Opioids trigger alpha 5 beta 1 integrin-mediated monocyte adhesion

Inflammatory reactions involve a network of chemical and molecular signals that initiate and maintain host response. In inflamed tissue, immune system cells generate opioid peptides that contribute to potent analgesia by acting on specific peripheral sensory neurons. In this study, we show that opioids also modulate immune cell function in vitro and in vivo. By binding to its specific receptor, the opioid receptor-specific ligand DPDPE triggers monocyte adhesion. Integrins have a key role in this process, as adhesion is abrogated in cells treated with specific neutralizing anti-alpha5beta1 integrin mAb. We found that DPDPE-triggered monocyte adhesion requires PI3Kgamma activation and involves Src kinases, the guanine nucleotide exchange factor Vav-1, and the small GTPase Rac1. DPDPE also induces adhesion of pertussis toxin-treated cells, indicating involvement of G proteins other than Gi. These data show that opioids have important implications in regulating leukocyte trafficking, adding a new function to their known effects as immune response modulators.

A de novo 1.1-1.6 Mb subtelomeric deletion of chromosome 20q13.33 in a patient with learning difficulties but without obvious dysmorphic features

We report on a de novo submicroscopic deletion of 20q13.33 identified by subtelomeric fluorescence in situ hybridization (FISH) in a 4-year-old girl with learning difficulties, hyperlaxity and strabismus, but without obvious dysmorphic features. Further investigations by array-based comparative genomic hybridization (array-CGH) and FISH analysis allowed us to delineate the smallest reported subterminal deletion of chromosome 20q, spanning a 1.1-1.6 Mb with a breakpoint localized between BAC RP5-887L7 and RP11-261N11. The genes CHRNA4 and KCNQ2 implicated in autosomal dominant epilepsy are included in the deletion interval. Subterminal 20q deletions as found in the present patient have, to our knowledge, only been reported in three patients. We review the clinical and behavioral phenotype of such "pure" subterminal 20q deletions.

Fructose-1,6-bisphosphate preserves intracellular glutathione and protects cortical neurons against oxidative stress

Fructose-1,6-bisphosphate (FBP), an endogenous intermediate of glycolysis, protects the brain against ischemia-reperfusion injury. The mechanisms of FBP protection after cerebral ischemia are not well understood. The current study was undertaken to determine whether FBP protects primary neurons against hypoxia and oxidative stress by preserving reduced glutathione (GSH). Cultures of pure cortical neurons were subjected to oxygen deprivation, a donor of nitric oxide and superoxide radicals (3-morpholinosydnonimine), an inhibitor of glutathione synthesis (L-buthionine-sulfoximine) or glutathione reductase (1,3-bis(2-chloroethyl)-1-nitrosourea) in the presence or absence of FBP (3.5 mM). Neuronal viability was determined using an 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay. FBP protected neurons against hypoxia-reoxygenation and oxidative stress under conditions of compromised GSH metabolism. The efficacy of FBP depended on duration of hypoxia and was associated with higher intracellular GSH concentration, an effect partly mediated via increased glutathione reductase activity.

The Protein-tyrosine-phosphatase SHP2 is phosphorylated on serine residues 576 and 591 by protein kinase C isoforms alpha, beta 1, beta 2, and eta

To study whether protein kinase C (PKC) isoforms can interact with protein-tyrosine-phosphatases (PTPs) which are connected to the insulin signaling pathway, we co-overexpressed PKC isoforms together with insulin receptor, docking proteins, and the PTPs SHP1 and SHP2 in human embryonic kidney (HEK) 293 cells. After phorbol ester induced activation of PKC isoforms alpha, beta 1, beta 2, and eta, we could show a defined gel mobility shift of SHP2, indicating phosphorylation on serine/threonine residues. This phosphorylation was not dependent on insulin receptor or insulin receptor substrate-1 (IRS-1) overexpression and did not occur for the closely related phosphatase SHP1. Furthermore, PKC phosphorylation of SHP2 was completely blocked by the PKC inhibitor bisindolylmaleimide and was not detectable when SHP2 was co-overexpressed with kinase negative mutants of PKC beta 1 and -beta 2. The phosphorylation also occurred on endogenous SHP2 in Chinese hamster ovary (CHO) cells stably overexpressing PKC beta 2. Using point mutants of SHP2, we identified serine residues 576 and 591 as phosphorylation sites for PKC. However, no change of phosphatase activity by TPA treatment was detected in an in vitro assay. In summary, SHP2 is phosphorylated on serine residues 576 and 591 by PKC isoforms alpha, beta 1, beta 2, and eta.

