Functional interaction between the homeoprotein CDX1 and the transcriptional machinery containing the TATA-binding protein

We have previously reported that the CDX1 homeoprotein interacts with the TATA-box binding protein (TBP) on the promoter of the glucose-6-phosphatase (G6Pase) gene. We show here that CDX1 interacts with TBP via the homeodomain and that the transcriptional activity additionally requires the N-terminal domain upstream of the homeodomain. CDX1 interacting with TBP is connected to members of the TFIID and Mediator complexes, two major elements of the general transcriptional machinery. Transcription luciferase assays performed using an altered-specificity mutant of TBP provide evidence for the functionality of the interaction between CDX1 and TBP. Unlike CDX1, CDX2 does not interact with TBP nor does it transactivate the G6Pase promoter. Swapping experiments between the domains of CDX1 and CDX2 indicate that, despite opposite functional effects of the homeoproteins on the G6Pase promoter, the N-terminal domains and homeodomains of both CDX1 and CDX2 have the intrinsic ability to activate transcription and to interact with TBP. However, the carboxy domains define the specificity of CDX1 and CDX2. Thus, intra-molecular interactions control the activity and partner recruitment of CDX1 and CDX2, leading to different molecular functions

When it’s okay to hit: How Turkish and U.S. preschoolers and adults make judgments about permissible and impermissible acts of force

To navigate their complex social worlds, children need to make judgments about when, if ever, it is okay to use force against others. By adulthood, most come to condemn violence in most situations yet accept or even encourage force in other situations, such as self-defense or contact sports. This research examined key factors expected to guide how preschoolers and adults make judgments about permissible and impermissible force. These factors included the antecedent events—preceding the force act—and the emotion attributed to the victim. In four studies with Turkish and U.S. preschoolers and adults, an interviewer presented participants with vignettes in which one child used force against another. The antecedent event significantly affected children's and, to an even greater extent, adults’ judgments about force. Participants were also more likely to judge force as permissible when they attributed positive or neutral emotions to the victim. Some cultural differences also emerged. The findings shed light on how children begin to draw moral distinctions between permissible and impermissible force

LE CONSEIL AGRICOLE AU CARREFOUR DU DEVELOPPEMENT SECTORIEL ET DU DEVELOPPEMENT TERRITORIAL :ACCOMPAGNER L'ACTIVITE AGRICOLE EN SITUATIONE

N° ISBN - 978-2-7380-1284-5International audienceThis paper provides a framework to analyse the undergoing changes in agricultural and rural development. As a result of these changes, agricultural extension is faced with the challenge of standing at the crossroads between sector development and territorial development, which is the issue analysed here. This paper contributes to a new conceptualization of agricultural activity, reaching beyond its technical, economic, and productive aspects so as to include cultural and political factors, as well as the spatial and time dimensions related to local and daily life activities. This leads to the establishment of a new approach of agricultural changes and their accompaniment, and of public policy guidelines, which places collective actions, together with their situated dimension, purposes, and knowledge, at the heart of the analysis. The subsequent conceptual framework has being tested in a number of French studies, which first results, reported in Part 2, can be synthesized as three major trends: territorial factors are progressively being integrated in agricultural advice, including in traditional farming sectors; the public and the objects of agricultural extension are diversifying; extension agents need to cooperate with the development agents of non-agricultural sector. All in all, the skills of the extension agents, and their ability to facilitate collective actions, are the most sensitive issues brought about by these new challenges

Assessment of Confounding Factors Affecting the Tumor Markers SMRP, CA125, and CYFRA21-1 in Serum

