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Magic mushrooms are fungi that produce psilocybin, an entheogen with long-term cultural use and a breakthrough compound for treatment of mental health disorders. Fungal populations separated by geography are candidates for allopatric speciation, yet species connectivity typically persists because there is minimal divergence at functional parts of mating compatibility genes. We studied whether connectivity is maintained across populations of a widespread species complex of magic mushrooms that has infiltrated the Northern Hemisphere from a hypothesised centre of origin in Australasia. We analysed 89 genomes of magic mushrooms to examine erosion of species connectivity in disparate populations with support from gene flow, kinship, structure, allelic diversity, and mating compatibility. We used comparative genomics and synteny to test whether the genes that produce psilocybin are under selection in natural populations of magic mushrooms. Despite phenotypic plasticity and intercontinental distribution, sexual compatibility is maintained across geographically isolated populations of magic mushrooms. Psilocybin loci have high allelic diversity and evidence of balancing selection. Australasia is the centre of origin of wood-degrading magic mushrooms and geographically separated populations are fully sexually compatible, despite minimal gene flow since differentiation from a shared ancestor. Movement of woodchips, mulch, or plants has most likely facilitated invasion of these mushrooms in the Northern Hemisphere. [ABSTRACT FROM AUTHOR]

This study tested the hypothesis that altered colonic blood flow may contribute to tissue damage during the development of colitis in the rabbit. This was achieved by using radioactive microspheres to measure colonic blood flow at various times after colitis induction with trinitrobenzene sulfonic acid. Significant colonic damage occurred 6 hours post colitis induction and persisted throughout the 5 day study. Blood flow to the muscularis propria and mucosa/muscularis mucosae compartments increased significantly from 5 minutes until one hour post induction. At 6 and 12 hours post induction colonic blood flow returned to control levels before increasing again from 24 to 96 hours. This second increase in flow was, however, predominantly in the mucosa/muscularis mucosae compartment. Blood flow in the stomach and non-gastrointestinal tissues did not change significantly at any time. These data demonstrate that increased colonic blood flow may be disrupted in the early stages of colitis and that this coincides with the onset of significant damage. It is concluded that maintenance of elevated colonic blood flow throughout the development of colitis may help to ameliorate subsequent tissue injury. [ABSTRACT FROM AUTHOR]

Introduction: Alcohol withdrawal is typically managed using benzodiazepines. However, modulation of both γ-aminobutyric acid-A and N-methyl-d-aspartate-receptors through ethanol provision may provide an alternative management strategy. This systematic review critically analyses the evidence surrounding the use of oral or intravenous ethanol for the management of alcohol withdrawal syndrome., Methods: Systematic searches of ProQuest - American Psychological Association, PsycInfo, MEDLINE and PubMed Central, Web of Science and Embase were performed (Prospero registration number: CRD42023425224). Search criteria were: Population = Patients receiving pharmacological interventions to treat or prevent alcohol withdrawal in a healthcare setting. Intervention = intravenous or enteral ethanol. Comparator = standard care, benzodiazepines, carbamazepine, adjunct medications including sedatives, or no comparator. Outcomes = complication rates, symptom scores, length of stay in healthcare settings. Exclusions were: preclinical studies, participants less than 18 years old, non-peer reviewed literature, poor study design or poor data quality. Study quality was assessed using an adapted National Institute for Health and Care Research quality tool. A narrative data synthesis approach was adopted., Results: Eight thousand two hundred and four studies were retrieved. Ten were included in the final analysis. Overall study quality was poor. Seven studies reported treatment outcomes that were comparable to a control arm or in which ethanol conferred no detrimental effect. Three studies reported positive outcomes, and one study reported worse outcomes following ethanol administration., Discussion: The review identified heterogeneity in study design and limited reporting surrounding patient demographics, patient alcohol use history and the practicalities of ethanol administration. As such, implementation of ethanol prescribing for the management of alcohol withdrawal is currently limited due to the quality and translatability of existing data surrounding its use., Conclusions: Further studies are required with more transparent and complete outcome reporting and practical implementation recommendations in order to facilitate the translation of ethanol prescribing for the management of alcohol withdrawal syndrome.

