Genotoxikus hatásra bekövetkező funkcionális és strukturális DNS változások = Functional and structural changes in DNA upon genotoxic effects

Morfológiai és biokémiai vizsgálataink arra utalnak, hogy a a genotoxikus hatások kategorizálhatók az okozott kromatin változások alapján. A kemotoxikus változások potenciális diagnosztikus jelentősége miatt vizsgáltuk a nehézfémek (elsősosrban kadmium) (Banfalvi et al., 2005), a gamma sugárzás (Nagy et al., 2004), az UVB sugárzás (Ujvárosi et al., 2007) és a carcinogén (dimetilnitrózamin) hatására bekövetkező kromatin változásokat (Trencsényi et al., 2007). Kadmium kezelés jellegzetes szakadásokat és nagy lyukakat hozott létre a sejtmagban. A gamma sugárzás preapoptotikus hatására: a. a sejtek és sejtmagok mérete megnőtt, b. DNA tartalmuk a sejtciklus minden szakaszában kisebb volt a normál kezeletlen populációhoz képest, c. a sejtciklus a korai S fázisban leállt (2,4 C értéknél), d. a kromatin kondenzálás annak fibrilláris szakaszában akadt el, e. az apoptotikus testek száma és nagysága a sejtciklus haladásávalfordítva arányos: sok apró apoptotikus testtel az S fázis elején és kevés nagy apoptotikus testtel az S fázis végén. A CHO sejtekben mért vizsgálatokat humán K562 sejteken megerősítettük. UVB sugárzás hatására a kromoszómák nem voltak láthatók, a sérülés hatására vékony összefüggő kromatin fátyol vonta be mind az interfázisos, mind a metafázisos kromoszómákat. | Morphological and biochemical studies after genotoxic treatments suggest that the consequences of various chromatin injuries can be categorized based on the assessment of injury-specific chromatin changes. Due to its diagnostic significance, we have started to determine and systematize the effects of heavy metals, primarily cadmium treatment (Banfalvi et al., 2005), gamma irradiation (Nagy et al., 2004) and UV irradiation (Ujvarosi et al., 2007). After cadmium treatment and have seen the same large extensive disruptions and holes in the nuclear membrane and sticky incompletely folded chromosomes typical for cadmium treatment (Nagy et al., 2004; Banfalvi et al., 2007). Preapoptotic changes upon γ-irradiation manifested as: (a) The cellular and nuclear sizes increased. (b) The DNA content was lower in each elutriated subpopulation of cells. (c) The progression of the cell cycle was arrested in the early S phase at 2.4 C value. (d) The chromatin condensation was blocked at its fibrillary stage. (e) The number and size of apoptotic bodies were inversely correlated with the progression of the cell cycle, with many small apoptotic bodies in early S phase and less but larger apoptotic bodies in late S phase (Nagy et al., 2004). Similar observations were made in K562 cells (Banfalvi et al., 2007). UV irradiation blocked chromatin condensation at its fibrillary stage, nuclear structures were blurred and covered with fibrillary chromatin, neither interphase nor metaphase chromosomes were visible

Fuzzy Implications: Some Recently Solved Problems

In this chapter we discuss some open problems related to fuzzy implications, which have either been completely solved or those for which partial answers are known. In fact, this chapter also contains the answer for one of the open problems, which is hitherto unpublished. The recently solved problems are so chosen to reflect the importance of the problem or the significance of the solution. Finally, some other problems that still remain unsolved are stated for quick reference

WNT/β-catenin signaling regulates mitochondrial activity to alter the oncogenic potential of melanoma in a PTEN-dependent manner

