6,617 research outputs found
Gene editing restores dystrophin expression in a canine model of Duchenne muscular dystrophy
Mutations in the gene encoding dystrophin, a protein that maintains muscle integrity and function, cause Duchenne muscular dystrophy (DMD). The deltaE50-MD dog model of DMD harbors a mutation corresponding to a mutational “hotspot” in the human DMD gene. We used adeno-associated viruses to deliver CRISPR gene editing components to four dogs and examined dystrophin protein expression 6 weeks after intramuscular delivery (n = 2) or 8 weeks after systemic delivery (n = 2). After systemic delivery in skeletal muscle, dystrophin was restored to levels ranging from 3 to 90% of normal, depending on muscle type. In cardiac muscle, dystrophin levels in the dog receiving the highest dose reached 92% of normal. The treated dogs also showed improved muscle histology. These large-animal data support the concept that, with further development, gene editing approaches may prove clinically useful for the treatment of DMD
Fluoxetine: a case history of its discovery and preclinical development
Introduction: Depression is a multifactorial mood disorder with a high prevalence worldwide. Until now, treatments for depression have focused on the inhibition of monoaminergic reuptake sites, which augment the bioavailability of monoamines in the CNS. Advances in drug discovery have widened the therapeutic options with the synthesis of so-called selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine.
Areas covered: The aim of this case history is to describe and discuss the pharmacokinetic and pharmacodynamic profiles of fluoxetine, including its acute effects and the adaptive changes induced after long-term treatment.
Furthermore, the authors review the effect of fluoxetine on neuroplasticity and adult neurogenesis. In addition, the article summarises the preclinical behavioural data available on fluoxetine’s effects on depressive-like behaviour,
anxiety and cognition as well as its effects on other diseases. Finally, the article describes the seminal studies validating the antidepressant effects of fluoxetine.
Expert opinion: Fluoxetine is the first selective SSRI that has a recognised clinical efficacy and safety profile. Since its discovery, other molecules that mimic its mechanism of action have been developed, commencing a new
age in the treatment of depression. Fluoxetine has also demonstrated utility in the treatment of other disorders for which its prescription has now been approved
Imprints of galaxy evolution on H ii regions Memory of the past uncovered by the CALIFA survey
H ii regions in galaxies are the sites of star formation and thus particular
places to understand the build-up of stellar mass in the universe. The line
ratios of this ionized gas are frequently used to characterize the ionization
conditions. We use the Hii regions catalogue from the CALIFA survey (~5000 H ii
regions), to explore their distribution across the classical [OIII]/Hbeta vs.
[NII]/Halpha diagnostic diagram, and how it depends on the oxygen abundance,
ionization parameter, electron density, and dust attenuation. We compared the
line ratios with predictions from photoionization models. Finally, we explore
the dependences on the properties of the host galaxies, the location within
those galaxies and the properties of the underlying stellar population. We
found that the location within the BPT diagrams is not totally predicted by
photoionization models. Indeed, it depends on the properties of the host
galaxies, their galactocentric distances and the properties of the underlying
stellar population. These results indicate that although H ii regions are short
lived events, they are affected by the total underlying stellar population. One
may say that H ii regions keep a memory of the stellar evolution and chemical
enrichment that have left an imprint on the both the ionizing stellar
population and the ionized gasComment: 18 pages, 8 figures, accepted for publishing in A&
The Mass-Metallicity relation explored with CALIFA: I. Is there a dependence on the star formation rate?
We present the results on the study of the global and local M-Z relation
based on the first data available from the CALIFA survey (150 galaxies). This
survey provides integral field spectroscopy of the complete optical extent of
each galaxy (up to 2-3 effective radii), with enough resolution to separate
individual HII regions and/or aggregations. Nearly 3000 individual HII
regions have been detected. The spectra cover the wavelength range between
[OII]3727 and [SII]6731, with a sufficient signal-to-noise to derive the oxygen
abundance and star-formation rate associated with each region. In addition, we
have computed the integrated and spatially resolved stellar masses (and surface
densities), based on SDSS photometric data. We explore the relations between
the stellar mass, oxygen abundance and star-formation rate using this dataset.
We derive a tight relation between the integrated stellar mass and the
gas-phase abundance, with a dispersion smaller than the one already reported in
the literature (0.07 dex). Indeed, this
dispersion is only slightly larger than the typical error derived for our
oxygen abundances. However, we do not find any secondary relation with the
star-formation rate, other than the one induced due to the primary relation of
this quantity with the stellar mass. We confirm the result using the 3000
individual HII regions, for the corresponding local relations.
