Danavorexton (TAK-925): an orexin receptor 2 agonist as a new 'arousal' agent.

A preclinical study in animals has further characterised a new 'arousal' agent. Danavorexton (TAK-925) is an agonist for orexin receptor 2 where it promotes recovery from inhalational and i.v. anaesthesia and opioid sedation. Although danavorexton reverses opioid sedation, it does not compromise analgesia. This could be a useful addition to the postoperative drug cupboard.

On an Aggregated Estimate for Human Mobility Regularities through Movement Trends and Population Density.

This article introduces an analytical framework that interprets individual measures of entropy-based mobility derived from mobile phone data. We explore and analyze two widely recognized entropy metrics: random entropy and uncorrelated Shannon entropy. These metrics are estimated through collective variables of human mobility, including movement trends and population density. By employing a collisional model, we establish statistical relationships between entropy measures and mobility variables. Furthermore, our research addresses three primary objectives: firstly, validating the model; secondly, exploring correlations between aggregated mobility and entropy measures in comparison to five economic indicators; and finally, demonstrating the utility of entropy measures. Specifically, we provide an effective population density estimate that offers a more realistic understanding of social interactions. This estimation takes into account both movement regularities and intensity, utilizing real-time data analysis conducted during the peak period of the COVID-19 pandemic.

Celebrating the first centenary of the British Journal of Anaesthesia: a century of discovery and dissemination.

In 2023, the British Journal of Anaesthesia commemorates its first century of publishing innovations in anaesthesia, pain, critical care and perioperative medicine. In honour of this special anniversary we outline a number of exciting initiatives to occur over the course of the year to commemorate this important milestone, and to highlight the many contributions that the British Journal of Anaesthesia has made to patient care, medical research, and medical education in our first 100 years.

British Journal of Anaesthesia: a leading publication and a registered charity.

The British Journal of Anaesthesia organisation is a registered charity comprised of two interlinked missions: provision of impactful publications and funding the generation and dissemination of research to the wider anaesthetic community. This centenary editorial highlights our charitable activity that covers funding of research infrastructure, meeting support and funding of a diverse portfolio of international research grants.

Genomic analyses inform on migration events during the peopling of Eurasia.

High-coverage whole-genome sequence studies have so far focused on a limited number of geographically restricted populations, or been targeted at specific diseases, such as cancer. Nevertheless, the availability of high-resolution genomic data has led to the development of new methodologies for inferring population history and refuelled the debate on the mutation rate in humans. Here we present the Estonian Biocentre Human Genome Diversity Panel (EGDP), a dataset of 483 high-coverage human genomes from 148 populations worldwide, including 379 new genomes from 125 populations, which we group into diversity and selection sets. We analyse this dataset to refine estimates of continent-wide patterns of heterozygosity, long- and short-distance gene flow, archaic admixture, and changes in effective population size through time as well as for signals of positive or balancing selection. We find a genetic signature in present-day Papuans that suggests that at least 2% of their genome originates from an early and largely extinct expansion of anatomically modern humans (AMHs) out of Africa. Together with evidence from the western Asian fossil record, and admixture between AMHs and Neanderthals predating the main Eurasian expansion, our results contribute to the mounting evidence for the presence of AMHs out of Africa earlier than 75,000 years ago.

Synthesis, Biological Activity and Molecular Docking of Chimeric Peptides Targeting Opioid and NOP Receptors.

Recently, mixed opioid/NOP agonists came to the spotlight for their favorable functional profiles and promising outcomes in clinical trials as novel analgesics. This study reports on two novel chimeric peptides incorporating the fragment Tyr-c[D-Lys-Phe-Phe]Asp-NH2 (RP-170), a cyclic peptide with high affinity for µ and κ opioid receptors (or MOP and KOP, respectively), conjugated with the peptide Ac-RYYRIK-NH2, a known ligand of the nociceptin/orphanin FQ receptor (NOP), yielding RP-170-RYYRIK-NH2 (KW-495) and RP-170-Gly3-RYYRIK-NH2 (KW-496). In vitro, the chimeric KW-496 gained affinity for KOP, hence becoming a dual KOP/MOP agonist, while KW-495 behaved as a mixed MOP/NOP agonist with low nM affinity. Hence, KW-495 was selected for further in vivo experiments. Intrathecal administration of this peptide in mice elicited antinociceptive effects in the hot-plate test; this action was sensitive to both the universal opioid receptor antagonist naloxone and the selective NOP antagonist SB-612111. The rotarod test revealed that KW-495 administration did not alter the mice motor coordination performance. Computational studies have been conducted on the two chimeras to investigate the structural determinants at the basis of the experimental activities, including any role of the Gly3 spacer.

