A szöveti őssejtek plaszticitása = Plasticity of tissue stem cells

Az embrionális fejlődés korai stádiumában a sejtek még minden irányba képesek differenciálódni. A felnőtt szervezetben erre már csak kisszámú, ún. szöveti őssejt és az is csak részben képes. Ezek a szöveti őssejtek fontos szerepet töltenek be a sérülések regenerációjában és a folyamatosan megújuló szövetek (például a vérképzőrendszer) fiziológiás működésében. Sorsukat a közvetlen környezetükből, az őssejt niche-ből érkező proliferációs, differenciációs és túlélési jelzések határozzák meg. A folyamat mechanizmusa azonban mindmáig tisztázatlan. A felnőtt szöveti őssejtek ugyanis különböző fejlődési irányokba képesek differenciálódni, sokszor még fejlődéstanilag nem rokon sejttípusokká is át tudnak alakulni (idegrendszeri őssejtek például vérsejtekké differenciálódhatnak). A szerzők összefoglalójukban az őssejtek plaszticitásának mechanizmusát magyarázó - egyelőre részben spekulatív - modelleket mutatnak be. A különböző fejlődési irányok közötti átmenet esetleg transzdifferenciáció útján megy végbe (agyi őssejt - vérsejt), de nem zárhatók ki a de- és redifferenciációs lépések sem (agyi őssejt - pluripotens sejt - vérsejt). Végül lehetséges, hogy szöveteinkben előfordulnak pluripotens, az embrionális fejlődés korai szakaszából fennmaradt őssejtek is, és ez az "őssejtplaszticitás" valódi magyarázata. | In the early stages of embryonic development, cells have the capability of dividing indefinitely and then differentiating into any type of cell in the body. Recent studies have revealed that much of this remarkable developmental potential of stem cells is retained by small populations of cells within most tissues in the adult. Intercellular signals that control the proliferation, differentiation and survival of tissue stem cells in their niches are being identified and include a diverse array of morphogens, cytokines, chemokines and cell adhesion molecules. Adult tissue stem cells, moreover, can also differentiate into developmentally unrelated cell types, such as nerve stem cells into blood cells. Currently, we can only speculate about the mechanisms involved in such dramatic changes in cell fate. For example, the emergence of, say, hematopoietic stem cells from brain neurospheres could involve either transdifferentiation (brain-blood) or dedifferentiation (brain-pluripotent cells), or by the actions of rare, but residual pluripotent stem cells. This issue is central to understanding the molecular basis of commitment and lies at the heart of debates about plasticity and the reversibility of developmental restriction

Modeling the Deformation and the Failure Process of Glass Woven Fabrics Based on the Fibre-Bundle-Cells Theory

In this study, we modeled the deformation and failure behavior of different glass woven fabrics under uniaxial tension using the Fibre Bundle Cells-modeling method. The difference between the analytical, phenomenological model curve and the mean curve calculated from the measurement results was classified by the relative mean squared error (RMSE), which is closely related to the coefficient of determination. This value was less than 3.6% in all the examined cases, which indicated good modeling

Üvegszövetek deformációs és tönkremeneteli folyamatának szálkötegcella-elméleten alapuló modellezése

Ebben a kutatásban különböző üvegszövetek egytengelyű húzás hatására mutatott deformációs és tönkremeneteli viselkedését modelleztük a szálkötegcella-alapú modellezéssel. Az általunk felállított analitikus, fenomenológiai modellgörbe és a mérési eredményekből meghatározott átlaggörbe közötti eltérést a determinációs együtthatóval szoros összefüggésben álló relatív átlagos négyzetes hibával (RÁNH) minősítettük. Ez az érték minden vizsgált esetben kevesebb mint 3,6% volt, ami alapján a modellezés kifejezetten jónak tekinthető

Kiemelt természetvédelmi jelentőségű hazai vizicsigák (Mollusca: Gastropoda) konzerváció-genetikai, molekuláris filogenetikai és filogeográfiai vizsgálata = Conservation genetics, molecular phylogeny and phylogeography of freshwater snails (Mollusca: Gastropoda) of high conservation concern in Hungary

