Synthese von Isochinolinalkaloiden und deren Elektrooxidation zu Morphinandienonen

Die vorliegende Arbeit beschreibt einen effektiven Zugang zu den Morphinandienonen, die potentielle Vorläufer von Morphinderivaten sind. Die an der biomimetischen Morphin-Synthese orientierte elektrooxidative Aryl-Aryl-Kupplung zu Morphinandienonen ermöglicht einen effektiven und leistungsfähigen Aufbau der Morphin-ABCD-Substruktur. Für den elektrochemischen Schlüsselschritt, der von 1-Benzylisochinolinalkaloiden ausgeht, ist die Bildung von vier verschiedenen Regioisomeren möglich. Zur Kontrolle der Regiochemie in diesem Schritt wurde einerseits die unerwünschte Kupplungsposition mit verschiedenen Substituenten blockiert. Weiterhin wurden Isochinolinalkaloide mit symmetrischen Benzylteil elektrooxidiert, woraus Morphinandienone in guter Ausbeute erhalten wurden. Es wurde damit ein effektiver Zugang zum vollständigen Morphin-ABCDE-Gerüst erhalten und damit ein neues Derivat des Naturstoffs Thebain synthetisiert

Reduced emotion recognition from nonverbal cues in anorexia nervosa

Objective: Recent models of anorexia nervosa (AN) emphasise the role of reduced emotion recognition ability (ERA) in the development and maintenance of the disorder. However, methodological limitations impede conclusions from prior research. The current study tries to overcome these limitations by examining ERA with an audio-visual measure that focuses strictly on multimodal nonverbal cues and allows to differentiate between ERA for different emotion categories. Method: Forty women with AN and 40 healthy women completed the Geneva Emotion Recognition Test. This test includes 83 video clips in which 10 actors express 14 different emotions while saying a pseudo-linguistic sentence without semantic meaning. All clips contain multimodal nonverbal cues (i.e., prosody, facial expression, gestures, and posture). Results: Patients with AN showed poorer ERA than the healthy control group (d = 0.71), particularly regarding emotions of negative valence (d = 0.26). Furthermore, a lower body weight (r = 0.41) and longer illness duration (ρ = -0.32) were associated with poorer ERA in the AN group. Conclusions: Using an ecologically valid instrument, the findings of the study support illness models emphasising poor ERA in AN. Directly addressing ERA in the treatment of AN with targeted interventions may be promising. Keywords: eating disorder; emotion recognition; social cognition; socio-emotional processing; theory of mind

Cytochrome P450 2B6 (CYP2B6) and constitutive androstane receptor (CAR) polymorphisms are associated with early discontinuation of efavirenz-containing regimens

Objectives Cytochrome P450 2B6 (CYP2B6) is responsible for the metabolic clearance of efavirenz and single nucleotide polymorphisms (SNPs) in the CYP2B6 gene are associated with efavirenz pharmacokinetics. Since the constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) correlate with CYP2B6 in liver, and a CAR polymorphism (rs2307424) and smoking correlate with efavirenz plasma concentrations, we investigated their association with early (<3 months) discontinuation of efavirenz therapy. Methods Three hundred and seventy-three patients initiating therapy with an efavirenz-based regimen were included (278 white patients and 95 black patients; 293 male). DNA was extracted from whole blood and genotyping for CYP2B6 (516G → T, rs3745274), CAR (540C → T, rs2307424) and PXR (44477T → C, rs1523130; 63396C → T, rs2472677; and 69789A → G, rs763645) was conducted. Binary logistic regression using the backwards method was employed to assess the influence of SNPs and demographics on early discontinuation. Results Of the 373 patients, 131 withdrew from therapy within the first 3 months. Black ethnicity [odds ratio (OR) = 0.27; P = 0.0001], CYP2B6 516TT (OR = 2.81; P = 0.006), CAR rs2307424 CC (OR = 1.92; P = 0.007) and smoking status (OR = 0.45; P = 0.002) were associated with discontinuation within 3 months. Conclusions These data indicate that genetic variability in CYP2B6 and CAR contributes to early treatment discontinuation for efavirenz-based antiretroviral regimens. Further studies are now required to define the clinical utility of these association

German evidence and consensus‐based (S3) guideline: Vaccination recommendations for the prevention of HPV‐associated lesions

Anogenital and oropharyngeal infections with human papilloma viruses (HPV) are common. Clinically manifest disease may significantly impact quality of life; the treatment of HPV-associated lesions is associated with a high rate of recurrence and invasive neoplasms, such as cervical, anal, vulvar, penile, and oropharyngeal cancers, which are characterized by significant morbidity and mortality. Vaccination against HPV is an effective and safe measure for the primary prevention of HPV-associated lesions, but immunization rates are still low in Germany. The present publication is an abridged version of the German evidence and consensus-based guideline "Vaccination recommendations for the prevention of HPV-associated lesions", which is available on the website of the German Association of the Scientific Medical Societies (AWMF). On the basis of a systematic review with meta-analyses, a representative panel developed and agreed upon recommendations for the vaccination of different populations against HPV. In addition, consensus-based recommendations were developed for specific issues relevant to everyday practice. Based on current evidence and a representative expert consensus, these recommendations are intended to provide guidance in a field in which there is often uncertainty and in which both patients and health care providers are sometimes confronted with controversial and emotionally charged points of view

