nEoS: Neutron Star Equation of State from hadron physics alone

We contribute a publicly available set of tables and code to provide Equations of State (EoS) for matter at neutron star densities. Our EoSes are constrained only by input from hadron physics and fundamental principles, without feedback from neutron star observations, and so without relying on General Relativity. They can therefore be used to test General Relativity itself, as well as modified gravity theories, with neutron star observables, without logical circularity. We have adapted state of the art results from NN chiral potentials for the low--density limit, pQCD results for the asymptotically high-density EoS, and use monotonicity and causality as the only restrictions for intermediate densities, for the EoS sets to remain as model-independent as is feasible today.Comment: 16 pages with 11 plot

Prevalence of tetrahydrobiopterine (BH4)-responsive alleles among Austrian patients with PAH deficiency: comprehensive results from molecular analysis in 147 patients

Phenylketonuria (PKU, MIM 261600) is an autosomal recessive disorder caused by mutations of the phenylalanine hydroxylase gene (PAH, GenBank U49897.1, RefSeq NM_000277). To date more than 560 variants of the PAH gene have been identified. In Europe there is regional distribution of specific mutations. Due to recent progress in chaperone therapy, the prevalence of BH4-responsive alleles gained therapeutic importance. Here we report the mutational spectrum of PAH deficiency in 147 unrelated Austrian families. Overall mutation detection rate was 98.6%. There was a total of 62 disease-causing mutations, including five novel mutations IVS4 + 6T>A, p.H290Y, IVS8-2A>G, p.A322V and p.I421S. The five most prevalent mutations found in patients were p.R408W, IVS12 + 1G>A, p.R261Q, p.R158Q and IVS2 + 5G>C. Neonatal phenylalanine levels before treatment were available in 114/147 patients. Prediction of BH4-responsiveness in patients with full genotypes was exclusively made according to published data. Among the 133 patients needing dietary treatment, 28.4% are expected to be BH4 "non-responsive", 4.5% are highly likely BH4-responsive, 35.8% are probably BH4-responsive while no interpretation was possible for 31.3%. The mutation data reflect the population history of Austria and provide information on the likely proportion of Austrian PKU patients that may benefit from BH4-therap

Mono- and combinational drug therapies for global viral pandemic preparedness

Broadly effective antiviral therapies must be developed to be ready for clinical trials, which should begin soon after the emergence of new life-threatening viruses. Here, we pave the way towards this goal by reviewing conserved druggable virus-host interactions, mechanisms of action, immunomodulatory properties of available broad-spectrum antivirals (BSAs), routes of BSA delivery, and interactions of BSAs with other antivirals. Based on the review, we concluded that the range of indications of BSAs can be expanded, and new pan- and cross-viral mono- and combinational therapies can be developed. We have also developed a new scoring algorithm that can help identify the most promising few of the thousands of potential BSAs and BSA-containing drug cocktails (BCCs) to prioritize their development during the critical period between the identification of a new virus and the development of virus-specific vaccines, drugs, and therapeutic antibodies.Peer reviewe

Synergistic Interferon-Alpha-Based Combinations for Treatment of SARS-CoV-2 and Other Viral Infections

Background: There is an urgent need for new antivirals with powerful therapeutic potential and tolerable side effects. Methods: Here, we tested the antiviral properties of interferons (IFNs), alone and with other drugs in vitro. Results: While IFNs alone were insufficient to completely abolish replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), IFNα, in combination with remdesivir, EIDD-2801, camostat, cycloheximide, or convalescent serum, proved to be more effective. Transcriptome and metabolomic analyses revealed that the IFNα–remdesivir combination suppressed SARS-CoV-2-mediated changes in Calu-3 cells and lung organoids, although it altered the homeostasis of uninfected cells and organoids. We also demonstrated that IFNα combinations with sofosbuvir, telaprevir, NITD008, ribavirin, pimodivir, or lamivudine were effective against HCV, HEV, FLuAV, or HIV at lower concentrations, compared to monotherapies. Conclusions: Altogether, our results indicated that IFNα can be combined with drugs that affect viral RNA transcription, protein synthesis, and processing to make synergistic combinations that can be attractive targets for further pre-clinical and clinical development against emerging and re-emerging viral infections

Focus: Implementing participation - Advancement of social services in analog and digital spaces

