On Robust Sequential Analysis - Kiefer-Weiss Optimal Testing under Interval Probability

Usual sequential testing procedures often are very sensitive against even small deviations from the `ideal model' underlying the hypotheses. This makes robust procedures highly desirable. To rely on a clearly defined optimality criterion, we incorporate robustness aspects directly into the formulation of the hypotheses considering the problem of sequentially testing between two interval probabilities (imprecise probabilities). We derive the basic form of the Kiefer-Weiss optimal testing procedure and show how it can be calculated by an easy-to-handle optimization problem. These results are based on the reinterpretation of our testing problem as the task to test between nonparametric composite hypotheses, which allows to adopt the framework of Pavlov (1991). From this we obtain a general result applicable to any interval probability field on a finite sample space, making the approach powerful far beyond robustness considerations, for instance for applications in artificial intelligence dealing with imprecise expert knowledge

A system for production of defective interfering particles in the absence of infectious influenza A virus

<div><p>Influenza A virus (IAV) infection poses a serious health threat and novel antiviral strategies are needed. Defective interfering particles (DIPs) can be generated in IAV infected cells due to errors of the viral polymerase and may suppress spread of wild type (wt) virus. The antiviral activity of DIPs is exerted by a DI genomic RNA segment that usually contains a large deletion and suppresses amplification of wt segments, potentially by competing for cellular and viral resources. DI-244 is a naturally occurring prototypic segment 1-derived DI RNA in which most of the PB2 open reading frame has been deleted and which is currently developed for antiviral therapy. At present, coinfection with wt virus is required for production of DI-244 particles which raises concerns regarding biosafety and may complicate interpretation of research results. Here, we show that cocultures of 293T and MDCK cell lines stably expressing codon optimized PB2 allow production of DI-244 particles solely from plasmids and in the absence of helper virus. Moreover, we demonstrate that infectivity of these particles can be quantified using MDCK-PB2 cells. Finally, we report that the DI-244 particles produced in this novel system exert potent antiviral activity against H1N1 and H3N2 IAV but not against the unrelated vesicular stomatitis virus. This is the first report of DIP production in the absence of infectious IAV and may spur efforts to develop DIPs for antiviral therapy.</p></div

Seroprevalence of viral infections in captive rhesus and cynomolgus macaques

Macaques serve as important animal models for biomedical research. Viral infection of macaques can compromise animal health as well as the results of biomedical research, and infected animals constitute an occupational health risk. Therefore, monitoring macaque colonies for viral infection is an important task. We used a commercial chip-based assay to analyze sera of 231 macaques for the presence of antibody responses against nine animal and human viruses. We report high seroprevalence of cytomegalovirus (CMV), lymphocryptovirus (LCV), rhesus rhadinovirus (RRV) and simian foamy virus (SFV) antibodies in all age groups. In contrast, antibodies against simian retrovirus type D (SRV/D) and simian T cell leukemia virus (STLV) were detected only in 5&thinsp;% and 10&thinsp;% of animals, respectively, and were only found in adult or aged animals. Moreover, none of the animals had antibodies against herpes B virus (BV), in keeping with the results of in-house tests previously used for screening. Finally, an increased seroprevalence of measles virus antibodies in animals with extensive exposure to multiple humans for extended periods of time was observed. However, most of these animals were obtained from external sources, and a lack of information on the measles antibody status of the animals at the time of arrival precluded drawing reliable conclusions from the data. In sum, we show, that in the colony studied, CMV, LCV, RRV and SFV infection was ubiquitous and likely acquired early in life while SRV/D and STLV infection was rare and likely acquired during adulthood.</p

