Positive expectations predict improved mental-health outcomes linked to psychedelic microdosing

Psychedelic microdosing describes the ingestion of near-threshold perceptible doses of classic psychedelic substances. Anecdotal reports and observational studies suggest that microdosing may promote positive mood and well-being, but recent placebo-controlled studies failed to fnd compelling evidence for this. The present study collected web-based mental health and related data using a prospective (before, during and after) design. Individuals planning a weekly microdosing regimen completed surveys at strategic timepoints, spanning a core four-week test period. Eightyone participants completed the primary study endpoint. Results revealed increased self-reported psychological well-being, emotional stability and reductions in state anxiety and depressive symptoms at the four-week primary endpoint, plus increases in psychological resilience, social connectedness, agreeableness, nature relatedness and aspects of psychological fexibility. However, positive expectancy scores at baseline predicted subsequent improvements in well-being, suggestive of a signifcant placebo response. This study highlights a role for positive expectancy in predicting positive outcomes following psychedelic microdosing and cautions against zealous inferences on its putative therapeutic value

Molecular biogeography of Mediterranean and southern African disjunctions as exemplified by pollen beetles of the Meligethes planiusculus species-group and related taxa (Coleoptera: Nitidulidae; Meligethinae)

We investigated the apparent disjunction expressed in two related assemblages of species of the genus Meligethes, i.e. M. fruticola and its allies in the Cape region of South Africa and the M. planiusculus group in the Mediterranean region. We also inferred possible dynamics in the radiation of the Meligethes planiusculus complex within Macaronesia utilizing morphological, molecular and bionomical data, exploring potential historical and palaeoecological scenarios regulated by a molecular clock dating system. We reconstructed phylogenetic relationships of the M. planiusculus complex and of related Mediterranean (M. tristis), tropical (M. scotti) and southern African (M. chevrolati, M. conformis, and M. fruticola) species, using COI mitochondrial gene sequences. Phylogenetic reconstructions support an unambiguous distinction of two major clades grouping European-Mediterranean M. canariensis, M. isoplexidis andM. planiusculus specimens in one clade and the South-African specimens related to M. fruticola in another. Molecular markers suggested that the European-Mediterranean taxon M. tristis is unambiguously more distantly related to the partly sympatric M. canariensis, M. isoplexidis and M. planiusculus, than to the geographically isolated Southern African taxon, M. fruticola. However, morphological data revealed that M. tristis is more closely related to M. planiusculus and its allies while occupying a position internal to the M. planiusculus species group, but external to the M. planiusculus complex. Results of divergence estimation analyses suggest a splitting between ancestors of the European-Mediterranean species of the M. planiusculus complex and that of the African species M. fruticola at ~21-23 MYA. Molecular results also demonstrated that the remaining Afrotropical species are more related to the M. planiusculus and M. fruticola complexes than to M. tristis. This evidence clearly indicates that the Holarctic M. planiusculus group represents a paraphyletic assemblage with heterochronic Afrotropical origin. The estimated times of divergence supports evidence from other researchers of an ‘Arid Corridor’, or of a ‘Central or Eastern High Africa Corridor’, which connected several times in the last twenty MY the European-Mediterranean and eastern/southern African areas, and facilitated species migration northwards and southwards. The dynamics of the Meligethes planiusculus complex radiation in Macaronesia apparently followed a contradictory biogeographical scenario than the sequence of events recently hypothesized for their host-plants (Echium, Boraginaceae)

PRAME Is a Golgi-Targeted Protein That Associates with the Elongin BC Complex and Is Upregulated by Interferon-Gamma and Bacterial PAMPs