The Sacred Ibis debate: The first test of evolution.

In 1798, Napoleon Bonaparte's army invaded Egypt, returning with many treasures including large numbers of Sacred Ibis mummies. The ancient Egyptians revered the ibis and mummified literally millions of them. The French naturalist Georges Cuvier used these mummies to challenge an emerging idea of the time, namely Jean-Baptiste Lamarck's theory of evolution. Cuvier detected no measurable differences between mummified Sacred Ibis and contemporary specimens of the same species. Consequently, he argued that this was evidence for the "fixity of species." The "Sacred Ibis debate" predates the so-called "Great Debate" between Cuvier and Geoffroy Saint-Hilaire and the publication of Darwin's On the Origin of Species five decades later. Cuvier's views and his study had a profound influence on the scientific and public perception of evolution, setting back the acceptance of evolutionary theory in Europe for decades.

Surgery and opioids: evidence-based expert consensus guidelines on the perioperative use of opioids in the United Kingdom.

There are significant concerns regarding prescription and misuse of prescription opioids in the perioperative period. The Faculty of Pain Medicine at the Royal College of Anaesthetists have produced this evidence-based expert consensus guideline on surgery and opioids along with the Royal College of Surgery, Royal College of Psychiatry, Royal College of Nursing, and the British Pain Society. This expert consensus practice advisory reproduces the Faculty of Pain Medicine guidance. Perioperative stewardship of opioids starts with judicious opioid prescribing in primary and secondary care. Before surgery, it is important to assess risk factors for continued opioid use after surgery and identify those with chronic pain before surgery, some of whom may be taking opioids. A multidisciplinary perioperative care plan that includes a prehabilitation strategy and intraoperative and postoperative care needs to be formulated. This may need the input of a pain specialist. Emphasis is placed on optimum management of pain pre-, intra-, and postoperatively. The use of immediate-release opioids is preferred in the immediate postoperative period. Attention to ensuring a smooth care transition and communication from secondary to primary care for those taking opioids is highlighted. For opioid-naive patients (patients not taking opioids before surgery), no more than 7 days of opioid prescription is recommended. Persistent use of opioid needs a medical evaluation and exclusion of chronic post-surgical pain. The lack of grading of the evidence of each individual recommendation remains a major weakness of this guidance; however, evidence supporting each recommendation has been rigorously reviewed by experts in perioperative pain management.

A phenomenological estimate of the true scale of CoViD-19 from primary data.

Estimation of the prevalence of undocumented SARS-CoV-2 infections is critical for understanding the overall impact of CoViD-19, and for implementing effective public policy intervention strategies. We discuss a simple yet effective approach to estimate the true number of people infected by SARS-CoV-2, using raw epidemiological data reported by official health institutions in the largest EU countries and the USA.

Ex vivo use of cell-permeable succinate prodrug attenuates mitochondrial dysfunction in blood cells obtained from carbon monoxide-poisoned individuals.

The purpose of this study was to evaluate a new pharmacological strategy using a first-generation succinate prodrug, NV118, in peripheral blood mononuclear cells (PBMCs) obtained from subjects with carbon monoxide (CO) poisoning and healthy controls. We obtained human blood cells from subjects with CO poisoning and healthy control subjects. Intact PBMCs from subjects in the CO and Control group were analyzed with high-resolution respirometry measured in pmol O2 per second per 10-6 PBMCs. In addition to obtaining baseline respiration, NV118 (100 µM) was injected, and the same parameters of respiration were obtained for comparison in PBMCs. We measured mitochondrial dynamics with microscopy with the same conditions. We enrolled 37 patients (17 in the CO group and 20 in the Control group for comparison) in the study. PMBCs obtained from subjects in the CO group had overall significantly lower respiration compared with the Control group (P < 0.0001). There was a significant increase in respiration with NV118, specifically with an increase in maximum respiration and respiration from complex II and complex IV (P < 0.0001). The mitochondria in PBMCs demonstrated an overall increase in net movement compared with the Control group. Our results of this study suggest that the therapeutic compound, NV118, increases respiration at complex II and IV as well as restoration of mitochondrial movement in PBMCs obtained from subjects with CO poisoning. Mitochondrial-directed therapy offers a potential future strategy with further exploration in vivo.

Biased versus Partial Agonism in the Search for Safer Opioid Analgesics.

