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Research in the 1980s suggested that young “metalheads” were at risk for poor developmental outcomes. No other study has assessed this group as adults; thus, we examined 1980s heavy metal groupies, musicians, and fans at middle age, using snowball sampling from Facebook. Online surveys assessed adverse childhood experiences, personality, adult attachment, and past and current functioning in 377 participants. Results revealed that metal enthusiasts did often experience traumatic and risky “sex, drugs, and rock-n-roll” lives. However, the “metalhead” identity also served as a protective factor against negative outcomes. They were significantly happier in their youth and better adjusted currently than either middle-aged or current college-age youth comparison groups. Thus, participation in fringe style cultures may enhance identity development in troubled youth.

A statistical framework applicable to Ring-LWE was outlined by Murphy and Player (IACR eprint 2019/452). Its applicability was demonstrated with an analysis of the decryption failure probability for degree-1 and degree-2 ciphertexts in the homomorphic encryption scheme of Lyubashevsky, Peikert and Regev (IACR eprint 2013/293). In this paper, we clarify and extend results presented by Murphy and Player. Firstly, we make precise the approximation of the discretisation of a Normal random variable as a Normal random variable, as used in the encryption process of Lyubashevsky, Peikert and Regev. Secondly, we show how to extend the analysis given by Murphy and Player to degree-k ciphertexts, by precisely characterising the distribution of the noise in these ciphertexts.

The UK’s Defence Science and Technology Laboratory (Dstl) is partnering with the US Naval Research Laboratory (NRL) on a joint mission to launch miniature sensors that will advance space weather measurement and modelling capabilities. The Coordinated Ionospheric Reconstruction Cubesat Experiment (CIRCE) comprises two 6U cube-satellites that will be launched into a near-polar low earth orbit (LEO), targeting 500 km altitude, in 2021. The UK contribution to CIRCE is the In situ and Remote Ionospheric Sensing (IRIS) suite, complementary to NRL sensors, and comprising three highly miniaturised payloads provided to Dstl by University College London (UCL), University of Bath, and University of Surrey/Surrey Satellite Technology Ltd (SSTL). One IRIS suite will be flown on each satellite, and incorporates an ion/neutral mass spectrometer, a tri-band global positioning system (GPS) receiver for ionospheric remote sensing, and a radiation environment monitor. From the US, NRL have provided two 1U Triple Tiny Ionospheric Photometers (Tri-TIPs) on each satellite (Nicholas et al., 2019), observing the ultraviolet 135.6 nm emission of atomic oxygen at night-time to characterize the two-dimensional distribution of electrons.

N-nitrosobenzylmethylamine (NBzMA) must be metabolically activated to exert its carcinogenic potential and is a potent inducer of tumors in the rat esophagus. The activation is believed to occur in the esophagus. Although the pathways of NBzMA metabolism are well studied, the principal cytochrome P450 enzyme(s) (P450) responsible for catalyzing its activation is unknown. Several preliminary studies have suggested that this enzyme may belong to the P450 2A family. We report here that P450 2A3 expressed in a baculovirus system metabolizes NBzMA, predominantly by methylene hydroxylation. To determine whether or not P450 2A3 is present in the rat esophagus, the relative level of P450 2A3 mRNA was determined by reverse transcriptase-polymerase chain reaction (RT-PCR). The mRNA levels of P450 2A3 were compared with the levels of P450 2A1 and 2A2 mRNA in the esophagus, liver, lung and nasal mucosa. P450 2A3 mRNA was detected in rat nasal mucosa, lung and esophagus, but not in liver, whereas P450 2A1 and 2A2 mRNAs were detected only in the liver. To determine the relative expression of P450 2A3 in each tissue, quantitative RT-PCR with PCR-MIMICS used as internal standards was performed. The expression level in the nasal mucosa was by far the greatest. The expression in the lung and esophagus was 60- and 1600-fold less, respectively. Using antibodies to P450 2A4/5 and P450 2A10/11 a 50kDa immunoreactive protein was detected in all three tissues by western blot analysis. This is consistent with the expression of P450 2A3 in these tissues. However, the amount of protein detected in the nasal mucosa was much greater than that in the esophagus or lung. The expression of P450 2A protein was similar in the lung and esophagus. The rate of coumarin 7-hydroxylation in cultured rat esophagus was very low. This is a reaction efficiently catalyzed by P450 2A5, 2A6 and 2A10. In summary, our results clearly demonstrate the presence of P450 2A3 protein and mRNA in the esophagus, but the amounts are low and may not be sufficient to account for NBzMA activation in this tissue. [ABSTRACT FROM PUBLISHER]

The ability of dietary isothiocyanates to inhibit the esophageal metabolism of N'-nitrosonornicotine (NNN) was examined in F344 rats. Following feeding of benzyl isothiocyanate (BITC), phenethyl isothiocynate (PEITC), 3-phenylpropyl isothiocyanate (PPITC) 4-phenylbutyl isothiocyanate (PBITC) or 6-phenylhexyl isothiocyanate for 2 weeks, rats were killed and the esophagi were incubated in vitro with [5-3H]NNN. While dietary BITC, PEITC and PBITC all decreased NNN metabolism, dietary PPITC had the greatest effect, yielding inhibition ranging from 55 to 91% of the control production of various NNN metabolites. To determine the chemopreventive efficacy of PPITC on NNN-induced esophageal tumorigenesis, rats were fed AIN-76A diets containing 0, 1.0 or 2.5 μmol/g PPITC and were given untreated drinking water or drinking water containing 5 p.p.m. NNN. After 87 weeks, the experiment was terminated and the esophageal tumors were counted. Rats that were given untreated drinking water developed no tumors. Rats that were given 5 p.p.m. NNN and unadulterated AIN-76A diet had an esophageal tumor incidence of 71% and a multiplicity of 1.57 tumors/animal. The two dietary concentrations of PPITC reduced the incidence and multiplicity of NNN-induced esophageal tumors by >95%. These results demonstrate the remarkable chemopreventive efficacy of PPITC in the NNN-induced esophageal tumor model. [ABSTRACT FROM PUBLISHER]

There is no linear hull effect in linear cryptanalysis.