Our results agree with the scenario in which gas recycling in galaxies, both
locally and globally, is much faster than other typical timescales, like that
of gas accretion by inflow and/or metal loss due to outflows. In essence,
late-type/disk dominated galaxies seem to be in a quasi-steady situation, with
a behavior similar to the one expected from an instantaneous
recycling/closed-box model.Comment: 19 Pages, 8 figures, Accepted for Publishing in Astronomy and
Astrophysics (A&A
Linfoma de Hodgkin refractario con afectación ósea y esplénica con rápida y completa respuesta a Nivolumab
Abstract [PB-062]
Introducción: En el linfoma de Hodgkin (LH) las alteraciones genéticas del cromosoma 9p24.1 de la célula de Reed-Sternberg, causan una sobreexpresión del ligando 1 de muerte programada (PDL-1), que conducen a una evasión del sistema inmune y resistencia terapéutica. Para pacientes que recaen después de un trasplante autólogo y de tratamiento con Brentuxumab, existen pocas posibilidades. Basándose en la sobreexpresión del PDL-1, los inhibidores de PD1/PDL1 son una opción. Nivolumab (anti PD1) ha demostrado eficacia en LH recaído/refractario (R/R). Presentamos un caso con respuesta clínica completa rápida en un LH refractario a Brentuximab y con gran afectación extranodal (ósea y esplénica).
Paciente y Métodos: Varón de 55 años diagnosticado de LH celularidad mixta estadio IIIA en Junio de 2005. 1ª línea: ABVDx6 y radioterapia mediastínica con RC. 2ª línea (Enero 2009) por recidiva cervical: Ifosfamida, Vinorelbina y Prednisona con RC. 3ª línea (Junio 2009) con afectación cervical y retoperitoneal: cisplatino, citarabina y dexametasona más radioterapia cervical con RC. 4ª línea (Enero 2011): MOPPx4 y Rituximab Gemcitabina con RC. Pasa a Hematología y se realiza autotrasplante en Noviembre de 2011 con RC. 5ª línea (Noviembre 2016) por afectación cervical, retroperitoneal, esplénica e iliaco: Brentuximabx4 y por mala respuesta se añade Bendamustinax3 con RC. Tras finalizar se realiza PET/TAC (Junio 2017) siendo negativo. En Agosto de 2017 importante clínica con síntomas constitucionales, pérdida de 10 Kg de peso en un mes. Analítica: Hb: 11, 5 g/dl, leucocitos: 2x109/l, plaquetas: 57x109/l. VSG: 120, PCR: 14 mg/dl, metabolismo hierro de proceso crónico. TAC: no adenopatías, esplenomegalia con lesiones. Biopsia de MO: afectación hodgkiniana. Se solicita Nivolumab. Mientras autorización se instaura Gemcitabina-Oxaliplatinox4 con mejoría clínica. Se realiza PET/TAC previo Nivolumab (Noviembre 2017): extensa afectación ósea esqueleto axial y huesos largos y afectación esplénica. Se inicia Nivolumab (16 Noviembre) a 3 mg/kg/ 14 días. Respuesta clínica óptima. No efectos secundarios, ni clínicos, ni analíticos. Tras 9 ciclos se realiza PET/TAC de control con RC. Por edad, hipertratado y deseo del paciente se descarta trasplante alogénico. Continúa tratamiento con Nivolumab, sin ningún efecto adverso y estando previsto discontinuar al año.
Conclusiones: Nivolumab es un fármaco que puede rescatar a pacientes con LH R/R a las terapias disponibles (trasplante y Brentuximab), donde las opciones son escasas. Puede servir como tratamiento puente para un trasplante alogénico y en pacientes no candidatos, como nuestro caso, su administración continua puede deparar en un aumento de la supervivencia libre de progresión y supervivencia global. Se necesita más investigación y seguimiento para valorar la duración de la respuesta y el tiempo o secuencia de administración
Synthetic Conjugates of Ursodeoxycholic Acid Inhibit Cystogenesis in Experimental Models of Polycystic Liver Disease
Altres ajuts: Suported by IKERBASQUE, Basque foundation for Science (M.J. Perugorria and J.M. Banales), Spain; "Junta de Castilla y Leon" (J.J.G. Marin: SA06P17); "Diputación Foral Gipuzkoa" (J.M. Banales: DFG15/010, DFG16/004; M.J. Perugorria: DFG18/114, DFG19/081), BIOEF (Basque Foundation for Innovation and Health Research: EiTB Maratoia BIO15/CA/016/BD to J.M. Banales), Department of Health of the Basque Country (J.M. Banales: 2017111010; M.J. Perugorria: 2019111024), and Euskadi RIS3 (J.M. Banales: 2016222001, 2017222014, and 2018222029; 2019222054); La Caixa Scientific Foundation (J.M. Banales: HR17-00601); "Fundación Científica de la Asociación Española Contra el Cáncer" (AECC Scientific Foundation, to J.M. Banales and J.J.G. Marin); and "Centro Internacional sobre el Envejecimiento", Spain (J.J.G. Marin: OLD-HEPAMARKER, 0348-CIE-6-E). A. Santos-Laso by the Basque Government (PRE_2018_2_0195), and Pui Y. Lee-Law by the European Association for the Study of the Liver (EASL; Sheila Sherlock Award). Basque Government (F.P. Cossío: IT-324-07). I. Rivilla had a