Opioids such as morphine-acting at the mu opioid receptor-are the mainstay for treatment of moderate to severe pain and have good efficacy in these indications. However, these drugs produce a plethora of unwanted adverse effects including respiratory depression, constipation, immune suppression and with prolonged treatment, tolerance, dependence and abuse liability. Studies in ß-arrestin 2 gene knockout (ßarr2(-/-)) animals indicate that morphine analgesia is potentiated while side effects are reduced, suggesting that drugs biased away from arrestin may manifest with a reduced-side-effect profile. However, there is controversy in this area with improvement of morphine-induced constipation and reduced respiratory effects in ßarr2(-/-) mice. Moreover, studies performed with mice genetically engineered with G-protein-biased mu receptors suggested increased sensitivity of these animals to both analgesic actions and side effects of opioid drugs. Several new molecules have been identified as mu receptor G-protein-biased agonists, including oliceridine (TRV130), PZM21 and SR-17018. These compounds have provided preclinical data with apparent support for bias toward G proteins and the genetic premise of effective and safer analgesics. There are clinical data for oliceridine that have been very recently approved for short term intravenous use in hospitals and other controlled settings. While these data are compelling and provide a potential new pathway-based target for drug discovery, a simpler explanation for the behavior of these biased agonists revolves around differences in intrinsic activity. A highly detailed study comparing oliceridine, PZM21 and SR-17018 (among others) in a range of assays showed that these molecules behave as partial agonists. Moreover, there was a correlation between their therapeutic indices and their efficacies, but not their bias factors. If there is amplification of G-protein, but not arrestin pathways, then agonists with reduced efficacy would show high levels of activity at G-protein and low or absent activity at arrestin; offering analgesia with reduced side effects or 'apparent bias'. Overall, the current data suggests-and we support-caution in ascribing biased agonism to reduced-side-effect profiles for mu-agonist analgesics.

Pharmacological Characterization of µ-Opioid Receptor Agonists with Biased G Protein or ß-Arrestin Signaling, and Computational Study of Conformational Changes during Receptor Activation.

In recent years, G protein vs. ß-arrestin biased agonism at opioid receptors has been proposed as an opportunity to produce antinociception with reduced adverse effects. However, at present this approach is highly debated, a reason why more information about biased ligands is required. While the practical relevance of bias in the case of µ-opioid receptors (MOP) still needs to be validated, it remains important to understand the basis of this bias of MOP (and other GPCRs). Recently, we reported two cyclopeptides with high affinity for MOP, the G protein biased Dmt-c[d-Lys-Phe-pCF3-Phe-Asp]NH2 (F-81), and the ß-arrestin 2 biased Dmt-c[d-Lys-Phe-Asp]NH2 (C-33), as determined by calcium mobilization assay and bioluminescence resonance energy transfer-based assay. The biased character of F-81 and C-33 has been further analyzed in the [35S]GTPγS binding assay in human MOP-expressing cells, and the PathHunter enzyme complementation assay, used to measure ß-arrestin 2 recruitment. To investigate the structural features of peptide-MOP complexes, we performed conformational analysis by NMR spectroscopy, molecular docking, and molecular dynamics simulation. These studies predicted that the two ligands form alternative complexes with MOP, engaging specific ligand-receptor contacts. This would induce different displays of the cytosolic side of the seven-helices bundle, in particular by stabilizing different angulations of helix 6, that could favor intracellular coupling to either G protein or ß-arrestin.

DNA barcoding a unique avifauna: an important tool for evolution, systematics and conservation.

BACKGROUND: DNA barcoding utilises a standardised region of the cytochrome c oxidase I (COI) gene to identify specimens to the species level. It has proven to be an effective tool for identification of avian samples. The unique island avifauna of New Zealand is taxonomically and evolutionarily distinct. We analysed COI sequence data in order to determine if DNA barcoding could accurately identify New Zealand birds. RESULTS: We sequenced 928 specimens from 180 species. Additional Genbank sequences expanded the dataset to 1416 sequences from 211 of the estimated 236 New Zealand species. Furthermore, to improve the assessment of genetic variation in non-endemic species, and to assess the overall accuracy of our approach, sequences from 404 specimens collected outside of New Zealand were also included in our analyses. Of the 191 species represented by multiple sequences, 88.5% could be successfully identified by their DNA barcodes. This is likely a conservative estimate of the power of DNA barcoding in New Zealand, given our extensive geographic sampling. The majority of the 13 groups that could not be distinguished contain recently diverged taxa, indicating incomplete lineage sorting and in some cases hybridisation. In contrast, 16 species showed evidence of distinct intra-species lineages, some of these corresponding to recognised subspecies. For species identification purposes a character-based method was more successful than distance and phylogenetic tree-based methods. CONCLUSIONS: DNA barcodes accurately identify most New Zealand bird species. However, low levels of COI sequence divergence in some recently diverged taxa limit the identification power of DNA barcoding. A small number of currently recognised species would benefit from further systematic investigations. The reference database and analysis presented will provide valuable insights into the evolution, systematics and conservation of New Zealand birds.

