Dynamic expression of groucho-related genes Grg1 and Grg3 in foregut endoderm and antagonism of differentiation

El pdf del artículo es el manuscrito de autor.While much is known about Groucho corepressors in Drosophila development, less is known about Grg homologs in mammalian embryogenesis. The transcription factors FoxA1 and FoxA2 are redundantly necessary for liver-inductive competence of the endoderm, and recently we found that FoxA factors bind Grg3, recruit the corepressor to FoxA target genes, and cause transcriptional repression, when Grg3 is ectopically expressed in adult liver cell lines that express little or no endogenous Grg. Unexpectedly, we now find that Grg1 and Grg3 mRNAs are co-expressed with FoxA factors in the foregut endoderm, prior to liver differentiation, though only Grg3 protein is expressed there. Grg3 mRNA and protein are extinguished at the onset of liver differentiation. Lentiviral delivery of Grg3 to explants of foregut endoderm suppresses liver gene induction. We suggest that Grg expression in the endoderm helps suppress the liver program and find that endodermal competence involves a balance between activators and corepressors.The research was supported by a grant from the Dirección General de Investigación SAF-2007-60614 (MICINN) and Salvador de Madariaga Program (MEC) to P.S., a FPI predoctoral fellowship (MICINN) to P.R., an NIH CA-009035-34 postdoctoral fellowship to D.E.M., and NIH grant R37GM36477 toK.S.Z.Peer Reviewe

Stable reduction of CCR5 by RNAi through hematopoietic stem cell transplant in non-human primates

RNAi is a powerful method for suppressing gene expression that has tremendous potential for therapeutic applications. However, because endogenous RNAi plays a role in normal cellular functions, delivery and expression of siRNAs must be balanced with safety. Here we report successful stable expression in primates of siRNAs directed to chemokine (c-c motif) receptor 5 (CCR5) introduced through CD34+ hematopoietic stem/progenitor cell transplant. After hematopoietic reconstitution, to date 14 months after transplant, we observe stably marked lymphocytes expressing siRNAs and consistent down-regulation of chemokine (c-c motif) receptor 5 expression. The marked cells are less susceptible to simian immunodeficiency virus infection ex vivo. These studies provide a successful demonstration that siRNAs can be used together with hematopoietic stem cell transplant to stably modulate gene expression in primates and potentially treat blood diseases such as HIV-1

HST and Palomar Imaging of GRB 990123: Implications for the Nature of Gamma-Ray Bursts and their Hosts

We report on HST and Palomar optical images of the field of GRB 990123, obtained on 8 and 9 February 1999. We find that the optical transient (OT) associated with GRB 990123 is located on an irregular galaxy, with magnitude V=24.20 +/- 0.15. The strong metal absorption lines seen in the spectrum of the OT, along with the low probability of a chance superposition, lead us to conclude that this galaxy is the host of the GRB. The OT is projected within the ~1'' visible stellar field of the host, nearer the edge than the center. We cannot, on this basis, rule out the galactic nucleus as the site of the GRB, since the unusual morphology of the host may be the result of an ongoing galactic merger, but our demonstration that this host galaxy has extremely blue optical to infrared colors more strongly supports an association between GRBs and star formation. We find that the OT magnitude on 1999 Feb 9.05, V = 25.45 +/- 0.15, is about 1.5 mag fainter than expected from extrapolation of the decay rate found in earlier observations. A detailed analysis of the OT light curve suggests that its fading has gone through three distinct phases: an early rapid decline (f_{nu} \propto t^{-1.6} for t < 0.1 days), a slower intermediate decline power-law decay (f_{nu} \propto t^{-1.1} for 0.1 < t < 2 days), and then a more rapid decay (at least as steep as (f_{\nu} \propto t^{-1.8} for t > 2 days). The break to steeper slope at late times may provide evidence that the optical emission from this GRB was highly beamed.Comment: Accepted for publication in Astrophysical Journal (Letters). Fourteen pages. Three encapsulated figure

Upregulation of SOCS-3 and PIAS-3 Impairs IL-12-Mediated Interferon-Gamma Response in CD56+ T Cells in HCV-Infected Heroin Users