Structural and functional studies of the human integrin $\alpha 4\beta 1$ (CD49d/CD29)

The integrin receptor $\alpha 4\beta 1$ is a cell surface heterodimer involved in a variety of highly regulated cellular interactions. The purpose of this dissertation was to identify and characterize unique structural and functional properties of the $\alpha 4\beta 1$ molecule that may be important for adhesion regulation and signal transduction. To study these properties and to establish a consensus sequence for the $\alpha 4$ subunit, cDNA encoding $\alpha 4$ was cloned and sequenced. A comparison with previously described human $\alpha 4$ sequences identified several substitutions in the $5\prime$ and $3\prime$ untranslated regions, and a nonsynonymous G to A transition in the coding region, resulting in a glutamine substitution for arginine. Further analysis of this single nucleotide substitution indicated that two variants of the $\alpha 4$ subunit exist, and when compared with three ancestrally-related species, the new form cloned in our laboratory was found to be evolutionarily conserved.^ The expression of $\alpha 4$ cDNA in transfected K562 erythroleukemia cells, and subsequent studies using flow cytofluorometric, immunochemical, and ligand binding/blocking analyses, confirmed $\alpha 4\beta 1$ as a receptor for fibronectin (FN) and vascular cell adhesion molecule-1 (VCAM-1), and provided a practical means of identifying two novel monoclonal antibody (mAb) binding epitopes on the $\alpha 4\beta 1$ complex that may play important roles in the regulation of leukocyte adhesion.^ To investigate the association of $\alpha 4\beta 1$-mediated adhesion with signals involved in the spreading of lymphocytes on FN, a quantitative method of analysis was developed using video microscopy and digital imaging. The results showed that HPB-ALL $(\alpha 4\beta 1\sp{\rm hi},\ \alpha 5\beta 1\sp-)$ cells could adhere and actively spread on human plasma FN, but not on control substrate. Many cell types which express different levels of the $\alpha 4\beta 1$ and $\alpha 5\beta 1$ FN binding integrins were examined for their ability to function in these events. Using anti-$\alpha 4$ and anti-$\alpha 5$ mAbs, it was determined that cell adhesion to FN was influenced by both $\beta 1$ integrins, while cell spreading was found to be dependent on the $\alpha 4\beta 1$ complex. In addition, inhibitors of phospholipase A$\sb2$ (PLA$\sb2$), 5-lipoxygenases, and cyclooxygenases blocked HPB-ALL cell spreading, yet had no effect on cell adhesion to FN, and the impaired spreading induced by the PLA$\sb2$ inhibitor cibacron blue was restored by the addition of exogenous arachidonic acid (AA). These results suggest that the interaction of $\alpha 4\beta 1$ with FN, the activation of PLA$\sb2,$ and the subsequent release of AA, may be involved in lymphocyte spreading. ^

Briefe eines Neulings an den Verfasser der politischen Gespräche aus dem Reiche der Todten : nebst beigedr. 3 Aufsätzen aus d. Gesprächen im Reiche d. Todten, wodurch diese Briefe veranlaßt sind

[Jakob Stern]

Ewaso Ngiro and Meru Ecosystems Elephant Corridors: Site 1-6

7 maps illustrating the elephant corridors in different sites of Ewaso Ngiro, Kenya.

Allerdurchlauchtigster Kurfürst! Allergnädigster Kurfürst und Herr! Die Verkündigung der deutschen Bundesversammlung vom 1. März d. J. fordert die deutschen Fürsten und Völker auf ...