The purpose of this analysis was to evaluate if serum levels of potential tumor markers for the diagnosis of malignant mesothelioma and lung cancer are affected by confounding factors in a surveillance cohort of workers formerly exposed to asbestos. SMRP, CA125, and CYFRA21-1 concentrations were determined in about 1,700 serum samples from 627 workers formerly exposed to asbestos. The impact of factors that could modify the concentrations of the tumor markers was examined with linear mixed models. SMRP values increased with age 1.02-fold (95% CI 1.01–1.03) and serum creatinine concentration 1.32-fold (95% CI 1.20–1.45). Levels differed by study centers and were higher after 40 years of asbestos exposure. CA125 levels increased with longer storage of the samples. CYFRA21-1 values correlated with age 1.02-fold (95% CI 1.01–1.02), serum creatinine 1.21-fold (95% CI 1.14–1.30) and varied by study centers due to differences in sample handling. Tumor marker concentrations are influenced by subject-related factors, sample handling, and storage. These factors need to be taken into account in screening routine

Development and validation of a knowledge-based score to predict Fried's frailty phenotype across multiple settings using one-year hospital discharge data: The electronic frailty score

Background: Most claims-based frailty instruments have been designed for group stratification of older populations according to the risk of adverse health outcomes and not frailty itself. We aimed to develop and validate a tool based on one-year hospital discharge data for stratification on Fried's frailty phenotype (FP). Methods: We used a three-stage development/validation approach. First, we created a clinical knowledge-driven electronic frailty score (eFS) calculated as the number of deficient organs/systems among 18 critical ones identified from the International Statistical Classification of Diseases and Related Problems, 10th Revision (ICD-10) diagnoses coded in the year before FP assessment. Second, for eFS development and internal validation, we linked individual records from the Lc65+ cohort database to inpatient discharge data from Lausanne University Hospital (CHUV) for the period 2004-2015. The development/internal validation sample included community-dwelling, non-institutionalised residents of Lausanne (Switzerland) recruited in the Lc65+ cohort in three waves (2004, 2009, and 2014), aged 65-70 years at enrolment, and hospitalised at the CHUV at least once in the year preceding the FP assessment. Using this sample, we selected the best performing model for predicting the dichotomised FP, with the eFS or ICD-10-based variables as predictors. Third, we conducted an external validation using 2016 Swiss nationwide hospital discharge data and compared the performance of the eFS model in predicting 13 adverse outcomes to three models relying on well-designed and validated claims-based scores (Claims-based Frailty Index, Hospital Frailty Risk Score, Dr Foster Global Frailty Score). Findings: In the development/internal validation sample (n = 469), 14·3% of participants (n = 67) were frail. Among 34 models tested, the best-subsets logistic regression model with four predictors (age and sex at FP assessment, time since last hospital discharge, eFS) performed best in predicting the dichotomised FP (area under the curve=0·71; F1 score=0·39) and one-year adverse health outcomes. On the external validation sample (n = 54,815; 153 acute care hospitals), the eFS model demonstrated a similar performance to the three other claims-based scoring models. According to the eFS model, the external validation sample showed an estimated prevalence of 56·8% (n = 31,135) of frail older inpatients at admission. Interpretation: The eFS model is an inexpensive, transportable and valid tool allowing reliable group stratification and individual prioritisation for comprehensive frailty assessment and may be applied to both hospitalised and community-dwelling older adults. Funding: The study received no external funding

Anr and Its Activation by PlcH Activity in Pseudomonas aeruginosa Host Colonization and Virulence

Pseudomonas aeruginosa hemolytic phospholipase C (PlcH) degrades phosphatidylcholine (PC), an abundant lipid in cell membranes and lung surfactant. A ΔplcHR mutant, known to be defective in virulence in animal models, was less able to colonize epithelial cell monolayers and was defective in biofilm formation on plastic when grown in lung surfactant. Microarray analyses found that strains defective in PlcH production had lower levels of Anr-regulated transcripts than the wild type. PC degradation stimulated the Anr regulon in an Anr-dependent manner under conditions where Anr activity was submaximal because of the presence of oxygen. Two PC catabolites, choline and glycine betaine (GB), were sufficient to stimulate Anr activity, and their catabolism was required for Anr activation. The addition of choline or GB to glucose-containing medium did not alter Anr protein levels, growth rates, or respiratory activity, and Anr activation could not be attributed to the osmoprotectant functions of GB. The Δanr mutant was defective in virulence in a mouse pneumonia model. Several lines of evidence indicate that Anr is important for the colonization of biotic and abiotic surfaces in both P. aeruginosa PAO1 and PA14 and that increases in Anr activity resulted in enhanced biofilm formation. Our data suggest that PlcH activity promotes Anr activity in oxic environments and that Anr activity contributes to virulence, even in the acute infection phase, where low oxygen tensions are not expected. This finding highlights the relationships among in vivo bacterial metabolism, the activity of the oxygen-sensitive regulator Anr, and virulence

