ischemic neurogenesis in ephrin-B3−/− mice is strongly enhanced, but fails to contribute to functional recovery because of caspase-3-mediated aggravation of ischemic injury in these animals. Our results suggest that ephrin-B3 might be an interesting target for overcoming some of the limitations of further cell-based therapies in stroke

Na+ imaging reveals little difference in action potential–evoked Na+ influx between axon and soma

Author Posting. © The Authors, 2010. This is the author's version of the work. It is posted here by permission of Nature Publishing Group for personal use, not for redistribution. The definitive version was published in Nature Neuroscience 13 (2010): 852-860, doi:10.1038/nn.2574.In cortical pyramidal neurons, the axon initial segment (AIS) plays a pivotal role in synaptic integration. It has been asserted that this property reflects a high density of Na+ channels in AIS. However, we here report that AP–associated Na+ flux, as measured by high–speed fluorescence Na+ imaging, is about 3 times larger in the rat AIS than in the soma. Spike evoked Na+ flux in the AIS and the first node of Ranvier is about the same, and in the basal dendrites it is about 8 times lower. At near threshold voltages persistent Na+ conductance is almost entirely axonal. Finally, we report that on a time scale of seconds, passive diffusion and not pumping is responsible for maintaining transmembrane Na+ gradients in thin axons during high frequency AP firing. In computer simulations, these data were consistent with the known features of AP generation in these neurons.Supported by US– Israel BSF Grant (2003082), Grass Faculty Grant from the MBL, NIH Grant (NS16295), Multiple Sclerosis Society Grant (PP1367), and a fellowship from the Gruss Lipper Foundation

Beyond the personal–anonymous divide: agency relations in powers of attorney in France in the eighteenth and nineteenth centuries

Powers of attorney are often interpreted as evidence of trust among the parties involved. We build a novel dataset of notarized powers of attorney, capturing a wide variety of agency relationships in four large French commercial cities in the eighteenth and nineteenth centuries, to test hypotheses on the relational basis of economic relationships. We find little support for the idea of a radical shift from personal to anonymous relationships during our period. Our results point to more nuanced transformations. The preference for proxies in the same occupation as the principal somewhat declined, while professional proxies emerged and principals used relational chains, especially involving notaries, to find proxies.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151849/1/ehr12784_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151849/2/ehr12784.pd