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Circadian omics analyses present investigators with large amounts of data to consider and many choices for methods of analysis. Visualization is crucial as rhythmicity can take many forms and p -values offer an incomplete picture. Yet statically viewing the entirety of high-throughput datasets is impractical, and there is often limited ability to assess the impact of choices, such as significance threshold cutoffs. Nitecap provides an intuitive and unified web-based solution to these problems. Through highly responsive visualizations, Nitecap enables investigators to see dataset-wide behavior. It supports deep analyses, including comparisons of two conditions. Moreover, it focuses upon ease-of-use and enables collaboration through dataset sharing. As an application, we investigated cross talk between peripheral clocks in adipose and liver tissues and determined that adipocyte clock disruption does not substantially modulate the transcriptional rhythmicity of liver but does advance the phase of core clock gene Bmal1 (Arntl) expression in the liver. Nitecap is available at nitecap.org and is free-to-use. [ABSTRACT FROM AUTHOR]

The document titled "156 Art as a Multiplier of Science Communication" discusses the use of art as a strategy to communicate clinical translational science (CTS). The authors propose a two-year pilot artist-in-residency program embedded in a Translational Research Immersion Program (TRIP) to achieve this goal. The program involves three phases: an immersive phase where the artist gains exposure to the scientific process, a productive phase where the artist conceptualizes CTS into works of art, and an engagement phase where the CTS workforce, artists, and community members come together around science-to-art materializations. The authors anticipate that this approach will strengthen the reputation of science in the public and enhance science communication. [Extracted from the article]

Current hypertension guidelines fail to provide a recommendation on when-to-treat, thus disregarding relevant circadian rhythms that regulate blood pressure (BP) level and 24 h patterning and medication pharmacokinetics and pharmacodynamics. The ideal purpose of ingestion-time (chronopharmacology, i.e. biological rhythm-dependent effects on the kinetics and dynamics of medications, and chronotherapy, i.e. the timing of pharmaceutical and other treatments to optimize efficacy and safety) trials should be to explore the potential impact of endogenous circadian rhythms on the effects of medications. Such investigations and outcome trials mandate adherence to the basic standards of human chronobiology research. In-depth review of the more than 150 human hypertension pharmacology and therapeutic trials published since 1974 that address the differential impact of upon-waking/morning versus at-bedtime/evening schedule of treatment reveals diverse protocols of sometimes suboptimal or defective design and conduct. Many have been "time-of-day," i.e. morning versus evening, rather than circadian-time-based, and some relied on wake-time office BP rather than around-the-clock ambulatory BP measurements (ABPM). Additionally, most past studies have been of too small sample size and thus statistically underpowered. As of yet, there has been no consensual agreement on the proper design, methods and conduct of such trials. This Position Statement recommends ingestion-time hypertension trials to follow minimum guidelines: (i) Recruitment of participants should be restricted to hypertensive individuals diagnosed according to ABPM diagnostic thresholds and of a comparable activity/sleep routine. (ii) Tested treatment-times should be selected according to internal biological time, expressed by the awakening and bed times of the sleep/wake cycle. (iii) ABPM should be the primary or sole method of BP assessment. (iv) The minimum-required features for analysis of the ABPM-determined 24 h BP pattern ought to be the asleep (not "nighttime") BP mean and sleep-time relative BP decline, calculated in reference to the activity/rest cycle per individual. (v) ABPM-obtained BP means should be derived by the so-called adjusted calculation procedure, not by inaccurate arithmetic averages. (vi) ABPM should be performed with validated and calibrated devices at least hourly throughout two or more consecutive 24 h periods (48 h in total) to achieve the highest reproducibility of mean wake-time, sleep-time and 48 h BP values plus the reliable classification of dipping status. (vii) Calculation of minimum required sample size in adherence with proper statistical methods must be provided. (viii) Hypertension chronopharmacology and chronotherapy trials should preferably be randomized double-blind, randomized open-label with blinded-endpoint, or crossover in design, the latter with sufficient washout period between tested treatment-time regimens. [ABSTRACT FROM AUTHOR]

