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During the 2013–2016 Ebola virus (EBOV) outbreak in West Africa, our team at USAMRIID evaluated the antiviral activity of a number of compounds, including favipiravir (T-705), in vitro and in mouse and nonhuman primate (NHP) models of Ebola virus disease. In this short communication, we present our findings for favipiravir in cell culture and in mice, while an accompanying paper presents the results of NHP studies. We confirmed previous reports that favipiravir has anti-EBOV activity in mice. Additionally, we found that the active form of favipiravir is generated in mice in tissues relevant for the pathogenesis of EBOV infection. Finally, we observed that protection can be achieved in mice down to 8 mg/kg/day, which is lower than the dosing regimens previously reported. An accompanying paper reports the results of treating nonhuman primates infected with EBOV or with Marburg virus with oral or intravenous favipiravir.

Favipiravir is a broad-spectrum antiviral agent that has demonstrated efficacy against Ebola virus (EBOV) in rodents. However, there are no published reports of favipiravir efficacy for filovirus infection of nonhuman primates (NHPs). Here we evaluated the pharmacokinetic profile of favipiravir in NHPs, as well as in vivo efficacy against two filoviruses, EBOV and Marburg virus (MARV). While no survival benefit was observed in two studies employing once- or twice-daily oral dosing of favipiravir during EBOV infection of NHPs, an antiviral effect was observed in terms of extended time-to-death and reduced levels of viral RNA. However, oral dosing in biosafety level-4 (BSL-4) presents logistical and technical challenges, and repeated anesthesia events may potentially worsen survival outcome in animals. For the third study of treatment of MARV infection, we therefore made use of catheters, jackets, and tethers for intravenous (IV) dosing and blood collection, which minimized the requirement for repeated anesthesia events. When MARV infection was treated with IV favipiravir, five of six animals (83%) survived infection, while all untreated NHPs succumbed. An accompanying report presents the results of favipiravir treatment of EBOV infection in mice.

Filoviruses cause disease with high case fatality rates and are considered biological threat agents. Licensed post-exposure therapies that can be administered by the oral route are desired for safe and rapid distribution and uptake in the event of exposure or outbreaks. Favipiravir or T-705 has broad antiviral activity and has already undergone phase II and is undergoing phase III clinical trials for influenza. Here we report the first use of T-705 against Ebola virus. T-705 gave 100% protection against aerosol Ebola virus E718 infection; protection was shown in immune-deficient mice after 14 days of twice-daily dosing. T-705 was also shown to inhibit Ebola virus infection in cell culture. T-705 is likely to be licensed for use against influenza in the near future and could also be used with a new indication for filovirus infection.

The bremsstrahl production of photons in dense matter is reinvestigated using the example of an exactly solvable quantum-mechanical model in one space dimension. Coherence phenomena between successive radiative scatterings among the constituents lead to a modification of the production cross section in the medium relative to the incoherent quasi-free prescription used in kinetic models. Analytic expressions for the correction factor have been derived comparing the quantum rates with the corresponding incoherent quasi-free rates. The result has implications for the kinetic description of all kinds of radiative processes in nucleus-nucleus collisions, both on the level of hadron and parton dynamics.

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Mast cells play a critical role in the initiation and propagation of several inflammatory diseases and are well known for their function in the allergic response. Fullerenes are a class of novel carbon allotropes with a wide variety of applications in biotechnology and medicine. Here we use a fullerene-based chemistry platform to develop and test several different fullerene derivatives to evaluate on cellular viability, anti-IgE receptor-mediated degranulation, and cytokine release from human skin mast cells (MC). The biological response depended on the properties of the addition group; some fullerene structures were effective inhibitors of degranulation and also blocked cytokine release, while others were ineffective. None were toxic to the cells using concentrations up to 100 µg/ml. Further, we demonstrate that mitochondrial membrane potential (MMP) closely paralleled IgE-mediated SMC degranulatory responses and this response was greatly inhibited by fullerene pre-incubation. Additionally, the fullerene inhibition was due to the inhibition of FcεRI-mediated MAP kinase activation. These findings suggest the biological properties of fullerene derivatives depends on the derivatization of the carbon cage which can be manipulated to compounds which may control those diseases associated with MC activation.

