Dark loops: contagion effects, consistency and chemosocial matrices in psychedelic-assisted therapy trials

What happens when an emerging programme of medical research overlaps with a surging social movement? In this article we draw on the anthropological term ‘chemosociality’ to describe forms of sociality born of shared chemical exposure. Psychedelic administration in the context of recent clinical trials appears to have been particularly chemosocial in nature. We argue that one consequence is that psychedelic-assisted therapy (PAT) clinical research trials tend to breach key assumptions underlying the logic of causal inference used to establish efficacy. We propose the concept of dark loops to describe forms of sociality variously emerging from, and impacting participant experiences in, PAT trials. These dark loops are not recorded, let alone incorporated into the causal pathways in the interpretation of psychedelic trial data to date. We end with three positions which researchers might adopt in response to these issues: chemosocial minimisation where research is designed to attenuate or eliminate the effects of dark loops in trials; chemosocial description where dark loops (and their impacts) are openly and candidly documented and chemosocial valorisation where dark loops are hypothesised to contribute to trial outcomes and actively drawn upon for positive effect. Our goal is to fold in an appreciation of how the increasingly-discussed hype surrounding psychedelic research and therapeutics continues to shape the phenomena under study in complex ways, even as trials become larger and more rigorous in their design

U. S. Grant Let Us Have Peace Plate

The amber-hued plate is a commemorative item released shortly after the death of Ulysses S. Grant. It features an embossed image of Grant at its center and is surrounded by text. The plate\u27s outer border features a decorative maple leaf design and is layered with text.https://scholarsjunction.msstate.edu/fvw-artifacts/3001/thumbnail.jp

Physical activity interventions for young people with increased risk of problematic substance use: a systematic review including different intervention formats

Objective: This systematic review investigates physical activity (PA) interventions for (1) reducing substance use and associated outcomes, (2) increasing physical activity, and (3) improving mental health in young people aged 12–25 years at increased risk for problematic substance use. Method: Four databases (PsycINFO, CINAHL, SPORTDiscus, and Medline) and grey literature, including hand searches, were searched (2021–2022). Non-randomized controlled or randomized controlled trials of a) multimodal or unimodal, short or long-term physical activity interventions in young people at increased risk of problematic substance use that b) investigated substance use outcomes were included. PA and mental health outcomes were explored where possible. Results: Sixty-one percent of the studies (k = 17/28) reported a significant improvement in outcomes related to tobacco (e.g., abstinence, cravings, withdrawal symptoms, smoking pattern), alcohol (e.g., quantity, frequency), or other substance use (e.g., frequency, quantity, recent use). Eight studies reported an increase in PA participation; two reported a beneficial effect on depression symptoms. The certainty of the evidence, i.e., the confidence in the reported effect estimates, was downgraded based on the risk of bias assessment. Findings should therefore be interpreted cautiously. Conclusions: A range of physical activity intervention formats and modalities may decrease substance use and associated outcomes and increase physical activity participation among people at risk for problematic substance use. Future research is warranted to better establish efficacy and investigate the effectiveness of implementing physical activity as part of treatment for substance use in young people

Mutant KLF1 in Adult Anemic Nan Mice Leads to Profound Transcriptome Changes and Disordered Erythropoiesis.

Anemic Nan mice carry a mutation (E339D) in the second zinc finger of erythroid transcription factor KLF1. Nan-KLF1 fails to bind a subset of normal KLF1 targets and ectopically binds a large set of genes not normally engaged by KLF1, resulting in a corrupted fetal liver transcriptome. Here, we performed RNAseq using flow cytometric-sorted spleen erythroid precursors from adult Nan and WT littermates rendered anemic by phlebotomy to identify global transcriptome changes specific to the Nan Klf1 mutation as opposed to anemia generally. Mutant Nan-KLF1 leads to extensive and progressive transcriptome corruption in adult spleen erythroid precursors such that stress erythropoiesis is severely compromised. Terminal erythroid differentiation is defective in the bone marrow as well. Principle component analysis reveals two major patterns of differential gene expression predicting that defects in basic cellular processes including translation, cell cycle, and DNA repair could contribute to disordered erythropoiesis and anemia in Nan. Significant erythroid precursor stage specific changes were identified in some of these processes in Nan. Remarkably, however, despite expression changes in large numbers of associated genes, most basic cellular processes were intact in Nan indicating that developing red cells display significant physiological resiliency and establish new homeostatic set points in vivo

Behaviour change techniques in physical activity-focused interventions for young people at risk of problematic substance use: a systematic review and meta-analysis.

Aim This systematic review investigates behaviour change techniques in interventions promoting physical activity for young people aged 12-25 years at heightened risk of problematic substance use, and the effect of these techniques on physical activity participation and substance use outcomes. Methods Four databases (PsycINFO, CINAHL, SPORTDiscus and Medline) were searched between November 2020 and November 2022 for randomized and non-randomized controlled studies according to inclusion criteria. Meta-analyses were calculated using weighted, standardized averages of effect sizes (Hedges' g). Results Twenty-eight studies were included, 14 studies in the meta-analysis (intervention n = 1328; control n = 845). Reported BCTs included behavioural instructions, social comparison and goal setting. There was a significant effect of behaviour change techniques on combined substance use outcomes, such as cravings and consumption, for interventions reporting multiple behaviour change techniques (g = -0.33, p < .001, 95% CI [-0.50,-0.16]) or one single behaviour change technique (g = -1.84, p < .001, 95% CI [-2.89,-0.8]). Limitations include unexplained variance and limited reporting of relevant behaviour change technique data in the included studies. Conclusion The results indicate that using behaviour change techniques in interventions that promote physical activity for young people has an effect on substance use. Further research needs to be completed comparing the impact of the number and type of behaviour change technique, and improved reporting of intervention content is required

A model of impaired Langerhans cell maturation associated with HPV induced epithelial hyperplasia.

