Human γδ T-Cells: from surface receptors to the therapy of high-risk leukemias

γδ T lymphocytes are potent effector cells, capable of efficiently killing tumor and leukemia cells. Their activation is mediated by γδ T-cell receptor (TCR) and by activating receptors shared with NK cells (e.g., NKG2D and DNAM-1). γδ T-cell triggering occurs upon interaction with specific ligands, including phosphoantigens (for Vγ9Vδ2 TCR), MICA-B and UL16 binding protein (for NKG2D), and PVR and Nectin-2 (for DNAM-1). They also respond to cytokines undergoing proliferation and release of cytokines/chemokines. Although at the genomic level γδ T-cells have the potential of an extraordinary TCR diversification, in tissues they display a restricted repertoire. Recent studies have identified various γδ TCR rearrangements following either hematopoietic stem cell transplantation (HSCT) or cytomegalovirus infection, accounting for their "adaptive" potential. In humans, peripheral blood γδ T-cells are primarily composed of Vγ9Vδ2 chains, while a minor proportion express Vδ1. They do not recognize antigens in the context of MHC molecules, thus bypassing tumor escape based on MHC class I downregulation. In view of their potent antileukemia activity and absence of any relevant graft-versus-host disease-inducing effect, γδ T-cells may play an important role in the successful clinical outcome of patients undergoing HLA-haploidentical HSCT depleted of TCR αβ T/CD19+ B lymphocytes to cure high-risk acute leukemias. In this setting, high numbers of both γδ T-cells (Vδ1 and Vδ2) and NK cells are infused together with CD34+ HSC and may contribute to rapid control of infections and leukemia relapse. Notably, zoledronic acid potentiates the cytolytic activity of γδ T-cells in vitro and its infusion in patients strongly promotes γδ T-cell differentiation and cytolytic activity; thus, treatment with this agent may contribute to further improve the patient clinical outcome after HLA-haploidentical HSCT depleted of TCR αβ T/CD19+ B lymphocytes

Variations of the spectral index of dust emissivity from Hi-GAL observations of the Galactic plane

Original article can be found at: http://www.aanda.org/ Copyright The European Southern ObservatoryContext. Variations in the dust emissivity are critical for gas mass determinations derived from far-infrared observations, but also for separating dust foreground emission from the Cosmic Microwave Background (CMB). Hi-GAL observations allow us for the first time to study the dust emissivity variations in the inner regions of the Galactic plane at resolution below 1°. Aims. We present maps of the emissivity spectral index derived from the combined Herschel PACS 160 μm, SPIRE 250 μm, 350 μm, and 500 μm data, and the IRIS 100 μm data, and we analyze the spatial variations of the spectral index as a function of dust temperature and wavelength in the two science demonstration phase Hi-GAL fields, centered at l = 30° and l = 59°. Methods. Applying two different methods, we determine both dust temperature and emissivity spectral index between 100 and 500 μm, at an angular resolution (θ) of 4'. Results. Combining both fields, the results show variations of the emissivity spectral index in the range 1.8–2.6 for temperatures between 14 and 23 K. The median values of the spectral index are similar in both fields, i.e. 2.3 in the range 100–500 μm, while the median dust temperatures are equal to 19.1 K and 16.0 K in the l = 30° and l = 59° field, respectively. Statistically, we do not see any significant deviations in the spectra from a power law emissivity between 100 and 500 μm. We confirm the existence of an inverse correlation between the emissivity spectral index and dust temperature, found in previous analyses.Peer reviewe