Introduction: Prescribing of ethanol may be an alternative to benzodiazepines for managing alcohol withdrawal syndrome. We present our experience of oral ethanol prescribing within an acute United Kingdom National Health Service setting., Methods: A retrospective review of patients presenting with alcohol withdrawal who were managed with oral ethanol or benzodiazepines was performed from data collected across two acute care settings. Ethanol prescribing inclusion: high risk of delirium tremens, or a history of harmful alcohol consumption (typically ≥30 units/day; in which 1 unit = 8 grams of alcohol; one standard United States drink = 14 grams of alcohol) or known to have a history of severe alcohol withdrawal, alcohol-related seizures or delirium tremens. Inverse propensity score weighting was used to partially account for variance between the two patient populations., Results: Fifty (82 per cent male; average age 50.9 years) and 93 (84 per cent male; average age 46.5 years) patients in receipt of benzodiazepines or ethanol, respectively, were included. The likelihood of hospital admission was significantly reduced when individuals were managed with ethanol (odds ratio 0.206 (95 per cent confidence interval; 0.066-0.641), Wald chi-square P  = 0.006). In those not admitted, the treatment type had no significant impact on length of stay or the number of occasions a pharmacological agent was required. In those admitted, treatment had no significant effect on length of stay., Discussion: We offer preliminary evidence to support a role of oral ethanol in the management of patients with alcohol withdrawal. We have implemented a robust and translatable guideline. Despite limitations in the data set the impact of ethanol in reducing the likelihood of admission remained significant., Conclusions: In individuals at significant risk of severe alcohol withdrawal, prescribing ethanol as part of a comprehensive care plan, may reduce unplanned admissions. The preliminary findings presented here warrant further assessment through prospective studies.

Fungi that are edible or fermentative were domesticated through selective cultivation of their desired traits. Domestication is often associated with inbreeding or selfing, which may fix traits other than those under selection, and causes an overall decrease in heterozygosity. A hallucinogenic mushroom, Psilocybe cubensis, was domesticated from its niche in livestock dung for production of psilocybin. It has caused accidental poisonings since the 1940s in Australia, which is a population hypothesized to be introduced from an unknown center of origin. We sequenced genomes of 38 isolates from Australia and compared them with 86 genomes of commercially available cultivars to determine (1) whether P. cubensis was introduced to Australia, and (2) how domestication has impacted commercial cultivars. Our analyses of genome-wide SNPs and single-copy orthologs showed that the Australian population is naturalized, having recovered its effective population size after a bottleneck when it was introduced, and it has maintained relatively high genetic diversity based on measures of nucleotide and allelic diversity. In contrast, domesticated cultivars generally have low effective population sizes and hallmarks of selfing and clonal propagation, including low genetic diversity, low heterozygosity, high linkage disequilibrium, and low allelic diversity of mating-compatibility genes. Analyses of kinship show that most cultivars are founded from related populations. Alleles in the psilocybin gene cluster are identical across most cultivars of P. cubensis with low diversity across coding sequence; however, unique allelic diversity in Australia and some cultivars may translate to differences in biosynthesis of psilocybin and its analogs., Competing Interests: Declaration of interests A.R.M. and C.A. are owners of Funky Fungus, a company that grows magic mushrooms to produce medicinal psilocybin. K.M. is the founder of Medicinal Genomics., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Epithelial secretion may play an important role in reducing bacterial colonization and translocation in intestine. If so, secretory dysfunction could result in increased susceptibility to infection and inflammation. We investigated whether long-term colonic secretory dysfunction occurs after a bout of colitis and if this is accompanied by an increase in bacterial colonization and translocation. Rats were studied 6 wk after induction of colitis with trinitrobenzene sulfonic acid when inflammation had completely resolved, and epithelial permeability was normal. Intestinal loops were stimulated with either Clostridium difficile toxin A or a phosphodiesterase inhibitor. In vitro, colonic tissue from previously sensitized rats was exposed to antigen (ovalbumin). Secretory responses to all three stimuli were suppressed in rats that had previously had colitis. These rats exhibited increased (16-fold) numbers of colonic aerobic bacteria and increased (>3-fold) bacterial translocation, similar to results in rats studied after resolution of enteritis. Postcolitis bacterial translocation was prevented by daily treatment with an inhibitor of inducible nitric oxide synthase. This study demonstrates that intestinal inflammation results in prolonged impairment of colonic epithelial secretion, which may contribute to increases in bacterial load and bacterial translocation. Epithelial dysfunction of this type could underlie an increased propensity for further bouts of inflammation, a hallmark of diseases such as inflammatory bowel disease.

