פרסומים

Once—it was in the time of the Corona epidemic—the Wind God appeared in my dream. It was just before dawn, and in the dream I was in India with a group of students and friends, but I didn’t know what to show them. I was out alone, searching for a suitable site. Early morning. At the edge of a field of ripening wheat, or maybe paddy. Suddenly a wild gust of wind passed through the sheaves, making them dance, then even lifting them out of the earth and setting them down again some distance away. There was a rhythm to this dance, syncopated, not too fast or too slow. Watching the scene, I knew it was the most beautiful sight I’d ever seen. I wanted to capture it on my camera, but it was over long before I’d finished my fumbling, so I missed it. It was a mistake even to try. Who would want to capture the wind? I waited for it to happen again, and indeed there came another burst, rippling through the growing grain, no less beautiful than before.

Acinar metaplasia is an initial step in a series of events that can lead to pancreatic cancer. Here we perform single-cell RNA-sequencing of mouse pancreas during the progression from preinvasive stages to tumor formation. Using a reporter gene, we identify metaplastic cells that originated from acinar cells and express two transcription factors, Onecut2 and Foxq1. Further analyses of metaplastic acinar cell heterogeneity define six acinar metaplastic cell types and states, including stomach-specific cell types. Localization of metaplastic cell types and mixture of different metaplastic cell types in the same pre-malignant lesion is shown. Finally, single-cell transcriptome analyses of tumor-associated stromal, immune, endothelial and fibroblast cells identify signals that may support tumor development, as well as the recruitment and education of immune cells. Our findings are consistent with the early, premalignant formation of an immunosuppressive environment mediated by interactions between acinar metaplastic cells and other cells in the microenvironment.

Acinar metaplasia is an initial step in a series of events that can lead to pancreatic cancer. Here we perform single-cell RNA-sequencing of mouse pancreas during the progression from preinvasive stages to tumor formation. Using a reporter gene, we identify metaplastic cells that originated from acinar cells and express two transcription factors, Onecut2 and Foxq1. Further analyses of metaplastic acinar cell heterogeneity define six acinar metaplastic cell types and states, including stomach-specific cell types. Localization of metaplastic cell types and mixture of different metaplastic cell types in the same pre-malignant lesion is shown. Finally, single-cell transcriptome analyses of tumor-associated stromal, immune, endothelial and fibroblast cells identify signals that may support tumor development, as well as the recruitment and education of immune cells. Our findings are consistent with the early, premalignant formation of an immunosuppressive environment mediated by interactions between acinar metaplastic cells and other cells in the microenvironment.

The discovery of giant viruses infecting eukaryotes from diverse ecosystems has revolutionized our understanding of the evolution of viruses and their impact on protist biology, yet knowledge on their replication strategies and transcriptome regulation remains limited. Here, we profile single-cell transcriptomes of the globally distributed microalga Emiliania huxleyi and its specific giant virus during infection. We detected profound heterogeneity in viral transcript levels among individual cells. Clustering single cells based on viral expression profiles enabled reconstruction of the viral transcriptional trajectory. Reordering cells along this path unfolded highly resolved viral genetic programs composed of genes with distinct promoter elements that orchestrate sequential expression. Exploring host transcriptome dynamics across the viral infection states revealed rapid and selective shutdown of protein-encoding nuclear transcripts, while the plastid and mitochondrial transcriptomes persisted into later stages. Single-cell RNA-seq opens a new avenue to unravel the life cycle of giant viruses and their unique hijacking strategies.

In contrast to normal regenerating tissue, resistance to Fas-and FasL-positive T cell-induced apoptosis were detected in myofibroblasts from fibrotic-lungs of humans and mice following bleomycin (BLM) exposure. In this study we show, decreased FLIP expression in lung-tissues with resolution of BLM-induced fibrosis and in isolated-lung fibroblasts, with decreased resistance to apoptosis. Using a FLIP-expression vector or a shFLIP-RNA, we further confirmed the critical need for FLIP to regain/lose susceptibility of fibrotic-lung myofibroblast to Fas-induced apoptosis. Our study further show that FLIP is regulated by SIRT1 (Sirtuin 1) deacetylase. Chimeric mice, with SIRT1-deficiency in deacetylase domain (H355Y-Sirt1y/y), specifically in mesenchymal cells, were not only protected from BLM-induced lung fibrosis but, as assessed following Ku70 immunoprecipitation, had also decreased Ku70-deacetylation, decreasedKu70/FLIP complex, and decreased FLIP levels in their lung myofibroblasts. In addition, myofibroblasts isolated from lungs of BLM-treated miR34a-knockout mice, exposed to a miR34a mimic, which we found here to downregulate SIRT1 in the luciferase assay, had a decreased Ku70-deacetylation indicating decrease in SIRT1 activity. Thus, SIRT1 may mediate, miR34a-regulated, persistent FLIP levels by deacetylation of Ku70 in lung myofibroblasts, promoting resistance to cell-death and lung fibrosis. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.

In contrast to normal regenerating tissue, resistance to Fas- and FasL-positive T cell-induced apoptosis were detected in myofibroblasts from fibrotic-lungs of humans and mice following bleomycin (BLM) exposure. In this study we show, decreased FLIP expression in lung-tissues with resolution of BLM-induced fibrosis and in isolated-lung fibroblasts, with decreased resistance to apoptosis. Using a FLIP-expression vector or a shFLIP-RNA, we further confirmed the critical need for FLIP to regain/lose susceptibility of fibrotic-lung myofibroblast to Fas-induced apoptosis. Our study further show that FLIP is regulated by SIRT1 (Sirtuin 1) deacetylase. Chimeric mice, with SIRT1-deficiency in deacetylase domain (H355Y-Sirt1(y/y)), specifically in mesenchymal cells, were not only protected from BLM-induced lung fibrosis but, as assessed following Ku70 immunoprecipitation, had also decreased Ku70-deacetylation, decreasedKu70/FLIP complex, and decreased FLIP levels in their lung myofibroblasts. In addition, myofibroblasts isolated from lungs of BLM-treated miR34a-knockout mice, exposed to a miR34a mimic, which we found here to downregulate SIRT1 in the luciferase assay, had a decreased Ku70-deacetylation indicating decrease in SIRT1 activity. Thus, SIRT1 may mediate, miR34a-regulated, persistent FLIP levels by deacetylation of Ku70 in lung myofibroblasts, promoting resistance to cell-death and lung fibrosis.

Cannabidiolic acid methyl ester (HU-580) is a more stable compound than cannabidiolic acid (CBDA) which has been shown to be effective in reducing nausea, anxiety, depression behaviors in animal models. Here we extend the investigation of this compound to determine its effect on the sleep-wake cycle in male Wistar rats. HU-580 dose-dependently (0.1, 1.0 or 100 μg/Kg, i.p.) prolonged wakefulness (W) and decreased slow wave sleep (SWS) duration whereas rapid eye movement sleep (REMS) showed no statistical change. In addition, the brain microdialysis probes either placed at nucleus accumbens (NAc) or into the basal forebrain in freely moving animals were used to evaluate the effects of HU-580 treatment on neurotransmitters related to the sleep-wake cycle modulation. HU-580 enhanced extracellular levels of dopamine, serotonin collected from NAc while adenosine and acetylcholine were increased in basal forebrain. In summary, HU-580 seems to possess wake-promoting pharmacological properties and enhances the levels of wake-related neurochemicals. This is the first report of effects of HU-580 on sleep modulation expanding the very limited existent data on the neurobiological effects of HU-580 on rats. © 2019 Elsevier Inc.

Snake and spider venoms have been developed by nature as a defense mechanism against predators or to immobilize their prey by blocking the cardiovascular, respiratory, and/or nervous systems. Consequently, predators are deterred from approaching their prey by painful sensations. At a molecular level, the targeted physiological systems are blocked or stimulated by peptide toxins which, once injected into the body, modulate, though not exclusively, important cell membrane ion channels and receptors. Millions of years of constant evolution have led to the evolvement of complex venom libraries of optimized protein toxins, making them more potent, more selective, resistant to proteases, less immunogenic, and improved in terms of pharmacokinetic (PK) properties. The resulting advantage is that they induce long-term and potent pharmacodynamic (PD) effects toward unique molecular targets of therapeutic importance such as coagulation cascade proteins, receptors, and ionic channels. This optimization process has been enabled by the diversification of peptide sequences (mainly by gene duplication) and an upscaling of the complexity of toxin peptide scaffold structures, through implementation of multiple disulfide bridges and sequence-active motif diversification, leading to a wide diversity of chemical structures. This combination of pharmaceutical properties has made venom toxins valuable both as pharmacological tools and as leads for drug development. These highly tunable molecules can be tailored to achieve desirable biocompatibility and biodegradability with simultaneously selective and potent therapeutic effects. This brief overview provides basic definitions, rules, and methodologies and describes successful examples of a few drugs developed from snake toxins that are currently used in the clinic for therapy of several diseases as well as new molecular entities in clinical development based on spider-venom-derived peptide toxins.

Studies of policy bubbles have so far ignored the possibility that a policy bubble in a given policy domain or jurisdiction may constitute an information event for another policy bubble that has been inflated elsewhere. In addition, studies of policy diffusion have paid little attention to the transmission of imperfect and wrongful policy valuations through social networks. To bridge these gaps, this article develops a theoretical framework and methodological toolbox for explaining the potential impact of interbubble dynamics on the sustainment of policy bubbles. This is achieved by focusing on: (i) the diffusion of interbubble connectivity information through social networks characterized by varying levels of segregation; (ii) the perceptions of distorted or corrected information by individuals at the receiving end as being factual, thus requiring no gap-filling by policy actors, or as an opinion that therefore requires gap-filling; (iii) the derived consequence in terms of simple or