Funder: National Health and Medical Research CouncilLangerhans cells (LC) are skin-resident antigen-presenting cells that regulate immune responses to epithelial microorganisms. Human papillomavirus (HPV) infection can promote malignant epithelial transformation. As LCs are considered important for controlling HPV infection, we compared the transcriptome of murine LCs from skin transformed by K14E7 oncoprotein and from healthy skin. We identified transcriptome heterogeneity at the single cell level amongst LCs in normal skin, associated with ontogeny, cell cycle, and maturation. We identified a balanced co-existence of immune-stimulatory and immune-inhibitory LC cell states in normal skin that was significantly disturbed in HPV16 E7-transformed skin. Hyperplastic skin was depleted of immune-stimulatory LCs and enriched for LCs with an immune-inhibitory gene signature, and LC-keratinocyte crosstalk was dysregulated. We identified reduced expression of interleukin (IL)-34, a critical molecule for LC homeostasis. Enrichment of an immune-inhibitory LC gene signature and reduced levels of epithelial IL-34 were also found in human HPV-associated cervical epithelial cancers

EPO does not promote interaction between the erythropoietin and beta-common receptors

A direct interaction between the erythropoietin (EPOR) and the beta-common (βc) receptors to form an Innate Repair Receptor (IRR) is controversial. On one hand, studies have shown a functional link between EPOR and βc receptor in tissue protection while others have shown no involvement of the βc receptor in tissue repair. To date there is no biophysical evidence to confirm a direct association of the two receptors either in vitro or in vivo. We investigated the existence of an interaction between the extracellular regions of EPOR and the βc receptor in silico and in vitro (either in the presence or absence of EPO or EPO-derived peptide ARA290). Although a possible interaction between EPOR and βc was suggested by our computational and genomic studies, our in vitro biophysical analysis demonstrates that the extracellular regions of the two receptors do not specifically associate. We also explored the involvement of the βc receptor gene (Csf2rb) under anaemic stress conditions and found no requirement for the βc receptor in mice. In light of these studies, we conclude that the extracellular regions of the EPOR and the βc receptor do not directly interact and that the IRR is not involved in anaemic stress.Karen S. Cheung Tung Shing, Sophie E. Broughton, Tracy L. Nero, Kevin Gillinder, Melissa D. Ilsley, Hayley Ramshaw, Angel F. Lopez, Michael D. W. Griffin, Michael W. Parker, Andrew C. Perkins, Urmi Dhaga

Neomorphic effects of the neonatal anemia (Nan-Eklf) mutation contribute to deficits throughout development

Transcription factor control of cell-specific downstream targets can be significantly altered when the controlling factor is mutated. We show that the semi-dominant neonatal anemia (Nan) mutation in the EKLF/KLF1 transcription factor leads to ectopic expression of proteins that are not normally expressed in the red blood cell, leading to systemic effects that exacerbate the intrinsic anemia in the adult and alter correct development in the early embryo. Even when expressed as a heterozygote, the Nan-EKLF protein accomplishes this by direct binding and aberrant activation of genes encoding secreted factors that exert a negative effect on erythropoiesis and iron use. Our data form the basis for a novel mechanism of physiological deficiency that is relevant to human dyserythropoietic anemia and likely other disease states

Fibroblast growth factor-1 (FGF-1) promotes adipogenesis by downregulation of carboxypeptidase A4 (CPA4) – a negative regulator of adipogenesis implicated in the modulation of local and systemic insulin sensitivity

Fibroblast growth factor-1 (FGF-1) promotes differentiation of human preadipocytes into mature adipocytes via modulation of a BMP and Activin Membrane-Bound Inhibitor (BAMBI)/Peroxisome proliferator-activated receptor (PPAR?)-dependent network. Here, we combined transcriptomic and functional investigations to identify novel downstream effectors aligned with complementary analyses of gene expression in human adipose tissue to explore relationships with insulin sensitivity. RNA-Seq and qRT-PCR analysis revealed significant down-regulation of carboxypeptidase A4 (CPA4) following FGF-1 treatment or induction of differentiation of human preadipocytes in a BAMBI/PPAR?-independent manner. siRNA-mediated knockdown of CPA4 resulted in enhanced differentiation of human preadipocytes. Furthermore, expression of CPA4 in subcutaneous adipose tissue correlated negatively with indices of local and systemic (liver and muscle) insulin sensitivity. These results identify CPA4 as a negative regulator of adipogenesis that is down-regulated by FGF-1 and a putative deleterious modulator of local and systemic insulin sensitivity. Further investigations are required to define the molecular mechanism(s) involved and potential therapeutic opportunities