Abstract Background Polymerase chain reaction (PCR) is used in directed sequencing for the discovery of novel polymorphisms. As the first step in PCR directed sequencing, effective PCR primer design is crucial for obtaining high-quality sequence data for target regions. Since current computational primer design tools are not fully tuned with stable underlying laboratory protocols, researchers may still be forced to iteratively optimize protocols for failed amplifications after the primers have been ordered. Furthermore, potentially identifiable factors which contribute to PCR failures have yet to be elucidated. This inefficient approach to primer design is further intensified in a high-throughput laboratory, where hundreds of genes may be targeted in one experiment. Results We have developed a fully integrated computational PCR primer design pipeline that plays a key role in our high-throughput directed sequencing pipeline. Investigators may specify target regions defined through a rich set of descriptors, such as Ensembl accessions and arbitrary genomic coordinates. Primer pairs are then selected computationally to produce a minimal amplicon set capable of tiling across the specified target regions. As part of the tiling process, primer pairs are computationally screened to meet the criteria for success with one of two PCR amplification protocols. In the process of improving our sequencing success rate, which currently exceeds 95% for exons, we have discovered novel and accurate computational methods capable of identifying primers that may lead to PCR failures. We reveal the laboratory protocols and their associated, empirically determined computational parameters, as well as describe the novel computational methods which may benefit others in future primer design research. Conclusion The high-throughput PCR primer design pipeline has been very successful in providing the basis for high-quality directed sequencing results and for minimizing costs associated with labor and reprocessing. The modular architecture of the primer design software has made it possible to readily integrate additional primer critique tests based on iterative feedback from the laboratory. As a result, the primer design software, coupled with the laboratory protocols, serves as a powerful tool for low and high-throughput primer design to enable successful directed sequencing.

Background: Environmental tobacco smoke has been classified by the Environmental Protection Agency as a carcinogen causally associated with lung cancer in adults, but there have been no reports of lung carcinogens or their metabolites in the body fluids or tissues of nonsmokers exposed to environmental tobacco smoke.Methods: Five male nonsmokers were exposed to sidestream cigarette smoke generated by machine smoking of reference cigarettes for 180 minutes on each of two days, six months apart. Sidestream smoke is the smoke that originates from the smoldering end of a cigarette between puffs. Twenty-four-hour urine samples were collected before and after exposure. The urine samples were analyzed for 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its glucuronide, which are metabolites of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a powerful lung carcinogen in rodents. NNAL is also a lung carcinogen in rodents.Results: The urinary excretion of the metabolites increased after exposure to sidestream smoke in all the men. The mean (+/- SD) amount of NNAL and NNAL glucuronide was significantly higher after exposure than at base line (33.9 +/- 20.0 vs. 8.4 +/- 11.2 ng per 24 hours [127 +/- 74 vs. 31 +/- 41 pmol per day], P < 0.001) and was correlated with urinary cotinine excretion (r = 0.89, P < 0.001). The nicotine concentrations in the air to which the men were exposed were comparable to those in a heavily smoke-polluted bar.Conclusions: Nonsmokers exposed to sidestream cigarette smoke take up and metabolize a lung carcinogen, which provides experimental support for the proposal that environmental tobacco smoke can cause lung cancer. [ABSTRACT FROM AUTHOR]

The role of serotonin in human behaviour is informed by approaches which allow in vivo modification of synaptic serotonin. However, characterising the effects of increased serotonin signalling in human models of behaviour is challenging given the limitations of available experimental probes, notably selective serotonin reuptake inhibitors. Here we use a now-accessible approach to directly increase synaptic serotonin in humans (a selective serotonin releasing agent) and examine its influence on domains of behaviour historically considered core functions of serotonin. Computational techniques, including reinforcement learning and drift diffusion modelling, explain participant behaviour at baseline and after week-long intervention. Reinforcement learning models reveal that increasing synaptic serotonin reduces sensitivity for outcomes in aversive contexts. Furthermore, increasing synaptic serotonin enhances behavioural inhibition, and shifts bias towards impulse control during exposure to aversive emotional probes. These effects are seen in the context of overall improvements in memory for neutral verbal information. Our findings highlight the direct effects of increasing synaptic serotonin on human behaviour, underlining its role in guiding decision-making within aversive and more neutral contexts, and offering implications for longstanding theories of central serotonin function., (© 2024. The Author(s).)