Objective: Our objective was to assess the role of the reportedly functional PTGS2 (prostaglandin-endoperoxide synthase 2/cyclooxygenase [COX] 2) promoter mutation −765G>C for the COX-2–inhibiting effects of celecoxib.Methods: Twenty healthy carriers of the −765GG genotype and −765CC genotype (n = 10 each) received 200 mg of celecoxib orally. Blood samples were drawn at baseline and at 1, 3, 6, 9, and 24 hours after administration. Plasma concentrations of celecoxib and concentrations of prostaglandin E2 (PGE2) produced by peripheral blood monocytes stimulated ex vivo with bacterial lipopolysaccharide (LPS) were analyzed by liquid chromatography–tandem mass spectrometry. Expression of COX-2 messenger ribonucleic acid and protein expression with and without LPS stimulation were analyzed by real-time polymerase chain reaction and Western blotting, respectively.Results: LPS induced PGE2 production (P < .001), and celecoxib reduced PGE2 production from 19.3 ± 7.2 ng/mL at baseline to 7.4 ± 4.8 ng/mL at 1 hour (P < .001). The effect of celecoxib lasted for 9 hours (repeated-measures ANOVA, P ≤ .001). Celecoxib inhibited PGE2 production at a potency (ie, 50% effective concentration [EC50]) of 155.1 ng/mL (95% confidence interval, 101.6-208.5 ng/mL) in the homozygous carriers of the PTGS2 wild-type −765G allele and at a potency (EC50) of 186.6 ng/mL (95% confidence interval, 142.6-230.5 ng/mL) in the homozygous carriers of the PTGS2 variant −765C allele, which was not statistically significantly different (P = .36). Baseline PGE2 concentrations, minimum baseline PGE2 concentrations, and areas under the PGE2 concentration versus time curve also did not differ between PTGS2 genotypes (P > .28). LPS up-regulated COX-2 messenger ribonucleic acid expression (P = .016) but was independent of genotype (P = .36). COX-2 protein expression was similar for both −765G>C genotypes (P = .63).Conclusion: The PTGS2 −765G>C single-nucleotide polymorphism does not modulate COX-2 inhibitory effects of celecoxib as assessed by an ex vivo whole blood assay. Thus the results indicate the need for further investigation toward PTGS2 pharmacogenetics–based prescription of celecoxib.Clinical Pharmacology & Therapeutics (2006) 80, 621–632; doi: 10.1016/j.clpt.2006.08.021 [ABSTRACT FROM AUTHOR]

Objective Our objective was to investigate whether codeine or one of its metabolites contributes substantially to central nervous effects independent from the cytochrome P450 (CYP) 2D6–mediated O-demethylation to morphine.Methods After oral administration of codeine, plasma concentrations of codeine and its metabolites, as well as pupil size as a measure of central nervous effects, were measured in 11 healthy volunteers representing poor, intermediate, extensive, and ultrarapid metabolizers for CYP2D6. Subsequently, the observed plasma morphine concentrations were mimicked by use of computerized morphine infusion, and the miotic effects were compared with those observed after codeine administration. The contribution of codeine, codeine-6-glucuronide, norcodeine, morphine, morphine-6-glucuronide, and normorphine to the miotic effects was analyzed by means of pharmacokinetic-pharmacodynamic modeling.Results The areas under the curve of the miotic effects after codeine were 1.7±2 times greater than after morphine (P <0.01). This contrasted to similar or even lower morphine concentrations after codeine than after morphine (area under the curve ratio, 0.5±0.4; P = .21). A pharmacokinetic-pharmacodynamic fit of the miotic effects by use of morphine as the only active moiety was most significantly (P<.0001) improved when codeine-6-glucuronide as a second active moiety was added.Conclusion CYP2D6-dependent formation of morphine does not explain exclusively the central nervous effects of codeine. Codeine-6-glucuronide is the most likely additional active moiety.Clinical Pharmacology & Therapeutics (2006) 79, 35–48; doi: 10.1016/j.clpt.2005.09.005 [ABSTRACT FROM AUTHOR]

