The U7 snRNP and the hairpin binding protein: Key players in histone mRNA metabolism.

Animal replication-dependent histone mRNAs are subject to several post-transcriptional regulatory processes. Their non-polyadenylated 3' ends are formed preferentially during S phase by a unique nuclear cleavage event. This requires the base pairing between U7 snRNA and a histone spacer element 3' of the cleavage site. Cleavage occurs preferentially after adenosine, at a fixed distance from the hybrid region. A conserved RNA hairpin just upstream of the cleavage site is recognised by the hairpin binding protein (HBP) that acts as an auxiliary processing factor, stabilising the interaction of the histone pre-mRNA with the U7 snRNP. The interaction between HBP and the RNA hairpin is very stable and HBP is also found associated with histone mRNAs on polysomes. The hairpin and presumably, HBP are also required for nuclear export and translation of histone mRNA. Furthermore, histone mRNAs are selectively destabilised in the G2 phase or upon inhibition of DNA synthesis and this regulation is also associated with the hairpin. Recently, HBP-encoding cDNAs were isolated from various organisms. Human, mouse and Xenopus laevis HBPs are similar, while the Caenorhabditis elegans protein has significant homology to the others only in a central RNA binding domain.Copyright 1997 Academic Press Limited

Linking Ah receptor mediated effects of sediments and impacts on fish to key pollutants in the Yangtze Three Gorges Reservoir, China – A comprehensive perspective

The Three Gorges Reservoir (TGR), created in consequence of the Yangtze River's impoundment by the Three Gorges Dam, faces numerous anthropogenic impacts that challenge its unique ecosystem. Organic pollutants, particularly aryl hydrocarbon receptor (AhR) agonists, have been widely detected in the Yangtze River, but only little research was yet done on AhR-mediated activities. Hence, in order to assess effects of organic pollution, with particular focus on AhR-mediated activities, several sites in the TGR area were examined applying the "triad approach". It combines chemical analysis, in vitro, in vivo and in situ investigations to a holistic assessment. Sediments and the benthic fish species Pelteobagrus vachellii were sampled in 2011/2012, respectively, to identify relevant endpoints. Sediment was tested in vitro with the ethoxyresorufin-O-deethylase (EROD) induction assay, and in vivo with the Fish Embryo Toxicity Test and Sediment Contact Assay with Danio rerio. Activities of phase I (EROD) and phase II (glutathione-S-transferase) biotransformation enzymes, pollutant metabolites and histopathological alterations were studied in situ in P. vachellii. EROD induction was tested in vitro and in situ to evaluate possible relationships. Two sites, near Chongqing and Kaixian city, were identified as regional hot-spots and further investigated in 2013. The sediments induced in the in vitro/in vivo bioassays AhR-mediated activities and embryotoxic/teratogenic effects - particularly on the cardiovascular system. These endpoints could be significantly correlated to each other and respective chemical data. However, particle-bound pollutants showed only low bioavailability. The in situ investigations suggested a rather poor condition of P. vachellii, with histopathological alterations in liver and excretory kidney. Fish from Chongqing city exhibited significant hepatic EROD induction and obvious parasitic infestations. The polycyclic aromatic hydrocarbon (PAH) metabolite 1-hydroxypyrene was detected in bile of fish from all sites. All endpoints in combination with the chemical data suggest a pivotal role of PAHs in the observed ecotoxicological impacts.

The Fatty Acid Biosynthesis Enzyme FabI Plays a Key Role in the Development of Liver-Stage Malarial Parasites

The fatty acid synthesis type II pathway has received considerable interest as a candidate therapeutic target in Plasmodium falciparum asexual blood-stage infections. This apicoplast-resident pathway, distinct from the mammalian type I process, includes FabI. Here, we report synthetic chemistry and transfection studies concluding that Plasmodium FabI is not the target of the antimalarial activity of triclosan, an inhibitor of bacterial FabI. Disruption of fabI in P. falciparum or the rodent parasite P. berghei does not impede blood-stage growth. In contrast, mosquito-derived, FabI-deficient P. berghei sporozoites are markedly less infective for mice and typically fail to complete liver-stage development in vitro. This defect is characterized by an inability to form intrahepatic merosomes that normally initiate blood-stage infections. These data illuminate key differences between liver- and blood-stage parasites in their requirements for host versus de novo synthesized fatty acids, and create new prospects for stage-specific antimalarial interventions.

