Virus Venetian Masked Ball: Does the Hepatitis Delta Virus Use Different Helper Viruses?

Changes in viral host cell tropism by e.g. changing receptor usage can lead to altered disease manifestations, requiring different treatment modalities. Hepatitis Delta virus (HDV), a small hepatotropic RNA virus, is known to depend on hepatitis B virus (HBV) envelope proteins for envelopment and spread. However, as HDV possesses the ability to replicate in non-hepatic cells and since envelopment of HDV was recently proposed to be mediated by non-HBV viruses, there might be an increased potential for altered host cell tropism of HDV due to differential envelope protein usage. This would have major clinical implications, as currently only HBV positive carriers are screened for HDV and specific therapeutic options only target HBV-dependent spread. Viruses that were proposed to mediate envelopment of HDV include hepatitis C virus (HCV) and vesicular stomatitis virus (VSV). As HDV is known for its liver tropism, I focused primarily on hepatitis C virus (HCV) as potential HBV-independent helper and aimed to evaluate the following questions: a) Does HDV make use of HCV envelope proteins? b) Can HDV be rendered susceptible for alternative helper usage by modification of HBV specificity determinants in HDV? c) What is the zoonotic potential of HDV via utilisation of non-human hepadnaviral helper viruses? I made use of different human cell culture systems based on RNA transfection or viral infection. Thereby, I was able to show efficient co-replication and co-infection of HDV and HCV in the same cell. However, production of HCV enveloped HDV particles was not observed. Based on plasmid transfection, I showed that HDV preferentially uses HBV with little, if any, envelopment by HCV or VSV. Based on sequence comparison to an animal Delta-like agent putatively using HBV-independent spread, I hypothesised that determinants specifically targeting the HBV envelope might hinder HDV from using alternative viral envelopes. However, eliminating HBV specificity determinants from HDV did not render HDV competent to use non-HBV envelopes. As the HDV-HBV interaction is mediated by a tryptophan-rich domain on HBV envelope proteins, I examined HCV and VSV envelope proteins for the presence of similar determinants. However, algorithm-based protein structure prediction did not detect such determinants, which is consistent with the almost exclusive envelopment of HDV by HBV. Last, I investigated various non-human hepadnaviruses for their capacity to provide helper function for HDV. To this end, I produced non-infectious self-assembling particles exclusively consisting of envelope proteins and preliminarily investigated secretion of HDV RNA mediated by these particles. Taken together, the data presented in this study support the current view that HDV most likely utilises exclusively HBV as helper virus, further arguing for co-evolution of these two viruses

The Vanity of Dogmatizing

Book review: Beyond the formalist-realist divide: The role of politics in judging. Brian Z. Tamanaha. Princeton University Press. 2010. Pp. xii + 252. Reviewed by Marc O. DeGirolami

Protein Phosphatase 1 (PP1) Is a Post-Translational Regulator of the Mammalian Circadian Clock

Circadian clocks coordinate the timing of important biological processes. Interconnected transcriptional and post-translational feedback loops based on a set of clock genes generate and maintain these rhythms with a period of about 24 hours. Many clock proteins undergo circadian cycles of post-translational modifications. Among these modifications, protein phosphorylation plays an important role in regulating activity, stability and intracellular localization of clock components. Several protein kinases were characterized as regulators of the circadian clock. However, the function of protein phosphatases, which balance phosphorylation events, in the mammalian clock mechanism is less well understood. Here, we identify protein phosphatase 1 (PP1) as regulator of period and light-induced resetting of the mammalian circadian clock. Down-regulation of PP1 activity in cells by RNA interference and in vivo by expression of a specific inhibitor in the brain of mice tended to lengthen circadian period. Moreover, reduction of PP1 activity in the brain altered light-mediated clock resetting behavior in mice, enhancing the phase shifts in either direction. At the molecular level, diminished PP1 activity increased nuclear accumulation of the clock component PER2 in neurons. Hence, PP1, may reduce PER2 phosphorylation thereby influencing nuclear localization of this protein. This may at least partially influence period and phase shifting properties of the mammalian circadian clock

The nuclear receptor REV-ERBα regulates Fabp7 and modulates adult hippocampal neurogenesis

The function of the nuclear receptor Rev-erbα (Nr1d1) in the brain is, apart from its role in the circadian clock mechanism, unknown. Therefore, we compared gene expression profiles in the brain between wild-type and Rev-erbα knock-out (KO) animals. We identified fatty acid binding protein 7 (Fabp7, Blbp) as a direct target of repression by REV-ERBα. Loss of Rev-erbα manifested in memory and mood related behavioral phenotypes and led to overexpression of Fabp7 in various brain areas including the subgranular zone (SGZ) of the hippocampus, where neuronal progenitor cells (NPCs) can initiate adult neurogenesis. We found increased proliferation of hippocampal neurons and loss of its diurnal pattern in Rev-erbα KO mice. In vitro, proliferation and migration of glioblastoma cells were affected by manipulating either Fabp7 expression or REV-ERBα activity. These results suggest an important role of Rev-erbα and Fabp7 in adult neurogenesis, which may open new avenues for treatment of gliomas as well as neurological diseases such as depression and Alzheimer