A noncoding C3435T mutation in exon 26 of the ABCB1 gene was found to be often associated with a G2677T(A) mutation in exon 21 encoding an Ala893Ser P-glycoprotein and with a noncoding C1236T mutation in exon 12. We developed a Pyrosequencing screening method that simultaneously detects all three mutations. After separate PCRs for each exon, the sequences around the potentially mutated nucleotide positions were simultaneously analyzed in a multiplex assay. The method was tested with DNA from 100 volunteers. Allele frequencies of the T1236, T2677, and T3435 alleles were 44, 42, and 50%, respectively. A mutation at position 3435 occurred together with a mutation at position 2677 or 1236 in 64 and 65% of the subjects, respectively. The most frequent haplotype, with 44.4%, was not mutated at all three positions, i.e., C1236, G2677, C3435. The second most frequent haplotype, with 37.1%, was mutated at all three positions, i.e., T1236, T2677, T3435. The most frequent genotype, with 36%, was heterozygously mutated at all three positions, i.e., C/T1236, G/T2677, C/T3435. The next most frequent genotypes were a homozygous nonmutated genotype, with 20%, and a homozygous mutated genotype, with 13%. [Copyright &y& Elsevier]

In light of a recent demonstration that probenecid enhanced the central nervous system (CNS) uptake of morphine-3-glucuronide (M3G), we investigated the consequences of probenecid co-administration for the spinal cord concentrations and antinociceptive effects of morphine-6-glucuronide (M6G) in rats. Spinal cord tissue concentrations of M6G were assessed by in-vivo microdialysis. Ten rats were administered M6G by intravenous infusion for 8 h, five of them additionally received an infusion of probenecid. Antinociceptive effects of M6G were assessed by means of formalin tests during the 8th h of the M6G infusion in another five rats that received M6G together with probenecid. Five additional rats per groups received probenecid only, M6G only and placebo. The inhibition of probenecid-sensitive transporters caused a raise in both plasma (statistically significant) and spinal cord tissue (not statistically significant) concentrations of M6G by a factor of 1.3, without affecting the tissue to plasma concentration ratio of M6G (0.0812±0.034 for M6G alone, 0.0824±0.021 for M6G plus probenecid). Co-administration of probenecid with M6G resulted in a significant reduction of the number of flinches by a factor of 2.5 as compared to M6G alone. The study showed that probenecid sensitive transporters play a role for the CNS concentrations of M6G via an increase of its plasma concentrations, but the effect of probenecid co-administration is small as compared to the reported effects on the CNS concentrations of M3G in rats. [Copyright &y& Elsevier]

Aging is associated with a number of physiologic changes including perturbed circadian rhythms; however, mechanisms by which rhythms are altered remain unknown. To test the idea that circulating factors mediate age-dependent changes in peripheral rhythms, we compared the ability of human serum from young and old individuals to synchronize circadian rhythms in culture. We collected blood from apparently healthy young (age 25-30) and old (age 70-76) individuals at 14:00 and used the serum to synchronize cultured fibroblasts. We found that young and old sera are equally competent at initiating robust ~24 hr oscillations of a luciferase reporter driven by clock gene promoter. However, cyclic gene expression is affected, such that young and old sera promote cycling of different sets of genes. Genes that lose rhythmicity with old serum entrainment are associated with oxidative phosphorylation and Alzheimer's Disease as identified by STRING and IPA analyses. Conversely, the expression of cycling genes associated with cholesterol biosynthesis increased in the cells entrained with old serum. Genes involved in the cell cycle and transcription/translation remain rhythmic in both conditions. We did not observe a global difference in the distribution of phase between groups, but found that peak expression of several clock-controlled genes ( PER3, NR1D1, NR1D2, CRY1, CRY2, and TEF ) lagged in the cells synchronized ex vivo with old serum. Taken together, these findings demonstrate that age-dependent blood-borne factors affect circadian rhythms in peripheral cells and have the potential to impact health and disease via maintaining or disrupting rhythms respectively., Competing Interests: JS, AM, NL, YL, CH, GG, CS, SZ No competing interests declared, AS Reviewing editor, eLife, (© 2023, Schwarz et al.)