Neuroinflammation by cytotoxic T-lymphocytes impairs retrograde axonal transport in an oligodendrocyte mutant mouse

Mice overexpressing proteolipid protein (PLP) develop a leukodystrophy-like disease involving cytotoxic, CD8+ T-lymphocytes. Here we show that these cytotoxic T-lymphocytes perturb retrograde axonal transport. Using fluorogold stereotactically injected into the colliculus superior, we found that PLP overexpression in oligodendrocytes led to significantly reduced retrograde axonal transport in retina ganglion cell axons. We also observed an accumulation of mitochondria in the juxtaparanodal axonal swellings, indicative for a disturbed axonal transport. PLP overexpression in the absence of T-lymphocytes rescued retrograde axonal transport defects and abolished axonal swellings. Bone marrow transfer from wildtype mice, but not from perforin- or granzyme B-deficient mutants, into lymphocyte-deficient PLP mutant mice led again to impaired axonal transport and the formation of axonal swellings, which are predominantly located at the juxtaparanodal region. This demonstrates that the adaptive immune system, including cytotoxic T-lymphocytes which release perforin and granzyme B, are necessary to perturb axonal integrity in the PLP-transgenic disease model. Based on our observations, so far not attended molecular and cellular players belonging to the immune system should be considered to understand pathogenesis in inherited myelin disorders with progressive axonal damage

Epidermal Langerhans Cells-A Target for HTLV-III/LAV Infection

Langerhans cells (LC) are bone marrow-derived, la+, CD1+, CD4+, ATPase+ dendritic antigen-presenting cells within the human epidermis. Since the CD4 molecule has been implicated as a receptor structure for HTLV-III/LAV (human T-cell leukemia virus/lymphadenopathy-associated virus), we asked whether LC from HTLV-III/LAV-seropositive individuals display signs of HTLV-III/LAV infection. In skin biopsies from 7/40 HTLV-III/LAV-infected persons (1 asymptomatic carrier, 2 patients with acquired immunodeficiency syndrome (AIDS)-related complex and 4 patients with AIDS), LC were the only epidermal cells to react with a monoclonal antibody specific for the HTLV-III core protein p17. A varying percentage of p17+ LC were morphologically altered with blunt dendrites and poorly demarcated cellular contours. In one of these biopsies, the presence of LC-associated viral particles characteristic of HTLV-III/LAV as well as cytopathic changes in approximately one-third of the LC population were demonstrated by electron microscopy. These results strongly suggest that LC may harbor HTLV-III/LAV. The infection of LC with this retrovirus may have deleterious consequences for the immunologic functions of this cell system and may thus contribute to both the acquisition of immunodeficiency and the infectious and neoplastic complications of AIDS

Rote Liste und Artenverzeichnis der Schnecken und Muscheln Baden-Württembergs

Die vorliegende Veröffentlichung umfasst zwei Grundbausteine. Zum einen die offizielle Rote Liste mit Nennung der Gefährdungskategorien, zum anderen ein revidiertes systematisches Gesamtartenverzeichnis der Mollusken Baden-Württembergs. Die Rote Liste dient zum schnellen Feststellen der jeweiligen Gefährdungskategorien der einzelnen Arten in Baden-Württemberg und ist wie üblich alphabetisch nach Gattungen geordnet. Sehr großer Wert wurde auf die sorgfältige Analyse der Ergebnisse gelegt (Kapitel 7). Das Gesamtartenverzeichnis dient der aktuellen systematischen Einordnung aller Arten, weshalb hier die Taxa im Kontext des wissenschaftlichen Systems der Mollusken aufgeführt werden. Im systematischen Artenverzeichnis soll der momentane Kenntnisstand über die Mollusken Baden-Württembergs in knapper Darstellung zum Ausdruck kommen. Hier sind auch die bekannten Unterarten aufgeführt und es werden zusätzliche Informationen zum Verbreitungstyp, zur Verbreitung (Vorkommen in den Naturräumen 3. Ordnung) sowie zur Ökologie (Zuordnung einzelner Arten zu bestimmten Biotoptypen) gegeben. Mit diesen Zusatzinformationen werden Rote Listen und Artenverzeichnisse zu Gradmessern der Biodiversitätsforschung. In über 130 ‚Anmerkungen‘ werden die entsprechenden Angaben zur Systematik, Verbreitung und Ökologie präzisiert und es wird auf die hierfür zu Grunde liegende Literatur verwiesen. Alle Angaben der Roten Liste sind auch im ausführlichen systematischen Artenverzeichnis enthalten. In beiden Listen sind die Arten mit ihrer laufenden Nummer aufgeführt. Damit ist ein problemloser Wechsel von der Roten Liste zu den Angaben im systematischen Artenverzeichnis gewährleistet. Der Forschungsstand findet sich vielfach in der historischen Literatur, die deshalb eine sorgfältige und kritische Berücksichtigung erfuhr (siehe Anmerkungen und Literaturverzeichnis). Einen unschätzbaren Wert haben in diesem Zusammenhang die zahlreichen Veröffentlichungen David Geyer‘s, die den Beginn der modernen Regionalfaunisik in Baden-Württemberg kennzeichnen. Ein eigenes Kapitel zur Forschungsgeschichte hätte jedoch den vorgegebenen Rahmen dieser Arbeit gesprengt

