Optical Modulation of Antibiotic Resistance by Photoswitchable Cystobactamids

The rise of antibiotic resistance causes a serious health care problem, and its counterfeit demands novel, innovative concepts. The combination of photopharmacology, enabling a light-controlled reversible modulation of drug activity, with antibiotic drug design has led to first photoswitchable antibiotic compounds derived from established scaffolds. In this study, we converted cystobactamids, gyrase-inhibiting natural products with an oligoaryl scaffold and highly potent antibacterial activities, into photoswitchable agents by inserting azobenzene in the N-terminal part and/or an acylhydrazone moiety near the C-terminus, yielding twenty analogs that contain mono- as well as double-switches. Antibiotic and gyrase inhibition properties could be modulated 3.4-fold and 5-fold by light, respectively. Notably, the sensitivity of photoswitchable cystobactamids towards two known resistance factors, the peptidase AlbD and the scavenger protein AlbA, was light-dependent. While irradiation of an analog with an N-terminal azobenzene with 365 nm light led to less degradation by AlbD, the AlbA-mediated inactivation was induced. This provides a proof-of-principle that resistance towards photoswitchable antibiotics can be optically controlled

DIMA - Annotation Guidelines for German Intonation

Kügler F, Smolibocki B, Arnold D, et al. DIMA - Annotation Guidelines for German Intonation. In: Proceedings of the 18th International Congress of Phonetic Sciences. Glasgow, Scotland; 2015: 317.This paper presents newly developed guidelines for prosodic annotation of German as a consensus system agreed upon by German intonologists. The DIMA system is rooted in the framework of autosegmental-metrical phonology. One important goal of the consensus is to make exchanging data between groups easier since German intonation is currently annotated according to different models. To this end, we aim to provide guidelines that are easy to learn. The guidelines were evaluated running an inter-annotator reliability study on three different speech styles (read speech, monologue and dialogue). The overall high κ between 0.76 and 0.89 (depending on the speech style) shows that the DIMA conventions can be applied successfully

DIMA - Annotation Guidelines for German Intonation

Kügler F, Smolibocki B, Arnold D, et al. DIMA - Annotation Guidelines for German Intonation. In: Proceedings of the 18th International Congress of Phonetic Sciences. Glasgow, Scotland; 2015: 317.This paper presents newly developed guidelines for prosodic annotation of German as a consensus system agreed upon by German intonologists. The DIMA system is rooted in the framework of autosegmental-metrical phonology. One important goal of the consensus is to make exchanging data between groups easier since German intonation is currently annotated according to different models. To this end, we aim to provide guidelines that are easy to learn. The guidelines were evaluated running an inter-annotator reliability study on three different speech styles (read speech, monologue and dialogue). The overall high κ between 0.76 and 0.89 (depending on the speech style) shows that the DIMA conventions can be applied successfully

Multi-professionelle und mono-professionelle Zusammenarbeit und ihre Verbindung zu den Einstellungen von Lehramtstudierenden zu Konzepten von schulischer Inklusion

