Striated Rootlet and Nonfilamentous Forms of Rootletin Maintain Ciliary Function

SummaryPrimary cilia are microtubule-based sensory organelles whose structures and functions must be actively maintained throughout animal lifespan to support signal transduction pathways essential for development and physiological processes such as vision and olfaction [1]. Remarkably, few cellular components aside from the intraflagellar transport (IFT) machinery are implicated in ciliary maintenance [2]. Rootletin, an evolutionarily conserved protein found as prominent striated rootlets or a nonfilamentous form, both of which are associated with cilium-anchoring basal bodies, represents a likely candidate given its well-known role in preventing ciliary photoreceptor degeneration in a mouse model [3, 4]. Whether rootletin is universally required for maintaining ciliary integrity, and if so, by what mechanism, remains unresolved. Here, we demonstrate that the gene disrupted in the previously isolated C. elegans chemosensory mutant che-10 encodes a rootletin ortholog that localizes proximally and distally to basal bodies of cilia harboring or lacking conspicuous rootlets. In vivo analyses reveal that CHE-10/rootletin maintains ciliary integrity partly by modulating the assembly, motility, and flux of IFT particles, which are critical for axoneme length control. Surprisingly, CHE-10/rootletin is also essential for stabilizing ciliary transition zones and basal bodies, roles not ascribed to IFT. Unifying these findings, we provide evidence that the underlying molecular defects in the che-10 mutant stem from disrupted organization/function of the periciliary membrane, affecting the efficient delivery of basal body-associated and ciliary components and resulting in cilium degeneration. Together, our cloning and functional analyses of C. elegans che-10 provide the first mechanistic insights into how filamentous and nonfilamentous forms of rootletin play essential roles in maintaining ciliary function in metazoans

Histoire des " Big Five " : OCEAN des cinq grands facteurs de la personnalité. Introduction du Big Five Inventory français ou BFI-FR

International audienceLa description de la personnalité a été conçue à partir d'une variété de points de vue théoriques et à différents niveaux d'abstraction. Dans l'étude de la personnalité, l'unité la plus fréquemment utilisée pour mesurer les différences individuelles a été le trait. Un consensus semble se dégager actuellement sur une taxonomie générale des traits de la personnalité, les cinq facteurs de la personnalité, connus sous le nom des " Big Five ", expression introduite par Goldberg. Le but de cet article est de resituer l'élaboration de la version originale du Big Five Inventory (BFI) de John, Donahue et Kentle (1991) dans son histoire, et parmi les autres tests disponibles le " TDA ou trait descriptive adjective " de Goldberg et le " NEO PI-R ou NEO personality inventory revised " de Costa et McCrae. La revue reprend les différents stades de conceptualisation des catégories qui furent élaborées à partir d'une sélection d'adjectifs de dictionnaires permettant de différencier un individu d'un autre. Seuls les traits seront utilisés pour l'élaboration des trois tests mentionnés. Les " Big Five " retrouvés à partir d'analyses factorielles peuvent se résumer en cinq facteurs réplicables connus sous le nom de OCEAN ou CANOE de la personnalité, moyen mnémotechnique pour E (Extraversion, Énergie, Enthousiasme) ; A (Agréabilité, Altruisme, Affection) ; C (Conscience, Contrôle, Contrainte) ; N (Émotions Négatives, Névrosisme, Nervosité) ; O (Ouverture, Originalité, Ouverture d'esprit), ordre établi par les auteurs du BFI. La structure des " Big Five " regroupe à un haut niveau d'abstraction les points communs de la plupart des systèmes existant sur la description de la personnalité et met à disposition un modèle descriptif intégré pour des recherches sur la personnalité

North Atlantic Craton architecture revealed by kimberlite-hosted crustal zircons

The Maniitsoq project is supported by the Ministry of Mineral Resources, Government of Greenland. NJG and PAC thank Australian Research Council grant FL160100168 for financial support. ON is supported by Australian Research Council grant FT140101062 and the Melbourne TIE team.Archean cratons are composites of terranes formed at different times, juxtaposed during craton assembly. Cratons are underpinned by a deep lithospheric root, and models for the development of this cratonic lithosphere include both vertical and horizontal accretion. How different Archean terranes at the surface are reflected vertically within the lithosphere, which might inform on modes of formation, is poorly constrained. Kimberlites, which originate from significant depths within the upper mantle, sample cratonic interiors. The North Atlantic Craton, West Greenland, comprises Eoarchean and Mesoarchean gneiss terranes – the latter including the Akia Terrane – assembled during the late Archean. We report U–Pb and Hf isotopic, and trace element, data measured in zircon xenocrysts from a Neoproterozoic (557 Ma) kimberlite which intruded the Mesoarchean Akia Terrane. The zircon trace element profiles suggest they crystallized from evolved magmas, and their Eo- to Neoarchean U–Pb ages match the surrounding gneiss terranes, and highlight that magmatism was episodic. Zircon Hf isotope values lie within two crustal evolution trends: a Mesoarchean trend and an Eoarchean trend. The Eoarchean trend is anchored on 3.8 Ga orthogneiss, and includes 3.6–3.5 Ga, 2.7 and 2.5–2.4 Ga aged zircons. The Mesoarchean Akia Terrane may have been built upon mafic crust, in which case all zircons whose Hf isotopes lie within the Eoarchean trend were derived from the surrounding Eoarchean gneiss terranes, emplaced under the Akia Terrane after ca. 2.97 or 2.7 Ga, perhaps during late Archean terrane assembly. Kimberlite-hosted peridotite rhenium depletion model ages suggest a late Archean stabilization for the lithospheric mantle. The zircon data support a model of lithospheric growth via tectonic stacking for the North Atlantic Craton.Publisher PDFPeer reviewe