Background: The serotonin 4 receptor (5-HT 4 R) is a promising target for the treatment of depression. Highly selective 5-HT 4 R agonists, such as prucalopride, have antidepressant-like and procognitive effects in preclinical models, but their clinical effects are not yet established., Aims: To determine whether prucalopride (a 5-HT 4 R agonist and licensed treatment for constipation) is associated with reduced incidence of depression in individuals with no past history of mental illness, compared with anti-constipation agents with no effect on the central nervous system., Method: Using anonymised routinely collected data from a large-scale USA electronic health records network, we conducted an emulated target trial comparing depression incidence over 1 year in individuals without prior diagnoses of major mental illness, who initiated treatment with prucalopride versus two alternative anti-constipation agents that act by different mechanisms (linaclotide and lubiprostone). Cohorts were matched for 121 covariates capturing sociodemographic factors, and historical and/or concurrent comorbidities and medications. The primary outcome was a first diagnosis of major depressive disorder (ICD-10 code F32) within 1 year of the index date. Robustness of the results to changes in model and population specification was tested. Secondary outcomes included a first diagnosis of six other neuropsychiatric disorders., Results: Treatment with prucalopride was associated with significantly lower incidence of depression in the following year compared with linaclotide (hazard ratio 0.87, 95% CI 0.76-0.99; P = 0.038; n = 8572 in each matched cohort) and lubiprostone (hazard ratio 0.79, 95% CI 0.69-0.91; P < 0.001; n = 8281). Significantly lower risks of all mood disorders and psychosis were also observed. Results were similar across robustness analyses., Conclusions: These findings support preclinical data and suggest a role for 5-HT 4 R agonists as novel agents in the prevention of major depression. These findings should stimulate randomised controlled trials to confirm if these agents can serve as a novel class of antidepressant within a clinical setting.

Background: After accounting for smoking history, lung cancer incidence is greater in African Americans than Whites. In the multiethnic cohort, total nicotine equivalents (TNE) are higher in African Americans than Whites at similar reported cigarettes per day. Greater toxicant uptake per cigarette may contribute to the greater lung cancer risk of African Americans., Methods: In a nested case-control lung cancer study within the Southern Community Cohort, smoking-related biomarkers were measured in 259 cases and 503 controls (40% White; 56% African American). TNE, the trans-3-hydroxycotinine/cotinine ratio, 4-(methylnitrosamino)-1-3-(pyridyl)-1-butanol (NNAL), mercapturic acid metabolites of volatile organic compounds, phenanthrene metabolites, cadmium (Cd), and (Z)-7-(1R,2R,3R,5S)-3,5-dihydroxy-2-[(E,3S)-3-hydroxyoct-1-enyl]cyclopenyl]hept-5-enoic acid were quantified in urine. Unconditional logistic regression was used to estimate the ORs and 95% confidence intervals (CI) for each biomarker and lung cancer risk., Results: TNE, NNAL, and Cd were higher in cases than controls (adjusted for age, race, sex, body mass index, and cigarettes per day). Among cases, these levels were higher in African Americans compared with Whites. After accounting for age, sex, body mass index, and pack-years, a one-SD increase in log-TNE (OR = 1.30; 95% CI, 1.10-1.54) and log-NNAL (OR = 1.27; 95% CI, 1.03-1.58 with TNE adjustment) was associated with lung cancer risk. In this study, in which NNAL concentration is relatively high, the association for log-TNE was attenuated after adjustment for log-NNAL., Conclusions: Smoking-related biomarkers provide additional information for lung cancer risk in smokers beyond smoking pack-years., Impact: Urinary NNAL, TNE, and Cd concentrations in current smokers, particularly African American smokers, may be useful for predicting lung cancer risk., (©2024 American Association for Cancer Research.)

Background: Reducing cigarette addictiveness has the potential to avert millions of yearly tobacco-related deaths worldwide. Substantially reducing nicotine in cigarettes decreases cigarette consumption, but no large clinical trial has determined the effects of reduced-nicotine cigarettes when other nicotine-containing products are available. The aim of this study was to examine the effects of reduced-nicotine cigarettes in the context of the availability of alternative nicotine delivery systems., Methods: In a U.S. six-site, open-label, parallel-arm study, smokers were randomized for twelve weeks to an experimental marketplace containing cigarettes with either 0.4 mg or 15.8 mg nicotine per gram of tobacco; all had access to non-combusted alternative nicotine delivery systems (e.g., e-cigarettes; medicinal nicotine). Group differences in the primary outcomes (cigarettes per day, number of smoke-free days) were examined using linear and negative binomial regression, respectively (Trial Registration: NCT03272685)., Findings: Among 438 randomized participants (mean [standard deviation (SD), range] age, 44.5 [11.9, 20-73] years, 225 [51.4%] women, 282 [64.4%] White and 339 [77.4%] trial completers), those in the 0.4 mg vs. 15.8 mg nicotine cigarette condition experienced significantly lower cigarettes per day at the end of intervention (mean [SD], 7.05 [7.88] vs. 12.95 [9.07], adjusted mean difference, -6.21 [95% CI, -7.66 to -4.75], P < 0.0001) and greater smoke-free days during intervention (mean [SD], 18.59 [27.97] vs. 5.06 [13.77], adjusted rate ratio, 4.25 [95% CI, 2.58-6.98], P < 0.0001)., Interpretation: A reduced-nicotine cigarette standard in the context of access to other non-combusted nicotine products has the potential to benefit public health., Funding: U.S. NIH/FDA U54DA03165., Competing Interests: DKH serves on the World Health Organization, Study Group on Tobacco Product Regulation, is a Special Government Employee for the U.S. Food and Drug Administration and serves on the Scientific Advisory Board for the Medical University of South Carolina Program Project Grant related to the use of nicotine products in a rapidly evolving nicotine marketplace. NLB serves as a consultant to Achieve Life Sciences and Qnovia, companies that are developing a new smoking cessation medications and has been an expert witness in litigation against tobacco companies. RDA serves as a consulting reviewer for Versar, a technology and management support company for the federal government, and provides advice to the Ministry of Health New Zealand. SC served on the Data Safety Monitoring Board for Truth Initiative and is an External Advisory Board for a tobacco research center grant at Yale University. JT serves on the External Advisory Board of a Center of Biomedical Research Excellence (COBRE) award at the University of Vermont Center on Behavior and Health, a Scientific Advisory Committee for a Wake University research project related to nicotine reduction (R01DA058264), a Data Safety Monitoring Board for the Yale University Center for Tobacco Regulatory Science (TCORS) and was a Deputy Editor for the journal Nicotine and Tobacco Research. ECD is a Special Government Employee for the U.S. Food and Drug Administration and a member of a technical advisory group for the Ministry of Health in New Zealand. All other authors have nothing to declare., (© 2024 The Author(s).)