The ratification of the UN Disability Rights Convention in Germany constitutes a new challenge for schools and teachers. In response, in 2015, the Conference of Education Ministers mandated that inclusion must be a topic within the first phase of teacher training. Many research studies emphasize the importance of professional collaboration for successful inclusive education at schools. Collaboration skills, however, must already have been taught in the first phase of teacher training. At the University of Wuppertal, Germany, a seminar-design was developed to offer teacher trainees the opportunity to gain knowledge about, and experience in, inclusive education and practice collaboration skills at the same time. The seminar comprises three parts: (1) academic course work at the university; (2) a practical phase at secondary schools around the city; and (3) a phase of reflection at the end. Teacher trainees work in either multi-professional tandems consisting of one teacher trainee for general education (GE), one teacher trainee for special educational needs (SEN), or in mono-professional tandems consisting of two teacher trainees for GE or two teacher trainees for SEN. A mixed-method approach is carried out to assess the association of mono-, as compared to multi-, professional collaboration with teacher trainees’ attitudes towards, and concepts of, inclusive education. Analysis is performed at three different testing times during the course of the seminar, thus enabling analysis of both the effect of academic course work and practical experience. Attitudes towards, and concepts of, inclusive education are anticipated to be predictors of classroom behavior and professional knowledge and behavior. It is also expected that interdisciplinary exchange in multi-professional tandems will be associated with higher professional knowledge. (DIPF/Orig.)Die Ratifizierung der UN-Behindertenrechtskonvention in Deutschland stellt eine neue Herausforderung für Schulen und Lehrer*innen dar. Daher beschloss die Hochschulrektorenkonferenz (HRK) im Jahr 2015, dass die Vorbereitung auf die schulische Inklusion bereits in der ersten Phase der Lehrer*innenbildung enthalten sein soll. In einer Reihe von wissenschaftlichen Studien wird die Bedeutung der professionellen Zusammenarbeit für eine erfolgreiche schulische Inklusion immer wieder betont. Dabei sollten die Kooperationskompetenzen der künftigen Lehrer*innen vorzugsweise schon in der ersten Phase der Lehrer*innenbildung trainiert und eingeübt werden. An der Bergischen Universität in Wuppertal wurde ein Seminarkonzept entwickelt, das den Lehramtsstudierenden die Möglichkeit bietet, Kenntnisse über und Erfahrungen im inklusiven Unterricht zu erlangen und gleichzeitig die Kooperationskompetenzen zu trainieren. Das Seminar besteht aus drei Phasen: i) einer universitären Phase, ii) einer praktischen Phase in einer Schule der Sekundarstufe I im Stadtgebiet und iii) einer Reflexionsphase. Die Lehramtsstudierenden arbeiten entweder in einem multi-professionellen Team bestehend aus einem Lehramtsstudierenden für die Regelschulpädagogik (RePä) und einem Lehramtsstudierenden für die Sonderpädagogik (SoPä), oder in einem mono-professionellen Team bestehend aus zwei Lehramtsstudierenden der RePä oder zwei Lehramtsstudierenden der SoPä. Die Auswirkung von multi-professioneller Kooperation auf die Einstellung der Lehramtsstudierenden zu und deren Konzepte von schulischer Inklusion wird mithilfe eines Mixed-Method-Ansatzes analysiert und verglichen mit der entsprechenden Auswirkung einer mono-professionellen Kooperation. Die Datenerhebung findet zu drei Messzeitpunkten im Laufe des Seminars statt, um sowohl den Effekt der universitären Phase als auch den Effekt der praktischen Erfahrung in den Schulen zu untersuchen. Sowohl die Einstellung zu als auch die Konzepte von schulischer Inklusion gelten als Prädiktoren für das Professionswissen und das Lehrerhandeln. Es wird erwartet, dass der interdisziplinäre Austausch in den multi-professionellen Teams zu einer positiveren Einstellung und einem höheren Professionswissen führt. (DIPF/Orig.

STAT3 Single Nucleotide Polymorphism rs4796793 SNP Does Not Correlate with Response to Adjuvant IFNα Therapy in Stage III Melanoma Patients

Interferon alpha (IFNα) is approved for adjuvant treatment of stage III melanoma in Europe and the US. Its clinical efficacy, however, is restricted to a subpopulation of patients while side effects occur in most of treated patients. Thus, the identification of predictive biomarkers would be highly beneficial to improve the benefit to risk ratio. In this regard, STAT3 is important for signaling of the IFNα receptor. Moreover, the STAT3 single-nucleotide polymorphism (SNP) rs4796793 has recently been reported to be associated with IFNα sensitivity in metastatic renal cell carcinoma. To translate this notion to melanoma, we scrutinized the impact of rs4796793 functionally and clinically in this cancer. Interestingly, melanoma cells carrying the minor allele of rs4796793 were the most sensitive to IFNα in vitro. However, we did not detect a correlation between SNP genotype and STAT3 mRNA expression for either melanoma cells or for peripheral blood lymphocytes. Next, we analyzed the impact of rs4796793 on the clinical outcome of 259 stage III melanoma patients of which one-third had received adjuvant IFNα treatment. These analyses did not reveal a significant association between the STAT3 rs4796793 SNP and patients' progression free or overall survival when IFNα treated and untreated patients were compared. In conclusion, STAT3 rs4796793 SNP is no predictive marker for the efficacy of adjuvant IFNα treatment in melanoma patients

DIMA – Annotation guidelines for German intonation

This paper presents newly developed guidelines for prosodic annotation of German as a consensus system agreed upon by German intonologists. The DIMA system is rooted in the framework of autosegmental-metrical phonology. One important goal of the consensus is to make exchanging data between groups easier since German intonation is currently annotated according to different models. To this end, we aim to provide guidelines that are easy to learn. The guidelines were evaluated running an inter-annotator reliability study on three different speech styles (read speech, monologue and dialogue). The overall high κ between 0.76 and 0.89 (depending on the speech style) shows that the DIMA conventions can be applied successfully

Patient-Reported Quality of Care for Osteoarthritis in General Practice in South Tyrol, Italy: Protocol for Translation, Validation and Assessment of the OsteoArthritis Quality Indicator Questionnaire (OA-QI)

