DIFFERENT MEASURES, DIFFERENT TRENDS – CONTRADICTIONS IN MACRO AND MICRO LEVEL GROWTH MEASURES

When focusing on business performance of a country, industry or an individual firm the performance of companies may be tracked using various measures. By simulating the behaviour of a simple firm, our model underlines that the choice of measurement unit determines what distortions we will face, and thus, using different measures we may end up identifying completely contradicting cycles at macro, mezzo, and micro level. On top of that, these cycles would radically change if firms examined changed their operational, investment or financing strategy or when structural changes happen in the economy. This may end in researchers analysing non-existing cycle changes and looking for nearly identical explanations of development differences for industries, regions or countries

Atg17/FIP200 localizes to perilysosomal Ref(2)P aggregates and promotes autophagy by activation of Atg1 in Drosophila.

Phagophore-derived autophagosomes deliver cytoplasmic material to lysosomes for degradation and reuse. Autophagy mediated by the incompletely characterized actions of Atg proteins is involved in numerous physiological and pathological settings including stress resistance, immunity, aging, cancer, and neurodegenerative diseases. Here we characterized Atg17/FIP200, the Drosophila ortholog of mammalian RB1CC1/FIP200, a proposed functional equivalent of yeast Atg17. Atg17 disruption inhibits basal, starvation-induced and developmental autophagy, and interferes with the programmed elimination of larval salivary glands and midgut during metamorphosis. Upon starvation, Atg17-positive structures appear at aggregates of the selective cargo Ref(2)P/p62 near lysosomes. This location may be similar to the perivacuolar PAS (phagophore assembly site) described in yeast. Drosophila Atg17 is a member of the Atg1 kinase complex as in mammals, and we showed that it binds to the other subunits including Atg1, Atg13, and Atg101 (C12orf44 in humans, 9430023L20Rik in mice and RGD1359310 in rats). Atg17 is required for the kinase activity of endogenous Atg1 in vivo, as loss of Atg17 prevents the Atg1-dependent shift of endogenous Atg13 to hyperphosphorylated forms, and also blocks punctate Atg1 localization during starvation. Finally, we found that Atg1 overexpression induces autophagy and reduces cell size in Atg17-null mutant fat body cells, and that overexpression of Atg17 promotes endogenous Atg13 phosphorylation and enhances autophagy in an Atg1-dependent manner in the fat body. We propose a model according to which the relative activity of Atg1, estimated by the ratio of hyper- to hypophosphorylated Atg13, contributes to setting low (basal) vs. high (starvation-induced) autophagy levels in Drosophila

Loss of Atg16 delays the alcohol-induced sedation response via regulation of Corazonin neuropeptide production in Drosophila

Autophagy defects lead to the buildup of damaged proteins and organelles, reduced survival during starvation and infections, hypersensitivity to stress and toxic substances, and progressive neurodegeneration. Here we show that, surprisingly, Drosophila mutants lacking the core autophagy gene Atg16 are not only defective in autophagy but also exhibit increased resistance to the sedative effects of ethanol, unlike Atg7 or Atg3 null mutant flies. This mutant phenotype is rescued by the re-expression of Atg16 in Corazonin (Crz)-producing neurosecretory cells that are known to promote the sedation response during ethanol exposure, and RNAi knockdown of Atg16 specifically in these cells also delays the onset of ethanol-induced coma. We find that Atg16 and Crz colocalize within these neurosecretory cells, and both Crz protein and mRNA levels are decreased in Atg16 mutant flies. Thus, Atg16 promotes Crz production to ensure a proper organismal sedation response to ethanol

Autophagosomal Syntaxin17-dependent lysosomal degradation maintains neuronal function in Drosophila

During autophagy, phagophores capture portions of cytoplasm and form double-membrane autophagosomes to deliver cargo for lysosomal degradation. How autophagosomes gain competence to fuse with late endosomes and lysosomes is not known. In this paper, we show that Syntaxin17 is recruited to the outer membrane of autophagosomes to mediate fusion through its interactions with ubisnap (SNAP-29) and VAMP7 in Drosophila melanogaster. Loss of these genes results in accumulation of autophagosomes and a block of autolysosomal degradation during basal, starvation-induced, and developmental autophagy. Viable Syntaxin17 mutant adults show large-scale accumulation of autophagosomes in neurons, severe locomotion defects, and premature death. These mutant phenotypes cannot be rescued by neuron-specific inhibition of caspases, suggesting that caspase activation and cell death do not play a major role in brain dysfunction. Our findings reveal the molecular mechanism underlying autophagosomal fusion events and show that lysosomal degradation and recycling of sequestered autophagosome content is crucial to maintain proper functioning of the nervous system