Sense of coherence, mental well-being and perceived preoperative hospital and surgery related stress in surgical patients with malignant, benign, and no neoplasms

Background: This prospective, cross-sectional, observational study examined associations between sense of coherence (SOC), mental well-being, and perceived preoperative hospital and surgery related stress of surgical patients with malignant, benign, and no neoplasms. The objective was to assess a putative association between SOC and preoperative stress, and to test for a statistical mediation by mental well-being. Method: The sample consisted of 4918 patients from diverse surgical fields, of which 945 had malignant neoplasms, 333 benign neoplasms, and 3640 no neoplasms. For each subsample, we conducted simple mediation analyses to test an indirect effect of SOC on preoperative stress mediated by mental well-being. The models were adjusted for age, gender, and essential medical factors. Results: Patient groups did not differ significantly regarding degrees of SOC and mental well-being (SOC, M [SD]: 12.31 [2.59], 12.02 [2.62], 12.18 [2.57]; mental well-being M [SD]: 59.26 [24.05], 56.89 [22.67], 57.31 [22.87], in patients with malignant, benign, and without neoplasms, respectively). Patients without neoplasms reported significantly lower stress (4.19 [2.86], M [SD]) than those with benign (5.02 [3.03], M [SD]) and malignant neoplasms (4.99 [2.93], M [SD]). In all three mediation models, SOC had significant direct effects on stress, with higher SOC being associated with lower stress (- 0.3170 [0.0407], - 0.3484 [0.0752], - 0.2919 [0.0206]; c' [SE], p < 0.001 in patients with malignant, benign, and without neoplasms, respectively). In patients with malignant neoplasms and without neoplasms, SOC showed small indirect effects on stress that were statistically mediated by well-being. Higher SOC was related to higher well-being, which in turn was related to lower stress. In patients with benign neoplasms, however, no significant indirect effects of SOC were found. Conclusions: SOC was directly associated with lower perceived hospital and surgery related stress, over and above the direct and mediation effects of mental well-being. Because the data are cross-sectional, conclusions implying causality cannot be drawn. Nevertheless, they indicate important relationships that can inform treatment approaches to reduce elevated preoperative stress by specifically addressing low SOC

Bereitschaft zur Impfung mit einem COVID‑19-Vakzin - Risikoeinschätzung, Impferfahrungen und Einstellung zu Behandlungsverfahren

Hintergrund: Impfungen stellen eine bedeutende Präventionsmaßnahme dar. Grundlegend für die Eindämmung der Coronapandemie mittels Durchimpfung der Gesellschaft ist eine ausgeprägte Impfbereitschaft. Ziel der Arbeit: Die Impfbereitschaft mit einem COVID‑19-Vakzin (Impfstoff gegen das Coronavirus) und deren Einflussfaktoren werden anhand einer Zufallsstichprobe der Gesamtbevölkerung in Deutschland untersucht. Material und Methoden: Die Studie basiert auf einer telefonischen Zufallsstichprobe und berücksichtigt ältere und vorerkrankte Personen ihrem Bevölkerungsanteil entsprechend. Die Ein-Themen-Bevölkerungsbefragung zur Impfbereitschaft (n = 2014) wurde im November/Dezember 2020 durchgeführt. Ergebnisse: Die Impfbereitschaft in der Stichprobe liegt bei rund 67 %. Vorerfahrungen mit Impfungen moderieren die Impfbereitschaft. Sie steigt bei Zugehörigkeit zu einer Risikogruppe. Der Glaube an die Wirksamkeit alternativer Heilmethoden und Befürwortung alternativer Behandlungsverfahren geht mit geringerer Impfbereitschaft einher. Ältere Menschen sind impfbereiter, kovariierend mit ihrer Einschätzung höherer Gefährdung bei Erkrankung. Ebenso ist die Ablehnung einer Impfung mit der Überschätzung von Nebenwirkungen assoziiert. Schlussfolgerung: Die Impfbereitschaft hängt mit Impferfahrungen und Einstellungen zu Gesundheitsbehandlungsverfahren allgemein zusammen. Die Überschätzung der Häufigkeit ernsthafter Nebenwirkungen bei Impfungen weist auf weit verbreitete Fehlinformationen hin.Background: Globally, vaccination is an important preventive measure. A pronounced willingness to vaccinate is fundamental for the containment of the Coronavirus pandemic by means of vaccination coverage of society. Objectives: The willingness to be vaccinated with a COVID‑19 (coronavirus vaccine) vaccine and its influencing factors are investigated using a random sample of the total population in Germany. Materials and methods: The study is based on a random telephone sample and considers older and previously ill persons according to their proportion in population. The single-topic study on willingness to be vaccinated (n = 2014) was conducted in November/December 2020. Results: The willingness to be vaccinated in the sample is around 67%. Previous experience with vaccinations moderates the willingness to vaccinate. It increases with membership to a risk population. Belief in the efficacy of alternative healing methods and advocacy of alternative treatment procedures are associated with lower willingness to be vaccinated. Older people are more willing to be vaccinated, covarying with their assessment of higher risk in case of illness. Similarly, rejection of vaccination is associated with overestimation of side effects. Conclusions: Willingness to vaccinate is related to vaccination experiences and attitudes towards health care procedures in general. The overestimation of the frequency of serious side effects with vaccinations indicates widespread misinformation