FIREBall-2: advancing TRL while doing proof-of-concept astrophysics on a suborbital platform

Here we discuss advances in UV technology over the last decade, with an emphasis on photon counting, low noise, high efficiency detectors in sub-orbital programs. We focus on the use of innovative UV detectors in a NASA astrophysics balloon telescope, FIREBall-2, which successfully flew in the Fall of 2018. The FIREBall-2 telescope is designed to make observations of distant galaxies to understand more about how they evolve by looking for diffuse hydrogen in the galactic halo. The payload utilizes a 1.0-meter class telescope with an ultraviolet multi-object spectrograph and is a joint collaboration between Caltech, JPL, LAM, CNES, Columbia, the University of Arizona, and NASA. The improved detector technology that was tested on FIREBall-2 can be applied to any UV mission. We discuss the results of the flight and detector performance. We will also discuss the utility of sub-orbital platforms (both balloon payloads and rockets) for testing new technologies and proof-of-concept scientific ideasComment: Submitted to the Proceedings of SPIE, Defense + Commercial Sensing (SI19

Efficient Genome-Wide Detection and Cataloging of EMS-Induced Mutations Using Exome Capture and Next-Generation Sequencing

Chemical mutagenesis efficiently generates phenotypic variation in otherwise homogeneous genetic backgrounds, enabling functional analysis of genes. Advances in mutation detection have brought the utility of induced mutant populations on par with those produced by insertional mutagenesis, but systematic cataloguing of mutations would further increase their utility. We examined the suitability of multiplexed global exome capture and sequencing coupled with custom-developed bioinformatics tools to identify mutations in well-characterized mutant populations of rice (Oryza sativa) and wheat (Triticum aestivum). In rice, we identified ∼18,000 induced mutations from 72 independent M2 individuals. Functional evaluation indicated the recovery of potentially deleterious mutations for >2600 genes. We further observed that specific sequence and cytosine methylation patterns surrounding the targeted guanine residues strongly affect their probability to be alkylated by ethyl methanesulfonate. Application of these methods to six independent M2 lines of tetraploid wheat demonstrated that our bioinformatics pipeline is applicable to polyploids. In conclusion, we provide a method for developing large-scale induced mutation resources with relatively small investments that is applicable to resource-poor organisms. Furthermore, our results demonstrate that large libraries of sequenced mutations can be readily generated, providing enhanced opportunities to study gene function and assess the effect of sequence and chromatin context on mutations

Cdx2 homeoprotein inhibits non-homologous end joining in colon cancer but not in leukemia cells

Cdx2, a gene of the paraHox cluster, encodes a homeodomain transcription factor that plays numerous roles in embryonic development and in homeostasis of the adult intestine. Whereas Cdx2 exerts a tumor suppressor function in the gut, its abnormal ectopic expression in acute leukemia is associated to a pro-oncogenic function. To try to understand this duality, we have hypothesized that Cdx2 may interact with different protein partners in the two tissues and set up experiments to identify them by tandem affinity purification. We show here that Cdx2 interacts with the Ku heterodimer specifically in intestinal cells, but not in leukemia cells, via its homeodomain. Ku proteins do not affect Cdx2 transcriptional activity. However, Cdx2 inhibits in vivo and in vitro the DNA repair activity mediated by Ku proteins in intestinal cells. Whereas Cdx2 does not affect the recruitment of Ku proteins and DNA-PKcs into the DNA repair complex, it inhibits DNA-PKcs activity. Thus, we report here a new function of Cdx2, acting as an inhibitor of the DNA repair machinery, that may contribute to its tumor suppressor function specifically in the gut