The anti-cancer effect of retinoic acid signaling in CRC occurs via decreased growth of ALDH+ colon cancer stem cells and increased differentiation of stem cells

Background: Tumorigenesis is driven by stem cell (SC) overpopulation. BecauseALDH is both a marker for SCs in many tissues and a key enzyme in retinoid acid (RA)signaling, we studied RA signaling in normal and malignant colonic SCs.Hypothesis: RA signaling regulates growth and differentiation of ALDH+ colonicSCs dysregulation of RA signaling contributes to SC overpopulation and colorectalcancer (CRC) development.Methods: We analyzed normal and malignant colonic tissues and CRC cell linesto see if retinoid receptors (RXR &RAR) are exclusively expressed in ALDH+ SCs,and if RA signaling changes during CRC development. We determined whether RAsignaling regulates cancer SC (CSC) proliferation, differentiation, sphere formation,and population size.Results: RXR &RAR were expressed in ALDH+ colonic SCs, but not in MCM2+proliferative cells. Western blotting/immunostaining of CRCs revealed that RAsignaling components become overexpressed in parallel with ALDH overexpression,which coincides with the known overpopulation of ALDH+ SCs that occurs during,and drives, CRC development. Treatment of SCs with all-trans retinoic acid (ATRA)decreased proliferation, sphere formation and ALDH+ SC population size, and induceddifferentiation along the neuroendocrine cell (NEC) lineage.Conclusions: Retinoid signaling, by regulating ALDH+ colonic CSCs, decreases SCproliferation, sphere formation, and population size, and increases SC differentiation toNECs. Dysregulation of RA signaling in colonic SCs likely contributes to overpopulationof ALDH+ SCs and CRC growth.Implications: That retinoid receptors RXR and RAR are selectively expressed inALDH+ SCs indicates RA signaling mainly occurs via ALDH+ SCs, which provides amechanism to selectively target CSCs. © 2018 Impact Journals LLC. All rights reserved

The bimodality of the 10k zCOSMOS-bright galaxies up to z ~ 1: a new statistical and portable classification based on the optical galaxy properties

Our goal is to develop a new and reliable statistical method to classify galaxies from large surveys. We probe the reliability of the method by comparing it with a three-dimensional classification cube, using the same set of spectral, photometric and morphological parameters.We applied two different methods of classification to a sample of galaxies extracted from the zCOSMOS redshift survey, in the redshift range 0.5 < z < 1.3. The first method is the combination of three independent classification schemes, while the second method exploits an entirely new approach based on statistical analyses like Principal Component Analysis (PCA) and Unsupervised Fuzzy Partition (UFP) clustering method. The PCA+UFP method has been applied also to a lower redshift sample (z < 0.5), exploiting the same set of data but the spectral ones, replaced by the equivalent width of H$\alpha$. The comparison between the two methods shows fairly good agreement on the definition on the two main clusters, the early-type and the late-type galaxies ones. Our PCA-UFP method of classification is robust, flexible and capable of identifying the two main populations of galaxies as well as the intermediate population. The intermediate galaxy population shows many of the properties of the green valley galaxies, and constitutes a more coherent and homogeneous population. The fairly large redshift range of the studied sample allows us to behold the downsizing effect: galaxies with masses of the order of $3\cdot 10^{10}$ Msun mainly are found in transition from the late type to the early type group at $z>0.5$, while galaxies with lower masses - of the order of $10^{10}$ Msun - are in transition at later epochs; galaxies with $M <10^{10}$ Msun did not begin their transition yet, while galaxies with very large masses ($M > 5\cdot 10^{10}$ Msun) mostly completed their transition before $z\sim 1$.Comment: 16 pages, 14 figures, accepted for publication in A&

Phosphorylation of iRhom2 Controls Stimulated Proteolytic Shedding by the Metalloprotease ADAM17/TACE

This deposit is composed by the main article plus the supplementary materials of the publication.Cell surface metalloproteases coordinate signaling during development, tissue homeostasis, and disease. TACE (TNF-α-converting enzyme), is responsible for cleavage ("shedding") of membrane-tethered signaling molecules, including the cytokine TNF, and activating ligands of the EGFR. The trafficking of TACE within the secretory pathway requires its binding to iRhom2, which mediates the exit of TACE from the endoplasmic reticulum. An important, but mechanistically unclear, feature of TACE biology is its ability to be stimulated rapidly on the cell surface by numerous inflammatory and growth-promoting agents. Here, we report a role for iRhom2 in TACE stimulation on the cell surface. TACE shedding stimuli trigger MAP kinase-dependent phosphorylation of iRhom2 N-terminal cytoplasmic tail. This recruits 14-3-3 proteins, enforcing the dissociation of TACE from complexes with iRhom2, promoting the cleavage of TACE substrates. Our data reveal that iRhom2 controls multiple aspects of TACE biology, including stimulated shedding on the cell surface.Fundação Calouste Gulbenkian; Worldwide Cancer Research grant: (14-1289); Marie Curie Career Integration Grant: (project no. 618769); Fundação para a Ciência e Tecnologia grants:( SFRH/BCC/52507/2014, PTDC/BEX-BCM/3015/2014, LISBOA-01-0145-FEDER-007660, FCT-ANR/NEU-NMC/0006/2013, PTDC/NEU-NMC/2459/2014, IF/00697/2014, SFRH/BPD/117216/2016); European Crohn’s and Colitis Organization, and COST grant: (BM1406).info:eu-repo/semantics/publishedVersio

