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Oral fluid (OF) is an advantageous matrix for cannabis detection, with on-site tests available for roadside drug-impaired driver screening. Limited data exist for device performance following consumption of vaporized cannabis, which reduces exposure to harmful combustion by-products. We assessed cannabinoid OF disposition, with and without alcohol, and evaluated on-site Dräger ® DrugTest 5000 performance (Dräger) following controlled vaporization of cannabis. Forty-three cannabis smokers (≥1×/3 months, ≤3 days/week) reported 10–16 h prior to dosing, and drank placebo or low-dose alcohol [target ~0.065 % peak breath-alcohol concentration (BrAC)] 10 min prior to inhaling 500 mg of placebo, low-dose [2.9 % ∆ 9 -tetrahydrocannabinol (THC)], or high-dose (6.7 % THC) vaporized cannabis (within-subjects; six possible alcohol–cannabis combinations; 19 completers). BrAC readings and OF (Quantisal™, Dräger) were collected before and up to 8.3 h post-dose. Median [range] maximum OF concentrations ( C max ) for low and high doses (no alcohol, N  = 19) were 848 [32.1–18,230] and 764 [25.1–23,680] µg/l THC; 6.0 [0–100] and 26.8 [1.0–1106] µg/l cannabidiol; 54.4 [1.8–941] and 29.7 [0–766] µg/l cannabinol; and 24.1 [0–686] and 18.0 [0–414] ng/l 11-nor-9-carboxy-THC (THCCOOH). Lack of significant differences in THC concentration between low doses and high doses indicated that participants may have titrated doses. THC, cannabidiol and cannabinol C max values were immediately post-inhalation, but metabolite THCCOOH t max showed interindividual variability. Concurrent alcohol did not affect OF cannabinoid concentrations or on-site test sensitivity. With a THC confirmation cutoff of 5 µg/l, Dräger sensitivity, specificity, and efficiency were 60.8, 98.2, and 82.5 %. Dräger had lower sensitivity after 6.7 % THC vaporization (53.8 %, THC ≥2 µg/l confirmation cutoff) than reported following smoking a 6.8 % THC cigarette, but high specificity (99.3 %) and comparable efficiency (65.0 %). Vaporized THC bioavailability may be lower than that when smoked. Confirmation cutoff, time course, intake histories, and additional cannabinoid analytes also affect OF interpretation.

Increased medical and legal cannabis intake is accompanied by greater use of cannabis vaporization and more cases of driving under the influence of cannabis. Although simultaneous Δ(9)-tetrahydrocannabinol (THC) and alcohol use is frequent, potential pharmacokinetic interactions are poorly understood. Here we studied blood and plasma vaporized cannabinoid disposition, with and without simultaneous oral low-dose alcohol. Thirty-two adult cannabis smokers (≥1 time/3 months, ≤3 days/week) drank placebo or low-dose alcohol (target approximately 0.065% peak breath-alcohol concentration) 10 min before inhaling 500 mg placebo, low-dose (2.9%) THC, or high-dose (6.7%) THC vaporized cannabis (6 within-individual alcohol-cannabis combinations). Blood and plasma were obtained before and up to 8.3 h after ingestion. Nineteen participants completed all sessions. Median (range) maximum blood concentrations (Cmax) for low and high THC doses (no alcohol) were 32.7 (11.4-66.2) and 42.2 (15.2-137) μg/L THC, respectively, and 2.8 (0-9.1) and 5.0 (0-14.2) μg/L 11-OH-THC. With alcohol, low and high dose Cmax values were 35.3 (13.0-71.4) and 67.5 (18.1-210) μg/L THC and 3.7 (1.4-6.0) and 6.0 (0-23.3) μg/L 11-OH-THC, significantly higher than without alcohol. With a THC detection cutoff of ≥1 μg/L, ≥16.7% of participants remained positive 8.3 h postdose, whereas ≤21.1% were positive by 2.3 h with a cutoff of ≥5 μg/L. Vaporization is an effective THC delivery route. The significantly higher blood THC and 11-OH-THC Cmax values with alcohol possibly explain increased performance impairment observed from cannabis-alcohol combinations. Chosen driving-related THC cutoffs should be considered carefully to best reflect performance impairment windows. Our results will help facilitate forensic interpretation and inform the debate on drugged driving legislation.