CD56(+) T cells are abundant in liver and play an important role in host innate immunity against viral infections, including hepatitis C virus (HCV) infection, a common infection among heroin abusers. We thus investigated the in vivo impact of heroin use or heroin use plus HCV infection on the CD56(+) T cell frequency and function.A total of 37 heroin users with (17) or without (20) HCV infection and 17 healthy subjects were included in the study. Although there was no significant difference in CD56(+) T cell frequency in PBMCs among three study groups, CD56(+) T cells isolated from the heroin users had significantly lower levels of constitutive interferon-gamma (IFN-gamma) expression than those from the normal subjects. In addition, when stimulated by interleukin (IL)-12, CD56(+) natural T cells from HCV-infected heroin users produced significantly lower levels of IFN-gamma than those from the normal subjects. This diminished ability to produce IFN-gamma by CD56(+) T cells was associated with the increased plasma HCV viral loads in the HCV-infected heroin users. Investigation of the mechanisms showed that although heroin use or heroin use plus HCV infection had little impact on the expression of the key positive regulators (IL-12 receptors, STAT-1, 3, 4, 5, JAK-2, and TYK-2) in IL-12 pathway, heroin use or heroin use plus HCV infection induced the expression of suppressor of cytokine signaling protein-3 (SOCS-3) and protein inhibitors of activated STAT-3 (PIAS-3), two key inhibitors of IL-12 pathway.These findings provide compelling in vivo evidence that heroin use or heroin use plus HCV infection impairs CD56(+) T cell-mediated innate immune function, which may account for HCV infection and persistence in liver

Pass-through core measurements of magnetic susceptibility and natural gamma ray, New Jersey Coastal Plain

We measured magnetic susceptibility (MS) and core gamma radiation (CGR) on 3162 ft (963.9 m) of core recovered by the New Jersey Coastal Plain Drilling Project (Ocean Drilling Program Leg 150X) at Island Beach, Atlantic City, and Cape May, New Jersey. Integration of core lithology, core/log (MS and CGR), and downhole gamma-ray (DGR) log studies have (1) documented the core/log expression of previously determined unconformities; (2) shown that MS is a proxy for glauconite percent in the New Jersey Coastal Plain; (3) illustrated a major change in sedimentation from shelfal glauconite evidenced by very high MS values to deltaic deposition with low MS values in the earliest Miocene (ca. 22 Ma); (4) shown that comparison of MS and CGR with DGR can be used to resolve discrepancies in depth between downhole logs and cores; and (5) shown that the CGR detects some zones noted in the lithology (e.g., phosphate rich zones) that are not resolved in the DGR

Rationale and study protocol for Unidas por la Vida (United for Life): A dyadic weight-loss intervention for high-risk Latina mothers and their adult daughters.

BackgroundHalf of Mexican-American women are under-active and nearly 78% are overweight/obese. The high lifetime risk of developing type 2 diabetes necessitates a culturally appropriate lifestyle intervention.PurposeUnidas por la Vida is a novel dyadic intervention that capitalizes on the centrality of family in Latino culture to mobilize an existing family dyad as a resource for health behavior change. The intervention aims to improve health behaviors and promote weight loss in two at-risk members of the same family: mothers with type 2 diabetes and their overweight/obese adult daughters who are at risk for developing diabetes.MethodsParticipants (N = 460 mother-adult daughter dyads) will be randomized into one of three conditions: 1) dyadic participation (mothers-daughters) in a lifestyle intervention; 2) individual participation (mothers alone; unrelated daughters alone) in a lifestyle intervention; and 3) mother-daughter dyads in a minimal intervention control group.ResultsThe primary outcome is weight loss. Secondary outcomes include physical activity, dietary intake, physiological measures (e.g. HbA1c), and body composition. Both the dyadic and individual interventions are expected to produce greater weight loss at 6, 12, and 18 months than those in minimal intervention control group, with women assigned to the dyadic intervention expected to lose more weight and to maintain the weight loss longer than women assigned to the individual intervention.ConclusionBecause health risks are often shared by multiple members of at-risk families, culturally appropriate, dyadic interventions have the potential to increase the success of behavior change efforts and to extend their reach to multiple family members.Trial registrationClinicalTrials.gov identifier NCT02741037

Durability of Treatment Effect Using a Drug-Coated Balloon for Femoropopliteal Lesions

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The First Provenance Challenge

The first Provenance Challenge was set up in order to provide a forum for the community to help understand the capabilities of different provenance systems and the expressiveness of their provenance representations. To this end, a Functional Magnetic Resonance Imaging workflow was defined, which participants had to either simulate or run in order to produce some provenance representation, from which a set of identified queries had to be implemented and executed. Sixteen teams responded to the challenge, and submitted their inputs. In this paper, we present the challenge workflow and queries, and summarise the participants contributions

Optical and Near Infrared Observations of the Afterglow of GRB 980329 from 15 Hours to 10 Days

We report I-band observations of the GRB 980329 field made on March 29 with the 1.34-m Tautenberg Schmidt telescope, R-, J- and K-band observations made on April 1 with the APO 3.5-m telescope, R- and I-band observations made on April 3 with the Mayall 4-m telescope at KPNO, and J- and K-band observations made between April 6 - 8 with the Keck-I 10-m telescope. We show that these and other reported measurements are consistent with a power-law fading of the optical/near infrared source that is coincident with the variable radio source VLA J0702+3850. This firmly establishes that this source is the afterglow of GRB 980329.Comment: Accepted to The Astrophysical Journal, 18 pages, LaTe