Mapping the column density and dust temperature structure of IRDCs with Herschel

Infrared dark clouds (IRDCs) are cold and dense reservoirs of gas potentially available to form stars. Many of these clouds are likely to be pristine structures representing the initial conditions for star formation. The study presented here aims to construct and analyze accurate column density and dust temperature maps of IRDCs by using the first Herschel data from the Hi-GAL galactic plane survey. These fundamental quantities, are essential for understanding processes such as fragmentation in the early stages of the formation of stars in molecular clouds. We have developed a simple pixel-by-pixel SED fitting method, which accounts for the background emission. By fitting a grey-body function at each position, we recover the spatial variations in both the dust column density and temperature within the IRDCs. This method is applied to a sample of 22 IRDCs exhibiting a range of angular sizes and peak column densities. Our analysis shows that the dust temperature decreases significantly within IRDCs, from background temperatures of 20-30 K to minimum temperatures of 8-15 K within the clouds, showing that dense molecular clouds are not isothermal. Temperature gradients have most likely an important impact on the fragmentation of IRDCs. Local temperature minima are strongly correlated with column density peaks, which in a few cases reach NH2 = 1 x 10^{23} cm^{-2}, identifying these clouds as candidate massive prestellar cores. Applying this technique to the full Hi-GAL data set will provide important constraints on the fragmentation and thermal properties of IRDCs, and help identify hundreds of massive prestellar core candidates.Comment: Accepted for publication in A&A Herschel special issu

Evidence of an interaction between FXR1 and GSK3 beta polymorphisms on levels of Negative Symptoms of Schizophrenia and their response to antipsychotics

Background: Genome-Wide Association Studies (GWASs) have identified several genes associated with Schizophrenia (SCZ) and exponentially increased knowledge on the genetic basis of the disease. In addition, products of GWAS genes interact with neuronal factors coded by genes lacking association, such that this interaction may confer risk for specific phenotypes of this brain disorder. In this regard, fragile X mental retardation syndrome-related 1 (FXR1) gene has been GWAS associated with SCZ. FXR1 protein is regulated by glycogen synthase kinase-3β (GSK3β), which has been implicated in pathophysiology of SCZ and response to antipsychotics (APs). rs496250 and rs12630592, two eQTLs (Expression Quantitative Trait Loci) of FXR1 and GSK3β, respectively, interact on emotion stability and amygdala/prefrontal cortex activity during emotion processing. These two phenotypes are associated with Negative Symptoms (NSs) of SCZ suggesting that the interaction between these SNPs may also affect NS severity and responsiveness to medication. Methods: To test this hypothesis, in two independent samples of patients with SCZ, we investigated rs496250 by rs12630592 interaction on NS severity and response to APs. We also tested a putative link between APs administration and FXR1 expression, as already reported for GSK3β expression. Results: We found that rs496250 and rs12630592 interact on NS severity. We also found evidence suggesting interaction of these polymorphisms also on response to APs. This interaction was not present when looking at positive and general psychopathology scores. Furthermore, chronic olanzapine administration led to a reduction of FXR1 expression in mouse frontal cortex. Discussion: Our findings suggest that, like GSK3β, FXR1 is affected by APs while shedding new light on the role of the FXR1/GSK3β pathway for NSs of SCZ

Intragastric gastric band migration: erosion: an analysis of multicenter experience on 177 patients

