1,485 research outputs found
Bone marrow MSC from pediatric patients with B-ALL highly immunosuppress T-cell responses but do not compromise CD19-CAR T-cell activity
Altres ajuts Funding Financial support for this work was obtained from the Obra Social La Caixa (LCF/PR/HR19/52160011), the Leo Messi Foundation, and the 'Heroes hasta la médula' initiative to PM. SRZ was supported by a Marie Sklodowska Curie Fellowship (GA 795833). MV is supported by a Juan de la Cierva fellowship from the MINECO. PM is an investigator of the Spanish Cell Therapy cooperative network (TERCEL).Background Although adoptive transfer of CD19-directed chimeric antigen receptor (CAR) T-cells (CD19-CAR T-cells) achieves high rates of complete response in patients with B-cell acute lymphoblastic leukemia (B-ALL), relapse is common. Bone marrow (BM) mesenchymal stem/stromal cells (BM-MSC) are key components of the hematopoietic niche and are implicated in B-ALL pathogenesis and therapy resistance. MSC exert an immunosuppressive effect on T-cells; however, their impact on CD19-CAR T-cell activity is understudied. Methods We performed a detailed characterization of BM-MSC from pediatric patients with B-ALL (B-ALL BM-MSC), evaluated their immunomodulatory properties and their impact on CD19-CAR T-cell activity in vitro using microscopy, qRT-PCR, ELISA, flow cytometry analysis and in vivo using a preclinical model of severe colitis and a B-ALL xenograft model. Results While B-ALL BM-MSC were less proliferative than those from age-matched healthy donors (HD), the morphology, immunophenotype, differentiation potential and chemoprotection was very similar. Likewise, both BM-MSC populations were equally immunosuppressive in vitro and anti-inflammatory in an in vivo model of severe colitis. Interestingly, BM-MSC failed to impair CD19-CAR T-cell cytotoxicity or cytokine production in vitro using B-ALL cell lines and primary B-ALL cells. Finally, the growth of NALM6 cells was controlled in vivo by CD19-CAR T-cells irrespective of the absence/presence of BM-MSC. Conclusions Collectively, our data demonstrate that pediatric B-ALL and HD BM-MSC equally immunosuppress T-cell responses but do not compromise CD19-CAR T-cell activity
5D UED: Flat and Flavorless
5D UED is not automatically minimally flavor violating. This is due to flavor
asymmetric counter-terms required on the branes. Additionally, there are likely
to be higher dimensional operators which directly contribute to flavor
observables. We document a mostly unsuccessful attempt at utilizing
localization in a flat extra dimension to resolve these flavor constraints
while maintaining KK-parity as a good quantum number. It is unsuccessful
insofar as we seem to be forced to add brane operators in such a way as to
precisely mimic the effects of a double throat warped extra dimension. In the
course of our efforts, we encounter and present solutions to a problem common
to many extra dimensional models in which fields are "doubly localized:"
ultra-light modes. Under scrutiny, this issue seems tied to an intrinsic
tension between maintaining Kaluza-Klein parity and resolving mass hierarchies
via localization.Comment: 27 pages, 6 figure
Adenosine A2A receptor modulation of hippocampal CA3-CA1 synapse plasticity during associative learning in behaving mice
© 2009 Nature Publishing Group All rights reservedPrevious in vitro studies have characterized the electrophysiological and molecular signaling pathways of adenosine tonic modulation on long-lasting synaptic plasticity events, particularly for hippocampal long-term potentiation(LTP). However, it remains to be elucidated
whether the long-term changes produced by endogenous adenosine in the efficiency of synapses are related to those required for
learning and memory formation. Our goal was to understand how endogenous activation of adenosine excitatory A2A receptors modulates the associative learning evolution in conscious behaving mice. We have studied here the effects of the application of a highly selective A2A receptor antagonist, SCH58261, upon a well-known associative learning paradigm - classical eyeblink conditioning. We used a trace paradigm, with a tone as the conditioned stimulus (CS) and an electric shock presented to the supraorbital nerve as the unconditioned stimulus(US). A single electrical pulse was presented to the Schaffer collateral–commissural pathway to evoke field EPSPs (fEPSPs) in the pyramidal CA1 area during the CS–US interval. In vehicle-injected animals, there was a progressive increase in the percentage of conditioning responses (CRs) and in the slope of fEPSPs through conditioning sessions, an effect that was completely prevented (and lost) in SCH58261 (0.5 mg/kg, i.p.)-injected animals. Moreover, experimentally evoked LTP was impaired in SCH58261- injected mice. In conclusion, the endogenous activation of adenosine A2A receptors plays a pivotal effect on the associative learning process and its relevant hippocampal circuits, including activity-dependent changes at the CA3-CA1 synapse.This study was supported by grants from the Spanish Ministry of Education and Research (BFU2005-01024 and BFU2005-02512), Spanish Junta de Andalucía (BIO-122 and CVI-02487), and the Fundación Conocimiento y Cultura of
the Pablo de Olavide University (Seville, Spain).B. Fontinha was in receipt of a studentship from a project grant (POCI/SAU-NEU/56332/2004) supported by Fundação para a Ciência e Tecnologia (FCT, Portugal), and of an STSM from Cost B30 concerted action of the EU
The stellar halo of the Galaxy
Stellar halos may hold some of the best preserved fossils of the formation
history of galaxies. They are a natural product of the merging processes that
probably take place during the assembly of a galaxy, and hence may well be the
most ubiquitous component of galaxies, independently of their Hubble type. This
review focuses on our current understanding of the spatial structure, the
kinematics and chemistry of halo stars in the Milky Way. In recent years, we
have experienced a change in paradigm thanks to the discovery of large amounts
of substructure, especially in the outer halo. I discuss the implications of
the currently available observational constraints and fold them into several
possible formation scenarios. Unraveling the formation of the Galactic halo
will be possible in the near future through a combination of large wide field
photometric and spectroscopic surveys, and especially in the era of Gaia.Comment: 46 pages, 16 figures. References updated and some minor changes.
