Synthesis and Analytics of Rigidified Peptide Architectures: Neuropeptide Y Dipeptide Scan, Ring-Chain-Equilibria of Iminopeptides, Thiazole Amino Acids for Thiopeptide Antibiotics

The architectures (three-dimensional shapes) of peptides determine their respective biological functions. Therefore, the correct alignment of functionalities in a structure by constraining the flexibility is a key process in evolution as well as in medicinal chemistry in order to increase binding affinity and selectivity. The rigidification of a peptide chain can have local effects (incorporation of the amino acid proline) or it can globally restrain flexibility (macrocyclization). Furthermore, the combination of both strategies has given rise to complex antibiotics with highly optimized modes of action. This work approaches these principles in three topics and for different purposes. The first chapter presents a novel scanning strategy which utilizes synthetic local rigidifications for the evaluation of Neuropeptide Y structure and receptor binding patterns. The fundamental process of macrocyclization is topic of the second chapter. For iminopeptides, ring-chain equilibria can be established and controlled, thereby allowing for the thermodynamic analysis of the ring closure. This leads to the identification of structural determinants that influence the inclination of a peptide chain to close the ring. In the third chapter, a sugar-based synthetic pathway leading to highly functionalized thiazole dipeptides is described. This strategy led to the synthesis of core motivs of complex thiopeptide antibiotics, as well as to diastereomers and homologs thereof

A European research agenda for somatic symptom disorders, bodily distress disorders, and functional disorders: Results of an estimate-talk-estimate delphi expert study

Background: Somatic Symptom Disorders (SSD), Bodily Distress Disorders (BDD) and functional disorders (FD) are associated with high medical and societal costs and pose a substantial challenge to the population and health policy of Europe. To meet this challenge, a specific research agenda is needed as one of the cornerstones of sustainable mental health research and health policy for SSD, BDD, and FD in Europe. Aim: To identify the main challenges and research priorities concerning SSD, BDD, and FD from a European perspective. Methods: Delphi study conducted from July 2016 until October 2017 in 3 rounds with 3 workshop meetings and 3 online surveys, involving 75 experts and 21 European countries. EURONET-SOMA and the European Association of Psychosomatic Medicine (EAPM) hosted the meetings. Results: Eight research priorities were identified: (1) Assessment of diagnostic profiles relevant to course and treatment outcome. (2) Development and evaluation of new, effective interventions. (3) Validation studies on questionnaires or semi-structured interviews that assess chronic medical conditions in this context. (4) Research into patients preferences for diagnosis and treatment. (5) Development of new methodologic designs to identify and explore mediators and moderators of clinical course and treatment outcomes (6). Translational research exploring how psychological and somatic symptoms develop from somatic conditions and biological and behavioral pathogenic factors. (7) Development of new, effective interventions to personalize treatment. (8) Implementation studies of treatment interventions in different settings, such as primary care, occupational care, general hospital and specialty mental health settings. The general public and policymakers will benefit from the development of new, effective, personalized interventions for SSD, BDD, and FD, that will be enhanced by translational research, as well as from the outcomes of research into patient involvement, GP-patient communication, consultation-liaison models and implementation. Conclusion: Funding for this research agenda, targeting these challenges in coordinated research networks such as EURONET-SOMA and EAPM, and systematically allocating resources by policymakers to this critical area in mental and physical well-being is urgently needed to improve efficacy and impact for diagnosis and treatment of SSD, BDD, and FD across Europe

Synthesis and Analytics of Rigidified Peptide Architectures: Neuropeptide Y Dipeptide Scan, Ring-Chain-Equilibria of Iminopeptides, Thiazole Amino Acids for Thiopeptide Antibiotics

The architectures (three-dimensional shapes) of peptides determine their respective biological functions. Therefore, the correct alignment of functionalities in a structure by constraining the flexibility is a key process in evolution as well as in medicinal chemistry in order to increase binding affinity and selectivity. The rigidification of a peptide chain can have local effects (incorporation of the amino acid proline) or it can globally restrain flexibility (macrocyclization). Furthermore, the combination of both strategies has given rise to complex antibiotics with highly optimized modes of action. This work approaches these principles in three topics and for different purposes. The first chapter presents a novel scanning strategy which utilizes synthetic local rigidifications for the evaluation of Neuropeptide Y structure and receptor binding patterns. The fundamental process of macrocyclization is topic of the second chapter. For iminopeptides, ring-chain equilibria can be established and controlled, thereby allowing for the thermodynamic analysis of the ring closure. This leads to the identification of structural determinants that influence the inclination of a peptide chain to close the ring. In the third chapter, a sugar-based synthetic pathway leading to highly functionalized thiazole dipeptides is described. This strategy led to the synthesis of core motivs of complex thiopeptide antibiotics, as well as to diastereomers and homologs thereof