In driving-under-the-influence cases, blood typically is collected approximately 1.5- 4 h after an incident, with unknown last intake time. This complicates blood Δ^sup 9^-tetrahydrocannabinol (THC) interpretation, owing to rapidly decreasing concentrations immediately after inhalation. We evaluated how decreases in blood THC concentration before collection may affect interpretation of toxicological results. Adult cannabis smokers (≥1×/3 months, ≤3 days/week) drank placebo or low-dose alcohol (approximately 0.065% peak breath alcohol concentration) 10 min before inhaling 500 mg placebo, 2.9%, or 6.7% vaporized THC (within-individuals), then took simulated drives 0.5-1.3 h postdose. Blood THC concentrations were determined before and up to 8.3 h postdose (limit of quantification 1 µg/L). In 18 participants, observed C^sub max^ (at 0.17 h) for active (2.9 or 6.7% THC) cannabis were [median (range)] 38.2 µg/L (11.4-137) without alcohol and 47.9 µg/L (13.0 -210) with alcohol. THC C^sub max^ concentration decreased 73.5% (3.3%- 89.5%) without alcohol and 75.1% (11.5%- 85.4%) with alcohol in the first half-hour after active cannabis and 90.3% (76.1%-100%) and 91.3% (53.8%-97.0%), respectively, by 1.4 h postdose. When residual THC (from previous self-administration) was present, concentrations rapidly decreased to preinhalation baselines and fluctuated around them. During-drive THC concentrations previously associated with impairment (≥8.2 µg/L) decreased to median <5 µg/L by 3.3 h postdose and >2 µg/L by 4.8 h postdose; only 1 participant had THC ≥5 µg/L after 3.3 h. Forensic blood THC concentrations may be lower than common per se cutoffs despite greatly exceeding them while driving. Concentrations during driving cannot be back-extrapolated because of unknown time after intake and interindividual variability in rates of decrease.

In driving-under-the-influence cases, blood typically is collected approximately 1.5-4 h after an incident, with unknown last intake time. This complicates blood Δ(9)-tetrahydrocannabinol (THC) interpretation, owing to rapidly decreasing concentrations immediately after inhalation. We evaluated how decreases in blood THC concentration before collection may affect interpretation of toxicological results. Adult cannabis smokers (≥1×/3 months, ≤3 days/week) drank placebo or low-dose alcohol (approximately 0.065% peak breath alcohol concentration) 10 min before inhaling 500 mg placebo, 2.9%, or 6.7% vaporized THC (within-individuals), then took simulated drives 0.5-1.3 h postdose. Blood THC concentrations were determined before and up to 8.3 h postdose (limit of quantification 1 μg/L). In 18 participants, observed Cmax (at 0.17 h) for active (2.9 or 6.7% THC) cannabis were [median (range)] 38.2 μg/L (11.4-137) without alcohol and 47.9 μg/L (13.0-210) with alcohol. THC Cmax concentration decreased 73.5% (3.3%-89.5%) without alcohol and 75.1% (11.5%-85.4%) with alcohol in the first half-hour after active cannabis and 90.3% (76.1%-100%) and 91.3% (53.8%-97.0%), respectively, by 1.4 h postdose. When residual THC (from previous self-administration) was present, concentrations rapidly decreased to preinhalation baselines and fluctuated around them. During-drive THC concentrations previously associated with impairment (≥8.2 μg/L) decreased to median <5 μg/L by 3.3 h postdose and <2 μg/L by 4.8 h postdose; only 1 participant had THC ≥5 μg/L after 3.3 h. Forensic blood THC concentrations may be lower than common per se cutoffs despite greatly exceeding them while driving. Concentrations during driving cannot be back-extrapolated because of unknown time after intake and interindividual variability in rates of decrease.

Centrally-acting Pituitary adenylate cyclase-activating polypeptide (PACAP) is involved in hypothalamo-pituitary-adrenocortical (HPA) and sympatho-adrenal (SA) responses to stress. Evidence for an intra-adrenal PACAPergic system is mounting although information is lacking about its responsiveness to different stressors, especially as it compares to responses seen in other adrenal stress systems involving glucocorticoids and catecholamines. My work examines the impact of various physiological, psychological, and environmental stressors on markers of HPA and HSA activity in the adrenal gland and hypothalamus. Markers evaluated in these studies include mRNA expression of adrenal PACAP, steroidogenic acute regulatory protein (StAR), a chaperone protein crucial for making cholesterol available for the initiation of steroid biosynthesis and melanocortin receptor accessory protein (MRAP), essential for trafficking of the adrenocorticotropic hormone receptor, melanocortin 2 (MC2R), CA biosynthetic enzymes tyrosine hydroxylase (TH), and phenylethanolamine N-methyltransferase (PNMT), which methylates norepinephrine to epinephrine. In addition, I attempted to place markers for altered gene expression within the context of current perceptions on the etiology of hypertension. Lastly, I developed a reproducible procedure for studying a possible non-invasive treatment for hypertension using the application of variable pressures during massage-like stroking in rats.