I am great, but only when I also want to dominate: Maladaptive narcissism moderates the relationship between adaptive narcissism and performance under pressure

Narcissism-performance research has focused on grandiose narcissism but has not examined the interaction between its so-called adaptive (reflecting over-confidence) and maladaptive (reflecting a domineering orientation) components. In this research, we tested interactions between adaptive and maladaptive narcissism using two motor tasks (basketball and golf in Experiments 1-2, respectively) and a cognitive task (letter transformation; Experiment 3). Across all experiments, adaptive narcissism predicted performance under pressure only when maladaptive narcissism was high. In the presence of maladaptive narcissism, adaptive narcissism also predicted decreased pre-putt time in Experiment 2 and an adaptive psychophysiological response in Experiment 3, reflecting better processing efficiency. Findings suggest that individuals high in both aspects of narcissism perform better under pressure thanks to superior task processing. In performance contexts, the terms “adaptive” and “maladaptive” – adopted from social psychology – are over-simplistic and inaccurate. We believe that self-inflated narcissism and dominant narcissism are better monikers for these constructs.N/

A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases

The NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome is a component of the inflammatory process, and its aberrant activation is pathogenic in inherited disorders such as cryopyrin-associated periodic syndrome (CAPS) and complex diseases such as multiple sclerosis, type 2 diabetes, Alzheimer's disease and atherosclerosis. We describe the development of MCC950, a potent, selective, small-molecule inhibitor of NLRP3. MCC950 blocked canonical and noncanonical NLRP3 activation at nanomolar concentrations. MCC950 specifically inhibited activation of NLRP3 but not the AIM2, NLRC4 or NLRP1 inflammasomes. MCC950 reduced interleukin-1 beta (IL-1 beta) production in vivo and attenuated the severity of experimental autoimmune encephalomyelitis (EAE), a disease model of multiple sclerosis. Furthermore, MCC950 treatment rescued neonatal lethality in a mouse model of CAPS and was active in ex vivo samples from individuals with Muckle-Wells syndrome. MCC950 is thus a potential therapeutic for NLRP3-associated syndromes, including autoinflammatory and autoimmune diseases, and a tool for further study of the NLRP3 inflammasome in human health and disease

Creative destruction in science

Drawing on the concept of a gale of creative destruction in a capitalistic economy, we argue that initiatives to assess the robustness of findings in the organizational literature should aim to simultaneously test competing ideas operating in the same theoretical space. In other words, replication efforts should seek not just to support or question the original findings, but also to replace them with revised, stronger theories with greater explanatory power. Achieving this will typically require adding new measures, conditions, and subject populations to research designs, in order to carry out conceptual tests of multiple theories in addition to directly replicating the original findings. To illustrate the value of the creative destruction approach for theory pruning in organizational scholarship, we describe recent replication initiatives re-examining culture and work morality, working parents\u2019 reasoning about day care options, and gender discrimination in hiring decisions. Significance statement It is becoming increasingly clear that many, if not most, published research findings across scientific fields are not readily replicable when the same method is repeated. Although extremely valuable, failed replications risk leaving a theoretical void\u2014 reducing confidence the original theoretical prediction is true, but not replacing it with positive evidence in favor of an alternative theory. We introduce the creative destruction approach to replication, which combines theory pruning methods from the field of management with emerging best practices from the open science movement, with the aim of making replications as generative as possible. In effect, we advocate for a Replication 2.0 movement in which the goal shifts from checking on the reliability of past findings to actively engaging in competitive theory testing and theory building. Scientific transparency statement The materials, code, and data for this article are posted publicly on the Open Science Framework, with links provided in the article

The Seventeenth Data Release of the Sloan Digital Sky Surveys: Complete Release of MaNGA, MaStar and APOGEE-2 Data

This paper documents the seventeenth data release (DR17) from the Sloan Digital Sky Surveys; the fifth and final release from the fourth phase (SDSS-IV). DR17 contains the complete release of the Mapping Nearby Galaxies at Apache Point Observatory (MaNGA) survey, which reached its goal of surveying over 10,000 nearby galaxies. The complete release of the MaNGA Stellar Library (MaStar) accompanies this data, providing observations of almost 30,000 stars through the MaNGA instrument during bright time. DR17 also contains the complete release of the Apache Point Observatory Galactic Evolution Experiment 2 (APOGEE-2) survey which publicly releases infra-red spectra of over 650,000 stars. The main sample from the Extended Baryon Oscillation Spectroscopic Survey (eBOSS), as well as the sub-survey Time Domain Spectroscopic Survey (TDSS) data were fully released in DR16. New single-fiber optical spectroscopy released in DR17 is from the SPectroscipic IDentification of ERosita Survey (SPIDERS) sub-survey and the eBOSS-RM program. Along with the primary data sets, DR17 includes 25 new or updated Value Added Catalogs (VACs). This paper concludes the release of SDSS-IV survey data. SDSS continues into its fifth phase with observations already underway for the Milky Way Mapper (MWM), Local Volume Mapper (LVM) and Black Hole Mapper (BHM) surveys