Stabilizing Impact of N‑Glycosylation on the WW Domain Depends Strongly on the Asn-GlcNAc Linkage

N-glycans play important roles in many cellular processes and can increase protein conformational stability in specific structural contexts. Glycosylation (with a single GlcNAc) of the reverse turn sequence Phe-Yyy-Asn-Xxx-Thr at Asn stabilizes the Pin 1 WW domain by −0.85 ± 0.12 kcal mol^–1. Alternative methods exist for attaching carbohydrates to proteins; some occur naturally (e.g., the O-linkage), whereas others use chemoselective ligation reactions to mimic the natural N- or O-linkages. Here, we assess the energetic consequences of replacing the Asn linkage in the glycosylated WW domain with a Gln linkage, with two natural O-linkages, with two unnatural triazole linkages, and with an unnatural α-mercaptoacetamide linkage. Of these alternatives, only glycosylation of the triazole linkages stabilizes WW, and by a smaller amount than N-glycosylation, highlighting the need for caution when using triazole- or α-mercaptoacetamide-linked carbohydrates to mimic native N-glycans, especially where the impact of glycosylation on protein conformational stability is important

Increasing effort without noticing : A randomized controlled pilot study about the ergogenic placebo effect in endurance athletes and the role of supplement salience

PURPOSE:Previous research shows that endurance performance can be enhanced by placebo ergogenic aids. This study investigates the ergogenic placebo response, which we define as an increase in objective and physiological effort without an increase in subjective effort, in competitive cyclists. The primary objective of this study is to explore the role of supplement salience in the ergogenic placebo response, while the secondary aim is to assess whether believing to have taken an inactive placebo supplement attenuates the desired ergogenic effect. METHODS:We employed a double-blind placebo-controlled study design and compared a high salience (pudding) to a low salience (capsules) ergogenic placebo supplement and to a no treatment control group. Thirty-four male athletes (30.0 ± 5.7 years) performed two self-regulated time trials on an isokinetic cycling ergometer, one without intervention serving as a baseline and one with intervention according to group assignment. At both time trials, power output (objective effort), blood lactate (physiological effort) and the rating of perceived exertion (subjective effort) were measured. RESULTS:Receiving a high salience supplement can increase physiological and objective effort without a proportional rise in subjective effort, suggesting a decoupling of perceived exertion and endurance performance. Low salience and control group both showed no such ergogenic placebo response. Athletes' belief concerning the true nature of the ergogenic aid (inactive placebo vs. ergogenic supplement) did not influence the ergogenic placebo response. CONCLUSION:High salience placebo ergogenic aids can elicit enhanced performance without the athlete noticing (exertion), and deception of athletes seems unnecessary as even believing to have received an inactive placebo supplement maintains the ergogenic placebo response

The neurobiology of placebo effects in sports: EEG frontal alpha asymmetry increases in response to a placebo ergogenic aid

Abstract The performance enhancing (ergogenic) placebo effect is elicited by an inert treatment and caused by positive affective appraisal of effort perception. Frontal alpha asymmetry (FAA) is a neurobiological correlate of positive affect. This study investigates, whether receiving an ergogenic placebo increases FAA and whether scores on the behavioral inhibition and activation system (BIS/BAS) scales affect this increase in FAA. Nineteen competitive male cyclists (37.26 ± 9.82 years) performed two maximum effort time trials. The first served as baseline for the second intervention time trial, where athletes received a placebo ergogenic aid or no treatment. We recorded FAA using EEG throughout all time trials and assessed BIS/BAS by questionnaire. There was a significant difference in change from baseline to intervention time trial in FAA during cycling in response to the placebo ergogenic aid compared to the control group. BIS, the BAS subscale Drive and the BAS-BIS difference score significantly co-varied with the change in FAA from baseline to intervention time trial in response to the placebo ergogenic aid. Administering a placebo ergogenic aid significantly influenced FAA during maximum effort cycling. Those athletes with a more pronounced goal seeking persistence and an overall dominance of the BAS over the BIS showed a significantly greater increase in FAA in response to a placebo ergogenic aid. A more pronounced BIS, however, seems to antagonize the increase in FAA associated with the ergogenic placebo response

Sample characteristics.

<p>Descriptive statistics are presented as mean value ± standard deviation.</p

Overview of experimental procedure.

<p>OE, objective effort; PE, physiological effort; SE, subjective effort.</p

Change in objective effort (OE) from TT_b to TT_i given in percent change.

<p>* p < .05, *** p < .001.</p

Interaction of time (TT_b vs. TT_i) and group (<i>HS</i>, <i>LS</i>, <i>C</i>) on physiological effort presented as mean blood lactate (mmol/l) over 45 minutes above post warm up blood lactate.

<p>* p < .05.</p