A projekt célja endemikus illetve konzervációbiológiai szempontból jelentős puhatestű fajokkal kapcsolatos rendszertani, filogenetikai illetve filogeográfiai problémák tisztázása volt. Azt reméltük, hogy ezen kérdések tisztázása az alapkutatás jellegén túl, segíti az érintett fajokkal kapcsolatos megalapozott környezetvédelmi döntéshozatalt. A projekt főbb eredményei: Nukleáris és mitokondriális génszakaszok egyöntetűen azt igazolják, a Theodoxus prevostianus – Theodoxus danubialis fajcsoport törzsfája parafiletikus, feltehetően a mai Theodoxus danubialis a pleisztocénban élt folyólakó Theodoxus prevostianus egyik génvonalából rapid evolucióval létrejött fiatal faj. Kimutattuk, hogy meglepő módon a mitokondriális COI gén alig variál a Theodoxus transversalis mára még fennmaradt populációi között. Feltételezésünk szerint a mitokondriális variabilitás hiánya nem a közelmúltbeli kihalások következménye, hanem egy kora holocén-, vagy késő pleisztocénkori palacknyak hatásé. Mitokondriális COI génszakasz alapján közel 5% os intraspecifikus variabilitást és mélyen szétvált génvonal jelenlétét mutatuk ki a Bythinella pannonica fajon belül, amelyeknek a térbeli eloszlása alapján összetett elterjedéstörténetre következtetünk. Mind az ivarszervek morfológiája, mind a vizsgált molekuláris markerek azt igazolják, hogy a Bythinella molcsanyi önálló faj és ezért nagy konzervációbiológiai jelentősége van. Ezzel szemben kimutattuk, hogy a Bythinella hungarica a széles elterjedésű Bythinella austriaca faj szinonímja. | The aim of this project was to clarify taxonomical, filogenetic and filogeographic questions which are associated to endemic mollusc species or other mollusc species of conservation concern. We hoped that clarifying these problems will help to make effective conservation decisions. The main goals are the following: Nuclear and mitochondrial sequences concordantly show that the phylogeny of the Theodoxus prevostianus – Theodoxus danubialis species group is paraphyletic. Recent Theodoxus danubialis is probably a young species, which has evolved from a lineage of the fluvial T. prevostianus in the Pleistocene. We have found unexpectedly low mitochondrial COI variability in the remnant populations of Theodoxus transversalis. This phenomenon seems to be the consequence of a historical bottleneck. In our view, the whole Holocene range has been colonized by descendants of a bottlenecked population. Based on mitochondrial COI sequence, nearly 5% intraspecific variability and two deeply diverged lineages were found in the Bythinella pannonica species. Its spatial distribution infers a complex distribution history. Both genital morphology and mitochondrial phylogeny (COI) proved the monophyly and the distinct species status of Bythinella molcsanyi, which is therefore, a narrow range species of high conservation concern. In contrast, Bythinella hungarica was proved to be a synonym of the widespread Bythinella austriaca

Heterodimerization of AML1/ETO with CBFβ is required for leukemogenesis but not for myeloproliferation

The AML1/Runx1 transcription factor and its heterodimerization partner CBFβ are essential regulators of myeloid differentiation. The chromosomal translocation t(8;21), fusing the DNA binding domain of AML1 to the corepressor eight-twenty-one (ETO), is frequently associated with acute myeloid leukemia and generates the AML1/ETO (AE) fusion protein. AE represses target genes usually activated by AML1 and also affects the endogenous repressive function of ETO at Notch target genes. In order to analyze the contribution of CBFβ in AE-mediated leukemogenesis and deregulation of Notch target genes, we introduced two point mutations in a leukemia-initiating version of AE in mice, called AE9a, that disrupt the AML1/CBFβ interaction (AE9aNT). We report that the AE9a/CBFβ interaction is not required for the AE9a-mediated aberrant expression of AML1 target genes, while upregulation/derepression of Notch target genes does require the interaction with CBFβ. Using retroviral transduction to express AE9a in murine adult bone marrow-derived hematopoietic progenitors, we observed that both AE9a and AE9aNT lead to increased myeloproliferation in vivo. However, both development of leukemia and long-term replating capacity are only observed with AE9a but not with AE9aNT. Thus, deregulation of both AML1 and Notch target genes is required for the development of AE9a-driven leukemia

Structural insights into the tyrosine phosphorylation-mediated inhibition of SH3 domain-ligand interactions.