Na 1 Nachlass Max Horkheimer, 634 - Aufsätze für die "Zeitschrift für Sozialforschung" und "Studies in Philosophy and Social Science" (p. IX 9.1-4-IX 10.1-7)

"Montaigne oder die Funktion der Skepsis" (GS 4, S.236-194), veröffentlicht in: Zeitschrift für Sozialforschung VII, 1938, S.1-54, englische Fassung des Aufsatzes, Typoskript, 69 Blatt; Exzerpte: Montaigne im Urteil der Nachwelt, Typoskripte, 29 Blatt; handschriftliche Stichworte zu Montaigne, 10 Blatt; 2 Zeitungsausschnitte; Leihscheine der Columbia University Library für Bücher über Montaigne; "Die Juden und Europa" (GS 4, S.308-331), veröffentlicht in: Studies in Philosophy and Social Science VIII, 1939, S. 115-137, a) Typoskript mit eigenhändigen Korrekturen, 31 Blatt, b) Typoskript mit eigenhändigen und handschriftlichen Korrekturen, 32 Blatt, c) Typoskript mit handschriftlichen Korrekturen, 27 Blatt, d) Typoskript mit handschriftlichen Korrekturen, Teilstücke, 16 Blatt, e) Typoskript mit eigenhändigen und handschriftlichen Korrekturen, 20 Blatt, f) überholte Formulierungen, Typoskript mit handschriftlichen Korrekturen, 10 Blatt; Bemerkungen zum Verhältnis von Liberalismus und Antisemitismus, a) Typoskript, 4 Blatt, b) Typoskript mit eigenhändigen Korrekturen, 9 Blatt (als Nachbemerkung zu: Ernst Engelberg: Exzerpt zu W. Frank und W. Grau), Typoskript, 1 Blatt; Exzerpte zu: Alvin Johnson, Honoré de Balzac, Guy de Maupassant, Paul Mahn, Marcel Proust, Anatole France, Marcel le Goff, Emile Zola, Typoskripte, 58 Blatt; Otto Kirchheimer: "Produktionswandel und Konzentrationstendenzen im Bankgewerbe", Typoskript, 2 Blatt; eigenhändige Adressennotiz, 1 Blatt; Otto Kirchheimer: "Reprivatisierungstendenzen des Faschismus", Typoskript mit eigenhändiger Ergänzung, 12 Blatt; Zeitungsausschnitte zur wirtschaftlichen Entwicklung, 1938, 8 Blatt;

CARD9 functions as a key regulator in monocyte homeostasis and pathogen clearance

Mononuclear phagocytes are designed to neutralize systemic bacterial and fungal infections. However, the exact regulation of these functions are largely unknown. CARD9 was first identified as an immune-specific adaptor protein of unclear function. Here, we have found that Card9 is specifically expressed in monocyte-origin cell populations. To better understand the biological function of Card9, we have generated Card9-deficient (Card9-/-) mice. Hematologic profiling and histological analysis of Card9-/- mice revealed a decreased leukocyte/myeloid cell count, delayed monocyte maturation in bone marrow as well as monocyte counts in the peripheral blood. Upon M-CSF stimulation, Card9-/- macrophages further exhibit a partial loss in IKK phosphorylation. As a consequence, in vivo challenge with Listeria monocytogenes in Card9-/- mice results in a higher susceptibility to infection-associated inflammation and fatality. Collectively, these data suggest that CARD9 is required for monocyte development and function. ^ At the cellular level, Card9-/- macrophages are defective in killing Listeria and the production of pro-inflammatory cytokines. Molecular characterizations have further demonstrated that CARD9 inducibly interacts with NOD2, controls p38 MAPK activation, and regulates ROS production during Listeria infections. Cytotrap screening showed that CARD9 could physically associate with various g&barbelow;uanine e&barbelow;xchange f&barbelow;actor (GEF) proteins that are essential for regulating ROS production. In summary, we have first identified and provided genetic evidence that CARD9 functions as a novel regulator during monocyte development and serves as an essential protein adaptor for p38 MAPK activation during bacterial clearance processes in macrophages. ^