Progranulin-Antikörper und hyperphosphoryliertes Progranulin in Vaskulitiden, Kollagenosen und Myositiden

Autoantikörper spielen eine große Rolle in der Diagnostik und Pathogenese von Vaskulitiden und Kollagenosen. So haben antineutrophile zytoplasmatische Antikörper (ANCA) nicht nur eine Rolle in der Diagnostik der ANCA-assoziierten Vaskulitiden, sondern besitzen auch einen besonderen pathogenetischen Stellenwert. Etablierte Autoantikörper wurden oftmals per Zufall entdeckt; eine systematische Suche nach Autoantikörpern erfolgte bei Vaskulitiden bisher nicht. Unserer Arbeitsgruppe gelang es mittels Proteinarray-basierter Screeninguntersuchungen Au-toantikörper gegen Progranulin (PGRN) in Seren von Patienten mit Granulomatose mit Poly-angiitis, eosinophile Granulomatose mit Polyangiitis, Panarteriitis nodosa und Riesenzellar-teriitis zu entdecken. Progranulin ist ein natürlicher Antagonist des Tumornekrosefaktors α (TNFα). Es wirkt durch hochaffine Bindung an den Tumornekrosefaktorrezeptor-1 und -2 und Death-rezeptor 3. An den beiden ersten antagonisiert Progranulin TNFα, am letztgenannten TNF-ähnliches Molekül 1A. Aufgrund der mutmaßlich proinflammatorischen Wirkung der Progranulin-Antikörper (PGRN-Ak) wurden weitere Seren von Patienten mit rheumatologisch-autoimmunen Erkrankungen untersucht. Mittels ELISA konnten wir das Vorkommen von PGRN-Ak in Seren von Patienten mit jeweils verschiedenen Vaskulitisformen, Kollagenosen und Myositiden untersuchen: Riesenzellarteriitis/Polymyalgia rheumatica (14/65), Takayasu Arteriitis (4/13), klassischer Panarteriitis nodosa (4/10), Granulomatose mit Polyangiitis (31/ 75), eosinophiler Granulomatose mit Polyangiitis (7/23), mikroskopischer Polyangiitis (7/19), ANCA-assoziierten Vaskulitiden (3/6), Morbus Behcet (2/8), undifferenzierte Kollagenose (5/17), Sjögren Syndrom/Sicca Syndrom (9/19), CREST (2/8), systemischer Sklerose (10/31), systemischem Lupus erythematodes (39/91), Antiphospholipidsyndrom (6/15)), Dermatomyo-sitis/Polymyositis (4/33). Zusätzlich wurden zwei Kontrollgruppen (immunologische Kontroll-gruppe (6/31), nicht-immunologische Kontrollgruppe (1/30)) untersucht. Es gelang der erstmalige Nachweis von PGRN-Ak in den untersuchten Erkrankungen und die Beschreibung einer vorläufigen Prävalenz. Es konnte gezeigt werden, dass ein Zusammenhang zwischen dem Auftreten von PGRN-Ak und einer aktiven Erkrankung im Bereich der klein- und mittelkalibrigen Gefäßvaskulitiden besteht. Des Weiteren lieferte diese Arbeit erste Ergeb-nisse in der Fragestellung des molekularen Mechanismus der Entstehung von PGRN-Ak. Durch die Untersuchung mittels isoelektrischer Fokussierung zeigte sich, dass PGRN ausschließlich bei PRGN-Ak positiven Patienten in einer zusätzlichen Isoform zu finden ist. Hier konnte nach-gewiesen werden, dass es sich um eine an Serin 81 hyperphosphorylierte PGRN Isoform handelt. Je nach Phosphorylierungsstatus des PGRN zeigten sich überdies unterschiedliche Spaltmuster von PGRN in Granuline.Autoantibodies play a crucial role in the diagnostic and pathogenesis of vasculitis and connec-tive tissue disorders. Antineutrophilic cytoplasmatic antibodies (ANCA) for example are not only used diagnostically but constitute a pathogenetic role. Todays established antibodies were often discovered by chance rather than by research. A systematic search for antibodies in vas-culitis has not happened so far. We found antibodies directed against Progranulin (PGRN) by screening of sera of patients with granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, panarteriitis nodosa and giant cell arteritis on proteinmacroarrays. PGRN is a physiologic antagonist to TNFα and TL1a. It inflicts its role by binding to TNFR-1, -2 and DR3. We screened sera of patients with different rheumatic diseases because of the presumed antiinflammatory role of PGRN-antibodies (PGRN-abs). By using ELISA we were able to identify PGRN-abs in sera of patients with vasculitis (Giant cell arteriitis/Polymyalgia rheumatica (14/65), Takayasu Arteri-tiis (4/13), classic Panarteriitis nodosa (4/10), granulomatosis with polyangiitis (31/ 75), eosin-ophilic granulomatosis with polyangiitis (7/23), mikroscopic polyangiitis (7/19), ANCA-assosiacted vaskulitis (3/6), Morbus Behcet (2/8)), connective tissue disorders (undifferantiated connective tissue disorder (5/17), Sjögrens syndrom/sicca syndrom (9/19), CREST (2/8), sys-temic sclerosis (10/31), systematic Lupus erythematodes (39/91), antiphospholipidsyndrom (6/15)), und myositis (dermatomyositis/polymyositis (4/33)). Additionally, two control groups were tested (autoimmune control (6/31), non-autoimmune control (1/30)). Not only were PGRN-abs firstly described in these diseases, but a first prevalance was established. Further-more, we found a significant correlation between disease activity in middle and small vessel vasculitis and PGRN-abs incidence. Also, this thesis contributed to the solution of why PGRN-abs appear. By isoelectric focusing we discovered that PGRN appears in a second isoform ex-clusively in PGRN-ab positive patients. This second isoform could be characterized as PGRN hyperphosphorylated at serine 81. Furthermore, we were able to show different cleavagepat-terns for PGRN into mature GRN based on the phosphorylationstatus of PGRN

