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Porcine cytomegalovirus (PCMV) infection is widely prevalent among pigs, and PCMV is one of the viruses which may be transmitted during xenotransplantation using pig cells, tissues, or organs. While human cytomegalovirus (HCMV) is a major risk factor for allotransplantation, it is still unclear whether PCMV is able to infect human cells or pose a risk for xenotransplantation. Previously, it was shown that transmission of PCMV after pig kidney to non-human primate transplantations resulted in a significantly reduced survival time of the transplanted organ. To detect PCMV, PCR-based and immunological methods were used. Screening of pigs by Western blot analyses using recombinant viral proteins revealed up to 100% of the tested animals to be infected. When the same method was applied to screen human sera for PCMV-reactive antibodies, positive Western blot results were obtained in butchers and workers in the meat industry as well as in normal blood donors. To exclude an infection of humans with PCMV, the sera were further investigated. PCMV is closely related to human herpesvirus-6 (HHV-6) and human herpesvirus-7 (HHV-7), and a sequence alignment of glycoprotein B suggests that the antibodies may cross-react with identical epitope sequences. HCMV is not related with PCMV, and no correlation between antibody reactivity against PCMV and HCMV was detected. These data indicate that antibodies against PCMV found in humans are cross-reactive antibodies against HHV-6.

Hypoxia is linked to therapeutic resistance and poor clinical prognosis for many tumor entities, including human papillomavirus (HPV)-positive cancers. Notably, HPV-positive cancer cells can induce a dormant state under hypoxia, characterized by a reversible growth arrest and strong repression of viral E6/E7 oncogene expression, which could contribute to therapy resistance, immune evasion and tumor recurrence. The present work aimed to gain mechanistic insights into the pathway(s) underlying HPV oncogene repression under hypoxia. We show that E6/E7 downregulation is mediated by hypoxia-induced stimulation of AKT signaling. Ablating AKT function in hypoxic HPV-positive cancer cells by using chemical inhibitors efficiently counteracts E6/E7 repression. Isoform-specific activation or downregulation of AKT1 and AKT2 reveals that both AKT isoforms contribute to hypoxic E6/E7 repression and act in a functionally redundant manner. Hypoxic AKT activation and consecutive E6/E7 repression is dependent on the activities of the canonical upstream AKT regulators phosphoinositide 3-kinase (PI3K) and mechanistic target of rapamycin (mTOR) complex 2 (mTORC2). Hypoxic downregulation of E6/E7 occurs, at least in part, at the transcriptional level. Modulation of E6/E7 expression by the PI3K/mTORC2/AKT cascade is hypoxia specific and not observed in normoxic HPV-positive cancer cells. Quantitative proteome analyses identify additional factors as candidates to be involved in hypoxia-induced activation of the PI3K/mTORC2/AKT signaling cascade and in the AKT-dependent repression of the E6/E7 oncogenes under hypoxia. Collectively, these data uncover a functional key role of the PI3K/mTORC2/AKT signaling cascade for viral oncogene repression in hypoxic HPV-positive cancer cells and provide new insights into the poorly understood cross talk between oncogenic HPVs and their host cells under hypoxia. Oncogenic HPV types are major human carcinogens. Under hypoxia, HPV-positive cancer cells can repress the viral E6/E7 oncogenes and induce a reversible growth arrest. This response could contribute to therapy resistance, immune evasion, and tumor recurrence upon reoxygenation. Here, we uncover evidence that HPV oncogene repression is mediated by hypoxia-induced activation of canonical PI3K/mTORC2/AKT signaling. AKT-dependent downregulation of E6/E7 is only observed under hypoxia and occurs, at least in part, at the transcriptional level. Quantitative proteome analyses identify additional factors as candidates to be involved in AKT-dependent E6/E7 repression and/or hypoxic PI3K/mTORC2/AKT activation. These results connect PI3K/mTORC2/AKT signaling with HPV oncogene regulation, providing new mechanistic insights into the cross talk between oncogenic HPVs and their host cells.

The Enhancer of Zeste 2 (EZH2) protein has been reported to stimulate cell growth in some cancers and is therefore considered to represent an interesting new target for therapeutic intervention. Here, we investigated a possible role of EZH2 for the growth control of colon cancer cells. RNA interference (RNAi)-mediated intracellular EZH2 depletion led to cell cycle arrest of colon carcinoma cells at the G1/S transition. This was associated with a reduction of cell numbers upon transient transfection of synthetic EZH2-targeting siRNAs and with inhibition of their colony formation capacity upon stable expression of vector-borne siRNAs. We furthermore tested whether EZH2 may repress the growth-inhibitory p27 gene, as reported for pancreatic cancer. However, expression analyses of colon cancer cell lines and colon cancer biopsies did not reveal a consistent correlation between EZH2 and p27 levels. Moreover, EZH2 depletion did not re-induce p27 expression in colon cancer cells, indicating that p27 repression by EZH2 may be cell- or tissue-specific. Whole genome transcriptome analyses identified cellular genes affected by EZH2 depletion in colon cancer cell lines. They included several cancer-associated genes linked to cellular proliferation or invasion, such as Dag1, MageD1, SDC1, Timp2, and Tob1. In conclusion, our results demonstrate that EZH2 depletion blocks the growth of colon cancer cells. These findings might provide benefits for the treatment of colon cancer.

Philosopher Friedrich Nietzsche and sociologist Norbert Elias are both famous for their influential interpretations of modern European culture as a whole. Nietzsche'sOn the Genealogy of Moralsand Elias'The Civilizing Processcrossed disciplinary boundaries with respect to both content and method, and both books are still of great contemporary interest. This volume brings international specialists together for the first time to explore the connections between these two works.

Kaposi's sarcoma–associated herpesvirus (KSHV) can infect endothelial cells, leading to the development of Kaposi's sarcoma in some individuals. The mechanisms underlying cell entry by KSHV are not fully elucidated. ahn et al. now report that ephrin receptor tyrosine kinase A2 (EphA2) acts as a cellular receptor for KSHV and show that blocking EphA2 inhibits infection of endothelial cells. Kaposi's sarcoma–associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma 1 , a highly vascularized tumor originating from lymphatic endothelial cells, and of at least two different B cell malignancies 2 , 3 . A dimeric complex formed by the envelope glycoproteins H and L (gH-gL) is required for entry of herpesviruses into host cells 4 . We show that the ephrin receptor tyrosine kinase A2 (EphA2) is a cellular receptor for KSHV gH-gL. EphA2 co-precipitated with both gH-gL and KSHV virions. Infection of human epithelial cells with a GFP-expressing recombinant KSHV strain, as measured by FACS analysis, was increased upon overexpression of EphA2. Antibodies against EphA2 and siRNAs directed against EphA2 inhibited infection of endothelial cells. Pretreatment of KSHV with soluble EphA2 resulted in inhibition of KSHV infection by up to 90%. This marked reduction of KSHV infection was seen with all the different epithelial and endothelial cells used in this study. Similarly, pretreating epithelial or endothelial cells with the soluble EphA2 ligand ephrinA4 impaired KSHV infection. Deletion of the gene encoding EphA2 essentially abolished KSHV infection of mouse endothelial cells. Binding of gH-gL to EphA2 triggered EphA2 phosphorylation and endocytosis, a major pathway of KSHV entry 5 , 6 . Quantitative RT-PCR and in situ histochemistry revealed a close correlation between KSHV infection and EphA2 expression both in cultured cells derived from human Kaposi's sarcoma lesions or unaffected human lymphatic endothelium, and in situ in Kaposi's sarcoma specimens, respectively. Taken together, our results identify EphA2, a tyrosine kinase with known functions in neovascularization and oncogenesis, as an entry receptor for KSHV.

The iron-chelating drug ciclopirox (CPX) may possess therapeutic potential for cancer treatment, including cervical cancer. As is observed for other chemotherapeutic drugs, CPX can induce senescence or apoptosis in cervical cancer cells which could differently affect their therapy response. The present study aims to gain insights into the determinants which govern the switch between senescence and apoptosis in cervical cancer cells. We performed proteome analyses, proliferation studies by live-cell imaging and colony formation assays, senescence and apoptosis assays, and combination treatments of CPX with inhibitors of oxidative phosphorylation (OXPHOS) or glycolysis. We found that CPX downregulates OXPHOS factors and facilitates the induction of apoptosis under limited glucose availability, an effect which is shared by classical OXPHOS inhibitors. Under increased glucose availability, however, CPX-induced apoptosis is prevented and senescence is induced, an activity which is not exerted by classical OXPHOS inhibitors, but by other iron chelators. Moreover, we show that the combination of CPX with glycolysis inhibitors blocks cervical cancer proliferation in a synergistic manner. Collectively, our results reveal that the phenotypic response of cervical cancer cells towards CPX is strongly dependent on glucose availability, link the pro-apoptotic and pro-senescent activities of CPX to its bifunctionality as an OXPHOS inhibitor and iron chelator, respectively, and provide a rationale for combining CPX with glycolysis inhibitors.

Friedrich Nietzsche und Norbert Elias haben zivilisationsgeschichtliche Entwürfe Europas vorgelegt, die unter den Bedingungen einer stetig voranschreitenden Globalisierung weiter an Bedeutung gewinnen werden.Die philosophische Brisanz ihres Zugriffs wird v.a.

In her article \"Science, Sexuality, and the Novels of Huxley and Houellebecq,\" Angela C. Holzer begins with an introduction to recent discourse about contemporary culture by Francis Fukuyama, notably in his book Our Posthuman Future (2001). Next, Holzer introduces twentieth-century literary representations of genetic engineering. Focusing on Huxley's Brave New World (1932) and on Houellebecq's Les Particules élémentaires (1998), Holzer discusses differences in \"utopian\" literature when linked to metaphysical aspects of reproduction and that are owing to changes in the life sciences and medicine. Further, Holzer explores the implications for poetics resulting from scientific developments and relates Houellebecq's perspectives to Zola's idea of the \"experimental novel\" and to Nietzsche's notions of science. Holzer traces Houllebecq's text and its \"reactionary politics\" to Romantic literature and the late nineteenth-century discussion of marriage, Christianity, and reproduction in Tolstoy's writing. The insight to be gathered is the interrelation between the development of modern science up to the completion of the Genome Project and its impact on poetics (i.e., on form) and on representation (i.e., content) of science and the scientist in the two novels at hand.

This dissertation uncovers the Roman discourse in late eighteenth century Germany by discussing the characterizations of ancient Rome in art history, historiography and literary theory. The last two decades of the eighteenth century experienced a renewed interest in Roman antiquity. This interest can be fathomed on a quantitative level – e.g. in an increase in translations of Latin authors – but it is also perceptible on a theoretical level. The emphasis on the importance of the Greek ideal in German culture after Winckelmann has tended to obscure the continuous reception of, and reflection on Roman antiquity. The negative view of Roman antiquity, especially on the early Roman Empire as part of a critique of French classicism developed by the Storm-and-Stress movement, was not a common attitude in Germany. An analysis of a wider range of texts – e.g. enlightenment children's books – shows that there was a heterogeneity of positions toward Rome. The last decades of the eighteenth century moreover demonstrated an interest in early Roman history and, after Edward Gibbon, in the later empire. Characterizations of a \"Roman epoch\" in world history came to be part of universal history, philosophies of history and literary history. Early Romanticism finally discovered the modernity of Roman antiquity in aesthetic and philosophical regard and postulated the continuing relevance of Rome while devaluing Greece. It thus paved the way for major contributions on Roman history and art history in the nineteenth century. The importance of Roman antiquity was now seen in its function as a culture of transformation. The first part engages Winckelmann's history of art and argues that Winckelmann increasingly engaged with the Roman tradition in his later works and, despite his provocative negation of a Roman style, developed a notion of Roman art. It was, moreover, not common practice to adopt Winckelmann's view on Rome in the decades following his death. F.A. Wolf and Wilhelm von Humboldt, C.G. Heyne and Friedrich Schlegel developed different visions of Rome after Winckelmann, which are also presented in part one. The second part deals with the historiographical discourse on Roman antiquity and especially with the ensuing popularization – translation, adaptation and transformation – of French and English historiography in Germany. It emphasizes the increasing importance of the Roman Empire in children's literature of the late Enlightenment. The third part focuses on the early modern genre of Roman antiquities, or “Altertümer”, and the ways in which it acquired a new relevance when enriched with autoptic elements that lead to a mixture of textually transmitted and observational knowledge. The fourth part engages the discourse of literary history and aesthetics and argues that during the last years of the eighteenth century, the discovery of the modernity of Roman culture lead to a new perspective on Roman antiquity that was decisive also for the theoretical discourse on Rome during the nineteenth century. The epilog sketches the reflections on the value of the study of Rome on a theoretical level in the historiography and cultural critique of Jacob Burckhardt and Friedrich Nietzsche.

Stress refers to a dynamic process in which the homeostasis of an organism is challenged, the outcome depending on the type, severity, and duration of stressors involved, the stress responses triggered, and the stress resilience of the organism. Importantly, the relationship between stress and the immune system is bidirectional, as not only stressors have an impact on immune function, but alterations in immune function themselves can elicit stress responses. Such bidirectional interactions have been prominently identified to occur in the gastrointestinal tract in which there is a close cross-talk between the gut microbiota and the local immune system, governed by the permeability of the intestinal mucosa. External stressors disturb the homeostasis between microbiota and gut, these disturbances being signaled to the brain multiple communication pathways constituting the gut-brain axis, ultimately eliciting stress responses and perturbations of brain function. In view of these relationships, the present article sets out to highlight some of the interactions between peripheral immune activation, especially in the visceral system, and brain function, behavior, and stress coping. These issues are exemplified by the way through which the intestinal microbiota as well as microbe-associated molecular patterns including lipopolysaccharide communicate with the immune system and brain, and the mechanisms whereby overt inflammation in the GI tract impacts on emotional-affective behavior, pain sensitivity, and stress coping. The interactions between the peripheral immune system and the brain take place along the gut-brain axis, the major communication pathways of which comprise microbial metabolites, gut hormones, immune mediators, and sensory neurons. Through these signaling systems, several transmitter and neuropeptide systems within the brain are altered under conditions of peripheral immune stress, enabling adaptive processes related to stress coping and resilience to take place. These aspects of the impact of immune stress on molecular and behavioral processes in the brain have a bearing on several disturbances of mental health and highlight novel opportunities of therapeutic intervention.