Caryophyllene Sesquiterpenes from a Chaetomium globosum Endophyte of the Canadian Medicinal Plant Empetrum nigrum.

Punctaporonins T (1) and U (2), new caryophyllene sesquiterpenes, were isolated with three known punctaporonins, A (3), B (4), and C (5), from the endophytic fungus Chaetomium globosum (TC2-041). The structures and relative configurations of punctaporonins T and U were elucidated based on a combination of HRESIMS, 1D/2D NMR spectroscopic analysis, and X-ray diffraction analysis, while their absolute configuration is presumed to be consistent with the co-isolated 3-5 on biogenetic arguments. Compound 1 showed weak inhibitory activity against both Mycobacterium tuberculosis and Staphylococcus aureus.

Tolypocaibols: Antibacterial Lipopeptaibols from a Tolypocladium sp. Endophyte of the Marine Macroalga Spongomorpha arcta.

Two new lipopeptaibols, tolypocaibols A (1) and B (2), and the mixed NRPS-polyketide-shikimate natural product maximiscin [(P/M)-3)] were isolated from a Tolypocladium sp. fungal endophyte of the marine alga Spongomorpha arcta. Analysis of NMR and mass spectrometry data revealed the amino acid sequences of the lipopeptaibols, which both comprise 11 residues with a valinol C-terminus and a decanoyl acyl chain at the N-terminus. The configuration of the amino acids was determined by Marfey's analysis. Tolypocaibols A (1) and B (2) showed moderate, selective inhibition against Gram-positive and acid-fast bacterial strains, while maximiscin [(P/M)-3)] showed moderate, broad-spectrum antibiotic activity.

Electrophysiological ventricular substrate of stroke: a prospective cohort study in the Atherosclerosis Risk in Communities (ARIC) study.

OBJECTIVES: The goal of the study was to determine an association of cardiac ventricular substrate with thrombotic stroke (TS), cardioembolic stroke (ES) and intracerebral haemorrhage (ICH). DESIGN: Prospective cohort study. SETTING: The Atherosclerosis Risk in Communities (ARIC) study in 1987-1989 enrolled adults (45-64 years), selected as a probability sample from four US communities (Minneapolis, Minnesota; Washington, Maryland; Forsyth, North Carolina; Jackson, Mississippi). Visit 2 was in 1990-1992, visit 3 in 1993-1995, visit 4 in 1996-1998 and visit 5 in 2011-2013. PARTICIPANTS: ARIC participants with analysable ECGs and no history of stroke were included (n=14 479; age 54±6 y; 55% female; 24% black). Ventricular substrate was characterised by cardiac memory, spatial QRS-T angle (QRS-Ta), sum absolute QRST integral (SAIQRST), spatial ventricular gradient magnitude (SVGmag), premature ventricular contractions (PVCs) and tachycardia-dependent intermittent bundle branch block (TD-IBBB) on 12-lead ECG at visits 1-5. OUTCOME: Adjudicated TS included a first definite or probable thrombotic cerebral infarction, ES-a first definite or probable non-carotid cardioembolic brain infarction. Definite ICH was included if it was the only stroke event. RESULTS: Over a median 24.5 years follow-up, there were 899 TS, 400 ES and 120 ICH events. Cox proportional hazard risk models were adjusted for demographics, cardiovascular disease, risk factors, atrial fibrillation, atrial substrate and left ventricular hypertrophy. After adjustment, PVCs (HR 1.72; 95% CI 1.02 to 2.92), QRS-Ta (HR 1.15; 95% CI 1.03 to 1.28), SAIQRST (HR 1.20; 95% CI 1.07 to 1.34) and time-updated SVGmag (HR 1.19; 95% CI 1.08 to 1.32) associated with ES. Similarly, PVCs (HR 1.53; 95% CI 1.03 to 2.26), QRS-Ta (HR 1.08; 95% CI 1.01 to 1.16), SAIQRST (HR 1.07; 95% CI 1.01 to 1.14) and time-updated SVGmag (HR 1.11; 95% CI 1.04 to 1.19) associated with TS. TD-IBBB (HR 3.28; 95% CI 1.03 to 10.46) and time-updated SVGmag (HR 1.23; 95% CI 1.03 to 1.47) were associated with ICH. CONCLUSIONS: PVC burden (reflected by cardiac memory) is associated with ischaemic stroke. Transient cardiac memory (likely through TD-IBBB) precedes ICH.