A note on quasi-robust cycle bases

We investigate here some aspects of cycle bases of undirected graphs that allow the iterative construction of all elementary cycles. We introduce the concept of quasi-robust bases as a generalization of the notion of robust bases and demonstrate that a certain class of bases of the complete bipartite graphs K m,n with m,n _> 5 is quasi-robust but not robust. We furthermore disprove a conjecture for cycle bases of Cartesian product graphs

In situ characterization of the functional degradation of a [001] orientated Fe–Mn–Al–Ni single crystal under compression using acoustic emission measurements

Acoustic emission (AE) measurements were conducted in situ during cyclic compressive loading on an [ 00 1 over line ] orientated single crystal of Fe-Mn-Al-Ni shape memory alloy to study functional degradation of its superelastic response. The acoustic investigations were corroborated by optical microscopy, employing video imaging, and transmission electron microscopy. The analysis of acoustic emissions recorded during repeated loading and unloading sessions revealed two categories of AE signals that are differed by their characteristics in time and frequency domains. These two distinct types of AE signals were related to two underlying mechanisms: (i) the nucleation and reverse transformation of stress-induced (twinned) martensite, and (ii) the lateral growth and shrinkage of one dominant martensite variant and related dislocation activities, respectively. In addition, an asymmetry in the AE activity during forward and reverse transformation during mechanical loading and unloading was detected. In particular, an unexpected high AE activity was observed during the superelastic unloading of martensitic microstructure from the point of maximum load/strain. This effect was attributed to the reverse transformation of small, tiny areas of martensite as well as to unpinning and annihilation effects related to dislocations. (c) 2021 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved

Pumilio2-deficient mice show a predisposition for epilepsy

Epilepsy is a neurological disease that is caused by abnormal hypersynchronous activities of neuronal ensembles leading to recurrent and spontaneous seizures in human patients. Enhanced neuronal excitability and a high level of synchrony between neurons seem to trigger these spontaneous seizures. The molecular mechanisms, however, regarding the development of neuronal hyperexcitability and maintenance of epilepsy are still poorly understood. Here, we show that pumilio RNA-binding family member 2 (Pumilio2;Pum2) plays a role in the regulation of excitability in hippocampal neurons of weaned and 5-month-old male mice. Almost complete deficiency of Pum2 in adult Pum2 gene-trap mice (Pum2 GT) causes misregulation of genes involved in neuronal excitability control. Interestingly, this finding is accompanied by the development of spontaneous epileptic seizures in Pum2 GT mice. Furthermore, we detect an age-dependent increase in Scn1a (Na(v)1.1) and Scn8a (Na(v)1.6) mRNA levels together with a decrease in Scn2a (Na(v)1.2) transcript levels in weaned Pum2 GT that is absent in older mice. Moreover, field recordings of CA1 pyramidal neurons show a tendency towards a reduced paired-pulse inhibition after stimulation of the Schaffer-collateral-commissural pathway in Pum2 GT mice, indicating a predisposition to the development of spontaneous seizures at later stages. With the onset of spontaneous seizures at the age of 5 months, we detect increased protein levels of Na(v)1.1 and Na(v)1.2 as well as decreased protein levels of Na(v)1.6 in those mice. In addition, GABA receptor subunit alpha-2 (Gabra2) mRNA levels are increased in weaned and adult mice. Furthermore, we observe an enhanced GABRA2 protein level in the dendritic field of the CA1 subregion in the Pum2 GT hippocampus. We conclude that altered expression levels of known epileptic risk factors such as Na(v)1.1, Na(v)1.2, Na(v)1.6 and GABRA2 result in enhanced seizure susceptibility and manifestation of epilepsy in the hippocampus. Thus, our results argue for a role of Pum2 in epileptogenesis and the maintenance of epilepsy

Совершенствование системы нормирования труда рабочих

Объект исследования - ЗАО "СИБУР-Транс". Предмет исследования – система нормирования труда на предприятия. Цель ВКР ? совершенствование системы нормирования труда на предприятии для активизации трудового потенциала на повышение производительности труда работников.The object of study - CJSC "SIBUR-TRANS". Subject of research - the system of regulation of labor in the enterprise. The purpose of WRC-improving the system of regulation of labor in the enterprise to enhance the labor potential to increase productivity of workers

SAPHO-Syndrom

The SAPHO syndrome is not a single entity but an inhomogeneous, nosologically heterogeneous complex of symptoms with unknown etiology and heterogeneous pathogenesis. Clinically subacute, recurrent or chronic disease processes and a common skin-bone association (skibo disease) can be found. Under the acronym SAPHO, chronically recurrent multifocal osteomyelitis (CRMO) is the most common disease that can occur in youth as well as adolescence. Spondylarthritis hyperostotica pustulo-psoriatica with the triad palmoplantar pustulosis, sternoclavicular hyperostosis and ossifying spinal manifestations is the most common SAPHO form found in adults. Abortive disease forms are the inflammatory anterior chest wall syndrome, extended sternoclavicular hyperostosis syndrome of the clavicle bone, acne CRMO and acne spondylarthritis. The SAPHO disease usually heals with a relatively favorable prognosis but there are also unfavorable courses with functional limitations. The diagnosis should be made based on clinical examination, imaging (x-ray, scintigraphy, magnetic resonance imaging) and/or histological bone biopsy analysis. Treatment should be interdisciplinary. Antibiotic treatment is obsolete. This article provides an overview of the SAPHO syndrome and a clinical-rheumatological imaging differentiation as well as classification of 35 cases at first presentation

Wirkeffekte multimodaler rheumatologischer physikalischer Behandlung

Die dargestellten eigenen Arbeiten sind im Fach Innere Medizin, Rheumatologie und Physikalische Medizin verfasst und können in drei sich thematisch entwickelnde und ergänzende Abschnitte eingeteilt werden. Die Arbeiten und ihre Limitationen werden innerhalb dieser Teilstücke zusammenhängend diskutiert, sodass die systematische Vorgehensweise und die stattgefundene wissenschaftliche Entwicklung nachvollzogen werden kann. Die drei Themenschwerpunkte umfassen (i) die erstmalige klinische Analyse der rheumatologischen multimodalen rheumatologischen Komplexbehandlung (MKRB) in einzelnen Kollektiven, (ii) die weiterführende, prospektive Untersuchung zur Wirksamkeit der MRKB und Beeinflussung des pro- und anti-inflammatorischen Zytokinmilieus als mögliches Korrelat der klinischen Wirkung und (iii) die Untersuchung klinischer und molekularer Effekte einzelner physikalischer Therapien und ihres Stellenwertes innerhalb der MRKB