Convexity of the zeros of some orthogonal polynomials and related functions

We study convexity properties of the zeros of some special functions that follow from the convexity theorem of Sturm. We prove results on the intervals of convexity for the zeros of Laguerre, Jacobi and ultraspherical polynomials, as well as functions related to them, using transformations under which the zeros remain unchanged. We give upper as well as lower bounds for the distance between consecutive zeros in several cases

NSs protein of Schmallenberg virus counteracts the antiviral response of the cell by inhibiting its transcriptional machinery

Bunyaviruses have evolved a variety of strategies to counteract the antiviral defence systems of mammalian cells. Here we show that the NSs protein of Schmallenberg virus (SBV) induces the degradation of the RPB1 subunit of RNA polymerase II and consequently inhibits global cellular protein synthesis and the antiviral response. In addition, we show that the SBV NSs protein enhances apoptosis in vitro and possibly in vivo, suggesting that this protein could be involved in SBV pathogenesis in different ways

Mutations in the Schmallenberg virus Gc glycoprotein facilitate cellular protein synthesis shutoff and restore pathogenicity of NSs deletion mutants in mice

Serial passage of viruses in cell culture has been traditionally used to attenuate virulence and identify determinants of viral pathogenesis. In a previous study, we found that a strain of Schmallenberg virus (SBV) serially passaged in tissue culture (termed SBVp32) unexpectedly displayed increased pathogenicity in suckling mice compared to wild type SBV. In this study, we mapped the determinants of SBVp32 virulence to the viral genome M segment. SBVp32 virulence is associated with the capacity of this virus to reach higher titers in the brains of experimentally infected suckling mice. We also found that the Gc glycoprotein, encoded by the M segment of SBVp32, facilitates host cell protein shutoff in vitro. Interestingly, while the M segment of SBVp32 is a virulence factor, we found that the S segment of the same virus confers by itself an attenuated phenotype to wild type SBV as has lost the ability to block the innate immune system of the host. Single mutations present in the Gc glycoprotein of SBVp32 are sufficient to compensate both the attenuated phenotype of the SBVp32 S segment and the attenuated phenotype of NSs deletion mutants. Our data also indicate that the SBVp32 M segment does not act as an IFN antagonist. Therefore SBV mutants can retain pathogenicity even when they are unable to fully control the production of IFN by the infected cells. Overall, this study suggests that the viral glycoprotein of orthobunyaviruses can compensate, at least in part, the function of NSs. In addition, we also provide evidence that the induction of total cellular protein shutoff by SBV is determined by multiple viral proteins while the ability to control the production of IFN maps to the NSs protein. Importance The identification of viral determinants of pathogenesis is key to the development of prophylactic and interventions measures. In this study we found that the bunyavirus Gc glycoprotein is a virulence factor. Importantly, we show that mutations in the Gc glycoprotein can restore pathogenicity of attenuated mutants resulting from deletions or mutations in the non-structural protein NSs. Our findings highlight the fact that careful consideration should be taken when designing live attenuated vaccines based on deletions of non-structural proteins since single mutations in the viral glycoproteins appear to revert attenuated mutants to virulent phenotypes

Erstellung und Realisierung einer institutionellen Forschungsdaten-Policy

Die Hochschulrektorenkonferenz hat 2015 Empfehlungen zum Forschungsdatenmanagement verfasst, worin den Hochschulen nahegelegt wurde eigene Forschungsdaten-Policies zu verabschieden. Ziel sei es, den Hochschulangehörigen mehr Orientierung im Forschungsdatenmanagement zu geben. Umfang, Inhalt und der Verabschiedungsprozess einer Forschungsdaten-Policy können jedoch stark voneinander abweichen. Die vorliegende Empfehlung sowie die zugehörigen Erfahrungsberichte geben einen Überblick über die verschiedenen Möglichkeiten der Gestaltung einer Policy sowie Wege zu deren Erstellung. Neben einer Definition von Forschungsdaten-Policies sowie einer tabellarischen Übersicht thematischer Bausteine werden Empfehlungen zur Erstellung und Verabschiedung gegeben

Biophotonic sensors with integrated Si3_{3}N4_{4}-organic hybrid (SiNOH) lasers for point-of-care diagnostics

Early and efficient disease diagnosis with low-cost point-of-care devices is gaining importance for personalized medicine and public health protection. Within this context, waveguide-(WG)-based optical biosensors on the silicon-nitride (Si$_{3}$N$_{4}$) platform represent a particularly promising option, offering highly sensitive detection of indicative biomarkers in multiplexed sensor arrays operated by light in the visible-wavelength range. However, while passive Si3N4-based photonic circuits lend themselves to highly scalable mass production, the integration of low-cost light sources remains a challenge. In this paper, we demonstrate optical biosensors that combine Si3N4 sensor circuits with hybrid on-chip organic lasers. These Si3N4-organic hybrid (SiNOH) lasers rely on a dye-doped cladding material that are deposited on top of a passive WG and that are optically pumped by an external light source. Fabrication of the devices is simple: The underlying Si3N4 WGs are structured in a single lithography step, and the organic gain medium is subsequently applied by dispensing, spin-coating, or ink-jet printing processes. A highly parallel read-out of the optical sensor signals is accomplished with a simple camera. In our proof-of-concept experiment, we demonstrate the viability of the approach by detecting different concentrations of fibrinogen in phosphate-buffered saline solutions with a sensor-length (L-)-related sensitivity of S/L = 0.16 rad nM−1 mm−1. To our knowledge, this is the first demonstration of an integrated optical circuit driven by a co-integrated low-cost organic light source. We expect that the versatility of the device concept, the simple operation principle, and the compatibility with cost-efficient mass production will make the concept a highly attractive option for applications in biophotonics and point-of-care diagnostics