Pandemic practice: Horror fans and morbidly curious individuals are more psychologically resilient during the COVID-19 pandemic.

One explanation for why people engage in frightening fictional experiences is that these experiences can act as simulations of actual experiences from which individuals can gather information and model possible worlds. Conducted during the COVID-19 pandemic, this study (n = 310) tested whether past and current engagement with thematically relevant media fictions, including horror and pandemic films, was associated with greater preparedness for and psychological resilience toward the pandemic. Since morbid curiosity has previously been associated with horror media use during the COVID-19 pandemic, we also tested whether trait morbid curiosity was associated with pandemic preparedness and psychological resilience during the COVID-19 pandemic. We found that fans of horror films exhibited greater resilience during the pandemic and that fans of "prepper" genres (alien-invasion, apocalyptic, and zombie films) exhibited both greater resilience and preparedness. We also found that trait morbid curiosity was associated with positive resilience and interest in pandemic films during the pandemic. Taken together, these results are consistent with the hypothesis that exposure to frightening fictions allow audiences to practice effective coping strategies that can be beneficial in real-world situations.

Evidence of Inverse Hall-Petch Behavior and Low Friction and Wear in High Entropy Alloys.

We present evidence of inverse Hall-Petch behavior for a single-phase high entropy alloy (CoCrFeMnNi) in ultra-high vacuum and show that it is associated with low friction coefficients (~0.3). Grain size measurements by STEM validate a recently proposed dynamic amorphization model that accurately predicts grain size-dependent shear strength in the inverse Hall-Petch regime. Wear rates in the initially soft (coarse grained) material were shown to be remarkably low (~10-6 mm3/N-m), the lowest for any HEA tested in an inert environment where oxidation and the formation of mixed metal-oxide films is mitigated. The combined high wear resistance and low friction are linked to the formation of an ultra-nanocrystalline near-surface layer. The dynamic amorphization model was also used to predict an average high angle grain boundary energy (0.87 J/m2). This value was used to explain cavitation-induced nanoporosity found in the highly deformed surface layer, a phenomenon that has been linked to superplasticity.

Assessing the Structure of the Five Factor Model of Personality (IPIP-NEO-120) in the Public Domain.

Assessment of individual differences in personality traits is arguably one of the hallmarks of psychological research. Testing the structural validity of trait measurements is paramount in this endeavor. In the current study, we investigated 30 facet traits in one of the accessible and comprehensive public-domain Five Factor Model (FFM) personality inventories, IPIP-NEO-120 (Johnson, 2014), using one of the largest US samples to date (N = 320,128). We present structural loadings for all trait facets organized into respective FFM-trait domain (Neuroticism, Extraversion, Openness, Agreeableness, and Conscientiousness). Both hierarchical second-order and bi-factor models showed tolerable model fit indices, using confirmatory factor analysis in a structural equation modeling (SEM) framework. Some facet traits were substantially more representative than others for their respective trait domain, which facilitate further discussions on FFM-construct content. We conclude that IPIP-NEO is sufficiently structurally robust for future use, for the benefit of research and practice in personality assessment.

Correcting a Longstanding Misconception about Social Roles and Personality: A Case Study in the Psychology of Science.

Psychologists often argue that sex roles direct different types of socializing behaviors toward males and females and that this differential treatment, in turn, leads to sex differences in personality. Widely cited in support of this thesis has been the Fels longitudinal study finding that dependency and passivity are stable from childhood to adulthood for females only and aggressiveness and sexuality for males only. The present article explains why the type of sex differences in personality stability cited by Fels researchers actually contradicts the view that sex role expectations cause these differences. The report suggests ways in which social learning theory, the dominant developmental paradigm of the 1960s, may have contributed to the misinterpretation of the Fels data and how the rise of social constructivism maintained this misinterpretation for decades. The article concludes by correcting misconceptions about biology and personality stability and by explaining why theories that incorporate biology are not only more adequate than social constructivism but also more effective in bringing about the changes in society that constructivists desire.