German Ageing Survey (DEAS): Instruments of the Fifth Wave 2014

Capi-Template for the face-to-face interview; Drop-off questionnaire; Short questionnaire for non-respondents; Occupational status card; Cards with personal codes; Answer options (excerpt); Digit-symbol test; Pulmonary function test

Gα_i Proteins are Indispensable for Hearing

Background/Aims: From invertebrates to mammals, Gαi proteins act together with their common binding partner Gpsm2 to govern cell polarization and planar organization in virtually any polarized cell. Recently, we demonstrated that Gαi3-deficiency in pre-hearing murine cochleae pointed to a role of Gαi3 for asymmetric migration of the kinocilium as well as the orientation and shape of the stereociliary (“hair”) bundle, a requirement for the progression of mature hearing. We found that the lack of Gαi3 impairs stereociliary elongation and hair bundle shape in high-frequency cochlear regions, linked to elevated hearing thresholds for high-frequency sound. How these morphological defects translate into hearing phenotypes is not clear. Methods: Here, we studied global and conditional Gnai3 and Gnai2 mouse mutants deficient for either one or both Gαi proteins. Comparative analyses of global versus Foxg1-driven conditional mutants that mainly delete in the inner ear and telencephalon in combination with functional tests were applied to dissect essential and redundant functions of different Gαi isoforms and to assign specific defects to outer or inner hair cells, the auditory nerve, satellite cells or central auditory neurons. Results: Here we report that lack of Gαi3 but not of the ubiquitously expressed Gαi2 elevates hearing threshold, accompanied by impaired hair bundle elongation and shape in high-frequency cochlear regions. During the crucial reprogramming of the immature inner hair cell (IHC) synapse into a functional sensory synapse of the mature IHC deficiency for Gαi2 or Gαi3 had no impact. In contrast, double-deficiency for Gαi2 and Gαi3 isoforms results in abnormalities along the entire tonotopic axis including profound deafness associated with stereocilia defects. In these mice, postnatal IHC synapse maturation is also impaired. In addition, the analysis of conditional versus global Gαi3-deficient mice revealed that the amplitude of ABR wave IV was disproportionally elevated in comparison to ABR wave I indicating that Gαi3 is selectively involved in generation of neural gain during auditory processing. Conclusion: We propose a so far unrecognized complexity of isoform-specific and overlapping Gαi protein functions particular during final differentiation processes

Eosinophilic granulomatosis with polyangiitis (Churg–Strauss) (EGPA) Consensus Task Force recommendations for evaluation and management

AbstractObjectiveTo develop disease-specific recommendations for the diagnosis and management of eosinophilic granulomatosis with polyangiitis (Churg–Strauss syndrome) (EGPA).MethodsThe EGPA Consensus Task Force experts comprised 8 pulmonologists, 6 internists, 4 rheumatologists, 3 nephrologists, 1 pathologist and 1 allergist from 5 European countries and the USA. Using a modified Delphi process, a list of 40 questions was elaborated by 2 members and sent to all participants prior to the meeting. Concurrently, an extensive literature search was undertaken with publications assigned with a level of evidence according to accepted criteria. Drafts of the recommendations were circulated for review to all members until final consensus was reached.ResultsTwenty-two recommendations concerning the diagnosis, initial evaluation, treatment and monitoring of EGPA patients were established. The relevant published information on EGPA, antineutrophil-cytoplasm antibody-associated vasculitides, hypereosinophilic syndromes and eosinophilic asthma supporting these recommendations was also reviewed.DiscussionThese recommendations aim to give physicians tools for effective and individual management of EGPA patients, and to provide guidance for further targeted research

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements