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Reactive oxygen species (ROS) are produced in various cell compartments by an array of enzymes and processes. An excess of ROS production can be hazardous for normal cell functioning, whereas at normal levels, ROS act as vital regulators of many signal transduction pathways and transcription factors. ROS production is affected by a wide range of viruses. However, to date, the impact of viral infections has been studied only in respect to selected ROS-generating enzymes. The role of several ROS-generating and -scavenging enzymes or cellular systems in viral infections has never been addressed. In this review, we focus on the roles of biogenic polyamines and oxidative protein folding in the endoplasmic reticulum (ER) and their interplay with viruses. Polyamines act as ROS scavengers, however, their catabolism is accompanied by H2O2 production. Hydrogen peroxide is also produced during oxidative protein folding, with ER oxidoreductin 1 (Ero1) being a major source of oxidative equivalents. In addition, Ero1 controls Ca2+ efflux from the ER in response to e.g., ER stress. Here, we briefly summarize the current knowledge on the physiological roles of biogenic polyamines and the role of Ero1 at the ER, and present available data on their interplay with viral infections.

More than 170 million patients worldwide are chronically infected with hepatitis C virus (HCV). Prevalence rates range from 0.5% in Northern European countries to 28% in some areas of Egypt. HCV is hepatotropic, and in many countries chronic hepatitis C is a leading cause of liver disease including fibrosis, cirrhosis and hepatocellular carcinoma. HCV persists in 50–85% of infected patients, and once chronic infection is established, spontaneous clearance is rare. HCV is a member of the Flaviviridae family, in which it forms its own genus. Many lines of evidence suggest that the HCV life cycle displays many differences to that of other Flaviviridae family members. Some of these differences may be due to the close interaction of HCV with its host’s lipid and particular triglyceride metabolism in the liver, which may explain why the virus can be found in association with lipoproteins in serum of infected patients. This review focuses on the molecular events underlying the HCV cell entry process and the respective roles of cellular co-factors that have been implied in these events. These include, among others, the lipoprotein receptors low density lipoprotein receptor and scavenger receptor BI, the tight junction factors occludin and claudin-1 as well as the tetraspanin CD81. We discuss the roles of these cellular factors in HCV cell entry and how association of HCV with lipoproteins may modulate the cell entry process.

How can the analysis of narrative structures contribute to the understanding of what makes a text´s "environmentality" (see Buell 2005:25)? By reading Call of the Wild from a narratological perspective and against the historicist foil of its discursive context, this paper seeks to illuminate how strategies of narration lend to an eco-centred reading - even despite the text´s apparent ethical orientation. The discursive circuit thus established enables a textual negotiation of diverging ethical convictions and aspects of compassion and giving voice to an animal. Eventually, reading and interpreting texts can thus be described as an "applied ethics" (Iovino 2010: 41) the features of which this essay seeks to describe as the "ethics of narrative strategies".

Patients with endometrial endometrioid carcinoma (EEC) that present with advanced primary disease and develop recurrences have a poor outcome. The phenotype of EEC metastases and recurrences is poorly studied. We evaluated the morphological features and ER-alpha/PRA/p53 immunohistochemical expression of a sample of 45 EEC metastases compared to matched primary tumors. Additionally, we studied methylation levels of ER-alpha/PRA gene promoters. The distribution of histological FIGO grade was significantly different in metastases, which disclosed higher grade than primary tumors (p = 0.005). Mitotic index was significantly lower in metastases compared to matched primary tumors (p

Cancer is characterized by a remarkable intertumoral, intratumoral, and cellular heterogeneity that might be explained by the cancer stem cell (CSC) and/or the clonal evolution models. CSCs have the ability to generate all different cells of a tumor and to reinitiate the disease after remission. In the clonal evolution model, a consecutive accumulation of mutations starting in a single cell results in competitive growth of subclones with divergent fitness in either a linear or a branching succession. Acute lymphoblastic leukemia (ALL) is a highly malignant cancer of the lymphoid system in the bone marrow with a dismal prognosis after relapse. However, stabile phenotypes and functional data of CSCs in ALL, the so-called leukemia-initiating cells (LICs), are highly controversial and the question remains whether there is evidence for their existence. This review discusses the concepts of CSCs and clonal evolution in respect to LICs mainly in B-ALL and sheds light onto the technical controversies in LIC isolation and evaluation. These aspects are important for the development of strategies to eradicate cells with LIC capacity. Common properties of LICs within different subclones need to be defined for future ALL diagnostics, treatment, and disease monitoring to improve the patients’ outcome in ALL.

Many studies have proved that oncogenic viruses develop redundant mechanisms to alter the functions of the tumor suppressor p53. Here we show that Epstein-Barr virus (EBV), via the oncoprotein LMP-1, induces the expression of ΔNp73α, a strong antagonist of p53. This phenomenon is mediated by the LMP-1 dependent activation of c-Jun NH2-terminal kinase 1 (JNK-1) which in turn favours the recruitment of p73 to ΔNp73α promoter. A specific chemical inhibitor of JNK-1 or silencing JNK-1 expression strongly down-regulated ΔNp73α mRNA levels in LMP-1-containing cells. Accordingly, LMP-1 mutants deficient to activate JNK-1 did not induce ΔNp73α accumulation. The recruitment of p73 to the ΔNp73α promoter correlated with the displacement of the histone-lysine N-methyltransferase EZH2 which is part of the transcriptional repressive polycomb 2 complex. Inhibition of ΔNp73α expression in lymphoblastoid cells (LCLs) led to the stimulation of apoptosis and up-regulation of a large number of cellular genes as determined by whole transcriptome shotgun sequencing (RNA-seq). In particular, the expression of genes encoding products known to play anti-proliferative/pro-apoptotic functions, as well as genes known to be deregulated in different B cells malignancy, was altered by ΔNp73α down-regulation. Together, these findings reveal a novel EBV mechanism that appears to play an important role in the transformation of primary B cells.

The role of HSP90 in stabilization of oncogenic tyrosine kinases made it an attractive therapeutic target for treating cancer but the molecular basis underlying the interaction between the HSP90 chaperone and client kinases is not elucidated yet. Using kinase inhibitors we show that the inactive conformation of ERBB2 does not interact with HSP90 chaperone and is thus not amenable to degradation upon HSP90 inhibitor treatment, while active ERBB2 kinase conformation promotes interaction with the HSP90 machinery and thus is degraded upon HSP90 inhibitor treatment. Interestingly, the kinase-chaperone interaction is disrupted in case of BCR-ABL and FLT3-ITD when bound to inhibitors irrespective of whether they block the kinase in an active or inactive conformation and thus our results indicate that the stability of the active kinase conformation varies between different kinases.

The IAPE (Intracisternal A-type Particles elements with an Envelope) family of murine endogenous retroelements is present at more than 200 copies in the mouse genome. We had previously identified a single copy that proved to be fully functional, i.e. which can generate viral particles budding out of the cell and infectious on a series of cells, including human cells. We also showed that IAPE are the progenitors of the highly reiterated IAP elements. The latter are now strictly intracellular retrotransposons, due to the loss of the envelope gene and re-localisation of the associated particles in the course of evolution. In the present study we searched for the cellular receptor of the IAPE elements, by using a lentiviral human cDNA library and a pseudotype assay on transduced cells. We identified Ephrin A4, a GPI-anchored molecule involved in several developmental processes, as a receptor for the IAPE pseudotypes. We also found that the other 4 members of the Ephrin A family -but not those of the closely related Ephrin B family- were also able to mediate IAPE cell entry, thus significantly increasing the amount of possible cell types susceptible to IAPE infection. We show that these include mouse germline cells, as illustrated by immunohistochemistry experiments, consistent with IAPE genomic amplification by successive re-infection. We propose that the uncovered properties of the identified receptors played a role in the accumulation of IAPE elements in the mouse genome, and in the survival of a functional copy.

BACKGROUND: Overexpression of the ERBB2 kinase is observed in about one-third of breast cancer patients and the dual ERBB1/ERBB2 kinase inhibitor lapatinib was recently approved for the treatment of advanced ERBB2-positive breast cancer. Mutations in the ERBB2 receptor have recently been reported in breast cancer at diagnosis and also in gastric, colorectal and lung cancer. These mutations may have an impact on the clinical responses achieved with lapatinib in breast cancer and may also have a potential impact on the use of lapatinib in other solid cancers. However, the sensitivity of lapatinib towards clinically observed ERBB2 mutations is not known. METHODOLOGY/PRINCIPAL FINDINGS: We cloned a panel of 8 clinically observed ERBB2 mutations, established stable cell lines and characterized their sensitivity towards lapatinib and alternative ERBB2 inhibitors. Both lapatinib-sensitive and lapatinib-resistant ERBB2 mutations were observed. Interestingly, we were able to generate lapatinib resistance mutations in wt-ERBB2 cells incubated with lapatinib for prolonged periods of time. This indicates that these resistance mutations may also cause secondary resistance in lapatinib-treated patients. Lapatinib-resistant ERBB2 mutations were found to be highly resistant towards AEE788 treatment but remained sensitive towards the dual irreversible inhibitors CL-387785 and WZ-4002. CONCLUSIONS/SIGNIFICANCE: Patients harbouring certain ERBB2 kinase domain mutations at diagnosis may not benefit from lapatinib treatment. Moreover, secondary lapatinib resistance may develop due to kinase domain mutations. Irreversible ERBB2 inhibitors may offer alternative treatment options for breast cancer and other solid tumor patients harbouring lapatinib resistance mutations. In addition, these inhibitors may be of interest in the scenario of secondary lapatinib resistance.