Long-Term Relapse-Free Survival by Interdisciplinary Collaboration in a Patient with Metastatic Pancreatic Cancer (UICC IV)

Introduction: The prognostic outlook for patients suffering from pancreatic cancer is generally poor. Particularly in cases of advanced and metastatic disease, long-term relapse-free survival may be achieved only in a few cases. Case Report: A 45-year-old patient presented with metastatic pancreatic cancer. Liver metastases had been intra-operatively confirmed by histology. Prior to initiating treatment, a portacath was surgically implanted. Subsequently, the patient received a weekly dose of 1,000 mg/m2 gemcitabine combined with 2,000 mg/m2 high-dose 5-fluorouracil as a 24-hour infusion for palliative treatment. As the patient was suffering from a stenosis of the ductus hepaticus communis, an endoprosthesis was primarily implanted. After 18 applications of chemotherapy during which only low toxic side effects such as nausea, vomiting and alopecia (NCI-CTC grade 1) presented, a partial remission of the primary tumor was observed. In the course of chemotherapy treatment, the carbohydrate antigen 19-9 tumor marker value normalized. Thus, the interdisciplinary tumor board of the University of Erlangen decided to perform a laparoscopy to evaluate the status of liver metastases after palliative chemotherapy treatment. Subsequently, the primary tumor could be completely resected (pT2, pN0, pM0, L0, V0, G2, R0); liver metastases were not observed. Eight years after the initial diagnosis, the patient is relapse-free, professionally fully integrated and presents with an excellent performance status. Conclusion: Patients suffering from metastatic pancreatic cancer may benefit from treatment combinations with palliative intent. In singular cases, patients may even have a curative treatment option, provided a close interdisciplinary collaboration exists

CRISPR/Cas9-Mediated Targeting of BPV-1-Transformed Primary Equine Sarcoid Fibroblasts

Equine sarcoids (EqS) are fibroblast-derived skin tumors associated with bovine papillomavirus 1 and 2 (BPV-1 and -2). Based on Southern blotting, the BPV-1 genome was not found to be integrated in the host cell genome, suggesting that EqS pathogenesis does not result from insertional mutagenesis. Hence, CRISPR/Cas9 implies an interesting tool for selectively targeting BPV-1 episomes or genetically anchored suspected host factors. To address this in a proof-of-concept study, we confirmed the exclusive episomal persistence of BPV-1 in EqS using targeted locus amplification (TLA). To investigate the CRISPR/Cas9-mediated editing of BPV-1 episomes, primary equine fibroblast cultures were established and characterized. In the EqS fibroblast cultures, CRISPR-mediated targeting of the episomal E5 and E6 oncogenes as well as the BPV-1 long control region was successful and resulted in a pronounced reduction of the BPV-1 load. Moreover, the deletion of the equine Vimentin (VIM), which is highly expressed in EqS, considerably decreased the number of BPV-1 episomes. Our results suggest CRISPR/Cas9-based gene targeting may serve as a tool to help further unravel the biology of EqS pathogenesis

Highly conserved serine residue 40 in HIV-1 p6 regulates capsid processing and virus core assembly

Background: The HIV-1 p6 Gag protein regulates the final abscission step of nascent virions from the cell membrane by the action of two late assembly (L-) domains. Although p6 is located within one of the most polymorphic regions of the HIV-1 gag gene, the 52 amino acid peptide binds at least to two cellular budding factors (Tsg101 and ALIX), is a substrate for phosphorylation, ubiquitination, and sumoylation, and mediates the incorporation of the HIV-1 accessory protein Vpr into viral particles. As expected, known functional domains mostly overlap with several conserved residues in p6. In this study, we investigated the importance of the highly conserved serine residue at position 40, which until now has not been assigned to any known function of p6. Results: Consistently with previous data, we found that mutation of Ser-40 has no effect on ALIX mediated rescue of HIV-1 L-domain mutants. However, the only feasible S40F mutation that preserves the overlapping pol open reading frame (ORF) reduces virus replication in T-cell lines and in human lymphocyte tissue cultivated ex vivo. Most intriguingly, L-domain mediated virus release is not dependent on the integrity of Ser-40. However, the S40F mutation significantly reduces the specific infectivity of released virions. Further, it was observed that mutation of Ser-40 selectively interferes with the cleavage between capsid (CA) and the spacer peptide SP1 in Gag, without affecting cleavage of other Gag products. This deficiency in processing of CA, in consequence, led to an irregular morphology of the virus core and the formation of an electron dense extra core structure. Moreover, the defects induced by the S40F mutation in p6 can be rescued by the A1V mutation in SP1 that generally enhances processing of the CA-SP1 cleavage site. Conclusions: Overall, these data support a so far unrecognized function of p6 mediated by Ser-40 that occurs independently of the L-domain function, but selectively affects CA maturation and virus core formation, and consequently the infectivity of released virions