Improving emotion recognition in anorexia nervosa: An experimental proof-of-concept study

Objective: Previous research has found increasing evidence for difficulties in emotion recognition ability (ERA) and social cognition in anorexia nervosa (AN), and recent models consider these factors to contribute to the development and maintenance of the disorder. However, there is a lack of experimental studies testing this hypothesis. Therefore, the present proof‐of‐concept study examined whether ERA can be improved by a single session of a computerized training in AN, and whether this has short‐term effects on eating disorder symptoms. Method: Forty inpatients (22.20 ± 7.15 years) with AN were randomly assigned to receive a single session of computerized training of ERA (TERA) or a sham training (training the recognition of different types of clouds). ERA, self‐reported eating disorder symptoms, and body mass index (BMI) were assessed within 3 days before and after training. Results: After training, both groups showed improved ERA, reduced self‐reported eating disorder symptoms, and an increased BMI. As compared to patients in the control group, patients who received TERA showed greater improvements in ERA and self‐reported eating disorder symptoms. Discussion: ERA can be effectively trained in patients with AN. Moreover, short‐term improvements in self‐reported eating disorder symptoms provide tentative support for the hypothesis that difficulties in ERA contribute to the maintenance of AN, and that specific trainings of ERA hold promise as an additional component in AN treatment. Future studies are needed to replicate these findings in larger samples, and to investigate long‐term effects and transfer into real‐world settings

A hydroxylamine probe for profiling S-acylated fatty acids on proteins

Reversible S-palmitoylation is a key regulatory mechanism of protein function and localization. There is increasing evidence that S-acylation is not restricted to palmitate but it includes shorter, longer, and unsaturated fatty acids. However, the diversity of this protein modification has not been fully explored. Herein, we report a chemical probe that combined with MS-based analysis allows the rapid detection and quantification of fatty acids linked to proteins. We have used this approach to profile the S-acylome and to show that the oncogene N-Ras is heterogeneously acylated with palmitate and palmitoleate. Studies on protein distribution in membrane subdomains with semisynthetic proteins revealed that unsaturated N-Ras presents an increased tendency toward clustering and higher insertion kinetic rate constants.This work was supported by the Max Planck Society (Max Planck Partner Group to G. T.) with partial support from the Ministerio de Economia and Competitividad (grant CTQ2013-44334-P). We acknowledge support of the publication fee by the CSIC Open Access Publication Support Initiative through its Unit of Information Resources for Research (URICI).Peer reviewe

Synthesis and characterization of synthetic polymer colloids colloidally stabilized by cationized starch oligomers

A method is developed for anchoring enzymatically degraded cationized starch as electrosteric stabilizers onto synthetic latices, using cerium(IV) to create free-radical grafting sites on the starch. Direct anchoring of debranched starch onto a poly (methyl methacrylate) seed latex yields a latex stabilized by well-defined oligosaccharides. Using a-amylase to randomly cleave starch to form (1 -> 4)-alpha-glucans, and a comonomer, N-isopropyl acrylamide (NIPAM), whose corresponding polymer exhibits a lower critical solution temperature (LCST), creates a means to synthesize block (or graft) oligomers of oligosaccharide and synthetic polymer, which are water soluble at room temperature. Above 30 degrees C, they become amphiphilic and form self-emulsifying nanoparticles (sometimes termed "frozen micelles") from which a synthetic latex is grown after addition of methyl methacrylate, the collapsed NIPAM-containing entities functioning as a type of in situ seed. This synthesis of stable synthetic latex particles is shown to have a high grafting efficiency. The starch fragments were characterized by (1)H solution-state NMR before grafting, and (13)C solid-state cross-polarization magic-angle spinning (CP-MAS) NMR was used to characterize the starch oligomers actually grafted on the final latex. (C) 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 1836-1852, 200

Combining Model-based Analysis and Testing

International audienceSafety standards like ISO 26262 and DO 178B/C require demonstrating the functional safety of the software. First, this implies demonstrating the functional correctness with respect to the specified requirements. Second, the absence of critical non-functional hazards has to be shown: violation of timing and storage space constraints, and runtimeerrors like division by zero or invalid pointer accesses. State-of-the-art solutions use model- based testing for showing functional program properties and abstract interpretation-based static analysis to prove the absence of non-functional program errors, but fail to integrate them. In this article we present an integrated approach for model- based testing and analysis addressing both aspects seamlessly. Model-level information like environment specifications and execution models are taken into account automatically. This reduces setup effort and improves analysis precision. Tests and analyses can be launched automatically and produce aggregated result reports. The integrated approach allows safety requirements of contemporary safety standards to be comprehensively addressed and the verification effort to be significantly reduced