Labelling patterns in tritiated folic acid and methotrexate have been examined by tritium nuclear magnetic resonance spectrometry. The results indicate that oxidative degradation with permanganate can give a false tritium distribution.

The cytoskeletal framework prepared by detergent lysis of suspension-grown HeLa cells is compared to the structure obtained from poliovirus-infected cells. This framework, which retains major features of cell morphology and carries the cellular polyribosomes as well as the major structural filaments, is profoundly reorganized following virus infection. This reorganization underlies, at least in part, the morphological changes termed the "cytopathic effect." These cytoskeletal changes appear related to the involvement of the framework with viral-specific metabolism. Extensive cytoskeleton alterations occur even when guanidine inhibits viral replication, and thus result from small amounts of early viral products. The normally spheroidal nucleus deforms, allowing a modified region of the cytoplasm to occupy a central position in the cell, and many membrane-enclosed vesicles peculiar to the infected cell are elaborated here. The skeleton preparation reveals that this region contains intermediate filaments arranged in a pattern unique to infected cells. Further changes occur when viral replication is permitted. The central region filaments become coated with darkly staining material which may be viral RNA. Numerous small particles appear on the filaments which resemble partially assembled virions. Mature virions, however, have no affinity for the cytoskeleton and appear to be free in the cytoplasm. Host cell messenger RNA, normally attached to the skeletal framework, is released in infected cells and is replaced by the viral-specific polyribosomes. The trabecular network which carries polyribosomes appears to be rearranged; the viral polyribosomes are located principally at the cell periphery and are excluded from the central region. The viral replication complex with its double-stranded RNA is also attached to the skeletal framework and may comprise the dark staining material coating the filaments of the central cell region.

1. Die allgemein als fur Lungentumor charakteristisch geltende Symptomentrias: Einseitigkeit, Homogenitat und scharfe Begrenzung des Schattens ist mehrdeutig. Das darf uns nicht wundernehmen, denn dieser Symptomenkomplex beweist nur gewisse grob-anatomische resp. physikalische Verhaltnisse, die wohl ofters, aber durchaus nicht immer bei Tumoren zutreffen, haufig aber auch bei anderen Affektionen vorkommen. Die wichtigsten Charakteristicades malignen Tumors, seine Agressivitat, sein substituierendes resp. destruierendes Wachsium finden in diesen Symptomen keinen Ausdruck. 2. Es gibt noch einige wenig beachtete oder wenig bekannte Symptome, die die Diagnose weiter zu fordern vermogen, weil sie wenigstens teilweise ihre Charakteristica aus der Malignitat des Tumors (expansives, infiltrativ-destruierendes Wachstum) herleiten. 3. Auch der Effekt einer Probebestrahlung, und zwar lokale und Allgemeinveranderungen erlauben unter Berucksichtigung strahlenbiologischer Erkenntnisse einen Schluβ auf die Natur des vorliegenden Prozesses. 4. Die Fullung der Bronchien mit Kontrastmitteln hat uns mitunter fur Lungentumor eindeutig beweisende Bilder geliefert. Ihre Symptomatologie muβ aus der speziellen Anatomie der Lungenprozesse abgeleitet werden.

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Summary Two methods of radiodiagnosis are discussed, the statistic-empirical and the analytical, in order to achieve a scientific approach to the reading of plain radiographs. The first-mentioned is used far more than the second but can only be applied with advantage in research if the conditions mentioned in the text are fulfilled and if a large amount of material is available. The analytical method, which is urged by the author and the Vienna school, makes more use of the possibilities of radiological investigations than the statistic-empirical; it is indispensable for research on clinical material. In teaching, the analytical method is preferable to the statistic-empirical. In practice, in dealing with single cases, especially in busy departments, a compromise between the two methods cannot be avoided. They are only admissible if they are not in conflict with scientific judgment.

Messenger RNA in eukaryotes is comprised of several abundance classes. Also, the decay of these unstable molecules shows at least two very different lifetimes. Two independent techniques are used here to examine the relation between message abundance and lifetime in cell lines from very different organisms. The methods give consistent results for each cell line; however, the two cell types show very different results. In brosophile cells, slowly decaying sequences fall in the abundant class while scarce sequences turn over rapidly. In contrast, in HeLa cells the abundant and scarce message classes are each comprised of long- and short-lived molecules.