postdoctoral contract from the Donostia International Physics Center.Background and Aims: Polycystic liver diseases (PLDs) are genetic disorders characterized by progressive development of symptomatic biliary cysts. Current surgical and pharmacological approaches are ineffective, and liver transplantation represents the only curative option. Ursodeoxycholic acid (UDCA) and histone deacetylase 6 inhibitors (HDAC6is) have arisen as promising therapeutic strategies, but with partial benefits. Approach and Results: Here, we tested an approach based on the design, synthesis, and validation of a family of UDCA synthetic conjugates with selective HDAC6i capacity (UDCA-HDAC6i). Four UDCA-HDAC6i conjugates presented selective HDAC6i activity, UDCA-HDAC6i #1 being the most promising candidate. UDCA orientation within the UDCA-HDAC6i structure was determinant for HDAC6i activity and selectivity. Treatment of polycystic rats with UDCA-HDAC6i #1 reduced their hepatomegaly and cystogenesis, increased UDCA concentration, and inhibited HDAC6 activity in liver. In cystic cholangiocytes UDCA-HDAC6i #1 restored primary cilium length and exhibited potent antiproliferative activity. UDCA-HDAC6i #1 was actively transported into cells through BA and organic cation transporters. Conclusions: These UDCA-HDAC6i conjugates open a therapeutic avenue for PLDs
Extreme Starbursts in the Local Universe
The "Extreme starbursts in the local universe" workshop was held at the
Insituto de Astrofisica de Andalucia in Granada, Spain on 21-25 June 2010.
Bearing in mind the advent of a new generation of facilities such as JWST,
Herschel, ALMA, eVLA and eMerlin, the aim of the workshop was to bring together
observers and theorists to review the latest results. The purpose of the
workshop was to address the following issues: what are the main modes of
triggering extreme starbursts in the local Universe? How efficiently are stars
formed in extreme starbursts? What are the star formation histories of local
starburst galaxies? How well do the theoretical simulations model the
observations? What can we learn about starbursts in the distant Universe
through studies of their local counterparts? How important is the role of
extreme starbursts in the hierarchical assembly of galaxies? How are extreme
starbursts related to the triggering of AGN in the nuclei of galaxies? Overall,
41 talks and 4 posters with their corresponding 10 minutes short talks were
presented during the workshop. In addition, the workshop was designed with
emphasis on discussions, and therefore, there were 6 discussion sessions of up
to one hour during the workshop. Here is presented a summary of the purposes of
the workshop as well as a compilation of the abstracts corresponding to each of
the presentations. The summary and conclusions of the workshop along with a
description of the future prospects by Sylvain Veilleux can be found in the
last section of this document. A photo of the assistants is included.Comment: worksho
Transition from Fireball to Poynting-flux-dominated Outflow in Three-Episode GRB 160625B
The ejecta composition is an open question in gamma-ray bursts (GRB) physics.
Some GRBs possess a quasi-thermal spectral component in the time-resolved
spectral analysis, suggesting a hot fireball origin. Others show a featureless
non-thermal spectrum known as the "Band" function, consistent with a
synchrotron radiation origin and suggesting that the jet is
Poynting-flux-dominated at the central engine and likely in the emission region
as well. There are also bursts showing a sub-dominant thermal component and a
dominant synchrotron component suggesting a likely hybrid jet composition. Here
we report an extraordinarily bright GRB 160625B, simultaneously observed in
gamma-rays and optical wavelengths, whose prompt emission consists of three
isolated episodes separated by long quiescent intervals, with the durations of
each "sub-burst" being 0.8 s, 35 s, and 212 s, respectively. Its high
brightness (with isotropic peak luminosity L
erg/s) allows us to conduct detailed time-resolved spectral analysis in each
episode, from precursor to main burst and to extended emission. The spectral
properties of the first two sub-bursts are distinctly different, allowing us to
observe the transition from thermal to non-thermal radiation between
well-separated emission episodes within a single GRB. Such a transition is a
clear indication of the change of jet composition from a fireball to a
Poynting-flux-dominated jet.Comment: Revised version reflecting the referees' comments. 27 pages, 11
figures, 5 tables. The final edited version will appear in Nature Astronom
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