HCV entry into cells is a multi-step and slow process. It is believed that the initial capture of HCV particles by glycosaminoglycans and/or lipoprotein receptors is followed by coordinated interactions with the scavenger receptor class B type I (SR-BI), a major receptor of high-density lipoprotein (HDL), the CD81 tetraspanin, and the tight junction protein Claudin-1, ultimately leading to uptake and cellular penetration of HCV via low-pH endosomes. Several reports have indicated that HDL promotes HCV entry through interaction with SR-BI. This pathway remains largely elusive, although it was shown that HDL neither associates with HCV particles nor modulates HCV binding to SR-BI. In contrast to CD81 and Claudin-1, the importance of SR-BI has only been addressed indirectly because of lack of cells in which functional complementation assays with mutant receptors could be performed. Here we identified for the first time two cell types that supported HCVpp and HCVcc entry upon ectopic SR-BI expression. Remarkably, the undetectable expression of SR-BI in rat hepatoma cells allowed unambiguous investigation of human SR-BI functions during HCV entry. By expressing different SR-BI mutants in either cell line, our results revealed features of SR-BI intracellular domains that influence HCV infectivity without affecting receptor binding and stimulation of HCV entry induced by HDL/SR-BI interaction. Conversely, we identified positions of SR-BI ectodomain that, by altering HCV binding, inhibit entry. Finally, we characterized alternative ectodomain determinants that, by reducing SR-BI cholesterol uptake and efflux functions, abolish HDL-mediated infection-enhancement. Altogether, we demonstrate that SR-BI is an essential HCV entry factor. Moreover, our results highlight specific SR-BI determinants required during HCV entry and physiological lipid transfer functions hijacked by HCV to favor infection.

Among a variety of spectrogram methods Short-Time Fourier Transform (STFT) and Continuous Wavelet Transform (CWT) were selected to analyse transients in non-stationary tremor signals. Depending on the properties of the tremor signal a more suitable representation of the signal is gained by CWT. Three selected broadband tremor signals from the volcanos Mt. Stromboli, Mt. Semeru and Mt. Pinatubo were analyzed using both methods. The CWT can also be used to extend the definition of coherency into a time-varying coherency spectrogram. An example is given using array data from the volcano Mt. Stromboli.

Active volcanoes usually generate highly non-stationary broadband tremor signals. Short-time shock events with a frequency content of several decades are superimposed on a stationary narrow band continuous tremor. Tremor signals of this type can be observed in the near field of many active volcanoes. In this paper we will demonstrate the analysis of such signals using a specific tremor signal of Mt. Stromboli (Sicily). We used the Best-Basis Algorithm (BBA) in order to compute a spectrogram which is adapted to signal properties on highly different scales. It turns out that the BBA can reveal better fitting properties of the tremor in the time-frequency plane compared to standard methods like Short-Time Fourier Transformation (STFT). Moreover, this very effective algorithm can be used for real time monitoring in the time-frequency plane, for data compression or for de-noising of the tremor signals.

Abstract Primary heart neoplasms are rare occurring with an estimated incidence of 0.0017-0.19%. Myxoma is the most prevalent primary heart tumor. The right atrium is an unusual localization, occurring only in 15-20% of myxoma cases. We report a rare case of a massive right atrial myxoma causing tricuspid valve obstruction and presenting as syncope and exertional dyspnea. This case illustrates the influence of myxoma's size, position and mobility as well as patient's body posture and respiration to the development of signs and symptoms. Three-dimensional echocardiography proved useful in surgery planning, allowing a better definition of the tumor outline and attachment.

Abstract Background Evolutionary biologists are often misled by convergence of morphology and this has been common in the study of bird evolution. However, the use of molecular data sets have their own problems and phylogenies based on short DNA sequences have the potential to mislead us too. The relationships among clades and timing of the evolution of modern birds (Neoaves) has not yet been well resolved. Evidence of convergence of morphology remain controversial. With six new bird mitochondrial genomes (hummingbird, swift, kagu, rail, flamingo and grebe) we test the proposed Metaves/Coronaves division within Neoaves and the parallel radiations in this primary avian clade. Results Our mitochondrial trees did not return the Metaves clade that had been proposed based on one nuclear intron sequence. We suggest that the high number of indels within the seventh intron of the β-fibrinogen gene at this phylogenetic level, which left a dataset with not a single site across the alignment shared by all taxa, resulted in artifacts during analysis. With respect to the overall avian tree, we find the flamingo and grebe are sister taxa and basal to the shorebirds (Charadriiformes). Using a novel site-stripping technique for noise-reduction we found this relationship to be stable. The hummingbird/swift clade is outside the large and very diverse group of raptors, shore and sea birds. Unexpectedly the kagu is not closely related to the rail in our analysis, but because neither the kagu nor the rail have close affinity to any taxa within this dataset of 41 birds, their placement is not yet resolved. Conclusion Our phylogenetic hypothesis based on 41 avian mitochondrial genomes (13,229 bp) rejects monophyly of seven Metaves species and we therefore conclude that the members of Metaves do not share a common evolutionary history within the Neoaves.

Abstract Trichophyton benhamiae is an emerging zoonotic dermatophyte. We present a case of a small animal stock infected with two Trichophyton species. T. benhamiae was isolated from 15 out of 26 (58%) guinea pigs including two morphologically different phenotypes. Eight guinea pigs were infected with T. benhamiae and T. mentagrophytes simultaneously. The animals showed alopecia and crusts or no clinical signs at all. T. benhamiae was not detected in rats, rabbits and mice kept in the same stock. [ABSTRACT FROM AUTHOR]