BACKGROUND: Laparoscopic adjustable gastric banding (LAGB) has proven to be a safe and effective surgical treatment for morbid obesity. It can be a simple, fast, reversible, anatomy-preserving procedure. Despite these advantages, its long-term efficacy came into question by the occurrence of complications such as intragastric band migration. Consistent information regarding this complication is still lacking. Treatment for migration is still being debated as well. Most of the inconsistencies of these data stem from the very low number of patients reported in single-center experiences or case reports. Lack of multicenter experience is evident. The aim of this study was to perform a retrospective analysis of data on intragastric migration in a large multicenter cohort of patients who underwent LAGB. METHODS: A retrospective multicenter study on LAGB patients was performed. Data had been entered into a prospective database of the Italian Group for LapBand(®) (GILB) since January 1997. Pars flaccida and perigastric positioning were considered along with different kinds of gastric bands by the same manufacturer. Time of diagnosis, mean body mass index (BMI), presentation symptoms, and conservative and surgical therapy of intragastric migration were considered. RESULTS: From January 1997 to December 2009, a total of 6,839 patients underwent LAGB and their data were recorded [5,660 females, 1,179 males; mean age 38.5 ± 18.2 years (range 21-62 years); mean BMI = 46.7 ± 7.7 kg/m(2) (range 37.3-68.3); excess weight (EW) 61.8 ± 25.4 kg (range 36-130); %EW 91.1 ± 32.4 % (range 21-112 %)]. A total of 177 of 6,839 (2.5 %) intragastric erosions were observed. According to the postoperative time of follow-up, the diagnosis of intragastric migration was made in 74 (41.8 %), 14 (7.9 %), 38 (21.4 %), 40 (22.6 %), 6 (3.4 %), and 4 (2.2 %) banded patients at 6-12, 24, 36, 48, 60, and 72 months after banding, respectively. Most of intragastric band migration during the first 2 years occurred in bands with no or a few milliliters of filling. In patients with late erosion, the bands were adjusted several times; no band was overfilled but one was filled to the maximum or submaximum with a maximum of two adjustments. Erosions diagnosed during the first 24 months were related to the experience of the surgical staff, while late erosions were not. CONCLUSIONS: Intragastric band migration or band erosion is a rare, disturbing, and usually not life-threatening complication of gastric banding. Its pathogenesis is probably linked to different mechanisms in early (technical failure in retrogastric passage) or late (band management) presentation. It is usually asymptomatic and there is no pathognomonic presentation. A wide range of therapeutic options are available, from simple endoscopic or laparoscopic removal to early or late band replacement or other bariatric procedure. More experience and more studies are needed to lower its presentation rate and definitively clarify its pathogenesis to address the right therapeutic option

Eddy-induced particle dispersion in the near-surface North Atlantic

Author Posting. © American Meteorological Society, 2012. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Physical Oceanography 42 (2012): 2206–2228, doi:10.1175/JPO-D-11-0191.1.This study investigates the anisotropic properties of the eddy-induced material transport in the near-surface North Atlantic from two independent datasets, one simulated from the sea surface height altimetry and one derived from real-ocean surface drifters, and systematically examines the interactions between the mean- and eddy-induced material transport in the region. The Lagrangian particle dispersion, which is widely used to characterize the eddy-induced tracer fluxes, is quantified by constructing the “spreading ellipses.” The analysis consistently demonstrates that this dispersion is spatially inhomogeneous and strongly anisotropic. The spreading is larger and more anisotropic in the subtropical than in the subpolar gyre, and the largest ellipses occur in the Gulf Stream vicinity. Even at times longer than half a year, the spreading exhibits significant nondiffusive behavior in some parts of the domain. The eddies in this study are defined as deviations from the long-term time-mean. The contributions from the climatological annual cycle, interannual, and subannual (shorter than one year) variability are investigated, and the latter is shown to have the strongest effect on the anisotropy of particle spreading. The influence of the mean advection on the eddy-induced particle spreading is investigated using the “eddy-following-full-trajectories” technique and is found to be significant. The role of the Ekman advection is, however, secondary. The pronounced anisotropy of particle dispersion is expected to have important implications for distributing oceanic tracers, and for parameterizing eddy-induced tracer transfer in non-eddy-resolving models.IR was supported by Grant NSF-OCE-0725796. IK would like to acknowledge support by the National Science foundation Grant OCE-0842834.2013-06-0

Hunting for Primordial Non-Gaussianity in the Cosmic Microwave Background

Since the first limit on the (local) primordial non-Gaussianity parameter, fNL, was obtained from COBE data in 2002, observations of the CMB have been playing a central role in constraining the amplitudes of various forms of non-Gaussianity in primordial fluctuations. The current 68% limit from the 7-year WMAP data is fNL=32+/-21, and the Planck satellite is expected to reduce the uncertainty by a factor of four in a few years from now. If fNL>>1 is found by Planck with high statistical significance, all single-field models of inflation would be ruled out. Moreover, if the Planck satellite finds fNL=30, then it would be able to test a broad class of multi-field models using the four-point function (trispectrum) test of tauNL>=(6fNL/5)^2. In this article, we review the methods (optimal estimator), results (WMAP 7-year), and challenges (secondary anisotropy, second-order effect, and foreground) of measuring primordial non-Gaussianity from the CMB data, present a science case for the trispectrum, and conclude with future prospects.Comment: 33 pages, 4 figures. Invited review, accepted for publication in the CQG special issue on nonlinear cosmological perturbations. (v2) References added. More clarifications are added to the second-order effect and the multi-field consistency relation, tauNL>=(6fNL/5)^2