ß-arrestin-biased agonism of ß-adrenergic receptor regulates Dicer-mediated microRNA maturation to promote cardioprotective signaling.

RATIONALE: MicroRNAs (miRs) are small, non-coding RNAs that function to post-transcriptionally regulate target genes. First transcribed as primary miR transcripts (pri-miRs), they are enzymatically processed by Drosha into premature miRs (pre-miRs) and further cleaved by Dicer into mature miRs. Initially discovered to desensitize ß-adrenergic receptor (ßAR) signaling, ß-arrestins are now well-appreciated to modulate multiple pathways independent of G protein signaling, a concept known as biased signaling. Using the ß-arrestin-biased ßAR ligand carvedilol, we previously showed that ß-arrestin1 (not ß-arrestin2)-biased ß1AR (not ß2AR) cardioprotective signaling stimulates Drosha-mediated processing of six miRs by forming a multi-protein nuclear complex, which includes ß-arrestin1, the Drosha microprocessor complex and a single-stranded RNA binding protein hnRNPA1. OBJECTIVE: Here, we investigate whether ß-arrestin-mediated ßAR signaling induced by carvedilol could regulate Dicer-mediated miR maturation in the cytoplasm and whether this novel mechanism promotes cardioprotective signaling. METHODS AND RESULTS: In mouse hearts, carvedilol indeed upregulates three mature miRs, but not their pre-miRs and pri-miRs, in a ß-arrestin 1- or 2-dependent manner. Interestingly, carvedilol-mediated activation of miR-466g or miR-532-5p, and miR-674 is dependent on ß2ARs and ß1ARs, respectively. Mechanistically, ß-arrestin 1 or 2 regulates maturation of three newly identified ßAR/ß-arrestin-responsive miRs (ß-miRs) by associating with the Dicer maturation RNase III enzyme on three pre-miRs of ß-miRs. Myocardial cell approaches uncover that despite their distinct roles in different cell types, ß-miRs act as gatekeepers of cardiac cell functions by repressing deleterious targets. CONCLUSIONS: Our findings indicate a novel role for ßAR-mediated ß-arrestin signaling activated by carvedilol in Dicer-mediated miR maturation, which may be linked to its protective mechanisms.

Ubiquitin and Ubiquitin-like proteins in cardiac disease and protection.

Post-translational modification represents an important mechanism to regulate protein function in cardiac cells. Ubiquitin (Ub) and ubiquitin-like proteins (UBLs) are a family of protein modifiers that share a certain extent of sequence and structure similarity. Conjugation of Ub or UBLs to target proteins is dynamically regulated by a set of UBL-specific enzymes and modulates the physical and physiological properties of protein substrates. Ub and UBLs control a strikingly wide spectrum of cellular processes and not surprisingly are involved in the development of multiple human diseases including cardiac diseases. Further identification of novel UBL targets will expand our understanding of the functional diversity of UBL pathways in physiology and pathology. Here we review recent findings on the mechanisms, proteome and functions of a subset of UBLs and highlight their potential impacts on the development and progression of various forms of cardiac diseases.

Determining the mode of action of anti-mycobacterial C17 diyne natural products using expression profiling: evidence for fatty acid biosynthesis inhibition.

BACKGROUND: The treatment of microbial infections is becoming increasingly challenging because of limited therapeutic options and the growing number of pathogenic strains that are resistant to current antibiotics. There is an urgent need to identify molecules with novel modes of action to facilitate the development of new and more effective therapeutic agents. The anti-mycobacterial activity of the C17 diyne natural products falcarinol and panaxydol has been described previously; however, their mode of action remains largely undetermined in microbes. Gene expression profiling was therefore used to determine the transcriptomic response of Mycobacterium smegmatis upon treatment with falcarinol and panaxydol to better characterize the mode of action of these C17 diynes. RESULTS: Our analyses identified 704 and 907 transcripts that were differentially expressed in M. smegmatis after treatment with falcarinol and panaxydol respectively. Principal component analysis suggested that the C17 diynes exhibit a mode of action that is distinct to commonly used antimycobacterial drugs. Functional enrichment analysis and pathway enrichment analysis revealed that cell processes such as ectoine biosynthesis and cyclopropane-fatty-acyl-phospholipid synthesis were responsive to falcarinol and panaxydol treatment at the transcriptome level in M. smegmatis. The modes of action of the two C17 diynes were also predicted through Prediction of Activity Spectra of Substances (PASS). Based upon convergence of these three independent analyses, we hypothesize that the C17 diynes inhibit fatty acid biosynthesis, specifically phospholipid synthesis, in mycobacteria. CONCLUSION: Based on transcriptomic responses, it is suggested that the C17 diynes act differently than other anti-mycobacterial compounds in M. smegmatis, and do so by inhibiting phospholipid biosynthesis.

