Connecting the Dots: Analyzing Synthetic Observations of Star-Forming Clumps in Molecular Clouds

In this paper, we investigate the extent to which observations of molecular clouds can correctly identify and measure star-forming clumps. We produced a synthetic column density map and a synthetic spectral-line data cube from the simulated collapse of a 5000 M$_{\odot}$ molecular cloud. By correlating the clumps found in the simulation to those found in the synthetic observations, clump masses derived from spectral-line data cubes were found to be quite close to the true physical properties of the clumps. We also find that the `observed' clump mass function derived from the column density map is shifted by a factor of ~ 3 higher than the true clump mass function, due to projection of low-density material along the line of sight. Alves et al. (2007) first proposed that a shift of a clump mass function to higher masses by a factor of 3 can be attributed to a star formation efficiency of 30 %. Our results indicate that this finding may instead be due to an overestimate of clump masses determined from column density observations.Comment: 8 pages, 7 figures, Accepted for publication in the Astrophysical Journa

The Wnt Receptor Ryk Reduces Neuronal and Cell Survival Capacity by Repressing FOXO Activity During the Early Phases of Mutant Huntingtin Pathogenicity

The Wnt receptor Ryk is an evolutionary-conserved protein important during neuronal differentiation through several mechanisms, including γ-secretase cleavage and nuclear translocation of its intracellular domain (Ryk-ICD). Although the Wnt pathway may be neuroprotective, the role of Ryk in neurodegenerative disease remains unknown. We found that Ryk is up-regulated in neurons expressing mutant huntingtin (HTT) in several models of Huntington's disease (HD). Further investigation in Caenorhabditis elegans and mouse striatal cell models of HD provided a model in which the early-stage increase of Ryk promotes neuronal dysfunction by repressing the neuroprotective activity of the longevity-promoting factor FOXO through a noncanonical mechanism that implicates the Ryk-ICD fragment and its binding to the FOXO co-factor β-catenin. The Ryk-ICD fragment suppressed neuroprotection by lin-18/Ryk loss-of-function in expanded-polyQ nematodes, repressed FOXO transcriptional activity, and abolished β-catenin protection of mutant htt striatal cells against cell death vulnerability. Additionally, Ryk-ICD was increased in the nucleus of mutant htt cells, and reducing γ-secretase PS1 levels compensated for the cytotoxicity of full-length Ryk in these cells. These findings reveal that the Ryk-ICD pathway may impair FOXO protective activity in mutant polyglutamine neurons, suggesting that neurons are unable to efficiently maintain function and resist disease from the earliest phases of the pathogenic process in HD. © 2014 Tourette et al

Integration of beta-Catenin, Sirtuin, and FOXO Signaling Protects from Mutant Huntingtin Toxicity

One of the current challenges of neurodegenerative disease research is to determine whether signaling pathways that are essential to cellular homeostasis might contribute to neuronal survival and modulate the pathogenic process in human disease. In Caenorhabditis elegans, sir-2.1/SIRT1 overexpression protects neurons from the early phases of expanded polyglutamine (polyQ) toxicity, and this protection requires the longevity-promoting factor daf-16/FOXO. Here, we show that this neuroprotective effect also requires the DAF-16/FOXO partner bar-1/beta-catenin and putative DAF-16-regulated gene ucp-4, the sole mitochondrial uncoupling protein (UCP) in nematodes. These results fit with a previously proposed mechanism in which the beta-catenin FOXO and SIRT1 proteins may together regulate gene expression and cell survival. Knockdown of beta-catenin enhanced the vulnerability to cell death of mutant-huntingtin striatal cells derived from the HdhQ111 knock-in mice. In addition, this effect was compensated by SIRT1 overexpression and accompanied by the modulation of neuronal UCP expression levels, further highlighting a cross-talk between beta-catenin and SIRT1 in the modulation of mutant polyQ cytoxicity. Taken together, these results suggest that integration of beta-catenin, sirtuin and FOXO signaling protects from the early phases of mutant huntingtin toxicity

Covalent Cysteine Targeting of Bruton's Tyrosine Kinase (BTK) Family by Withaferin-A Reduces Survival of Glucocorticoid-Resistant Multiple Myeloma MM1 Cells