Vapor detection is a noncontact sampling method, which is a less invasive means of explosives screening than physical swiping. Explosive vapor detection is a challenge due to the low levels of vapors available for detection. This study demonstrates that the parts-per-quadrillion sensitivity of atmospheric flow tube-mass spectrometry (AFT-MS) combined with a high-volume air sampler enables standoff detection of trace explosives vapor at distances of centimeters to meters. Standoff detection of explosives vapor was possible both upstream and downstream of the vapor source relative to room air currents. RDX vapor from a saturated source was detected at up to 2.5 m. Vapors from RDX residue and nitroglycerin residue were detected at distances up to 0.5 m. The sampling can be optimized by accounting for air movement in the room or environment, which could further extend standoff detection distances. Using AFT-MS with a high-volume sampler could also be effective for standoff vapor detection of drugs and additional chemical threats and could be useful for security screening applications such as at mail facilities, border crossings, and security checkpoints., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The impact of tobacco exposure on health varies by race and ethnicity and is closely tied to internal nicotine dose, a marker of carcinogen uptake. DNA methylation is strongly responsive to smoking status and may mediate health effects, but study of associations with internal dose is limited. We performed a blood leukocyte epigenome-wide association study (EWAS) of urinary total nicotine equivalents (TNEs; a measure of nicotine uptake) and DNA methylation measured using the MethylationEPIC v1.0 BeadChip (EPIC) in six racial and ethnic groups across three cohort studies. In the Multiethnic Cohort Study (discovery, n = 1994), TNEs were associated with differential methylation at 408 CpG sites across >250 genomic regions (p < 9 × 10 -8 ). The top significant sites were annotated to AHRR, F2RL3, RARA, GPR15, PRSS23, and 2q37.1, all of which had decreasing methylation with increasing TNEs. We identified 45 novel CpG sites, of which 42 were unique to the EPIC array and eight annotated to genes not previously linked with smoking-related DNA methylation. The most significant signal in a novel gene was cg03748458 in MIR383;SGCZ. Fifty-one of the 408 discovery sites were validated in the Singapore Chinese Health Study (n = 340) and the Southern Community Cohort Study (n = 394) (Bonferroni corrected p < 1.23 × 10 -4 ). Significant heterogeneity by race and ethnicity was detected for CpG sites in MYO1G and CYTH1. Furthermore, TNEs significantly mediated the association between cigarettes per day and DNA methylation at 15 sites (average 22.5%-44.3% proportion mediated). Our multiethnic study highlights the transethnic and ethnic-specific methylation associations with internal nicotine dose, a strong predictor of smoking-related morbidities., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Polycomb group proteins have a critical role in silencing transcription during development. It is commonly proposed that Polycomb-dependent changes in genome folding, which compact chromatin, contribute directly to repression by blocking the binding of activating complexes. Recently, it has also been argued that liquid-liquid demixing of Polycomb proteins facilitates this compaction and repression by phase-separating target genes into a membraneless compartment. To test these models, we used Optical Reconstruction of Chromatin Architecture to trace the Hoxa gene cluster, a canonical Polycomb target, in thousands of single cells. Across multiple cell types, we find that Polycomb-bound chromatin frequently explores decompact states and partial mixing with neighboring chromatin, while remaining uniformly repressed, challenging the repression-by-compaction or phase-separation models. Using polymer simulations, we show that these observed flexible ensembles can be explained by 'spatial feedback'-transient contacts that contribute to the propagation of the epigenetic state (epigenetic memory), without inducing a globular organization., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Affective biases can change how past events are recalled from memory. To capture mechanisms underlying affective memory formation, recall, and bias, we studied value-based decision-making (VBDM) between reward memories encoded in different mood states. Our findings suggest that following discrete affective events, created by large magnitude wins and losses on a Wheel of Fortune (WoF), healthy volunteers display an overall positive memory bias [favoring higher probability shapes learned after a WoF win compared with those learnt after a WoF loss outcome]. During this VBDM process, participants' pupils constrict before decision-onset for higher-value choices, and remained dilated for a sustained period after choice. Sustained pupil dilation was particularly sensitive to the reward values of abstract memories encoded in a positive mood. Taken together, we demonstrate that experimentally induced affective memories are recalled with a positive bias, and pupil-linked central arousal systems are actively engaged during VBDM between affective and non-affective memories., Competing Interests: CJH has received consultancy fees from P1vital Ltd., Janssen Pharmaceuticals, Sage Therapeutics, Pfizer, Zogenix, Compass Pathways, and Lundbeck. SEM has received consultancy fees from Zogenix, Sumitomo Dainippon Pharma, P1vital Ltd., UCB Pharma and Janssen Pharmaceuticals. CJH and SEM hold grant income from Zogenix, UCB Pharma, Syndesi and Janssen Pharmaceuticals. The other authors report no conflicts of interest., (© 2024 The Author(s).)