Antimycobacterial triterpenes from the Canadian medicinal plant Sarracenia purpurea.

ETHNOPHARMACOLOGICAL RELEVANCE: The purple pitcher plant, Sarracenia purpurea, is a medicinal plant used by the Canadian First Nations to treat a wide variety of illnesses. The Mi'kmaq and Wolastoqiyik (Maliseet) peoples of Eastern Canada have traditionally used infusions of S. purpurea for the treatment of tuberculosis-like symptoms. Previous investigations have shown methanolic extracts of S. purpurea to possess antimycobacterial activity. AIM OF THE STUDY: To isolate and identify antimycobacterial constituents from S. purpurea. MATERIALS AND METHODS: Methanolic extracts of S. purpurea were subjected to bioassay guided fractionation using the microplate resazurin assay (MRA) to assess inhibitory activity against Mycobacterium tuberculosis strain H37Ra. The antimycobacterial constituents were identified by NMR, MS and polarimetry. RESULTS: The triterpenes betulinaldehyde, ß-sitosterol, betulinic acid, and ursolic acid were isolated from S. purpurea. Betulinaldehyde, betulinic acid, and ursolic acid exhibited MICs of 450, 950, and 450µM and IC50s of 98, 169, and 93µM against M. tuberculosis H37Ra respectively whilst ß-sitosterol was inactive (MIC and IC50 of >1000µM). CONCLUSIONS: Betulinaldehyde, betulinic acid, and ursolic acid were identified as the principal constituents responsible for the antimycobacterial activity of S. purpurea. This work is consistent with the ethnopharmacological use of S. purpurea by Canadian First Nations as a treatment against infectious diseases.

Antimycobacterial Natural Products from Endophytes of the Medicinal Plant Aralia nudicaulis.

Antimycobacterial extracts of a Penicillium sp. (isolate HL4-159-41B) and a Coniothyrium sp. (isolate HL6-097-027B) isolated from the rhizomes of the Canadian medicinal plant Aralia nudicaulis were found to contain palitantin (1) and botrallin (2), craterellin C (3), mycosporulone (4), spiromassaritone (5), and massarigenin D (6) respectively. Bioassays against Mycobacterium tuberculosis H37Ra revealed that 1 - 4 possess moderate antimycobacterial activity.

Isolation of Phomopsolide A and 6(E)-Phomopsolide A as Antimycobacterial Natural Products from an Unidentified Endophyte of the Canadian Medicinal Plant Heracleum maximum.

An extract of an unidentified endophyte from the Canadian medicinal plant Heracleum maximum exhibited a unique metabolomic profile and significant antimycobacterial activity against Mycobacterium tuberculosis H37Ra. Bioassay guided fractionation of the extract led to the isolation of phomopsolide A (1) and 6(E)-phomopsolide A (2). This is the first report of antimycobacterial activity for 1 and 2.

Polyketides from an Endophytic Aspergillus fumigatus Isolate Inhibit the Growth of Mycobacterium tuberculosis and MRSA.

The crude extract of Aspergillusfumigatus isolate AF3-093A, an endophyte of the brown alga Fucus vesiculosus, showed significant antimicrobial activity in initial bioactivity screens. Bioassay-guided fractionation of the extract led to the isolation of flavipin, chaetoglobosin A and chaetoglobosin B, all of which inhibited the growth of Staphylococcus aureus, methicillin-resistant S. aureus and Mycobacterium tuberculosis H37Ra. The antimycobacterial activity of these compounds has not been previously reported.