Full-resolution version available at
http://www.astro.rug.nl/~ahelmi/stellar-halo-review.pd
(De)Constructing a Natural and Flavorful Supersymmetric Standard Model
Using the framework of deconstruction, we construct simple, weakly-coupled
supersymmetric models that explain the Standard Model flavor hierarchy and
produce a flavorful soft spectrum compatible with precision limits. Electroweak
symmetry breaking is fully natural; the mu-term is dynamically generated with
no B mu-problem and the Higgs mass is easily raised above LEP limits without
reliance on large radiative corrections. These models possess the distinctive
spectrum of superpartners characteristic of "effective supersymmetry": the
third generation superpartners tend to be light, while the rest of the scalars
are heavy.Comment: 36 pages, 4 figures ; v2: references added, expanded discussion of
FCNC
Global Analysis of the Higgs Candidate with Mass ~ 125 GeV
We analyze the properties of the Higgs candidate with mass ~ 125 GeV
discovered by the CMS and ATLAS Collaborations, constraining the possible
deviations of its couplings from those of a Standard Model Higgs boson. The
CMS, ATLAS and Tevatron data are compatible with Standard Model couplings to
massive gauge bosons and fermions, and disfavour several types of composite
Higgs models unless their couplings resemble those in the Standard Model. We
show that the couplings of the Higgs candidate are consistent with a linear
dependence on particle masses, scaled by the electroweak scale ~ 246 GeV, the
power law and the mass scale both having uncertainties ~ 20%.Comment: 22 pages, 9 figures, v2 incorporates experimental data released
during July 2012 and corrected (and improved) treatment of mass dependence of
coupling
Internal mammary artery dilatation in a patient with aortic coarctation, aortic stenosis, and coronary disease. Case report
The ideal surgical approach is unclear in adult patients with coarctation of the aorta that is associated with other cardiovascular pathologies that require intervention. Standard median sternotomy allows simultaneous, coronary revascularization surgery, valve replacement and repair of aortic coarctation. However the collateral circulation and the anatomy of the mammary arteries must be determined, to avoid possible complications. We report a case of a 69 year-old man with aortic coarctation, aortic stenosis, coronary artery disease and internal mammary artery dilatation who underwent concomitant surgical procedures through a median sternotomy
Role of computed tomography imaging for transcatheter valvular repair/insertion
During the last decade, the development of transcatheter based therapies has provided feasible therapeutic options for patients with symptomatic severe valvular heart disease who are deemed inoperable. The promising results of many nonrandomized series and recent landmark trials have increased the number of percutaneous transcatheter valve procedures in high operative risk patients. Pre-procedural imaging of the anatomy of the aortic or mitral valve and their spatial relationships is crucial to select the most appropriate device or prosthesis and to plan the percutaneous procedure. Multidetector row computed tomography provides 3-dimensional volumetric data sets allowing unlimited plane reconstructions and plays an important role in pre-procedural screening and procedural planning. This review will describe the evolving role of multidetector row computed tomography in patient selection and strategy planning of transcatheter aortic and mitral valve procedures
Structural Characterization of Two New Quaternary Chalcogenides: CuCo2InTe4 and CuNi2InTe4
The crystal structure of the chalcogenide compounds CuCo2InTe4 and CuNi2InTe4, two new members of the I-II2-III-VI4 family, were characterized by Rietveld refinement using X-ray powder diffraction data. Both materials crystallize in the tetragonal space group I4 2m (No. 121), Z = 2, with a stannite-type structure, with the binaries CoTe and NiTe as secondary phases
Phenomenology and Cosmology of an Electroweak Pseudo-Dilaton and Electroweak Baryons
In many strongly-interacting models of electroweak symmetry breaking the
lowest-lying observable particle is a pseudo-Goldstone boson of approximate
scale symmetry, the pseudo-dilaton. Its interactions with Standard Model
particles can be described using a low-energy effective nonlinear chiral
Lagrangian supplemented by terms that restore approximate scale symmetry,
yielding couplings of the pseudo-dilaton that differ from those of a Standard
Model Higgs boson by fixed factors. We review the experimental constraints on
such a pseudo-dilaton in light of new data from the LHC and elsewhere. The
effective nonlinear chiral Lagrangian has Skyrmion solutions that may be
identified with the `electroweak baryons' of the underlying
strongly-interacting theory, whose nature may be revealed by the properties of
the Skyrmions. We discuss the finite-temperature electroweak phase transition
in the low-energy effective theory, finding that the possibility of a
first-order electroweak phase transition is resurrected. We discuss the
evolution of the Universe during this transition and derive an
order-of-magnitude lower limit on the abundance of electroweak baryons in the
absence of a cosmological asymmetry, which suggests that such an asymmetry
would be necessary if the electroweak baryons are to provide the cosmological
density of dark matter. We revisit estimates of the corresponding
spin-independent dark matter scattering cross section, with a view to direct
detection experiments.Comment: 34 pages, 4 figures, additional references adde
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