Every Dickens novel contains many different images of Dickens himself: Dickens the social critic, the benevolent Christian, the beloved entertainer, and so on. Such images were not only familiar to millions of readers in Dickens's own day; they continue to shape our own critical encounters with Dickens in the present. Modern literary critics have long debated the question of Dickens's \"true identity\"; and they still disagree about whether he was \"really\" a radical or a conservative, a visionary or a bourgeois, a romantic or a realist. My view is that Dickens created the possibilities we now consider, moving among his different personae in order to manage his career and maintain his enormous popularity. Instead of trying to decide which one of these images was the most accurate and authentic, I prefer to ask how they all were constructed, to see them as products of an ongoing dialogue between the author and his contemporary audience. This approach is especially appropriate to the case of an author like Dickens--one who was not only a great writer, but also a public figure, a celebrity, and cultural icon. Almost from the beginning of his literary career, Dickens enjoyed the kind of fame now reserved for movie stars and rock bands: he was recognized everywhere and, at times, actually mobbed by surging crowds. Much of this project could be described as an attempt to understand what this experience of fame meant to Dickens's writing. In every chapter, I have tried to explore what fame did to Dickens and what Dickens did to remain famous. First, I consider Nicholas Nickleby (1838-1839), the novel in which Dickens is said to have established himself as something more than an \"infant phenomenon.\" Next, I go on to David Copperfield (1849-1850), showing how this book reflects Dickens's anxieties about his personal reputation and his status as a conspicuous public figure. Finally, I examine Great Expectations (1860-1861) as a kind of come-back for Dickens, in which he responds to complaints about the dark tone of his recent work.

We used extensive data from a long-term study of great tits (Parus major) in the United Kingdom and Netherlands to better understand how genetic signatures of selection translate into variation in fitness and phenotypes. We found that genomic regions under differential selection contained candidate genes for bill morphology and used genetic architecture analyses to confirm that these genes, especially the collagen gene COL4A5, explained variation in bill length. COL4A5 variation was associated with reproductive success, which, combined with spatiotemporal patterns of bill length, suggested ongoing selection for longer bills in the United Kingdom. Last, bill length and COL4A5 variation were associated with usage of feeders, suggesting that longer bills may have evolved in the United Kingdom as a response to supplementary feeding.

Dimethylsulfoniopropionate (DMSP) and its catabolite dimethyl sulfide (DMS) are key marine nutrients 1 , 2 that have roles in global sulfur cycling 2 , atmospheric chemistry 3 , signalling 4 , 5 and, potentially, climate regulation 6 , 7 . The production of DMSP was previously thought to be an oxic and photic process that is mainly confined to the surface oceans. However, here we show that DMSP concentrations and/or rates of DMSP and DMS synthesis are higher in surface sediment from, for example, saltmarsh ponds, estuaries and the deep ocean than in the overlying seawater. A quarter of bacterial strains isolated from saltmarsh sediment produced DMSP (up to 73 mM), and we identified several previously unknown producers of DMSP. Most DMSP-producing isolates contained dsyB 8 , but some alphaproteobacteria, gammaproteobacteria and actinobacteria used a methionine methylation pathway independent of DsyB that was previously only associated with higher plants. These bacteria contained a methionine methyltransferase gene ( mmtN )—a marker for bacterial synthesis of DMSP through this pathway. DMSP-producing bacteria and their dsyB and/or mmtN transcripts were present in all of the tested seawater samples and Tara Oceans bacterioplankton datasets, but were much more abundant in marine surface sediment. Approximately 1 × 10 8 bacteria g −1 of surface marine sediment are predicted to produce DMSP, and their contribution to this process should be included in future models of global DMSP production. We propose that coastal and marine sediments, which cover a large part of the Earth’s surface, are environments with high levels of DMSP and DMS productivity, and that bacteria are important producers of DMSP and DMS within these environments. Bacterial dimethylsulfoniopropionate (DMSP) production was recently demonstrated in surface oceans. Here the authors show that bacterial production is higher in sediment from coastal areas and the deep ocean, and identify an alternative pathway for its synthesis, indicating that coastal and marine sediments are important sources of this climate-relevant metabolite.

Dimethylsulfoniopropionate (DMSP) is a globally important organosulfur molecule and the major precursor for dimethyl sulfide. These compounds are important info-chemicals, key nutrients for marine microorganisms, and are involved in global sulfur cycling, atmospheric chemistry and cloud formation 1 – 3 . DMSP production was thought to be confined to eukaryotes, but heterotrophic bacteria can also produce DMSP through the pathway used by most phytoplankton 4 , and the DsyB enzyme catalysing the key step of this pathway in bacteria was recently identified 5 . However, eukaryotic phytoplankton probably produce most of Earth’s DMSP, yet no DMSP biosynthesis genes have been identified in any such organisms. Here we identify functional dsyB homologues, termed DSYB , in many phytoplankton and corals. DSYB is a methylthiohydroxybutryate methyltransferase enzyme localized in the chloroplasts and mitochondria of the haptophyte Prymnesium parvum , and stable isotope tracking experiments support these organelles as sites of DMSP synthesis. DSYB transcription levels increased with DMSP concentrations in different phytoplankton and were indicative of intracellular DMSP. Identification of the eukaryotic DSYB sequences, along with bacterial dsyB , provides the first molecular tools to predict the relative contributions of eukaryotes and prokaryotes to global DMSP production. Furthermore, evolutionary analysis suggests that eukaryotic DSYB originated in bacteria and was passed to eukaryotes early in their evolution. Identification of functional dsyB gene homologues for dimethylsulfoniopropionate production in eukaryotic phytoplankton allows estimation of the relative contributions of eukaryotes and prokaryotes to the global pool, and indicates that this enzyme originated in bacteria.