Dust temperature tracing the ISRF intensity in the Galaxy

New observations with Herschel allow accurate measurement of the equilibrium temperature of large dust grains heated by the interstellar radiation field (ISRF), which is critical in deriving dust column density and masses. We present temperature maps derived from the Herschel SPIRE and PACS data in two fields along the Galactic plane, obtained as part of the Hi-GAL survey during the Herschel science demonstration phase (SDP). We analyze the distribution of the dust temperature spatially, as well as along the two lines-of-sight (LOS) through the Galaxy. The zero-level offsets in the Herschel maps were established by comparison with the IRAS and Planck data at comparable wavelengths. We derive maps of the dust temperature and optical depth by adjusting a detailed model for dust emission at each pixel. The dust temperature maps show variations in the ISRF intensity and reveal the intricate mixture of the warm dust heated by massive stars and the cold filamentary structures of embedded molecular clouds. The dust optical depth at 250 μm is well correlated with the gas column density, but with a significantly higher dust emissivity than in the solar neighborhood. We correlate the optical depth with 3-D cubes of the dust extinction to investigate variations in the ISRF strength and dust abundance along the line of sight through the spiral structure of the Galaxy. We show that the warmest dust along the LOS is located in the spiral arms of the Galaxy, and we quantify their respective IR contribution

Hi-GAL, theHerschelinfrared Galactic Plane Survey: photometric maps and compact source catalogues

Aims. We present the first public release of high-quality data products (DR1) from Hi-GAL, the Herschel infrared Galactic Plane Survey. Hi-GAL is the keystone of a suite of continuum Galactic plane surveys from the near-IR to the radio and covers five wavebands at 70, 160, 250, 350 and 500 µm, encompassing the peak of the spectral energy distribution of cold dust for 8 < T < 50 K. This first Hi-GAL data release covers the inner Milky Way in the longitude range 68◦ > t > −70◦ in a |b| ≤ 1◦ latitude strip. ∼ ∼ ∼ ∼ Methods. Photometric maps have been produced with the ROMAGAL pipeline, which optimally capitalizes on the excellent sensitivity and stability of the bolometer arrays of the Herschel PACS and SPIRE photometric cameras. It delivers images of exquisite quality and dynamical range, absolutely calibrated with Planck and IRAS, and recovers extended emission at all wavelengths and all spatial scales, from the point-spread function to the size of an entire 2◦ × 2◦ “tile” that is the unit observing block of the survey. The compact source catalogues were generated with the CuTEx algorithm, which was specifically developed to optimise source detection and extraction in the extreme conditions of intense and spatially varying background that are found in the Galactic plane in the thermal infrared. Results. Hi-GAL DR1 images are cirrus noise limited and reach the 1σ-rms predicted by the Herschel Time Estimators for parallel-mode obser- vations at 6011 s−1 scanning speed in relatively low cirrus emission regions. Hi-GAL DR1 images will be accessible through a dedicated web-based image cutout service. The DR1 Compact Source Catalogues are delivered as single-band photometric lists containing, in addition to source posi- tion, peak, and integrated flux and source sizes, a variety of parameters useful to assess the quality and reliability of the extracted sources. Caveats and hints to help in this assessment are provided. Flux completeness limits in all bands are determined from extensive synthetic source experiments and greatly depend on the specific line of sight along the Galactic plane because the background strongly varies as a function of Galactic longitude. Hi-GAL DR1 catalogues contain 123210, 308509, 280685, 160972, and 85460 compact sources in the five bands