Mutagenic analysis of the HIV restriction factor shiftless

The interferon-induced host cell protein shiftless (SFL) was reported to inhibit human immunodeficiency virus (HIV) infection by blocking the –1 programmed ribosomal frameshifting (–1PRF) required for expression of the Gag-Pol polyprotein. However, it is not clear how SFL inhibits –1PRF. To address this question, we focused on a 36 amino acids comprising region (termed required for antiviral activity (RAA)) that is essential for suppression of –1PRF and HIV infection and is missing from SFL short (SFLS), a splice variant of SFL with unknown function. Here, we confirm that SFL, but not SFLS, inhibits HIV –1PRF and show that inhibition is cell-type-independent. Mutagenic and biochemical analyses demonstrated that the RAA region is required for SFL self-interactions and confirmed that it is necessary for ribosome association and binding to the HIV RNA. Analysis of SFL mutants with six consecutive amino-acids-comprising deletions in the RAA region suggests effects on binding to the HIV RNA, complete inhibition of –1PRF, inhibition of Gag-Pol expression, and antiviral activity. In contrast, these amino acids did not affect SFL expression and were partially dispensable for SFL self-interactions and binding to the ribosome. Collectively, our results support the notion that SFL binds to the ribosome and the HIV RNA in order to block –1PRF and HIV infection, and suggest that the multimerization of SFL may be functionally important

First-principles molecular-dynamics simulations of a hydrous silica melt: Structural properties and hydrogen diffusion mechanism

We use {\it ab initio} molecular dynamics simulations to study a sample of liquid silica containing 3.84 wt.% H$_2$O.We find that, for temperatures of 3000 K and 3500 K,water is almost exclusively dissolved as hydroxyl groups, the silica network is partially broken and static and dynamical properties of the silica network change considerably upon the addition of water.Water molecules or free O-H groups occur only at the highest temperature but are not stable and disintegrate rapidly.Structural properties of this system are compared to those of pure silica and sodium tetrasilicate melts at equivalent temperatures. These comparisons confirm the picture of a partially broken tetrahedral network in the hydrous liquid and suggest that the structure of the matrix is as much changed by the addition of water than it is by the addition of the same amount (in mole %) of sodium oxide. On larger length scales, correlations are qualitatively similar but seem to be more pronounced in the hydrous silica liquid. Finally, we study the diffusion mechanisms of the hydrogen atoms in the melt. It turns out that HOSi$_2$ triclusters and SiO dangling bonds play a decisive role as intermediate states for the hydrogen diffusion.Comment: 25 pages, 18 figures. submitte

Novel virus related to Kaposi’s sarcoma-associated herpesvirus from a monkey (Colobus guereza) suffering from primary effusion lymphoma

No abstract available

Evaluation of Clinical and Immunological Markers for predicting Virological Failure in a HIV/AIDS treatment cohort in Busia, Kenya

In resource-limited settings where viral load (VL) monitoring is scarce or unavailable, clinicians must use immunological and clinical criteria to define HIV virological treatment failure. This study examined the performance of World Health Organization (WHO) clinical and immunological failure criteria in predicting virological failure in HIV patients receiving antiretroviral therapy (ART)

Influenza and SARS-coronavirus activating proteases TMPRSS2 and HAT are expressed at multiple sites in human respiratory and gastrointestinal tracts.

The type II transmembrane serine proteases TMPRSS2 and HAT activate influenza viruses and the SARS-coronavirus (TMPRSS2) in cell culture and may play an important role in viral spread and pathogenesis in the infected host. However, it is at present largely unclear to what extent these proteases are expressed in viral target cells in human tissues. Here, we show that both HAT and TMPRSS2 are coexpressed with 2,6-linked sialic acids, the major receptor determinant of human influenza viruses, throughout the human respiratory tract. Similarly, coexpression of ACE2, the SARS-coronavirus receptor, and TMPRSS2 was frequently found in the upper and lower aerodigestive tract, with the exception of the vocal folds, epiglottis and trachea. Finally, activation of influenza virus was conserved between human, avian and porcine TMPRSS2, suggesting that this protease might activate influenza virus in reservoir-, intermediate- and human hosts. In sum, our results show that TMPRSS2 and HAT are expressed by important influenza and SARS-coronavirus target cells and could thus support viral spread in the human host