Disentangling Immediate Adaptive Introgression from Selection on Standing Introgressed Variation in Humans.

Recent studies have reported evidence suggesting that portions of contemporary human genomes introgressed from archaic hominin populations went to high frequencies due to positive selection. However, no study to date has specifically addressed the postintrogression population dynamics of these putative cases of adaptive introgression. Here, for the first time, we specifically define cases of immediate adaptive introgression (iAI) in which archaic haplotypes rose to high frequencies in humans as a result of a selective sweep that occurred shortly after the introgression event. We define these cases as distinct from instances of selection on standing introgressed variation (SI), in which an introgressed haplotype initially segregated neutrally and subsequently underwent positive selection. Using a geographically diverse data set, we report novel cases of selection on introgressed variation in living humans and shortlist among these cases those whose selective sweeps are more consistent with having been the product of iAI rather than SI. Many of these novel inferred iAI haplotypes have potential biological relevance, including three that contain immune-related genes in West Siberians, South Asians, and West Eurasians. Overall, our results suggest that iAI may not represent the full picture of positive selection on archaically introgressed haplotypes in humans and that more work needs to be done to analyze the role of SI in the archaic introgression landscape of living humans.

Hot topics in opioid pharmacology: mixed and biased opioids.

Analgesic design and evaluation have been driven by the desire to create high-affinity high-selectivity mu (µ)-opioid peptide (MOP) receptor agonists. Such ligands are the mainstay of current clinical practice, and include morphine and fentanyl. Advances in this sphere have come from designing pharmacokinetic advantage, as in rapid metabolism for remifentanil. These produce analgesia, but also the adverse-effect profile that currently defines this drug class: ventilatory depression, tolerance, and abuse liability. The MOP receptor is part of a family, and there are significant functional interactions between other members of the family (delta [δ]-opioid peptide [DOP], kappa [κ]-opioid peptide [KOP], and nociceptin/orphanin FQ receptor [NOP]). Experimentally, MOP agonism and DOP antagonism produce anti-nociception (animals) with no tolerance, and low doses of MOP and NOP ligands synergise to antinociceptive advantage. In this latter context, the lack of effect of NOP agonists on ventilation is an additional advantage. Recent development has been to move towards low-selectivity multifunctional 'mixed ligands', such as cebranopadol, or ligand mixtures, such as Targinact®. Moreover, the observation that ß-arrestin coupling underlies the side-effect profile for MOP ligands (from knockout animal studies) led to the discovery of biased (to G-protein and away from ß-arrestin intracellular signalling) MOP ligands, such as oliceridine. There is sufficient excitement in the opioid field to suggest that opioid analgesics without significant side-effects may be on the horizon, and the 'opioid Holy Grail' might be in reach.

N/OFQ-NOP System in Peripheral and Central Immunomodulation.

Classical opioids (µ: mu, MOP; δ: delta, DOP and κ: kappa, KOP) variably affect immune function; they are immune depressants and there is good clinical evidence in the periphery. In addition, there is evidence for a central role in the control of a number of neuropathologies, e.g., neuropathic pain. Nociceptin/Orphanin FQ (N/OFQ) is the endogenous ligand for the N/OFQ peptide receptor, NOP; peripheral and central activation can modulate immune function. In the periphery, NOP activation generally depresses immune function, but unlike classical opioids this is in part driven by NOP located on circulating immune cells. Peripheral activation has important implications in pathologies like asthma and sepsis. NOP is expressed on central neurones and glia where activation can modulate glial function. Microglia, as resident central 'macrophages', increase/infiltrate in pain and following trauma; these changes can be reduced by N/OFQ. Moreover, the interaction with other glial cell types such as the ubiquitous astrocytes and their known cross talk with microglia open a wealth of possibilities for central immunomodulation. At the whole animal level, clinical ligands with wide central and peripheral distribution have the potential to modulate immune function, and defining the precise nature of that interaction is important in mitigating or even harnessing the adverse effect profile of these important drugs.

