47 research outputs found
Basal LAT-diacylglycerol-RasGRP1 Signals in T Cells Maintain TCRα Gene Expression
In contrast to the well-characterized T cell receptor (TCR) signaling pathways that induce genes that drive T cell development or polarization of naïve CD4 T cells into the diverse TH1, TH2, TH17 and Treg lineages, it is unclear what signals maintain specific gene expression in mature resting T cells. Resting T cells residing in peripheral lymphoid organs exhibit low-level constitutive signaling. Whereas tonic signals in B cells are known to be critical for survival, the roles of tonic signals in peripheral T cells are unknown. Here we demonstrate that constitutive signals in Jurkat T cell lines are transduced via the adapter molecule LAT and the Ras exchange factor RasGRP1 to maintain expression of TCRα mRNA and surface expression of the TCR/CD3 complex. Independent approaches of reducing basal activity through the LAT-diacylglycerol-RasGRP pathway led to reduced constitutive Ras-MEK-ERK signals and decreased TCRα mRNA and surface TCR expression in Jurkat cells. However, loss of TCR expression takes several days in these cell line experiments. In agreement with these in vitro approaches, inducible deletion of Lat in vivo results in reduced TCRα mRNA- and surface TCR- expression in a delayed temporal manner as well. Lastly, we demonstrate that loss of basal LAT-RasGRP signals appears to lead to silencing or repression of TCRα transcription. We postulate that basal LAT-diacylglycerol-RasGRP signals fulfill a regulatory function in peripheral T lymphocytes by maintaining proper gene expression programs
The 2MASS Redshift Survey - Description and Data Release
We present the results of the 2MASS Redshift Survey (2MRS), a ten-year
project to map the full three-dimensional distribution of galaxies in the
nearby Universe. The 2 Micron All-Sky Survey (2MASS) was completed in 2003 and
its final data products, including an extended source catalog (XSC), are
available on-line. The 2MASS XSC contains nearly a million galaxies with Ks <=
13.5 mag and is essentially complete and mostly unaffected by interstellar
extinction and stellar confusion down to a galactic latitude of |b|=5 deg for
bright galaxies. Near-infrared wavelengths are sensitive to the old stellar
populations that dominate galaxy masses, making 2MASS an excellent starting
point to study the distribution of matter in the nearby Universe.
We selected a sample of 44,599 2MASS galaxies with Ks =5
deg (>= 8 deg towards the Galactic bulge) as the input catalog for our survey.
We obtained spectroscopic observations for 11,000 galaxies and used
previously-obtained velocities for the remainder of the sample to generate a
redshift catalog that is 97.6% complete to well-defined limits and covers 91%
of the sky. This provides an unprecedented census of galaxy (baryonic mass)
concentrations within 300 Mpc.
Earlier versions of our survey have been used in a number of publications
that have studied the bulk motion of the Local Group, mapped the density and
peculiar velocity fields out to 50 Mpc, detected galaxy groups, and estimated
the values of several cosmological parameters.
Additionally, we present morphological types for a nearly-complete sub-sample
of 20,860 galaxies with Ks = 10 deg.Comment: Accepted for publication in The Astrophysical Journal Supplement
Series. The 2MRS catalogs and a version of the paper with higher-resolution
figures can be found at http://tdc-www.harvard.edu/2mrs
The wide-field, multiplexed, spectroscopic facility WEAVE : survey design, overview, and simulated implementation
Funding for the WEAVE facility has been provided by UKRI STFC, the University of Oxford, NOVA, NWO, Instituto de AstrofĂsica de Canarias (IAC), the Isaac Newton Group partners (STFC, NWO, and Spain, led by the IAC), INAF, CNRS-INSU, the Observatoire de Paris, RĂ©gion Ăle-de-France, CONCYT through INAOE, Konkoly Observatory (CSFK), Max-Planck-Institut fĂŒr Astronomie (MPIA Heidelberg), Lund University, the Leibniz Institute for Astrophysics Potsdam (AIP), the Swedish Research Council, the European Commission, and the University of Pennsylvania.WEAVE, the new wide-field, massively multiplexed spectroscopic survey facility for the William Herschel Telescope, will see first light in late 2022. WEAVE comprises a new 2-degree field-of-view prime-focus corrector system, a nearly 1000-multiplex fibre positioner, 20 individually deployable 'mini' integral field units (IFUs), and a single large IFU. These fibre systems feed a dual-beam spectrograph covering the wavelength range 366-959 nm at R ⌠5000, or two shorter ranges at R ⌠20,000. After summarising the design and implementation of WEAVE and its data systems, we present the organisation, science drivers and design of a five- to seven-year programme of eight individual surveys to: (i) study our Galaxy's origins by completing Gaia's phase-space information, providing metallicities to its limiting magnitude for ⌠3 million stars and detailed abundances for ⌠1.5 million brighter field and open-cluster stars; (ii) survey ⌠0.4 million Galactic-plane OBA stars, young stellar objects and nearby gas to understand the evolution of young stars and their environments; (iii) perform an extensive spectral survey of white dwarfs; (iv) survey âŒÂ 400 neutral-hydrogen-selected galaxies with the IFUs; (v) study properties and kinematics of stellar populations and ionised gas in z 1 million spectra of LOFAR-selected radio sources; (viii) trace structures using intergalactic/circumgalactic gas at z > 2. Finally, we describe the WEAVE Operational Rehearsals using the WEAVE Simulator.PostprintPeer reviewe
The wide-field, multiplexed, spectroscopic facility WEAVE: Survey design, overview, and simulated implementation
WEAVE, the new wide-field, massively multiplexed spectroscopic survey
facility for the William Herschel Telescope, will see first light in late 2022.