All coffee types decrease the risk of adverse clinical outcomes in chronic liver disease: A UK Biobank study

Abstract Background Chronic liver disease (CLD) is a growing cause of morbidity and mortality worldwide, particularly in low to middle-income countries with high disease burden and limited treatment availability. Coffee consumption has been linked with lower rates of CLD, but little is known about the effects of different coffee types, which vary in chemical composition. This study aimed to investigate associations of coffee consumption, including decaffeinated, instant and ground coffee, with chronic liver disease outcomes. Methods A total of 494,585 UK Biobank participants with known coffee consumption and electronic linkage to hospital, death and cancer records were included in this study. Cox regression was used to estimate hazard ratios (HR) of incident CLD, incident CLD or steatosis, incident hepatocellular carcinoma (HCC) and death from CLD according to coffee consumption of any type as well as for decaffeinated, instant and ground coffee individually. Results Among 384,818 coffee drinkers and 109,767 non-coffee drinkers, there were 3600 cases of CLD, 5439 cases of CLD or steatosis, 184 cases of HCC and 301 deaths from CLD during a median follow-up of 10.7 years. Compared to non-coffee drinkers, coffee drinkers had lower adjusted HRs of CLD (HR 0.79, 95% CI 0.72–0.86), CLD or steatosis (HR 0.80, 95% CI 0.75–0.86), death from CLD (HR 0.51, 95% CI 0.39–0.67) and HCC (HR 0.80, 95% CI 0.54–1.19). The associations for decaffeinated, instant and ground coffee individually were similar to all types combined. Conclusion The finding that all types of coffee are protective against CLD is significant given the increasing incidence of CLD worldwide and the potential of coffee as an intervention to prevent CLD onset or progression

Pharmacometabolomics reveals racial differences in response to atenolol treatment.

Antihypertensive drugs are among the most commonly prescribed drugs for chronic disease worldwide. The response to antihypertensive drugs varies substantially between individuals and important factors such as race that contribute to this heterogeneity are poorly understood. In this study we use metabolomics, a global biochemical approach to investigate biochemical changes induced by the beta-adrenergic receptor blocker atenolol in Caucasians and African Americans. Plasma from individuals treated with atenolol was collected at baseline (untreated) and after a 9 week treatment period and analyzed using a GC-TOF metabolomics platform. The metabolomic signature of atenolol exposure included saturated (palmitic), monounsaturated (oleic, palmitoleic) and polyunsaturated (arachidonic, linoleic) free fatty acids, which decreased in Caucasians after treatment but were not different in African Americans (p<0.0005, q<0.03). Similarly, the ketone body 3-hydroxybutyrate was significantly decreased in Caucasians by 33% (p<0.0001, q<0.0001) but was unchanged in African Americans. The contribution of genetic variation in genes that encode lipases to the racial differences in atenolol-induced changes in fatty acids was examined. SNP rs9652472 in LIPC was found to be associated with the change in oleic acid in Caucasians (p<0.0005) but not African Americans, whereas the PLA2G4C SNP rs7250148 associated with oleic acid change in African Americans (p<0.0001) but not Caucasians. Together, these data indicate that atenolol-induced changes in the metabolome are dependent on race and genotype. This study represents a first step of a pharmacometabolomic approach to phenotype patients with hypertension and gain mechanistic insights into racial variability in changes that occur with atenolol treatment, which may influence response to the drug

The Innate Mononuclear Phagocyte Network Depletes B Lymphocytes through Fc Receptor–dependent Mechanisms during Anti-CD20 Antibody Immunotherapy

Anti-CD20 antibody immunotherapy effectively treats non-Hodgkin's lymphoma and autoimmune disease. However, the cellular and molecular pathways for B cell depletion remain undefined because human mechanistic studies are limited. Proposed mechanisms include antibody-, effector cell–, and complement-dependent cytotoxicity, the disruption of CD20 signaling pathways, and the induction of apoptosis. To identify the mechanisms for B cell depletion in vivo, a new mouse model for anti-CD20 immunotherapy was developed using a panel of twelve mouse anti–mouse CD20 monoclonal antibodies representing all four immunoglobulin G isotypes. Anti-CD20 antibodies rapidly depleted the vast majority of circulating and tissue B cells in an isotype-restricted manner that was completely dependent on effector cell Fc receptor expression. B cell depletion used both FcγRI- and FcγRIII-dependent pathways, whereas B cells were not eliminated in FcR common γ chain–deficient mice. Monocytes were the dominant effector cells for B cell depletion, with no demonstrable role for T or natural killer cells. Although most anti-CD20 antibodies activated complement in vitro, B cell depletion was completely effective in mice with genetic deficiencies in C3, C4, or C1q complement components. That the innate monocyte network depletes B cells through FcγR-dependent pathways during anti-CD20 immunotherapy has important clinical implications for anti-CD20 and other antibody-based therapies