Ancient mtDNA sequences from the First Australians revisited.

The publication in 2001 by Adcock et al. [Adcock GJ, et al. (2001) Proc Natl Acad Sci USA 98(2):537-542] in PNAS reported the recovery of short mtDNA sequences from ancient Australians, including the 42,000-y-old Mungo Man [Willandra Lakes Hominid (WLH3)]. This landmark study in human ancient DNA suggested that an early modern human mitochondrial lineage emerged in Asia and that the theory of modern human origins could no longer be considered solely through the lens of the "Out of Africa" model. To evaluate these claims, we used second generation DNA sequencing and capture methods as well as PCR-based and single-primer extension (SPEX) approaches to reexamine the same four Willandra Lakes and Kow Swamp 8 (KS8) remains studied in the work by Adcock et al. Two of the remains sampled contained no identifiable human DNA (WLH15 and WLH55), whereas the Mungo Man (WLH3) sample contained no Aboriginal Australian DNA. KS8 reveals human mitochondrial sequences that differ from the previously inferred sequence. Instead, we recover a total of five modern European contaminants from Mungo Man (WLH3). We show that the remaining sample (WLH4) contains ∼1.4% human DNA, from which we assembled two complete mitochondrial genomes. One of these was a previously unidentified Aboriginal Australian haplotype belonging to haplogroup S2 that we sequenced to a high coverage. The other was a contaminating modern European mitochondrial haplotype. Although none of the sequences that we recovered matched those reported by Adcock et al., except a contaminant, these findings show the feasibility of obtaining important information from ancient Aboriginal Australian remains.

Quantifying Interactions of Nucleobase Atoms with Model Compounds for the Peptide Backbone and Glutamine and Asparagine Side Chains in Water.

Alkylureas display hydrocarbon and amide groups, the primary functional groups of proteins. To obtain the thermodynamic information that is needed to analyze interactions of amides and proteins with nucleobases and nucleic acids, we quantify preferential interactions of alkylureas with nucleobases differing in the amount and composition of water-accessible surface area (ASA) by solubility assays. Using an established additive ASA-based analysis, we interpret these thermodynamic results to determine interactions of each alkylurea with five types of nucleobase unified atoms (carbonyl sp2O, amino sp3N, ring sp2N, methyl sp3C, and ring sp2C). All alkylureas interact favorably with nucleobase sp2C and sp3C atoms; these interactions become more favorable with an increasing level of alkylation of urea. Interactions with nucleobase sp2O are most favorable for urea, less favorable for methylurea and ethylurea, and unfavorable for dialkylated ureas. Contributions to overall alkylurea-nucleobase interactions from interactions with each nucleobase atom type are proportional to the ASA of that atom type with proportionality constant (interaction strength) α, as observed previously for urea. Trends in α-values for interactions of alkylureas with nucleobase atom types parallel those for corresponding amide compound atom types, offset because nucleobase α-values are more favorable. Comparisons between ethylated and methylated ureas show interactions of amide compound sp3C with nucleobase sp2C, sp3C, sp2N, and sp3N atoms are favorable while amide sp3C-nucleobase sp2O interactions are unfavorable. Strongly favorable interactions of urea with nucleobase sp2O but weakly favorable interactions with nucleobase sp3N indicate that amide sp2N-nucleobase sp2O and nucleobase sp3N-amide sp2O hydrogen bonding (NH···O═C) interactions are favorable while amide sp2N-nucleobase sp3N interactions are unfavorable. These favorable amide-nucleobase hydrogen bonding interactions are prevalent in specific protein-nucleotide complexes.

A recent bottleneck of Y chromosome diversity coincides with a global change in culture.

It is commonly thought that human genetic diversity in non-African populations was shaped primarily by an out-of-Africa dispersal 50-100 thousand yr ago (kya). Here, we present a study of 456 geographically diverse high-coverage Y chromosome sequences, including 299 newly reported samples. Applying ancient DNA calibration, we date the Y-chromosomal most recent common ancestor (MRCA) in Africa at 254 (95% CI 192-307) kya and detect a cluster of major non-African founder haplogroups in a narrow time interval at 47-52 kya, consistent with a rapid initial colonization model of Eurasia and Oceania after the out-of-Africa bottleneck. In contrast to demographic reconstructions based on mtDNA, we infer a second strong bottleneck in Y-chromosome lineages dating to the last 10 ky. We hypothesize that this bottleneck is caused by cultural changes affecting variance of reproductive success among males.