WEAVE comprises a new 2-degree field-of-view prime-focus corrector system, a
nearly 1000-multiplex fibre positioner, 20 individually deployable 'mini'
integral field units (IFUs), and a single large IFU. These fibre systems feed a
dual-beam spectrograph covering the wavelength range 366959\,nm at
, or two shorter ranges at . After summarising the
design and implementation of WEAVE and its data systems, we present the
organisation, science drivers and design of a five- to seven-year programme of
eight individual surveys to: (i) study our Galaxy's origins by completing
Gaia's phase-space information, providing metallicities to its limiting
magnitude for 3 million stars and detailed abundances for
million brighter field and open-cluster stars; (ii) survey million
Galactic-plane OBA stars, young stellar objects and nearby gas to understand
the evolution of young stars and their environments; (iii) perform an extensive
spectral survey of white dwarfs; (iv) survey
neutral-hydrogen-selected galaxies with the IFUs; (v) study properties and
kinematics of stellar populations and ionised gas in cluster galaxies;
(vi) survey stellar populations and kinematics in field galaxies
at ; (vii) study the cosmic evolution of accretion
and star formation using million spectra of LOFAR-selected radio sources;
(viii) trace structures using intergalactic/circumgalactic gas at .
Finally, we describe the WEAVE Operational Rehearsals using the WEAVE
Simulator.Comment: 41 pages, 27 figures, accepted for publication by MNRA
The wide-field, multiplexed, spectroscopic facility WEAVE: Survey design, overview, and simulated implementation
WEAVE, the new wide-field, massively multiplexed spectroscopic survey facility for the William Herschel Telescope, will see first light in late 2022. WEAVE comprises a new 2-degree field-of-view prime-focus corrector system, a nearly 1000-multiplex fibre positioner, 20 individually deployable 'mini' integral field units (IFUs), and a single large IFU. These fibre systems feed a dual-beam spectrograph covering the wavelength range 366â959\,nm at RâŒ5000, or two shorter ranges at RâŒ20000. After summarising the design and implementation of WEAVE and its data systems, we present the organisation, science drivers and design of a five- to seven-year programme of eight individual surveys to: (i) study our Galaxy's origins by completing Gaia's phase-space information, providing metallicities to its limiting magnitude for âŒ3 million stars and detailed abundances for âŒ1.5 million brighter field and open-cluster stars; (ii) survey âŒ0.4 million Galactic-plane OBA stars, young stellar objects and nearby gas to understand the evolution of young stars and their environments; (iii) perform an extensive spectral survey of white dwarfs; (iv) survey âŒ400 neutral-hydrogen-selected galaxies with the IFUs; (v) study properties and kinematics of stellar populations and ionised gas in z1 million spectra of LOFAR-selected radio sources; (viii) trace structures using intergalactic/circumgalactic gas at z>2. Finally, we describe the WEAVE Operational Rehearsals using the WEAVE Simulator
31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two
Background
The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd.
Methods
We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background.
Results
First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001).
Conclusions
In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival
A História da Alimentação: balizas historiogråficas
Os M. pretenderam traçar um quadro da HistĂłria da Alimentação, nĂŁo como um novo ramo epistemolĂłgico da disciplina, mas como um campo em desenvolvimento de prĂĄticas e atividades especializadas, incluindo pesquisa, formação, publicaçÔes, associaçÔes, encontros acadĂȘmicos, etc. Um breve relato das condiçÔes em que tal campo se assentou faz-se preceder de um panorama dos estudos de alimentação e temas correia tos, em geral, segundo cinco abardagens Ia biolĂłgica, a econĂŽmica, a social, a cultural e a filosĂłfica!, assim como da identificação das contribuiçÔes mais relevantes da Antropologia, Arqueologia, Sociologia e Geografia. A fim de comentar a multiforme e volumosa bibliografia histĂłrica, foi ela organizada segundo critĂ©rios morfolĂłgicos. A seguir, alguns tĂłpicos importantes mereceram tratamento Ă parte: a fome, o alimento e o domĂnio religioso, as descobertas europĂ©ias e a difusĂŁo mundial de alimentos, gosto e gastronomia. O artigo se encerra com um rĂĄpido balanço crĂtico da historiografia brasileira sobre o tema