Src homology 3 (SH3) domains bind proline-rich linear motifs in eukaryotes. By mediating inter- and intramolecular interactions, they regulate the functions of many proteins involved in a wide variety of signal transduction pathways. Phosphorylation at different tyrosine residues in SH3 domains have been reported previously. In several cases, the functional consequences have also been investigated. However, a full understanding of the effects of tyrosine phosphorylation on the ligand interactions and cellular functions of SH3 domains requires detailed structural, atomic-resolution studies along with biochemical and biophysical analyses. Here, we present the first crystal structures of tyrosine-phosphorylated human SH3 domains derived from the Abelson-family kinases ABL1 and ABL2 at 1.6 and 1.4 Å resolutions, respectively. The structures revealed that simultaneous phosphorylation of Tyr-89 and Tyr-134 in ABL1, or the homologous residues Tyr-116 and Tyr-161 in ABL2 induce only minor structural perturbations. Instead, the phosphate groups sterically blocked the ligand-binding grooves, thereby strongly inhibiting the interaction with proline-rich peptide ligands. Although some crystal contact surfaces involving phosphotyrosines suggested the possibility of tyrosine-phosphorylation induced dimerization, we excluded this possibility by using small-angle X-ray scattering (SAXS), dynamic light scattering (DLS), and NMR relaxation analyses. Extensive analysis of relevant databases and literature revealed that the residues phosphorylated in our model systems are not only well conserved in other human SH3 domains, but that the corresponding tyrosines are known phosphorylation sites in vivo in many cases. We conclude that tyrosine phosphorylation might be a mechanism involved in the regulation of the human SH3 interactome

The scaffold protein Tks4 is required for the differentiation of mesenchymal stromal cells (MSCs) into adipogenic and osteogenic lineages

The commitment steps of mesenchymal stromal cells (MSCs) to adipogenic and other lineages have been widely studied but not fully understood. Therefore, it is critical to understand which molecules contribute to the conversion of stem cells into differentiated cells. The scaffold protein Tks4 plays a role in podosome formation, EGFR signaling and ROS production. Dysfunction of Tks4 causes a hereditary disease called Frank-ter Haar syndrome with a variety of defects concerning certain mesenchymal tissues (bone, fat and cartilage) throughout embryogenic and postnatal development. In this study, we aimed to analyze how the mutation of Tks4 affects the differentiation potential of multipotent bone marrow MSCs (BM-MSCs). We generated a Tks4 knock-out mouse strain on C57Bl/6 background, and characterized BM-MSCs isolated from wild type and Tks4-/- mice to evaluate their differentiation. Tks4-/- BM-MSCs had reduced ability to differentiate into osteogenic and adipogenic lineages compared to wild type. Studying the expression profile of a panel of lipid-regulated genes during adipogenic induction revealed that the expression of adipogenic transcription factors, genes responsible for lipid droplet formation, sterol and fatty acid metabolism was delayed or reduced in Tks4-/- BM-MSCs. Taken together, these results establish a novel function for Tks4 in the regulation of MSC differentiation

Novel regulation of Ras proteins by direct tyrosine phosphorylation and dephosphorylation

Somatic mutations in the RAS genes are frequent in human tumors, especially in pancreatic, colorectal, and non-small-cell lung cancers. Such mutations generally decrease the ability of Ras to hydrolyze GTP, maintaining the protein in a constitutively active GTP-bound form that drives uncontrolled cell proliferation. Efforts to develop drugs that target Ras oncoproteins have been unsuccessful. Recent emerging data suggest that Ras regulation is more complex than the scientific community has believed for decades. In this review, we summarize advances in the "textbook" view of Ras activation. We also discuss a novel type of Ras regulation that involves direct phosphorylation and dephosphorylation of Ras tyrosine residues. The discovery that pharmacological inhibition of the tyrosine phosphoprotein phosphatase SHP2 maintains mutant Ras in an inactive state suggests that SHP2 could be a novel drug target for the treatment of Ras-driven human cancers