Background: Cognitive deficits are often comorbid with mood disorders and can cause significant functional impairment even after resolution of the primary mood symptoms. We do not currently have pharmacological treatments that adequately address these deficits. 5-HT 4 receptor agonists show promise as potential procognitive agents in animal and early human translational studies. Optimal cognitive performance in humans is directly associated with appropriate functional connectivity between specific resting-state neural networks. However, so far the effect of 5-HT 4 receptor agonism on resting-state functional connectivity (rsFC) in the brain in humans is unknown., Methods: We collected resting-state functional magnetic resonance imaging scans from 50 healthy volunteers, of whom 25 received 6 days × 1 mg prucalopride (a highly selective 5-HT 4 receptor agonist) and 25 received placebo in a randomized double-blind design., Results: Network analyses identified that participants in the prucalopride group had enhanced rsFC between the central executive network and the posterior/anterior cingulate cortex. Seed analyses also showed greater rsFC between the left and right rostral anterior cingulate cortex and the left lateral occipital cortex, and reduced rsFC between the hippocampus and other default mode network regions., Conclusions: Similar to other potentially procognitive medications, low-dose prucalopride in healthy volunteers appeared to enhance rsFC between regions involved in cognitive networks and reduce rsFC within the default mode network. This suggests a mechanism for the behavioral cognitive enhancement previously seen with 5-HT 4 receptor agonists in humans and supports the potential for 5-HT 4 receptor agonists to be used in clinical psychiatric populations., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

MLL/KMT2A amplifications and translocations are prevalent in infant, adult, and therapy-induced leukemia. However, the molecular contributor(s) to these alterations are unclear. Here, we demonstrate that histone H3 lysine 9 mono- and di-methylation (H3K9me1/2) balance at the MLL/KMT2A locus regulates these amplifications and rearrangements. This balance is controlled by the crosstalk between lysine demethylase KDM3B and methyltransferase G9a/EHMT2. KDM3B depletion increases H3K9me1/2 levels and reduces CTCF occupancy at the MLL/KMT2A locus, in turn promoting amplification and rearrangements. Depleting CTCF is also sufficient to generate these focal alterations. Furthermore, the chemotherapy doxorubicin (Dox), which associates with therapy-induced leukemia and promotes MLL/KMT2A amplifications and rearrangements, suppresses KDM3B and CTCF protein levels. KDM3B and CTCF overexpression rescues Dox-induced MLL/KMT2A alterations. G9a inhibition in human cells or mice also suppresses MLL/KMT2A events accompanying Dox treatment. Therefore, MLL/KMT2A amplifications and rearrangements are controlled by epigenetic regulators that are tractable drug targets, which has clinical implications., Competing Interests: Declaration of interests J.R.W. has served or is serving as a consultant or advisor for Qsonica, Salarius Pharmaceuticals, Daiichi Sankyo, Inc., Vyne Therapeutics, and Lily Asia Ventures. J.R.W. also receives funding for research from Salarius Pharmaceuticals and Oryzon Genomics. O.G. is a scientific cofounder and shareholder of EpiCypher, Inc., K36 Therapeutics, Inc., and Alternative Bio, Inc. J.J. received research funds from Celgene Corporation, Levo Therapeutics, Inc., Cullgen, Inc., and Cullinan Oncology, Inc. J.J. is a cofounder and equity shareholder in Cullgen, Inc., a scientific cofounder and scientific advisory board member of Onsero Therapeutics, Inc., and a consultant for Cullgen, Inc., EpiCypher, Inc., and Accent Therapeutics, Inc. C.D. receives research funds from Janssen outside the submitted work., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Tobacco smoke exposure increases the risk and severity of lower respiratory tract infections in children, yet the mechanisms remain unclear. We hypothesized that tobacco smoke exposure would modify the lower airway microbiome., Methods: Secondary analysis of a multicenter cohort of 362 children between ages 31 days and 18 years mechanically ventilated for >72 h. Tracheal aspirates from 298 patients, collected within 24 h of intubation, were evaluated via 16 S ribosomal RNA sequencing. Smoke exposure was determined by creatinine corrected urine cotinine levels ≥30 µg/g., Results: Patients had a median age of 16 (IQR 568) months. The most common admission diagnosis was lower respiratory tract infection (53%). Seventy-four (20%) patients were smoke exposed and exhibited decreased richness and Shannon diversity. Smoke exposed children had higher relative abundances of Serratia spp., Moraxella spp., Haemophilus spp., and Staphylococcus aureus. Differences were most notable in patients with bacterial and viral respiratory infections. There were no differences in development of acute respiratory distress syndrome, days of mechanical ventilation, ventilator free days at 28 days, length of stay, or mortality., Conclusion: Among critically ill children requiring prolonged mechanical ventilation, tobacco smoke exposure is associated with decreased richness and Shannon diversity and change in microbial communities., Impact: Tobacco smoke exposure is associated with changes in the lower airways microbiome but is not associated with clinical outcomes among critically ill pediatric patients requiring prolonged mechanical ventilation. This study is among the first to evaluate the impact of tobacco smoke exposure on the lower airway microbiome in children. This research helps elucidate the relationship between tobacco smoke exposure and the lower airway microbiome and may provide a possible mechanism by which tobacco smoke exposure increases the risk for poor outcomes in children., (© 2023. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Background: Adolescent major depressive disorder (MDD) is associated with disrupted processing of emotional stimuli and difficulties in cognitive reappraisal. Little is known however about how current pharmacotherapies act to modulate the neural mechanisms underlying these key processes. The current study therefore investigated the neural effects of fluoxetine on emotional reactivity and cognitive reappraisal in adolescent depression., Methods: Thirty-one adolescents with MDD were randomised to acute fluoxetine (10 mg) or placebo. Seventeen healthy adolescents were also recruited but did not receive any treatment for ethical reasons. During functional magnetic resonance imaging (fMRI), participants viewed aversive images and were asked to either experience naturally the emotional state elicited ('Maintain') or to reinterpret the content of the pictures to reduce negative affect ('Reappraise'). Significant activations were identified using whole-brain analysis., Results: No significant group differences were seen when comparing Reappraise and Maintain conditions. However, when compared to healthy controls, depressed adolescents on placebo showed reduced visual activation to aversive pictures irrespective of the condition. The depressed adolescent group on fluoxetine showed the opposite pattern, i.e. increased visuo-cerebellar activity in response to aversive pictures, when compared to depressed adolescents on placebo., Conclusions: These data suggest that depression in adolescence may be associated with reduced visual processing of aversive imagery and that fluoxetine may act to reduce avoidance of such cues. This could reflect a key mechanism whereby depressed adolescents engage with negative cues previously avoided. Future research combining fMRI with eye-tracking is nonetheless needed to further clarify these effects.