An improved zebrafish transcriptome annotation for sensitive and comprehensive detection of cell type-specific genes

The zebrafish is ideal for studying embryogenesis and is increasingly applied to model human disease. In these contexts, RNA-sequencing (RNA-seq) provides mechanistic insights by identifying transcriptome changes between experimental conditions. Application of RNA-seq relies on accurate transcript annotation for a genome of interest. Here, we find discrepancies in analysis from RNA-seq datasets quantified using Ensembl and RefSeq zebrafish annotations. These issues were due, in part, to variably annotated 3\u27 untranslated regions and thousands of gene models missing from each annotation. Since these discrepancies could compromise downstream analyses and biological reproducibility, we built a more comprehensive zebrafish transcriptome annotation that addresses these deficiencies. Our annotation improves detection of cell type-specific genes in both bulk and single cell RNA-seq datasets, where it also improves resolution of cell clustering. Thus, we demonstrate that our new transcriptome annotation can outperform existing annotations, providing an important resource for zebrafish researchers

MENA Confers Resistance to Paclitaxel in Triple-Negative Breast Cancer

Taxane therapy remains the standard of care for triple-negative breast cancer. However, high frequencies of recurrence and progression in treated patients indicate that metastatic breast cancer cells can acquire resistance to this drug. The actin regulatory protein MENA and particularly its invasive isoform, MENAINV , are established drivers of metastasis. MENAINV expression is significantly correlated with metastasis and poor outcome in human patients with breast cancer. We investigated whether MENA isoforms might play a role in driving resistance to chemotherapeutics. We find that both MENA and MENAINV confer resistance to the taxane paclitaxel, but not to the widely used DNA-damaging agents doxorubicin or cisplatin. Furthermore, paclitaxel treatment does not attenuate growth of MENAINV -driven metastatic lesions. Mechanistically, MENA isoform expression alters the ratio of dynamic and stable microtubule populations in paclitaxel-treated cells. MENA expression also increases MAPK signaling in response to paclitaxel treatment. Decreasing ERK phosphorylation by cotreatment with MEK inhibitor restored paclitaxel sensitivity by driving microtubule stabilization in MENA isoform-expressing cells. Our results reveal a novel mechanism of taxane resistance in highly metastatic breast cancer cells and identify a combination therapy to overcome such resistance

The TRiC/CCT chaperone is implicated in Alzheimer's disease based on patient GWAS and an RNAi screen in Aβ-expressing Caenorhabditis elegans.

The human Aβ peptide causes progressive paralysis when expressed in the muscles of the nematode worm, C. elegans. We have exploited this model of Aβ toxicity by carrying out an RNAi screen to identify genes whose reduced expression modifies the severity of this locomotor phenotype. Our initial finding was that none of the human orthologues of these worm genes is identical with the genome-wide significant GWAS genes reported to date (the "white zone"); moreover there was no identity between worm screen hits and the longer list of GWAS genes which included those with borderline levels of significance (the "grey zone"). This indicates that Aβ toxicity should not be considered as equivalent to sporadic AD. To increase the sensitivity of our analysis, we then considered the physical interactors (+1 interactome) of the products of the genes in both the worm and the white+grey zone lists. When we consider these worm and GWAS gene lists we find that 4 of the 60 worm genes have a +1 interactome overlap that is larger than expected by chance. Two of these genes form a chaperonin complex, the third is closely associated with this complex and the fourth gene codes for actin, the major substrate of the same chaperonin

lynx1 Supports Neuronal Health in the Mouse Dorsal Striatum During Aging: an Ultrastructural Investigation

Nicotinic acetylcholine receptors have been shown to participate in neuroprotection in the aging brain. Lynx protein modulators dampen the activity of the cholinergic system through direct interaction with nicotinic receptors. Although lynx1 null mutant mice exhibit augmented learning and plasticity, they also exhibit macroscopic vacuolation in the dorsal striatum as they age, detectable at the optical microscope level. Despite the relevance of the lynx1 gene to brain function, little is known about the cellular ultrastructure of these age-related changes. In this study, we assessed degeneration in the dorsal striatum in 1-, 3-, 7-, and 13-month-old mice, using optical and transmission electron microscopy. We observed a loss of nerve fibers, a breakdown in nerve fiber bundles, and a loss of neuronal nuclei in the 13-month-old lynx1 null striatum. At higher magnification, these nerve fibers displayed intracellular vacuoles and disordered myelin sheaths. Few or none of these morphological alterations were present in younger lynx1 null mutant mice or in heterozygous lynx1 null mutant mice at any age. These data indicate that neuronal health can be maintained by titrating lynx1 dosage and that the lynx1 gene may participate in a trade-off between neuroprotection and augmented learning