Protein foszfatáz 2A szerepe a human endothelium barrier funkciójának szabályozásában = Role of protein phosphatase 2A in the regulation of human endothelial barrier function

Tüdő artéria endothel modell rendszerben tanulmányoztuk a protein foszfatáz 2A (PP2A) szerepét. Eredményeink arra utalnak, hogy a PP2A aktívan részt vesz az endothelium barrier funkciójának citoszkeletális fehérjéken keresztül történő regulációjában. Overexpresszált PP2A a barrier diszfunkciót kiváltó ágensek (thrombin, nokodazol) hatását az aktin citoszkeletonra és a mikrotubulusokra mérsékli/megszünteti. Két potenciális citoszkeletális szubsztrátot azonosítottunk, a tau és a Hsp27 fehérjét, amelyeknek szerepe lehet az agonista-indukált citoszkeleton átrendeződésben és permeabilitás változásban. A PP2A aktivitás ezen fehérjék foszforilációs szintjét befolyásolja és ezáltal része lehet az endothel sejtek citoszkeletonjában a mikrotubulusok és a mikrofilamentumok közötti párbeszéd és a barrier funkció szabályozásának. Továbbá kimutattuk, hogy a MYPT fehérje család egyik kevésbé jellemzett tagja, a TIMAP, ami egy membrán-asszociált fehérje, specifikusan kölcsönhat a protein foszfatáz 1 (PP1) béta izoformájával, ami valószínűsíti, hogy a PP1 regulátora. A TIMAP a barrier funkciót pozitívan szabályozza, ezt az RNS interferenciával TIMAP-depletált sejtek vizsgálatával mutattuk ki. Eredményeink alapján feltételezhető, hogy a TIMAP az ERM (ezrin/radixin/moezin) fehérjék PKA indukált szabályozásában vesz részt és ez a TIMAP-mediált endothel barrier védő hatás része lehet. | The role of protein phosphatase 2A (PP2A) in pulmonary artery endothelial cells was studied. Our results suggest the direct involvement of PP2A in the regulation of cytoskeleton proteins and endothelial barrier maintenance. PP2A overexpression attenuated or diminished thrombin- or nocodazole-induced effects on microfilaments and microtubule. We identified two potential substrates of PP2A, tau and Hsp27, which potentially could be involved in agonist-induced cytoskeleton rearrangement and change in permeability. PP2A regulates the phosphorylation level of these proteins, and as a consequence, it is involved in the regulation of the crosstalk between microfilaments and microtubule, and barrier function. Further, we found specific interaction between the beta isoform of protein phosphatase 1 (PP1) and TIMAP, a less characterized member of the MYPT family, implying its regulatory role in PP1 activity. Using siRNA technique we showed that TIMAP is a positive regulator of the endothelial barrier function. Our results also suggest the involvement of TIMAP in PKA-mediated ERM (ezrin/radixin/moesin) dephosphorylation and the connection of this dephosphorylation in TIMAP-mediated EC barrier protection

Three in One: The VLBI Radio View of the X-ray Quasar RX J1456.0+5048

RX J1456.0+5048 is a prominent X-ray source detected by ROSAT. There is ~100-mJy level radio emission associated with the X-ray source. However, interferometric observations with increasing angular resolution revealed that three distinct objects located within 2 arcmin are responsible for the measured total flux density. Whether these radio sources lining up in the sky are physically associated or just seen close to each other in projection is not immediately clear. In fact, incorrect cross-identification of the X-ray, optical and radio sources can already be found in the literature. Here we summarise the current knowledge about this intriguing group of objects, where two of the three sources show compact radio emission detected with very long baseline interferometry (VLBI). We present a VLBI image of one of them for the first time, based on archival European VLBI Network (EVN) data taken at 5 GHz.Comment: 5 pages, 2 figures. To appear in the proceedings of the European VLBI Network Mini-Symposium and Users' Meeting 2021, Proceedings of Science, PoS(EVN2021)00

Juvenile Huntington’s disease skin fibroblasts respond with elevated parkin level and increased proteasome activity as a potential mechanism to counterbalance the pathological consequences of mutant Huntingtin protein

Huntington’s disease (HD) is an inherited neurodegenerative disorder, caused by an abnormal polyglutamine (polyQ) expansion in the huntingtin protein (Htt). Mitochondrial dysfunction and impairment of the ubiquitin-proteasome system (UPS) are hallmarks of HD neurons. The extraneural manifestations of HD are still unclear. We investigated the crosstalk between mitochondria and proteolytic function in skin fibroblasts from juvenile HD patients. We found reduced mitosis, increased cell size, elevated ROS and increased mitochondrial membrane potential in juvenile HD fibroblasts, while cellular viability was maintained. Mitochondrial OXPHOS analysis did not reveal significant differences compared to control. However, the level of mitochondrial fusion and fission proteins was significantly lower and branching in the mitochondria network was reduced. We hypothesized that juvenile HD fibroblasts counterbalance cellular damage and mitochondrial network deficit with altered proteasome activity to promote cell survival. Our data reveal that juvenile HD fibroblasts exhibit higher proteasome activity, which was associated with elevated gene and protein expression of parkin. Moreover, we demonstrate elevated proteasomal degradation of the mitochondrial fusion protein Mfn1 in diseased cells compared to control cells. Our data suggest that juvenile HD fibroblasts respond to mutant polyQ expansion of Htt with enhanced proteasome activity and faster turnover of specific UPS substrates to protect cells

Az újkori külföldi magyar egyetemjárás adattárának összegyűjtése és kiadása = Assembling and Publishing of Documentation Concerning the Peregrination of Hungarians to Abroad Universities