We have characterised a-novel Aspergillus nidulans gene encoding a 'two-component' signalling protein (tcsA). tcsA encodes both a histidine kinase domain and a response regulator domain similar to those found in bacterial, lower eukaryotic and plant members of the two-component family of proteins, while two PAS domains in the amino-terminal region of the predicted tcsA product may monitor the signal which regulates a tcsA histidine kinase-response regulator phosphorelay. While tcsA is nonessential for vegetative growth, cells lacking the gene are unable to produce conidia on standard Aspergillus growth media. However, tcsA is not absolutely required for production since this defect is suppressed by growth on 1 M sorbitol.

Extraintestinal manifestations of inflammatory bowel disease are numerous. This study examined the effects of two models of acute colitis on cerebral blood flow (CBF) and permeability of the blood-brain barrier in rabbits. CBF (measured with radiolabeled microspheres), or the extraction ratio or permeability-surface area (PS) product of the blood-brain barrier to fluorescein and FITC-dextran, was measured 48 h after colitis induction with acetic acid (HAc) or trinitrobenzene sulfonic acid (TNBS). PS product for fluorescein increased (P < 0.05) in TNBS colitis (1.33 x 10(-5) +/- 0.52 x 10(-5) ml/s and 0.48 x 10(-5) +/- 0.13 x 10(-5) ml/s (mean +/- SE) for treated (n = 14) and untreated (n = 10) animals, respectively. PS product for the larger FITC-dextran was not different in TNBS colitis (0.24 x 10(-5) +/- 0.09 x 10(-5) ml/s, n = 7) compared with untreated controls (0.19 x 10(-5) +/- 0.04 x 10(-5) ml/s, n = 8). PS product for fluorescein increased (P < 0.01) in HAc colitis compared with vehicle (2.66 x 10(-5) +/- 1.46 x 10(-5) ml/s and 0.33 x 10(-5) +/- 0.05 x 10(-5) ml/s, respectively; n = 6 in each group). The extraction of fluorescein from the blood to the brain increased by 75% during TNBS colitis when compared with vehicle (P < 0.05). CBF and cerebrovascular resistance did not change from the untreated control after TNBS colitis. Our data suggest that, irrespective of induction method, acute colitis increases the permeability of the blood-brain barrier to small molecules without changing CBF.

Endogenous glucocorticoids are known to play a role in the regulation of the inflammatory response possibly by modulating pro- and anti-inflammatory cytokine expression. We examined endogenous glucocorticoid secretion, hepatic damage, tumor necrosis factor-alpha (TNF-alpha), and interleukin-10 (IL-10) mRNA expression and release in rats treated with carbon tetrachloride (CCl4) after treatment with vehicle or a glucocorticoid receptor antagonist (RU-486). Rats treated with CCl4 demonstrated striking elevations of plasma corticosterone levels. Inhibition of endogenous glucocorticoid activity by pretreatment with the glucocorticoid receptor antagonist RU-486 resulted in augmented CCl4-mediated hepatotoxicity, as reflected by histology and serum transaminase levels, which were independent of alterations in serum TNF-alpha levels or hepatic mRNA expression. CCl4 treatment resulted in enhanced hepatic IL-10 mRNA expression and elevated serum IL-10 levels, which were markedly attenuated by glucocorticoid receptor blockade. In summary, significant endogenous glucocorticoid release occurs during acute toxic liver injury in the rat and suppresses the inflammatory response independent of effects on TNF-alpha but possibly by upregulating hepatic IL-10 production.