Clinical depression is a common, debilitating and heterogenous disorder. Existing treatments for depression are inadequate for a significant minority of patients and new approaches are urgently needed. A wealth of evidence implicates the serotonin 1A (5-HT 1A ) receptor in the pathophysiology of depression. Stimulation of the 5-HT 1A receptor is an existing therapeutic target for treating depression and anxiety, using drugs such as buspirone and tandospirone. However, activation of 5-HT 1A raphe autoreceptors has also been suggested to be responsible for the delay in the therapeutic action of conventional antidepressants such as selective serotonin reuptake inhibitors (SSRIs). This narrative review provides a brief overview of the 5-HT 1A receptor, the evidence implicating it in depression and in the effects of conventional antidepressant treatment. We highlight that pre- and post-synaptic 5-HT 1A receptors may have divergent roles in the pathophysiology and treatment of depression. To date, developing this understanding to progress therapeutic discovery has been limited, partly due to a paucity of specific pharmacological probes suitable for use in humans. The development of 5-HT 1A 'biased agonism', using compounds such as NLX-101, offers the opportunity to further elucidate the roles of pre- and post-synaptic 5-HT 1A receptors. We describe how experimental medicine approaches can be helpful in profiling the effects of 5-HT 1A receptor modulation on the different clinical domains of depression, and outline some potential neurocognitive models that could be used to test the effects of 5-HT 1A biased agonists., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Evidence suggests inflammation may be a key mechanism by which psychosocial stress, including loneliness, predisposes to depression. Observational and clinical studies have suggested simvastatin, with its anti-inflammatory properties, may have a potential use in the treatment of depression. Previous experimental medicine trials investigating 7-day use of statins showed conflicting results, with simvastatin displaying a more positive effect on emotional processing compared with atorvastatin. It is possible that statins require longer administration in predisposed individuals before showing the expected positive effects on emotional processing., Aims: Here, we aim to test the neuropsychological effects of 28-day simvastatin administration versus placebo, in healthy volunteers at risk for depression owing to loneliness., Method: This is a remote experimental medicine study. One hundred participants across the UK will be recruited and randomised to either 28-day 20 mg simvastatin or placebo in a double-blind fashion. Before and after administration, participants will complete an online testing session involving tasks of emotional processing and reward learning, processes related to vulnerability to depression. Working memory will also be assessed and waking salivary cortisol samples will be collected. The primary outcome will be accuracy in identifying emotions in a facial expression recognition task, comparing the two groups across time.

This article reviews foundational scholarship related to leader development, including implications of the integrative theory of leader development and the dynamic model of leader development across the lifespan. Authors provide a rationale for why college is a critical juncture for creating ethical and inclusive leaders for the future and offer suggestions for ways to enhance leadership education., (© 2023 Wiley Periodicals, LLC.)

Although population-level analyses revealed significant roles for CTCF and cohesin in mammalian genome organization, their contributions at the single-cell level remain incompletely understood. Here, we used a super-resolution microscopy approach to measure the effects of removal of CTCF or cohesin in mouse embryonic stem cells. Single-chromosome traces revealed cohesin-dependent loops, frequently stacked at their loop anchors forming multi-way contacts (hubs), bridging across TAD boundaries. Despite these bridging interactions, chromatin in intervening TADs was not intermixed, remaining separated in distinct loops around the hub. At the multi-TAD scale, steric effects from loop stacking insulated local chromatin from ultra-long range (>4 Mb) contacts. Upon cohesin removal, the chromosomes were more disordered and increased cell-cell variability in gene expression. Our data revise the TAD-centric understanding of CTCF and cohesin and provide a multi-scale, structural picture of how they organize the genome on the single-cell level through distinct contributions to loop stacking., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Carcinogen and toxicant uptake by e-cigarette users have not been fully evaluated. In the study reported here, we recruited 30 e-cigarette users, 63 nonsmokers, and 33 cigarette smokers who gave monthly urine samples over a period of 4-6 months. Their product use status was confirmed by measurements of exhaled CO, urinary total nicotine equivalents, cyanoethyl mercapturic acid (CEMA), and total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol. Urinary biomarkers of exposure to the carcinogens acrolein (3-hydroxypropyl mercapturic acid, 3-HPMA), benzene ( S -phenyl mercapturic acid, SPMA), acrylonitrile (CEMA), and a combination of crotonaldehyde, methyl vinyl ketone, and methacrolein (3-hydroxy-1-methylpropyl mercapturic acid, HMPMA) were quantified at each visit. Data from subject visits with CEMA > 27 pmol/mL were excluded from the statistical analysis of the results because of possible unreported exposures to volatile combustion products such as secondhand cigarette smoke or marijuana smoke exposure; this left 22 e-cigarette users with 4 or more monthly visits and all 63 nonsmokers. Geometric mean levels of 3-HPMA (1249 versus 679.3 pmol/mL urine) were significantly higher ( P = 0.003) in e-cigarette users than in nonsmokers, whereas levels of SPMA, CEMA, and HMPMA did not differ between these two groups. All analytes were significantly higher in cigarette smokers than in either e-cigarette users or nonsmokers. The results of this unique multimonth longitudinal study demonstrate consistent significantly higher uptake of the carcinogen acrolein in e-cigarette users versus nonsmokers, presenting a warning signal regarding e-cigarette use.