Publisher Summary This chapter presents the experimental results that suggest an interrelation between cellular topology and nucleic acid metabolism. Gentle lysis of HeLa cells with a nonionic detergent reveals an elaborate remnant structure that retains much of the cellular morphology. Electron micrographs and biochemical studies show that a majority of the protein synthetic apparatus remains affixed to this “cytoskeleton.” It discusses that the skeleton structure possibly plays an important role in cytoplasmic RNA metabolism. Two of the small RNA species found in mammalian cells, ScK and ScL, are intimately associated with the cytoskeleton, and ScL is, in part, associated with membranes. The function of these molecules is unknown, but there is the possibility that they serve a structural role and may help determine the architecture of the cytoskeleton. If so, then RNA metabolism could play a direct role in determining cellular topology. The nucleus also has a “skeletal” structure, although much less can be visualized in this case. Many of the small RNA species are found localized in this nuclear skeleton, suggesting that they also may play a role in either structure or function determination. The chapter reviews that the experiments indicates an aspect of the metazoan cell with no obvious counterpart in bacteria—that is, an interrelation between spatial organization and RNA metabolism.

A method is described by which HeLa cells can be fractionated to reveal a skeletal-like structure in the cytoplasm. This cytoskeleton has many of the cell's ultrastructural features, such as 100A filaments, microfilaments, centrioles, and microspikes, although most of the cellular protein, membranes, and microtubules have been extracted. Associated with the cytoskeleton are most of the polysomal, but not the monomeric, ribosomes. These polysomes are distributed throughout the cytoskeleton except in the region of the 100A filaments, which resembles the distribution in intact cells. Degradation of mRNA with low levels of ribonuclease releases most ribosomes from the cytoskeleton. Prior disaggregation of polyribosomes in vivo releases ribosomes but not mRNA. Cytochalasin B administered in vivo releases the mRNA from the cytoskeleton. These results suggest an attachment of polyribosomes to the cytoskeleton via mRNA.

Es wurde im allgemeinen Teile bereits ausgefuhrt, das nur jene Erkrankungen der Pleura der Rontgenuntersuchung zuganglich sind, die zu Verdrangung der lufthaltigen Lunge fuhren. Dabei darf die Schichtdicke des verdrangenden Gewebes nicht allzu klein sein, da sonst die Strahlenabsorption in ihm so gering ist, das sie sich in einer fur das Auge erkennbaren Helligkeitsveranderung des Lungenbildes nicht aussprechen konnte. Aus diesem Grunde sind z. B. zarte fibrinose Auflagerungen oder dunne Schwarten gewohnlich nicht oder hochstens durch den Vergleich mit den korrespondierenden Stellen der gesunden Seite als zarte Schleier wahrnehmbar, und zwar aus sinnesphysiologischen Grunden (Weber-Fechnersches Gesetz, s. physiologische Literatur) am ehesten noch in den Bereichen von geringerer allgemeiner Helligkeit, also vor allem uber den wegen ihrer geringeren Tiefe und schlechteren Durchluftung normalerweise weniger hellen Lungenspitzen.

Es ist bei einer klinischen Darstellung der Thoraxtumoren unmoglich, sie auf die Besprechung der Neubildungen im streng pathologisch-anatomischen Sinne zu beschranken. Eine Reihe von Erkrankungen, die die pathologische Anatomie zu den infektiosen Granulationsgeschwulsten, zu den Hyperplasien, zu den Misbildungen oder zu den parasitaren Erkrankungen rechnet, last sich klinisch und auch rontgenologisch, sowohl in bezug auf die Symptomatologie, als den Verlauf, teilweise auch die Therapie von den echten Geschwulsten, den „Blastomen“ haufig nicht abtrennen. Es mus deshalb auch an dieser Stelle der Begriff des Tumors im weiteren, klinischen Sinne gefast werden. Neben den benignen und malignen Blastomen muss also in dieser Monographie auch eine Reihe im Thorax vorkommender Erkrankungen aus den oben genannten Gruppen zur Besprechung gelangen, wie die Lymphogranulome, die im Bereiche des Thorax lokalisierte Leukamie, der Echinokokkus, die Dermoidcysten und Teratome usw.

Die folgenden Ausfuhrungen basieren zum grosen Teil auf den Lehrsatzen der „allgemeinen Rontgenologie“.

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