Hapten-induced colitis is a widely used model for the study of the intestinal inflammation and for the testing of novel therapies. However, the hapten utilized in this model, trinitrobenzene sulfonic acid, is difficult to obtain in some countries. We therefore compared this hapten to two structurally related haptens to determine if they could be substituted for trinitrobenzene sulfonic acid in terms of inducing chronic colitis in the rat. Rats received one of the three haptens intracolonically, and the severity of colonic inflammation was assessed 3 and 14 days later. Dinitrobenzene sulfonic acid produced colonic inflammation and ulceration that was indistinguishable from that induced by trinitrobenzene sulfonic acid at both time points. On the other hand, dinitrochlorobenzene produced acute colitis (3 days postadministration), but by Day 14 this inflammation had subsided. Dinitrobenzene sulfonic acid and trinitrobenzene sulfonic acid produced comparable levels of granulocyte infiltration into the colon (as measured by tissue myeloperoxidase activity and histology) at both time points. These studies suggest that for studies of up to at least 2 weeks in duration, dinitrobenzene sulfonic acid and trinitrobenzene sulfonic acid produce comparable levels of colonic inflammation. Dinitrobenzene sulfonic acid therefore offers a useful and less expensive alternative to trinitrobenzene sulfonic acid.

1. Platelet-activating factor can be synthesized by two distinct biochemical pathways and is degraded by a number of enzymes, the first step of which is deacetylation by a specific acetyl hydrolase. 2. The biochemical pathway of platelet-activating factor synthesis de novo and the first step in platelet-activating factor degradation have been investigated for the first time in incubates of normal human colon mucosa and in inflamed mucosa from patients with inflammatory bowel disease. 3. In the presence of 100 mumol/l CDP-choline and 100 mumol/l hexadecyl acetyl glycerol, homogenates from inflamed mucosa synthesized significantly greater platelet-activating factor [851 +/- 574 pmol/mg of protein (mean +/- SEM) in 90 min incubation] than normal mucosa [105 +/- 61 pmol/mg of protein in 90 min incubation] (P < 0.05). 4. Under the same conditions of assay, the percentage turnover to inactive lyso-platelet-activating factor was similar in inflamed mucosa (35.5 +/- 9.4%) and normal mucosa (42.7 +/- 8.5%) in 90 min (P > 0.05). 5. The identity of platelet-activating factor was confirmed by HPLC, by its mobility on TLC and by the ability of WEB 2170, a selective platelet-activating factor receptor antagonist, to block its platelet-aggregatory action. 6. These findings confirm the presence of the pathway for the synthesis de novo of the potently proinflammatory platelet-activating factor in human colon mucosa in inflammatory bowel disease.

The catabolism of platelet-activating factor (PAF) and lyso PAF by a supernatant fraction of human colon mucosa homogenates has been studied in vitro. PAF is initially catabolized to lyso PAF by mucosal enzymes via removal of its acetyl group. Incubates in Ca(2+)-free Tris with EDTA showed that the acetyl hydrolase was Ca2+ independent. Addition of the hydrolase inhibitor, phenyl methyl sulphonyl fluoride, significantly reduced the catabolism of PAF. Lyso PAF was further catabolized in at least two ways. An acyl group was incorporated into the sn-2 position of lyso PAF to give 1-O-alkyl-2-acyl-sn-glycero-3-phosphocholine (alkyl acyl GPC); this step was Ca2+ independent as shown by omitting Ca2+ and adding EDTA to the incubate. Formation of alkyl acyl GPC was confirmed by HPLC. Alternatively, choline was removed from the head group of lyso PAF by a calcium-dependent lyso phospholipase D. Under the experimental conditions utilized a neutral lipid product was formed but significant amounts of the intermediate lysophosphatidic acid could not be detected. A substance with a chromatographic mobility of Rf = 0.8 on TLC plates having an intact phosphorylcholine head group was also formed but has not yet been identified. It is concluded that the human colon mucosa contains enzymes that actively catabolize pro-inflammatory PAF and lyso PAF.