Background: Evidence-based recommendations for the treatment of knee and hip osteoarthritis are similar internationally. Nevertheless, clinical practice varies across countries. Instruments for measuring quality have been developed to improve health care through targeted interventions. Studies on health service quality must consider the structural and cultural characteristics of countries, because each of their strengths and weaknesses differ. However, such instruments for health-related patient-reported outcomes for osteoarthritis have not yet been validated in German and Italian languages. Objectives: In order to be able to set targeted measures for the improvement of prevention and non-surgical treatment of osteoarthritis in South Tyrol, Italy, the quality of care must be recorded. Therefore, the aim of the project is to update, translate, and validate the OsteoArthritis Quality Indicator (OA-QI) questionnaire version 2, an established and validated questionnaire in Norwegian and English, for Germany and Italy. The second aim is to determine the quality of care for osteoarthritis of the hip and knee in a sample of patients who consult general practice in South Tyrol, and for comparison with patients who are admitted to rehabilitative spa-treatments for osteoarthritis in the state of Salzburg, Austria. Discussion: The results of this study will enable the identification and closure of gaps in osteoarthritis care. Although it is expected that body weight and exercise will play special roles, other areas of nonsurgical care might also be involved

Efficient in vivo priming by vaccination with recombinant NY-ESO-1 protein and CpG in antigen naive prostate cancer patients

PURPOSE: NY-ESO-1, one of the most immunogenic tumor antigens, is expressed in 15% to 25% of metastatic prostate cancers. The immunological and clinical effects of vaccination with recombinant NY-ESO-1 protein combined with CpG as adjuvant were evaluated. EXPERIMENTAL DESIGN: In a phase I clinical study, patients with advanced prostate cancer were vaccinated with recombinant NY-ESO-1 protein (100 μg) mixed with CpG 7909 (2.5 mg) every 3 weeks intradermally for 4 doses. Objectives of the study were the safety of the vaccine and changes of specific humoral and cellular immunological responses to NY-ESO-1 in relation to detectable NY-ESO-1 expression in the individual tumor. RESULTS: All 12 baseline sero-negative patients developed high-titer NY-ESO-1 antibody responses. B-cell epitope mapping identified NY-ESO-1 p91-110 to be recognized most frequently by vaccine-induced antibodies. Two patients developed significant antibody titers against the adjuvant CpG. NY-ESO-1-specific CD4+ and/or CD8+ T-cell responses were induced in 9 patients (69%). Five of these 9 patients did not express NY-ESO-1 in the autologous tumor. Postvaccine CD8+ T-cell clones recognized and lyzed HLA-matched tumor cell lines in an antigen-specific manner. CONCLUSION: Our data provide clear evidence for the capacity of NY-ESO-1 protein/CpG vaccine to induce integrated antigen-specific immune responses in vivo and to efficiently prime CD8+ T-cell responses in NY-ESO-1 antigen-negative patients. Our results may also support further clinical vaccination protocols with NY-ESO-1 protein not only focused on the treatment of existing cancer, but also to prevent further development of NY-ESO-1 positive cancers in vivo

The nuclear export inhibitor aminoratjadone is a potent effector in extracellular-targeted drug conjugates.

The concept of targeted drug conjugates has been successfully translated to clinical practice in oncology. Whereas the majority of cytotoxic effectors in drug conjugates are directed against either DNA or tubulin, our study aimed to validate nuclear export inhibition as a novel effector principle in drug conjugates. For this purpose, a semisynthetic route starting from the natural product ratjadone A, a potent nuclear export inhibitor, has been developed. The biological evaluation of ratjadones functionalized at the 16-position revealed that oxo- and amino-analogues had very high potencies against cancer cell lines (e.g. 16R-aminoratjadone 16 with IC50 = 260 pM against MCF-7 cells, or 19-oxoratjadone 14 with IC50 = 100 pM against A-549 cells). Mechanistically, the conjugates retained a nuclear export inhibitory activity through binding CRM1. To demonstrate a proof-of-principle for cellular targeting, folate- and luteinizing hormone releasing hormone (LHRH)-based carrier molecules were synthesized and coupled to aminoratjadones as well as fluorescein for cellular efficacy and imaging studies, respectively. The Trojan-Horse conjugates selectively addressed receptor-positive cell lines and were highly potent inhibitors of their proliferation. For example, the folate conjugate FA-7-Val-Cit-pABA-16R-aminoratjadone had an IC50 of 34.3 nM, and the LHRH conjugate d-Orn-Gose-Val-Cit-pABA-16R-aminoratjadone had an IC50 of 12.8 nM. The results demonstrate that nuclear export inhibition is a promising mode-of-action for extracellular-targeted drug conjugate payloads