Preferentially expressed antigen in melanoma (PRAME) has been described as a cancer-testis antigen and is associated with leukaemias and solid tumours. Here we show that PRAME gene transcription in leukaemic cell lines is rapidly induced by exposure of cells to bacterial PAMPs (pathogen associated molecular patterns) in combination with type 2 interferon (IFNγ). Treatment of HL60 cells with lipopolysaccharide or peptidoglycan in combination with IFNγ resulted in a rapid and transient induction of PRAME transcription, and increased association of PRAME transcripts with polysomes. Moreover, treatment with PAMPs/IFNγ also modulated the subcellular localisation of PRAME proteins in HL60 and U937 cells, resulting in targeting of cytoplasmic PRAME to the Golgi. Affinity purification studies revealed that PRAME associates with Elongin B and Elongin C, components of Cullin E3 ubiquitin ligase complexes. This occurs via direct interaction of PRAME with Elongin C, and PRAME colocalises with Elongins in the Golgi after PAMP/IFNγ treatment. PRAME was also found to co-immunoprecipitate core histones, consistent with its partial localisation to the nucleus, and was found to bind directly to histone H3 in vitro. Thus, PRAME is upregulated by signalling pathways that are activated in response to infection/inflammation, and its product may have dual functions as a histone-binding protein, and in directing ubiquitylation of target proteins for processing in the Golgi

A study of inter-individual variability in the Phase II metabolism of xenobiotics in human skin

YesUnderstanding skin metabolism is key to improve in vitro to in vivo extrapolations used to inform risk assessments of topically applied products. However, published literature is scarce and usually covers a limited and non-representative number of donors. We developed a protocol to handle and store ex vivo skin samples post-surgery and prepare skin S9 fractions to measure the metabolic activity of Phase II enzymes. Preincubation of an excess of cofactors at 37 °C for fifteen minutes in the S9 before introduction of the testing probe, greatly increased the stability of the enzymes. Using this standardised assay, the rates of sulphation (SULT) and glucuronidation (UGT) of 7-hydroxycoumarin, methylation (COMT) of dopamine and N-acetylation (NAT) of procainamide were measured in the ng/mg protein/h (converted to ng/cm2/h) range in eighty-seven individuals. Glutathione conjugation (GST) of 1-chloro-2,4-dinitrobenzene was assessed in a smaller pool of fifty donors; the metabolic rate was much faster and measured over six minutes using a different methodology to express rates in μg/mg protein/min (converted to μg/cm2/min). A comprehensive statistical analysis of these results was carried out, separating donors by age, gender and metabolic rate measured

Resolving the ancestry of Austronesian-speaking populations

There are two very different interpretations of the prehistory of Island Southeast Asia (ISEA), with genetic evidence invoked in support of both. The “out-of-Taiwan” model proposes a major Late Holocene expansion of Neolithic Austronesian speakers from Taiwan. An alternative, proposing that Late Glacial/postglacial sea-level rises triggered largely autochthonous dispersals, accounts for some otherwise enigmatic genetic patterns, but fails to explain the Austronesian language dispersal. Combining mitochondrial DNA (mtDNA), Y-chromosome and genome-wide data, we performed the most comprehensive analysis of the region to date, obtaining highly consistent results across all three systems and allowing us to reconcile the models. We infer a primarily common ancestry for Taiwan/ISEA populations established before the Neolithic, but also detected clear signals of two minor Late Holocene migrations, probably representing Neolithic input from both Mainland Southeast Asia and South China, via Taiwan. This latter may therefore have mediated the Austronesian language dispersal, implying small-scale migration and language shift rather than large-scale expansion

Fossils, fish and tropical forests: prehistoric human adaptations on the island frontiers of Oceania

Oceania is a key region for studying human dispersals, adaptations and interactions with other hominin populations. Although archaeological evidence now reveals occupation of the region by approximately 65–45 000 years ago, its human fossil record, which has the best potential to provide direct insights into ecological adaptations and population relationships, has remained much more elusive. Here, we apply radiocarbon dating and stable isotope approaches to the earliest human remains so far excavated on the islands of Near and Remote Oceania to explore the chronology and diets of the first preserved human individuals to step across these Pacific frontiers. We demonstrate that the oldest human (or indeed hominin) fossil outside of the mainland New Guinea-Aru area dates to approximately 11 800 years ago. Furthermore, although these early sea-faring populations have been associated with a specialized coastal adaptation, we show that Late Pleistocene–Holocene humans living on islands in the Bismarck Archipelago and in Vanuatu display a persistent reliance on interior tropical forest resources. We argue that local tropical habitats, rather than purely coasts or, later, arriving domesticates, should be emphasized in discussions of human diets and cultural practices from the onset of our species' arrival in this part of the world.1. Introduction 2. Background (a) Human colonization of near and remote Oceania (b) Stable isotope analysis and past human adaptations in the tropics 3. Methods (a) Radiocarbon dating (b) Stable isotope analysis (c) Phytolith analysis of dental calculus 4. Results (a) Radiocarbon dating and Bayesian modelling (b) Stable isotope analysis (c) Phytolith analysis of dental calculus 5. Discussion and conclusio