Aberrant regulation of WNT/β-catenin signaling has a crucial role in the onset and progression of cancers, where the effects are not always predictable depending on tumor context. In melanoma, for example, models of the disease predict differing effects of the WNT/β-catenin pathway on metastatic progression. Understanding the processes that underpin the highly context-dependent nature of WNT/β-catenin signaling in tumors is essential to achieve maximal therapeutic benefit from WNT inhibitory compounds. In this study, we have found that expression of the tumor suppressor, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), alters the invasive potential of melanoma cells in response to WNT/β-catenin signaling, correlating with differing metabolic profiles. This alters the bioenergetic potential and mitochondrial activity of melanoma cells, triggered through regulation of pro-survival autophagy. Thus, WNT/β-catenin signaling is a regulator of catabolic processes in cancer cells, which varies depending on the metabolic requirements of tumors

Primary alterations during the development of hidradenitis suppurativa

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic, inflammatory disease of the apocrine gland‐rich (AGR) skin region. The initial steps of disease development are not fully understood, despite intense investigations into immune alterations in lesional HS skin. OBJECTIVES: We aimed to systematically investigate the inflammatory molecules involved in three stages of HS pathogenesis, including healthy AGR, non‐lesional HS and lesional HS skin, with the parallel application of multiple mRNA and protein‐based methods. METHODS: Immune cell counts (T cells, dendritic cells, macrophages), Th1/Th17‐related molecules (IL‐12B, TBX21, IFNG, TNFA, IL‐17, IL10, IL‐23A, TGFB1, RORC, CCL20), keratinocyte‐related sensors (TLR2,4), mediators (S100A7, S100A8, S100A9, DEFB4B, LCN2, CAMP, CCL2) and pro‐inflammatory molecules (IL1B, IL6, TNFA, IL‐23A) were investigated in the three groups by RNASeq, RT‐qPCR, immunohistochemistry and immunofluorescence. RESULTS: Epidermal changes were already detectable in non‐lesional HS skin; the epidermal occurrence of antimicrobial peptides (AMPs), IL‐1β, TNF‐α and IL‐23 was highly upregulated compared with healthy AGR skin. In lesional HS epidermis, TNF‐α and IL‐1β expression remained at high levels while AMPs and IL‐23 increased even more compared with non‐lesional skin. In the dermis of non‐lesional HS skin, signs of inflammation were barely detectable (vs. AGR), while in the lesional dermis, the number of inflammatory cells and Th1/Th17‐related mediators were significantly elevated. CONCLUSIONS: Our findings that non‐lesional HS epidermal keratinocytes produce not only AMPs and IL‐1β but also high levels of TNF‐α and IL‐23 confirm the driver role of keratinocytes in HS pathogenesis and highlight the possible role of keratinocytes in the transformation of non‐inflammatory Th17 cells (of healthy AGR skin) into inflammatory cells (of HS) via the production of these mediators. The fact that epidermal TNF‐α and IL‐23 appear also in non‐lesional HS seems to prove these cytokines as excellent therapeutic targets

Engineered hexavalent Fc proteins with enhanced Fc-gamma receptor avidity provide insights into immune-complex interactions

Tania Rowley et al. present multivalent Fc molecules with enhanced avidity for Fc gamma receptors in order to improve the treatment of autoantibody-mediated human diseases. They found several key amino acids involved in Fc receptor binding interactions

Lawson criterion for ignition exceeded in an inertial fusion experiment

For more than half a century, researchers around the world have been engaged in attempts to achieve fusion ignition as a proof of principle of various fusion concepts. Following the Lawson criterion, an ignited plasma is one where the fusion heating power is high enough to overcome all the physical processes that cool the fusion plasma, creating a positive thermodynamic feedback loop with rapidly increasing temperature. In inertially confined fusion, ignition is a state where the fusion plasma can begin "burn propagation" into surrounding cold fuel, enabling the possibility of high energy gain. While "scientific breakeven" (i.e., unity target gain) has not yet been achieved (here target gain is 0.72, 1.37 MJ of fusion for 1.92 MJ of laser energy), this Letter reports the first controlled fusion experiment, using laser indirect drive, on the National Ignition Facility to produce capsule gain (here 5.8) and reach ignition by nine different formulations of the Lawson criterion