Introduction: As the science base around the potential benefits of a reduced-nicotine standard for cigarettes grows, information on the potential effects on adolescent smokers is a high priority. The aim of this randomized trial was to test the influence of 3-week exposure to reduced nicotine cigarettes in a sample of adolescent daily smokers., Aims and Methods: In this double-blind, two-arm, randomized controlled trial (NCT0258731), following a 1-week baseline, adolescent daily smokers not currently intending to quit (ages 15-19 years, n = 66 randomized) were urn randomized to use either very low nicotine content (VLNC; 0.4 mg/g; n = 33) or normal nicotine content (NNC, 15.8 mg/g; n = 33) research cigarettes for 3 weeks. Participants attended five study sessions at our clinical laboratory. The primary outcome was average total cigarettes smoked per day (CPD; including both study and non-study cigarettes) at week 3., Results: Stepwise regression results demonstrated that compared with NNC cigarettes (n = 31), assignment to VLNC cigarettes (n = 29), was associated with 2.4 fewer CPD on average than NNC assignment (p < .05) week 3 when controlling for covariates (p < .01, Cohen's d = 0.52 n = 60 completed all procedures). VLNC cigarettes were also associated with lower levels of craving reduction than NNC cigarettes (Questionnaire on Smoking Urges Factor 2, p < .05). No group differences were found for secondary outcomes., Conclusions: Adolescent participants assigned to VLNC use for 3 weeks smoked fewer total CPD relative to the NNC group. Overall, data suggest that a VLNC policy would reduce cigarette smoking in adolescents who smoke, but high rates of incomplete adherence suggest that youth may seek alternative sources of nicotine in this scenario., Implications: The US Food and Drug Administration may enact a reduced-nicotine product standard that would affect all commercially available cigarettes. One important population affected by this policy would be adolescents who smoke. This study, the first clinical trial of VLNC cigarettes in adolescents, demonstrates that adolescents switched to VLNC cigarettes for 3 weeks reduced their CPD relative to the normal-nicotine cigarette control group, without leading to increased respiratory symptoms or increased withdrawal. Biomarkers indicated the use of other sources of nicotine, suggesting that such a policy will need to consider approaches to assist in transitioning away from smoking., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: While cigarette smoking is the leading cause of lung cancer, the majority of smokers do not develop the disease over their lifetime. The inter-individual differences in risk among smokers may in part be due to variations in exposure to smoking-related toxicants., Methods: Using data from a subcohort of 2,309 current smokers at the time of urine collection from the Multiethnic Cohort Study, we prospectively evaluated the association of ten urinary biomarkers of smoking-related toxicants [total nicotine equivalents (TNE), a ratio of total trans-3'-hydroxycotinine (3-HCOT)/cotinine (a phenotypic measure of CYP2A6 enzymatic activity), 4-(methylnitrosamino)-1-3-(pyridyl)-1-butanol (NNAL), S-phenylmercapturic acid (SPMA), 3-hydroxypropyl mercapturic acid (3-HPMA), phenanthrene tetraol (PheT), 3-hydroxyphenanthrene (PheOH), the ratio of PheT/PheOH, cadmium (Cd), and (Z)-7-(1R,2R,3R,5S)-3,5-dihydroxy-2-[(E,3S)-3-hydroxyoct-1-enyl]cyclopenyl]hept-5-enoic acid (8-iso-PGF2α)] with lung cancer risk (n = 140 incident lung cancer cases over an average of 13.4 years of follow-up). Lung cancer risk was estimated using Cox proportional hazards models., Results: After adjusting for decade of birth, sex, race/ethnicity, body mass index, self-reported pack-years, creatinine, and urinary TNE (a biomarker of internal smoking dose), a one SD increase in log total 3-HCOT/cotinine (HR, 1.33; 95% CI, 1.06-1.66), 3-HPMA (HR, 1.41; 95% CI, 1.07-1.85), and Cd (HR, 1.45; 95% CI, 1.18-1.79) were each associated with increased lung cancer risk., Conclusions: Our study demonstrates that urinary total 3-HCOT/cotinine, 3-HPMA, and Cd are positively associated with lung cancer risk. These findings warrant replication and consideration as potential biomarkers for smoking-related lung cancer risk., Impact: These biomarkers may provide additional information on lung cancer risk that is not captured by self-reported smoking history or TNE. See related commentary by Etemadi et al., p. 289., (©2022 American Association for Cancer Research.)

