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Background: Survey research found poorer baseline immune fitness for self-reported hangover-sensitive drinkers compared to hangover-resistant drinkers. However, up to now a limited number of clinical studies revealed mixed results regarding the relationship between the concentrations of biomarkers of systemic inflammation in blood or saliva with hangover severity, and could not differentiate between hangover-sensitive drinkers and hangover-resistant drinkers. The aim of this study was to assess immune fitness and saliva biomarkers of systemic inflammation at multiple timepoints following an alcohol day and alcohol-free control day., Methods: The study had a semi-naturalistic design. In the evening before the test days, participants were not supervised. They could drink ad libitum drinking on the alcohol test day and refrained from drinking alcohol on the control day. Activities and behaviors on the alcohol and control day were reported the follow morning. On both test days, from 09:30 to 15:30, hourly assessments of immune fitness (single-item scale) and overall hangover severity (single-item scale) were made and saliva samples were collected for biomarker assessments., Results: N = 14 hangover-resistant drinkers and n = 15 hangover-sensitive drinkers participated in the study. The amount of alcohol consumed on the alcohol day did not significantly differ between the hangover-resistant group (mean (SD) of 13.5 (7.9) alcoholic drinks) and the hangover-sensitive group (mean (SD) of 12.4 (4.4) alcoholic drinks). All hangover-sensitive drinkers reported having a hangover following the alcohol day (overall hangover severity score 6.1 (on a 0-10 scale) at 09:30, gradually decreasing to 3.3 at 15:30), whereas the hangover-resistant drinkers reported no hangover. On the control day, immune fitness of the hangover-sensitive group was significantly poorer than the hangover-resistant group. On the alcohol day, both groups showed a significant reduction in immune fitness. The effect was evident throughout the day, but significantly more pronounced in the hangover-sensitive group than the hangover-resistant group. No significant differences between the groups were found at any time point on the two test days for saliva concentrations of Interleukin (IL)-1β, IL-6, IL-8, and tumor necrosis factor (TNF)-α., Conclusions: Whereas hangover-sensitive drinkers reported a hangover following an alcohol day and hangover-resistant drinkers did not, both groups reported significantly reduced immune fitness throughout the day. However, the reduction in immune fitness among hangover-sensitive drinkers was significantly more pronounced in comparison to the hangover-resistant group., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Johan Garssen is a part-time employee of Nutricia Research and received research grants from Nutricia research foundation, Top Institute Pharma, Top Institute Food and Nutrition, GSK, STW, NWO, Friesland Campina, CCC, Raak-Pro, and EU. Over the past 3 years, Joris Verster has acted as a consultant/advisor for Eisai, KNMP, Red Bull, Sen-Jam Pharmaceutical, and Toast! The other authors declare no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The combination of negative mental and physical symptoms which can be experienced after a single episode of alcohol consumption, starting when blood alcohol concentration (BAC) approaches zero, are collectively referred to as the alcohol hangover. Previous research revealed that 10 to 20% of drinkers claim not to experience next-day hangovers. Past studies were usually limited to single timepoint assessments. The aim of the current semi-naturalistic study was to compare the next-day effects of an evening of alcohol consumption of self-reported hangover-resistant drinkers (n = 14) with those of a group of self-reported hangover-sensitive drinkers (n = 15) at hourly timepoint throughout the day (09:30 until 15:30). Assessments of 23 hangover symptoms, mood (Profiles of Mood States-Short Form), and daytime sleepiness (Karolinska Sleepiness Scale) were made hourly after both an alcohol day and an alcohol-free control day. Additional morning assessments were made for mood (State-Trait Anxiety Inventory-Y, Beck's Depression Inventory-II), risk-taking behavior (RT-18), past night sleep (Groningen Sleep Quality Scale), alcohol consumption, and activities during the test days. No significant differences were found regarding the amount of alcohol consumed and the total sleep time of the two groups. The hangover-sensitive group reported having a hangover as well as the presence of a variety of hangover-related symptoms, which were most severe in the morning and then gradually decreased during the day. The most frequently reported and most severe symptoms were sleepiness and fatigue, concentration problems, and headache. In contrast, the hangover-resistant group reported the absence of a hangover and the presence and severity of next-day symptoms did not significantly differ from the control day, except for increased fatigue and reduced vigor. The next-day effects on sleepiness-related complaints and vigor were significantly more pronounced among hangover-sensitive drinkers compared to hangover-resistant drinkers. In conclusion, contrary to hangover-resistant drinkers, hangover-sensitive drinkers report a variety of hangover symptoms that gradually ease during the day, but are still present in the afternoon.