A kutatás 4 éve alatt két egyetemi város (Bécs 1867-1890) és Graz (1867-1918) , valamint a Brünni Műegyetem kivételével teljes egészében befejeztük az európai újkori egyetemjárás adattárának készítését. A munka természetesen nemcsak az elmúlt 4 évben, hanem az azt megelőző évtizedben is folyt, és jelenleg mintegy 85000 külföldi beiratkozást regisztráltunk, amelyeket egységes elektronikus adatbázisba vittünk. A fent említett hiányok pótlása folyamatban van, tehát remélhető, hogy 2007 folyamán a francia nyelvterület kivételével teljessé válik a magyarországi egyetemjárás 1526 és 1919 közötti adatainak feltárása. A francia és belga egyetemekre járt magyarok kutatásához tekintettel a teljesen más forrástípusokra, az eddigiektől eltérő módszert kell alkalmazni, és komoly helyszini kutatást végezni, amelynek érdekében új OTKA pályázatot kívánok benyújtani. A beiratkozókról esetenként 10-10 adat áll rendelkezésre, ezekből ''A magyarországi diákok egyetemjárása az újkorban'' című sorozatunkban eddig 14 kötetet jelentettünk meg, és további 6 van előkészületben. Ezek felsorolását mellékelten nyújtom be. A fenti nagyon konkrét ereddményeken kívül mintegy 12 nemzetközi konferencián tájékoztattuk a résztvevőket kutatásaink eredményeiről, többek között Svájcban, Németországban, Ausztriában, Ukrajnában, Romániában, Dániában és Olaszországban. Köteteinket több külföldi szaklapban ismertették illetve előadásaink konferenci kötetekben jelentek meg. | During the four years of research ? except for the universities of Vienna (1867-1890) and Graz (1867-1918) ? we have successfully completed the repertory of Hungarian university peregrination to Europe at the early modern period. The work was being done not only during the past for years, but also in the preceding decade, so as a result we have recorded 85,000 registrations, all of which are processed into an electronic database. Quest after Hungarian students at the universities of France and Belgium requires a completely new method and a deeper local research, for the aim of which I would like to apply for another OTKA-support with a new project. Eventually there are 10 items available for each registrated student in our database, on the basis of which we have already published 14 volumes as parts of our series Hungarian peregrination to foreign Universities in Modern Times?, and there are six more volumes in preparation for the future, a list of which is attached. Beside these concrete results we presented papers at 12 different international conferences, e.g. in Switzerland, Germany, Austria, Ukraine, Romania, Denmark and Italy. The published volumes were reviewed in several international journals and the papers given were published in the acts of the conferences we had participated in

The Proteasome Activators Blm10/PA200 Enhance the Proteasomal Degradation of N-Terminal Huntingtin.

The Blm10/PA200 family of proteasome activators modulates the peptidase activity of the core particle (20S CP). They participate in opening the 20S CP gate, thus facilitating the degradation of unstructured proteins such as tau and Dnm1 in a ubiquitin- and ATP-independent manner. Furthermore, PA200 also participates in the degradation of acetylated histones. In our study, we use a combination of yeast and human cell systems to investigate the role of Blm10/PA200 in the degradation of N-terminal Huntingtin fragments (N-Htt). We demonstrate that the human PA200 binds to N-Htt. The loss of Blm10 in yeast or PA200 in human cells results in increased mutant N-Htt aggregate formation and elevated cellular toxicity. Furthermore, Blm10 in vitro accelerates the proteasomal degradation of soluble N-Htt. Collectively, our data suggest N-Htt as a new substrate for Blm10/PA200-proteasomes and point to new approaches in Huntington\u27s disease (HD) research

Proteasomes associated with the Blm10 activator protein antagonize mitochondrial fission through degradation of the fission protein Dnm1

L

Promoter analysis of the rabbit POU5F1 gene and its expression in preimplantation stage embryos

Background: The POU5F1 gene encodes the octamer-binding transcription factor-4 (Oct4). It is crucial in the regulation of pluripotency during embryonic development and widely used as molecular marker of embryonic stem cells (ESCs). The objective of this study was to identify and to analyse the promoter region of rabbit POU5F1 gene; furthermore to examine its expression pattern in preimplantation stage rabbit embryos. [br/] Results: The upstream region of rabbit POU5F1 was subcloned sequenced and four highly conserved promoter regions (CR1-4) were identified. The highest degree of similarity on sequence level was found among the conserved domains between rabbit and human. Among the enhancers the proximal enhancer region (PE-1A) exhibited the highest degree of homology (96.4%). Furthermore, the CR4 regulator domain containing the distal enhancer (DE-2A) was responsible for stem cell-specific expression. Also, BAC library screen revealed the existence of a processed pseudogene of rabbit POU5F1. The results of quantitative real-time PCR experiments showed that POU5F1 mRNA was abundantly present in oocytes and zygotes, but it was gradually reduced until the activation of the embryonic genome, thereafter a continuous increase in POU5F1 mRNA level was observed until blastocyst stage. By using the XYClone laser system the inner cell mass (ICM) and trophoblast portions of embryos were microdissected and examined separately and POU5F1 mRNA was detected in both cell types. [br/] Conclusion: In this study we provide a comparative sequence analysis of the regulatory region of rabbit POU5F1 gene. Our data suggest that the POU5F1 gene is strictly regulated during early mammalian development. We proposed that the well conserved CR4 region containing the DE-2A enhancer is responsible for the highly conserved ESC specific gene expression. Notably, we are the first to report that the rabbit POU5F1 is not restricted to ICM cells only, but it is expressed in trophoblast cells as well. This information may be well applicable to investigate further the possible phylogenetic role and the regulation of POU5F1 gene