Smoking intensity varies across smokers and is influenced by individual variability in the metabolism of nicotine, the major addictive agent in tobacco. Therefore, lung cancer risk, which varies by racial ethnic group, is influenced by the primary catalyst of nicotine metabolism, cytochrome P450 2A6 (CYP2A6). In smokers, CYP2A6 catalyzes nicotine 5'-oxidation. In vitro , CYP2A6 also catalyzes, to a much lower extent, 2'-oxidation, which leads to the formation of 4-hydroxy-4-(3-pyridyl) butanoic acid (hydroxy acid). The urinary concentration of hydroxy acid has been quantified in only a few small studies of White smokers. To quantitatively assess the importance of nicotine 2'-oxidation in smokers, an LC-MS/MS-based method was developed for the analysis of nicotine and ten metabolites in urine. The concentrations of nicotine and these metabolites were measured in 303 smokers (99 Whites, 99 Native Hawaiians, and 105 Japanese Americans), and the relative metabolism of nicotine by four pathways was determined. Metabolism by these pathways was also compared across quartiles of CYP2A6 activity (measured as the plasma ratio of 3-hydroxycotinine to cotinine). As reported previously and consistent with their average CYP2A6 activity, nicotine 5'-oxidation was highest in Whites and lowest in Japanese Americans. Nicotine N -glucuronidation and N -oxidation increased with decreasing CYP2A6 activity. However, the relative urinary concentration of hydroxy acid (mean, 2.3%; 95% CI, 2.2-2.4%) did not vary by ethnic group or by CYP2A6 activity. In summary, CYP2A6 is not an important catalyst of nicotine 2'-oxidation in smokers, nor does nicotine 2'-oxidation compensate for decreased CYP2A6 activity.

Background: The COVID-19 pandemic highlighted the need for mental health interventions that can be easily disseminated during a crisis. Behavioural activation (BA) is a cost-effective treatment that can be administered by non-specialists; however, it is unclear whether it is still effective during a time of lockdown and social distancing, when opportunities for positive activity are significantly constrained., Methods: Between May and October 2020, we randomised 68 UK participants with mild to moderate low mood to either a 4-week online programme of non-specialist administered BA or to a passive control group. Before and after the intervention, we collected self-report data on mood and COVID-related disruption, as well as measuring emotional cognition as an objective marker of risk for depression., Results: In comparison to the control group, the BA group showed a significant decrease in depression, anxiety and anhedonia after the intervention, as well as an increase in self-reported activation and social support. Benefits persisted at 1-month follow-up. BA also decreased negative affective bias on several measures of the Facial Emotion Recognition Task and early change in bias was associated with later therapeutic gain. Participants rated the intervention as highly acceptable., Conclusion: This study highlights the benefits of online BA that can be administered by non-specialists after brief training. These findings can help inform the policy response towards the rising incidence of mental health problems during a crisis situation such as a pandemic. They also highlight the use of objective cognitive markers of risk across different treatment modalities.

Experimental tasks comparing participants' performance for categorising, remembering, and recognising positive and negative words are widely used in the emotional cognitive domain. Such tasks are commonly used in experimental psychology and psychiatry research, and have been shown to be sensitive biomarkers of depression and antidepressant drug action [1,2]. In addition, several of these tasks investigate self-referential processing i.e., the processing of information relevant to oneself; this has been shown to modify the way emotional words are encoded and remembered and may be a target that is amenable to treatment [3,4]. In practice, the development of such tasks for implementation in research studies often depends on the selection and matching of words according to characteristics such as valence or arousal, imageability, word frequency and word length to investigate differences in a chosen domain of interest whilst keeping important confounds constant. This introduces a need for ratings covering a range of word attributes that have been shown to affect processing. In particular, ratings of self-referential valence (how positively or negatively subjects feel about a word when this is used to describe themselves/their circumstances) have been seldom included in databases, despite the frequent investigation of the concept in research [1,5]. Other important attributes often considered in the process of matching and selection are word imageability and subjective frequency [6,7]. To facilitate the word selection and matching process required in cognitive-emotional task development, the present dataset provides subjective ratings for 150 positive and 150 negative adjectives describing personality characteristics. Across four online surveys, the 300 words were rated on self-referential valence, imageability and subjective frequency by representative samples of 200 UK-based, English-speaking adults. Basic demographics and data on depressive symptoms and state anxiety were collected from all participants. Comprehensive descriptive statistics and word length were calculated for each of the 300 words. All data cleaning and statistical analysis was performed in R. Our work is based on years of experience using the Oxford Emotional Task Battery [1,5] and may be particularly relevant for researchers using self-referential cognitive tasks with UK-based samples., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships which have or could be perceived to have influenced the work reported in this article., (© 2022 Published by Elsevier Inc.)

Impaired cognition is often overlooked in the clinical management of depression, despite its association with poor psychosocial functioning and reduced clinical engagement. There is an outstanding need for new treatments to address this unmet clinical need, highlighted by our consultations with individuals with lived experience of depression. Here we consider the evidence to support different pharmacological approaches for the treatment of impaired cognition in individuals with depression, including treatments that influence primary neurotransmission directly as well as novel targets such as neurosteroid modulation. We also consider potential methodological challenges in establishing a strong evidence base in this area, including the need to disentangle direct effects of treatment on cognition from more generalised symptomatic improvement and the identification of sensitive, reliable and objective measures of cognition., (© 2022. The Author(s).)