Biology subjects

Bauer, G.

Publications and source records attributed to Bauer, G..

3 recordsLinked to original sources

bioRxiv2022

Iron-catalyzed antagonism between NO and H2O2 / HOCl causes mutual exclusivity of HOCl- and NO/peroxynitrite-mediated apoptosis-inducing signaling

Membrane-associated NADPH oxidase of malignant cells drives intercellular apoptosis-inducing HOCl- and NO/peroxynitrite signaling. Cells from late stages of oncogenesis, i. e. bona fide tumor cells, interfere with these signaling pathways through expression of membrane-associated catalase. Transformed cells and tumor cells with inhibited catalase show mutual exclusivity of apoptosis-inducing NO/peroxynitrite and HOCl signaling. H2O2 is the substrate for HOCl synthesis by DUOX-coded peroxidase. However, at high concentrations of H2O2, HOCl signaling is abrogated through the reaction between excess H2O2 and HOCl. Experimental increase in the NO concentration through addition of NO donors, induction of NO synthase (NOS), addition or the NOS substrate arginine, or inhibition of NO dioxygenase(NOD) leads to the inhibition of HOCl signaling, but also to abrogation of H2O2-mediated interference with HOCl signaling. Vice versa, an increase in extracellular H2O2 through increasing the cell density, gamma irradiation or addition of glucose oxidase inhibits NO/peroxynitrite signaling. These mutual reactions between NO and H2O2/HOCl are catalyzed by an iron-mediated reaction cycle, which allows consumption of NO by H2O2/HOCl and vice versa. These reactions explain the preferences of tumor cell lines for NO/peroxynitrite or HOCl signaling after inhibition of their protective catalase, as well as the differential expression of these pathways dependent on the degree of catalase inhibition. The understanding of these reactions allows to rationally modulate quality and strength of ROS/RNS-dependent apoptosis-inducing signaling pathways of malignant cells. The knowledge about these reactions should allow to optimize strategies for tumor therapy that are based on reactivation of intercellular ROS/RNS-dependent apoptosis-inducing signaling of tumor cells. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC="FIGDIR/small/498603v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@4fbdb6org.highwire.dtl.DTLVardef@130063forg.highwire.dtl.DTLVardef@1ea2e67org.highwire.dtl.DTLVardef@18c85cb_HPS_FORMAT_FIGEXP M_FIG C_FIG Highlights* NADPH oxidase and peroxidase drive apoptosis-inducing HOCl signaling * NADPH oxidase and NO synthase drive apoptosis-inducing NO/peroxynitrite signaling * H2O2 establishes and interferes with HOCl signaling, dependent on its concentration * NO inhibits HOCl signaling and abrogates H2O2-dependent inhibition of HOCl signaling * H2O2 interferes with NO/peroxnitrite signaling * Mutual interactions of NO and H2O2 are catalysed by an iron-mediated reaction cycle

biochemistry↗

bioRxiv2021

Human Neural Stem Cells Differentiate and Integrate, Innervating Implanted zQ175 Huntington's Disease Mouse Striatum

Huntingtons disease (HD), a genetic neurodegenerative disorder, primarily impacts the striatum and cortex with progressive loss of medium-sized spiny neurons (MSNs) and pyramidal neurons, disrupting cortico-striatal circuitry. A promising regenerative therapeutic strategy of transplanting human neural stem cells (hNSCs) is challenged by the need for long-term functional integration. We previously described that hNSCs transplanted into the striatum of HD mouse models differentiated into electrophysiologically active immature neurons, improving behavior and biochemical deficits. Here we show that 8-month implantation of hNSCs into the striatum of zQ175 HD mice ameliorates behavioral deficits, increases brain-derived neurotrophic factor (BDNF) and reduces mutant Huntingtin (mHTT) accumulation. Patch clamp recordings, immunohistochemistry and electron microscopy demonstrates that hNSCs differentiate into diverse neuronal populations, including MSN- and interneuron-like cells. Remarkably, hNSCs receive synaptic inputs, innervate host neurons, and improve membrane and synaptic properties. Overall, the findings support hNSC transplantation for further evaluation and clinical development for HD.

neuroscience↗

bioRxiv2020

Nanoscale Chromatin Imaging and Analysis (nano-ChIA) platform bridges 4-D chromatin organization with molecular function

In eukaryotic cells, chromatin structure is linked to transcription processes through the regulation of genome organization. Extending across multiple length-scales - from the nucleosome to higher-order three-dimensional structures - chromatin is a dynamic system which evolves throughout the lifetime of a cell. However, no individual technique can fully elucidate the behavior of chromatin organization and its relation to molecular function at all length- and timescales at both a single-cell and a cell population level. Herein, we present a multi-technique nanoscale Chromatin Imaging and Analysis (nano-ChIA) platform that bridges electron tomography and optical superresolution imaging of chromatin conformation and transcriptional processes, with resolution down to the level of individual nucleosomes, with high-throughput, label-free analysis of chromatin packing and its dynamics in live cells. Utilizing nano-ChIA, we observed that chromatin is localized into spatially separable packing domains, with an average diameter of around 200 nm, sub-Mb genomic size, and an internal fractal structure. The chromatin packing behavior of these domains is directly influenced by active gene transcription. Furthermore, we demonstrated that the chromatin packing domain structure is correlated among progenitor cells and all their progeny, indicating that the organization of chromatin into fractal packing domains is heritable across cell division. Further studies employing the nano-ChIA platform have the potential to provide a more coherent picture of chromatin structure and its relation to molecular function.

genomics↗