Estimating parameters for probabilistic linkage of privacy-preserved datasets.

Background: Probabilistic record linkage is a process used to bring together person-based records from within the same dataset (de-duplication) or from disparate datasets using pairwise comparisons and matching probabilities. The linkage strategy and associated match probabilities are often estimated through investigations into data quality and manual inspection. However, as privacy-preserved datasets comprise encrypted data, such methods are not possible. In this paper, we present a method for estimating the probabilities and threshold values for probabilistic privacy-preserved record linkage using Bloom filters. Methods: Our method was tested through a simulation study using synthetic data, followed by an application using real-world administrative data. Synthetic datasets were generated with error rates from zero to 20% error. Our method was used to estimate parameters (probabilities and thresholds) for de-duplication linkages. Linkage quality was determined by F-measure. Each dataset was privacy-preserved using separate Bloom filters for each field. Match probabilities were estimated using the expectation-maximisation (EM) algorithm on the privacy-preserved data. Threshold cut-off values were determined by an extension to the EM algorithm allowing linkage quality to be estimated for each possible threshold. De-duplication linkages of each privacy-preserved dataset were performed using both estimated and calculated probabilities. Linkage quality using the F-measure at the estimated threshold values was also compared to the highest F-measure. Three large administrative datasets were used to demonstrate the applicability of the probability and threshold estimation technique on real-world data. Results: Linkage of the synthetic datasets using the estimated probabilities produced an F-measure that was comparable to the F-measure using calculated probabilities, even with up to 20% error. Linkage of the administrative datasets using estimated probabilities produced an F-measure that was higher than the F-measure using calculated probabilities. Further, the threshold estimation yielded results for F-measure that were only slightly below the highest possible for those probabilities. Conclusions: The method appears highly accurate across a spectrum of datasets with varying degrees of error. As there are few alternatives for parameter estimation, the approach is a major step towards providing a complete operational approach for probabilistic linkage of privacy-preserved datasets

Large Observatory for x-ray Timing (LOFT-P): a Probe-class mission concept study

LOFT-P is a concept for a NASA Astrophysics Probe-Class (<$1B) X-ray timing mission, based on the LOFT concept originally proposed to ESAs M3 and M4 calls. LOFT-P requires very large collecting area (>6 m^2, >10x RXTE), high time resolution, good spectral resolution, broad-band spectral coverage (2-30 keV), highly flexible scheduling, and an ability to detect and respond promptly to time-critical targets of opportunity. It addresses science questions such as: What is the equation of state of ultra dense matter? What are the effects of strong gravity on matter spiraling into black holes? It would be optimized for sub-millisecond timing to study phenomena at the natural timescales of neutron star surfaces and black hole event horizons and to measure mass and spin of black holes. These measurements are synergistic to imaging and high-resolution spectroscopy instruments, addressing much smaller distance scales than are possible without very long baseline X-ray interferometry, and using complementary techniques to address the geometry and dynamics of emission regions. A sky monitor (2-50 keV) acts as a trigger for pointed observations, providing high duty cycle, high time resolution monitoring of the X-ray sky with ~20 times the sensitivity of the RXTE All-Sky Monitor, enabling multi-wavelength and multi-messenger studies. A probe-class mission concept would employ lightweight collimator technology and large-area solid-state detectors, technologies which have been recently greatly advanced during the ESA M3 study. Given the large community interested in LOFT (>800 supporters, the scientific productivity of this mission is expected to be very high, similar to or greater than RXTE (~2000 refereed publications). We describe the results of a study, recently completed by the MSFC Advanced Concepts Office, that demonstrates that LOFT-P is feasible within a NASA probe-class mission budget.Comment: Proc. SPIE 9905, Space Telescopes and Instrumentation 2016: Ultraviolet to Gamma Ray, 99054Y (July 18, 2016