Digitale Informations- und Kommunikationstechnologien gewinnen als fester Bestandteil zunehmend Bedeutung in den alltäglichen Lebenswelten einer wachsenden Zahl von Menschen. Ihre Entwicklung und selbstverständliche Nutzung schreiten in einem immer rasanteren Tempo voran; die vielfältigen Anwendungsmöglichkeiten adressieren längst alle Lebensbereiche. Während der Digitalisierung von Kommunikationsprozessen zuweilen demokratisierende Kräfte zugesprochen werden, scheint eine kritische Reflexion möglicher Potentiale und Auswirkungen digitaler Informations- und Kommunikationstechnologien auf Teilhabedynamiken in unterschiedlichen Lebensbereichen dringend erforderlich. Die Autorinnen und Autoren möchten mit dieser SI:SO-Schwerpunktausgabe einen Beitrag zu einer kritischen Reflexion digitaler Innovationen und ihrer Auswirkungen auf die zukünftige Gestaltung sozialer Dienste leisten. Mit der zweisprachigen Ausgabe ist zudem die Hoffnung verbunden, diesen Beitrag auch einem europäischen und weltweiten Publikum zugänglich zu machen.Digital information and communications technologies are becoming an increasingly important part in everyday life of a growing number of people. Their development and natural use are progressing even faster with a wide range of possible applications addressing all areas of life. While the digitization of communication processes is sometimes said to have democratizing forces, critical reflection on the potential and impact of digital information and communication technologies on participation dynamics in different areas of life seems urgently needed. The Authors would like to contribute to a critical reflection on digital innovations and their impact on the future design of social services. The bilingual edition further aims to make this contribution accessible to a European and global audience

Common Nodes of Virus-Host Interaction Revealed Through an Integrated Network Analysis

Viruses are one of the major causes of acute and chronic infectious diseases and thus a major contributor to the global burden of disease. Several studies have shown how viruses have evolved to hijack basic cellular pathways and evade innate immune response by modulating key host factors and signaling pathways. A collective view of these multiple studies could advance our understanding of virus-host interactions and provide new therapeutic perspectives for the treatment of viral diseases. Here, we performed an integrative meta-analysis to elucidate the 17 different host-virus interactomes. Network and bioinformatics analyses showed how viruses with small genomes efficiently achieve the maximal effect by targeting multifunctional and highly connected host proteins with a high occurrence of disordered regions. We also identified the core cellular process subnetworks that are targeted by all the viruses. Integration with functional RNA interference (RNAi) datasets showed that a large proportion of the targets are required for viral replication. Furthermore, we performed an interactome-informed drug re-purposing screen and identified novel activities for broad-spectrum antiviral agents against hepatitis C virus and human metapneumovirus. Altogether, these orthogonal datasets could serve as a platform for hypothesis generation and follow-up studies to broaden our understanding of the viral evasion landscape.Peer reviewe

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Perspektiven in der Frühpädagogik unter Berücksichtigung von Professionalisierung am Beispiel des Anti-Bias-Ansatzes

CD-ROM (Anhang 2: Interviews etc.) Die Sozialisationsinstanz Kindergarten/Kita steht mehr denn je im Fokus des bildungswissenschaftlichen Interesses, zumal die Wichtigkeit und Bedeutung der ersten Lebensjahre eines Menschen für die kognitive, emotionale und soziale Entwicklung erkannt wurde. Diese stellt ein Fundament für die weitere (Bildungs)Biografie dar. Parallel dazu ist eine zunehmende Diversität an Lebensformen sowie unterschiedlichen Ausgangsvoraussetzungen im frühpädagogischen Bereich zu beobachten. Dies ist mit entsprechenden Herausforderungen verknüpft und erfordert eine hohe Ausbildungsqualität der pädagogisch Tätigen. In diesem Kontext befasst sich diese Arbeit mit einem inklusiven frühpädagogischen Modell, dem Anti-Bias-Ansatz (USA) bzw. der vorurteilsbewussten Bildung und Erziehung (Deutschland) vor dem Hintergrund des aktuellen Professionalisierungsdiskurses sowie aktuellen Strömungen des Heterogenitätsdiskurses. Zur empirischen Beantwortung der Forschungsfragen werden ExpertInneninterviews durchgeführt. Es zeigt sich, dass die Anti-Bias-Arbeit ein neues Bewusstsein generiert, das den Blick auf die eigene Haltung sowie für institutionelle Diskriminierung nachhaltig schärft, um allen Kindern positiv besetzte Lern- und Bildungsprozesse zu ermöglichen. Dies ist mit dem Erwerb von Kompetenzen verknüpft, die sich in einem veränderten Wahrnehmungs- und Handlungswissen zeigen, das in dieser Charakterisierung so bisher nicht im Professionalisierungsdiskurs thematisiert wurde. Ferner zeigen sich bei den ExpertInnen Veränderungen, die auf eine neue habituelle Prägung schließen lassen.More than ever, and especially because the importance of the first years of human life for cognitive, emotional and social development has been recognized, educational sciences/early childhood education focus on pre-schools as an agent of socialization. This development in the early years creates the foundation for a person‘s further (educational) biography. At the same time, a rising diversity of ways of life as well as of varying starting conditions in the field of early childhood education can be observed. Accordingly, this matter of fact is tied up with certain challenges and requires a high quality of training for educational staff. In this context, the following dissertation examines an inclusive early childhood educational model, the Anti-Bias-Approach (USA) respectively the Prejudice Aware Education (Germany) against the background of the present discourse on professionalization as well as the current trends of the discourse on heterogeneity. Experts have been interviewed in order to empirically answer the research questions. The results show that the Anti-Bias-Work generates a new awareness, which lastingly sharpens the view of one’s own attitude as well as of institutional discrimination so that positive learning processes are made possible for all children. This is connected with the acquisition of competences and appear in a different perceptual and action knowledge, which so far has not been made a subject in the discussion of professionalization. In addition, the experts show changes in their behaviour, which allows to imply a new habitual stamping