Sex hormone-binding globulin provides a novel entry pathway for estradiol and influences subsequent signaling in lymphocytes via membrane receptor

The complex effects of estradiol on non-reproductive tissues/cells, including lymphoid tissues and immunocytes, have increasingly been explored. However, the role of sex hormone binding globulin (SHBG) in the regulation of these genomic and non-genomic actions of estradiol is controversial. Moreover, the expression of SHBG and its internalization by potential receptors, as well as the influence of SHBG on estradiol uptake and signaling in lymphocytes has remained unexplored. Here, we found that human and mouse T cells expressed SHBG intrinsically. In addition, B lymphoid cell lines as well as both primary B and T lymphocytes bound and internalized external SHBG, and the amount of plasma membrane-bound SHBG decreased in B cells of pregnant compared to non-pregnant women. As potential mediators of this process, SHBG receptor candidates expressed by lymphocytes were identified in silico, including estrogen receptor (ER) alpha. Furthermore, cell surface-bound SHBG was detected in close proximity to membrane ERs while highly colocalizing with lipid rafts. The SHBG-membrane ER interaction was found functional since SHBG promoted estradiol uptake by lymphocytes and subsequently influenced Erk1/2 phosphorylation. In conclusion, the SHBG-SHBG receptor-membrane ER complex participates in the rapid estradiol signaling in lymphocytes, and this pathway may be altered in B cells in pregnant women

The Ccz1-Mon1-Rab7 module and Rab5 control distinct steps of autophagy

The small GTPase Rab5 promotes recruitment of the Ccz1-Mon1 guanosine exchange complex to endosomes to activate Rab7, which facilitates endosome maturation and fusion with lysosomes. How these factors function during autophagy is incompletely understood. Here we show that autophagosomes accumulate due to impaired fusion with lysosomes upon loss of the Ccz1-Mon1-Rab7 module in starved Drosophila fat cells. In contrast, autophagosomes generated in Rab5 null mutant cells normally fuse with lysosomes during the starvation response. Consistent with that, Rab5 is dispensable for the Ccz1-Mon1-dependent recruitment of Rab7 to PI3P-positive autophagosomes, which are generated by the action of the Atg14-containing Vps34 PI3 kinase complex. Finally, we find that Rab5 is required for proper lysosomal function. Thus, the Ccz1-Mon1-Rab7 module is required for autophagosome-lysosome fusion, whereas Rab5 loss interferes with a later step of autophagy: the breakdown of autophagic cargo within lysosomes

Depresszív tüneteket és öngyilkossági gondolatokat befolyásoló tényezők gyulladásos bélbetegségben szenvedők körében: Multicentrikus tanulmány

Bevezetés: A gyulladásos bélbetegség olyan kórkép, mely a diagnózistól kezdve élethosszig hatással van a betegek fizi- kális és pszichés egészségi állapotára és életminőségére. Célkitűzés: Megvizsgálni gyulladásos bélbetegek körében a depresszív tünetek és az öngyilkossági gondolatok előfor- dulásának gyakoriságát, valamint az ezekkel összefüggésben lévő betegség- és terápiaspecifikus tényezőket. Módszer: A vizsgálatban 300 fő vett részt (átlagéletkor 38,8 év, férfiak 47%, nők 53%). A depresszív tüneteket (PHQ-9), öngyilkossági gondolatokat (PHQ-9 9. tétele), a reménytelenség mértékét (Beck Reménytelenség Skála) és a beteg- séggel összefüggő jóllét mértékét (SIBDQ) vizsgáltuk online formában. Eredmények: A vizsgálati személyek 28,6%-a mutatott depresszív tüneteket, és 9,3%-uk a magas rizikójú csoportba tartozik a reménytelenség tekintetében. Öngyilkossági gondolatokat a válaszadók 16%-a jelzett, ebből magas rizikót a minta 5,3%-a mutatott. A lineáris regressziós modell eredménye alapján a depresszív tüneteket magyarázó tényezők közé tartozik a reménytelenség mértéke, a bélen kívüli tünet fennállása, fájdalomcsillapító rendszeres szedése, a női nem, valamint a betegség aktivitása. Következtetés: A vizsgálatunkban szereplő gyulladásos bélbetegek öngyilkossági gondolatainak és depresszív tünetei- nek előfordulási aránya a nemzetközi adatokkal egyezően magas, amire kiemelt figyelmet érdemes fordítani a betegek pszichés vezetése során. A pszichológiai tényezők rendszeres vizsgálata és kezelése fontos része kell hogy legyen a betegek gondozásának, mivel javíthat a páciensek szubjektív állapotán, és a betegség lefolyására is pozitív hatással lehet