Welsch (Projektbearbeiter): Veröffentlichung der Märzforderungen in Kurfürstentum Hessen-Kassel: Meinungs-, Glaubens- und Gewissensfreiheit, Öffentlichkeit der Justiz sowie baldige Einberufung der Ständeversammlung. "Geben Allerhöchstdieselben uns eine entsprechende Zusicherung, so werden Sie sehen, welcher Jubel Ihnen aus dem ganzen Lande entgegenschallen wird!" Verfaßt anläßlich des Aufrufs der Bundesversammlung zur Eintracht und Beachtung der Gesetze vom 1. März 1848

Na 1 Nachlass Max Horkheimer, 674 - Forschungsprojekte über Antisemitismus, Vorurteil, Autorität: Einzeluntersuchungen (p. IX 141.1-24- IX 142.1-6)

Bettelheim, Bruno; Janowitz, Morris: "A Study on Anxiety and Social Aggression Among Different Groups of War Veterans", 1945-1947; Über die Anfälligkeit der Veteranen für antisemitische Propaganda, Typoskript, englisch, 1 Blatt; "Preliminary Study on the Evaluation of Intolerance Propaganda". Typoskript, 29 Blatt; "Isolationg the Patterns of Intolerance". Typoskript, 30 Blatt; "Distribution of Ethic Intolerance". Typsokript, 18 Blatt; "The Social Characteristics of the Intolerant". Typoskript, 22 Blatt; "Addendum to Social Characteristics of the Intolerant". Typoskript, 16 Blatt; "Impact of War Experiences". Typoskript, 26 Blatt; "Pattern on Sterepotypes". Typoskript, 14 Blatt; "Appendix No. 1: Schedule of Questions Employed in Interview". Typoskript, 6 Blatt; "Appendix No. 2: The Verteran´s Comment on the Interview Situation". Typoskript, 7 Blatt; "Preliminary Report of the Evaluation of Tolerance Propaganda". Typoskript, 19 Blatt; Einleitung zur Beschreibung des Forschungsprojekts, Typoskript, englisch, 1 Blatt; "Instructions for Interviewers". Typoskript, 2 Blat; "Questionaire". Typoskrip, 10 Blatt; "Prupose of the Investigation". Typoskript, 4 Blatt; "Schedule for Interviewers". Typoskript, 6 Blatt; "Appendix: Chicago Veterans Project". Typoskript, 3 Blatt; Memodanden zu Sitzungen mit Bruno Bettelheim, Edward Shils und Theodor W. Adorno; Memorandum 03.04.1945, Typoskript, 2 Blatt; Memorandum 15.03.1945; a) Typoskript, 3 Blatt; b) Typoskript, 4 Blatt; Memorandum 07.03.1945; a) Typoskript, 5 Blatt; b) Typoskript, 6 Blatt; University of Chicago: 1 Brief an Max Horkheimer, Chicago, 29.10.1945; University of Chicago, 1 Brief an Edward Shils undBruno Bettelheim, Chicago, 05.07.1945; Fine, Benjamin: "For Education against Intolerance and Prejudice"; Sonderdruck aus: The Menorah Journal, 1944, Vol. XXXII, No. 2, S. 161-180; Drucksachen, Materialien, 10 Blatt; Ackerman, Nathan W.: zum 'Psychoanalyst Project', 1945-1946; "Towards a Dynamic definition of Anti-Semitism". Typoskript, 13 Blatt; "The Use of Psychoanalytic Case Histories for the Study of Anti-Semitism". Typoskript, 14 Blatt; "Case Material Summary", Tabelle, 5 Blatt; "From for the Collection of Clinical Data on Anti-Minority and Anti-Semitic Attitudes". Als Typoskript vervielfältigt, 5 Blatt; "Case 2". Typoskript, 5 Blatt; "Case 24". Typoskript, 8 Blatt;

Na 1 Nachlass Max Horkheimer, 693 - "German Economy, Politics and Culture, 1900-1933" (p. IX 168 1.a)-d))

"German Economy, Politics and Culture, 1900-1933. A Research Project of the International Institute of Social Research" (1940):; 1. Umriß des Forschungsprojekts, a) Fassung vom 29.7.1940, Typoskript, 55 Blatt, b)-d) Fassung vom 6.6.1940: b) Typoskript, 55 Blatt, c) Typoskript mit handschriftlichen Korrekturen, 60 Blatt, d) Typoskript, 60 Blatt;