Die Umsatzbesteuerung von Finanzdienstleistungen

Das österreichische Umsatzsteuerrecht kennt bereits seit dem UStG 1972 eine unechte Steuerbefreiung für bestimmte Finanzdienstleistungen. Obwohl sich der Finanzdienstleistungssektor im Laufe der Zeit durch Globalisierung, neue Finanzprodukte und technologischen Fortschritt massiv veränderte, bestehen die vor mehr als 30 Jahren festgelegten Bestimmungen des UStG 1972 im Kern bis heute. Der Hauptgrund für die Befreiung von Finanzumsätzen ist in erster Linie technischer Natur, da die Bemessungsgrundlage nur schwer zu ermitteln wäre. Zudem soll durch die Steuerbefreiung eine Verteuerung von Krediten, Wertpapieren und anderen Finanzprodukten vermieden werden. Die unechte Umsatzsteuerbefreiung bestimmter Finanzdienstleistungen führt allerdings in der Praxis zu Schwierigkeiten. Zentrales Problem ist die Nichtgewährung des Vorsteuerabzugs, wodurch es zu Verstößen gegen das Neutralitäts- und Verbrauchsteuerprinzip kommt. Das wesentliche Ziel dieser Arbeit ist es daher, mögliche Verstöße des § 6 Abs 1 Z 8 UStG gegen die Grundprinzipien des Umsatzsteuerrechts aufzuarbeiten und kritisch zu analysieren sowie verschiedene Lösungsansätze zu deren Beseitigung vorzustellen.eingereicht von Eva Maria Windisch, LL.B.Universität Linz, Masterarbeit, 2018(VLID)310632

Identification and Tracking of Antiviral Drug Combinations

Combination therapies have become a standard for the treatment for HIV and hepatitis C virus (HCV) infections. They are advantageous over monotherapies due to better efficacy, reduced toxicity, as well as the ability to prevent the development of resistant viral strains and to treat viral co-infections. Here, we identify new synergistic combinations against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), echovirus 1 (EV1), hepatitis C virus (HCV) and human immunodeficiency virus 1 (HIV-1) in vitro. We observed synergistic activity of nelfinavir with convalescent serum and with purified neutralizing antibody 23G7 against SARS-CoV-2 in human lung epithelial Calu-3 cells. We also demonstrated synergistic activity of nelfinavir with EIDD-2801 or remdesivir in Calu-3 cells. In addition, we showed synergistic activity of vemurafenib with emetine, homoharringtonine, anisomycin, or cycloheximide against EV1 infection in human lung epithelial A549 cells. We also found that combinations of sofosbuvir with brequinar or niclosamide are synergistic against HCV infection in hepatocyte-derived Huh-7.5 cells, and that combinations of monensin with lamivudine or tenofovir are synergistic against HIV-1 infection in human cervical TZM-bl cells. These results indicate that synergy is achieved when a virus-directed antiviral is combined with another virus- or host-directed agent. Finally, we present an online resource that summarizes novel and known antiviral drug combinations and their developmental status.Peer reviewe