N -Methylated amino acids ( N -MeAAs) are privileged residues of naturally occurring peptides critical to bioactivity. However, de novo discovery from ribosome display is limited by poor incorporation of N -methylated amino acids into the nascent peptide chain attributed to a poor EF-Tu affinity for the N -methyl-aminoacyl-tRNA. By reconfiguring the tRNA's T-stem region to compensate and tune the EF-Tu affinity, we conducted Random nonstandard Peptides Integrated Discovery (RaPID) display of a macrocyclic peptide (MCP) library containing six different N -MeAAs. We have here devised a "pool-and-split" enrichment strategy using the RaPID display and identified N -methylated MCPs against three species of prokaryotic metal-ion-dependent phosphoglycerate mutases. The enriched MCPs reached 57% N -methylation with up to three consecutively incorporated N -MeAAs, rivaling natural products. Potent nanomolar inhibitors ranging in ortholog selectivity, strongly mediated by N -methylation, were identified. Co-crystal structures reveal an architecturally related Ce-2 Ipglycermide active-site metal-ion-coordinating Cys lariat MCP, functionally dependent on two cis N -MeAAs with broadened iPGM species selectivity over the original nematode-selective MCPs. Furthermore, the isolation of a novel metal-ion-independent Staphylococcus aureus iPGM inhibitor utilizing a phosphoglycerate mimetic mechanism illustrates the diversity of possible chemotypes encoded by the N -MeAA MCP library.

Backbone macrocyclic structures are often found in diverse bioactive peptides and contribute to greater conformational rigidity, peptidase resistance, and potential membrane permeability compared to their linear counterparts. Therefore, such peptide scaffolds are an attractive platform for drug-discovery endeavors. Recent advances in synthetic methods for backbone macrocyclic peptides have enabled the discovery of novel peptide drug candidates against diverse targets. Here, we overview recent technical advancements in the synthetic methods including 1) enzymatic synthesis, 2) chemical synthesis, 3) split-intein circular ligation of peptides and proteins (SICLOPPS), and 4) in vitro translation system combined with genetic code reprogramming. We also discuss screening methodologies compatible with those synthetic methodologies, such as one-beads one-compound (OBOC) screening compatible with the synthetic method 2, cell-based assay compatible with 3, limiting-dilution PCR and mRNA display compatible with 4., (Copyright © 2020 Shinbara, Liu, van Neer, Katoh and Suga.)

Introduction: The aim of this study was to investigate the usefulness of ethyl glucuronide (EtG) and ethyl sulfate (EtS) as biomarkers of the hangover state., Methods: Thirty-sixhealthy social drinkers participated in this study, being of naturalistic design. Eighteen participants experience regular hangovers (the hangover group), whereas the other 18 claim to not experience a hangover (the hangover-immune group). On a control day (alcohol-free) day and a post-alcohol day, urine EtG and EtS concentrations were determined and hangover severity assessed., Results: Urinary EtG and EtS concentrations were significantly increased on post-alcohol day compared to the control day (p = .0001). Both EtG and EtS concentrations did not significantly correlate with the overall hangover score, nor with the estimated peak blood alcohol concentrations and number of alcoholic drinks. EtG correlated significantly only with the individual hangover symptom "headache" (p = .033; r = .403). No significant correlations were found with the EtG to EtS ratio. EtG and EtS concentrations significantly correlated with urine ethanol concentrations., Conclusions: Although urine EtG and EtS concentration did not significantly correlate to estimated peak blood alcohol concentrations or the number of alcoholic drinks consumed, a significant correlation was found with urine ethanol concentration. However, urine EtG and EtS concentrations did not significantly correlate with overall hangover severity., (© 2017 The Authors. Human Psychopharmacology: Clinical & Experimental Published by John Wiley & Sons Ltd.)