Simple Summary Glucocorticoid therapy resistance in B-cell malignancies is often associated with constitutive activation of tyrosine kinases. Novel anticancer drugs targeting hyperactivated tyrosine kinases, such as Bruton's tyrosine kinase (BTK), have, therefore, gained much interest over the past few decades and have already been approved for clinical use. In this study, we compared the therapeutic efficacy of the phytochemical kinase inhibitor withaferin A with the clinically approved BTK inhibitor ibrutinib to target hyperactivated tyrosine kinase signaling in glucocorticoid-resistant multiple myeloma cells. Our results demonstrate that withaferin A-induced cell death of glucocorticoid-resistant MM1R cells involves covalent cysteine targeting of multiple Hinge-6 domain type tyrosine kinases of the kinase cysteinome classification, including BTK. Multiple myeloma (MM) is a hematological malignancy characterized by plasma cells' uncontrolled growth. The major barrier in treating MM is the occurrence of primary and acquired therapy resistance to anticancer drugs. Often, this therapy resistance is associated with constitutive hyperactivation of tyrosine kinase signaling. Novel covalent kinase inhibitors, such as the clinically approved BTK inhibitor ibrutinib (IBR) and the preclinical phytochemical withaferin A (WA), have, therefore, gained pharmaceutical interest. Remarkably, WA is more effective than IBR in killing BTK-overexpressing glucocorticoid (GC)-resistant MM1R cells. To further characterize the kinase inhibitor profiles of WA and IBR in GC-resistant MM cells, we applied phosphopeptidome- and transcriptome-specific tyrosine kinome profiling. In contrast to IBR, WA was found to reverse BTK overexpression in GC-resistant MM1R cells. Furthermore, WA-induced cell death involves covalent cysteine targeting of Hinge-6 domain type tyrosine kinases of the kinase cysteinome classification, including inhibition of the hyperactivated BTK. Covalent interaction between WA and BTK could further be confirmed by biotin-based affinity purification and confocal microscopy. Similarly, molecular modeling suggests WA preferably targets conserved cysteines in the Hinge-6 region of the kinase cysteinome classification, favoring inhibition of multiple B-cell receptors (BCR) family kinases. Altogether, we show that WA's promiscuous inhibition of multiple BTK family tyrosine kinases represents a highly effective strategy to overcome GC-therapy resistance in MM

Analyse des propriétés d'un variant d'épissage de la cycline B et caractérisation d'un de ses partenaires

La cycline B est un des régulateurs clef du cycle cellulaire, associée à Cdc2 elle formele MPF (Maturation Promoting Factor). Ce complexe contrôle la transition entre phases G2 etM du cycle cellulaire. Au laboratoire, un variant d'épissage de la cycline B d'oursin a étédécouvert. Il lui manque la partie C-terminale, dans laquelle certains résidus sont trèsconservés.Au cours de ce travail, le même variant a été cloné chez l'étoile de mer. Sespartenaires ont été recherchés par criblage de banque en double hybride chez la levure ainsiqu'en chromatographie d'affinité. Cette dernière technique a permis d'isoler une protéine de15kDa (P15) qui s'associe à la cycline B même en l'absence de Cdc2. Une particularité decette protéine est d'exister sous trois formes alléliques. La P15 est localisée au niveau dufuseau de division. Des exprériences de micro-injections ont montré qu'elle joue un rôle dansla sortie de méiose, vraisemblablement en liaison avec la dégradation de la cycline B.Parallèlement, le rôle des résidus manquant chez le variant d'épissage a été étudié parla mutagénèse du C-terminal de Clb2 de levure. Ces résidus sont importants pour lalocalisation de la cycline mais aussi pour son association correcte avec Cdc2

Analyse des propriétés d'un variant d'épissage de la cycline B et caractérisation d'un de ses partenaires

BANYULS/MER-Observ.Océanol. (660162201) / SudocPARIS-AgroParisTech Centre Paris (751052302) / SudocSudocFranceF

First record of spawning and embryonic development in Octopus macropus (Mollusca: Cephalopoda)

A female Octopus macropus , the first ever observed spawning, attached eggs (4·0×1·2 mm, with a chorion stalk 4 mm in length) individually or in clusters to a hard substrate, and brooded them till hatching. Hatchlings measured 4·0 mm in dorsal mantle length, 5·5 mm in total length and were planktonic; their short arms had seven suckers each, the outer demi-branch of each gill had ten lamellae. The chromatophore pattern confirmed an earlier identification of young individuals from the plankton (Naef, 1923)

The pro-apoptotic activity of a vertebrate Bar-like homeobox gene plays a key role in patterning the Xenopus neural plate by limiting the number of chordin- and shh-expressing cells

International audienceTargeted disruption of effectors molecules of the apoptotic pathway have demonstrated the occurrence and magnitude of early programmed cell death (EPCD), a form of apoptosis that affects proliferating and newly differentiated cells in vertebrates, and most dramatically cells of the central nervous system (CNS). Little is known about the molecular pathways controlling apoptosis at these early developmental stages, as the roles of EPCD during patterning of the developing nervous system. We describe a new function, in Xenopus neurodevelopment, for a highly conserved homeodomain protein Barhl2. Barhl2 promotes apoptosis in the Xenopus neuroectoderm and mesoderm, acting as a transcriptional repressor, through a mechanism that cannot be attributed to an unspecific cellular stress response. We show that the pro-apoptotic activity of Barhl2 is essential during normal neural plate formation as it limits the number of chordin- and Xshh-expressing cells in the prospective notochord and floorplate, which act as organizing centers. Our findings show that Barhl2 is part of a pathway regulating EPCD. They also provide evidence that apoptosis plays an important role in regulating the size of organizing centers