The stone adze and obsidian assemblage from the Talasiu site, Kingdom of Tonga

Typological and geochemical analyses of stone adzes and other stone tools have played a significant role in identifying directionality of colonisation movements in early migratory events in the Western Pacific. In later phases of Polynesian prehistory, stone adzes are important status goods which show substantial spatial and temporal variation. However, there is a debate when standardisation of form and manufacture appeared, whether it can be seen in earliest populations colonising the Pacific or whether it is a later development. We present in this paper a stone adze and obsidian tool assemblage from an early Ancestral Polynesian Society Talasiu site on Tongatapu, Kingdom of Tonga. The site shows a wide variety of adze types; however, if raw material origin is taken into account, emerging standardisation in adze form might be detected. We also show that Tongatapu was strongly connected in a network of interaction to islands to the North, particularly Samoa, suggesting that these islands had permanent populations

An RNA interference-based screen of transcription factor genes identifies pathways necessary for sensory regeneration in the avian inner ear

Sensory hair cells of the inner ear are the mechano-electric transducers of sound and head motion. In mammals, damage to sensory hair cells leads to hearing or balance deficits. Non-mammalian vertebrates such as birds can regenerate hair cells after injury. In a previous study, we characterized transcription factor gene expression during chicken hair cell regeneration. In those studies, a laser micro-beam or ototoxic antibiotics were used to damage the sensory epithelia (SE). The current study focused on 27 genes that were up-regulated in regenerating SE compared to untreated SE in the previous study. Those genes were knocked down by siRNA, to determine their requirement for supporting cell proliferation and to measure resulting changes in the larger network of gene expression. We identified 11 genes necessary for proliferation and also identified novel interactive relationships between many of them. Defined components of the WNT, PAX and AP1 pathways were shown to be required for supporting cell proliferation. These pathways intersect on WNT4, which is also necessary for proliferation. Among the required genes, the CCAAT enhancer binding protein, CEBPG, acts downstream of Jun Kinase and JUND in the AP1 pathway. The WNT co-receptor LRP5 acts downstream of CEBPG as does the transcription factor BTAF1. Both of these genes are also necessary for supporting cell proliferation. This is the first large scale screen of its type and suggests an important intersection between the AP1 pathway, the PAX pathway and WNT signaling in the regulation of supporting cell proliferation during inner ear hair cell regeneration

Landesque capital as an alternative to food storage in Melanesia: Irrigated taro terraces in New Georgia, Solomon Islands

In the Pacific islands, subsistence diversity made possible continuous production of food while welldeveloped exchange networks redistributed these foodstuffs as well as items within the prestige economy. All these were aspects of the ‘storage structures’ that enabled social and nutritional value to be saved, accumulated and later mobilised. In addition, there were investments in the land, landesque capital, which secured future food surpluses and so provided an alternative to food storage, in a region where the staple foods were mostly perishable, yams excepted, and food preservation was difficult. Landesque capital included such long-term improvements to productivity as terraces, mounds, irrigation channels, drainage ditches, soil structural changes and tree planting. These investments provided an effective alternative to food storage and made possible surplus production for exchange purposes. As an example, in the New Georgia group of the western Solomon Islands irrigated terraces, termed ruta, were constructed for growing the root crop taro (Colocasia esculenta). Surplus taro from ruta enabled inland groups to participate in regional exchange networks and so obtain the shell valuables that were produced by coastal groups. In this paper, we reconstruct how this exchange system worked in New Georgia using ethno-archaeological evidence, we chart its prehistoric rise and post-colonial fall, and we outline the factors that constrained its long-term expansion.Our gratitude for support during earlier fieldwork in the New Georgia group has already been expressed in previous publications. The 2014 project was supported by the Smuts Fund and Foreign Travel Fund, University of Cambridge, and by St John’s College, Cambridge.This is the accepted manuscript. The final version is available from Maney at http://dx.doi.org/10.1179/1749631414Y.000000004