Tuning π-Acceptor/σ-Donor Ratio of the 2-Isocyanoazulene Ligand: Non-Fluorinated Rival of Pentafluorophenyl Isocyanide and Trifluorovinyl Isocyanide Discovered

Isocyanoazulenes (CNAz) constitute a relatively new class of isocyanoarenes that offers rich structural and electronic diversification of the organic isocyanide ligand platform. This article considers a series of 2-isocyano-1,3-X2-azulene ligands (X = H, Me, CO2Et, Br, and CN) and the corresponding zero-valent complexes thereof, [(OC)5Cr(2-isocyano-1,3-X2-azulene)]. Air- and thermally stable, X-ray structurally characterized 2-isocyano-1,3-dimethylazulene may be viewed as a non-benzenoid aromatic congener of 2,6-dimethyphenyl isocyanide (2,6-xylyl isocyanide), a longtime “workhorse” aryl isocyanide ligand in coordination chemistry. Single crystal X-ray crystallographic {Cr–CNAz bond distances}, cyclic voltametric {E1/2(Cr0/1+)}, 13C NMR {δ(13CN), δ(13CO)}, UV-vis {dπ(Cr) → pπ*(CNAz) Metal-to-Ligand Charge Transfer}, and FTIR {νN≡C, νC≡O, kC≡O} analyses of the [(OC)5Cr(2-isocyano-1,3-X2-azulene)] complexes provided a multifaceted, quantitative assessment of the π-acceptor/σ-donor characteristics of the above five 2-isocyanoazulenes. In particular, the following inverse linear relationships were documented: δ(13COtrans) vs. δ(13CN), δ(13COcis) vs. δ(13CN), and δ(13COtrans) vs. kC≡O,trans force constant. Remarkably, the net electron withdrawing capability of the 2-isocyano-1,3-dicyanoazulene ligand rivals those of perfluorinated isocyanides CNC6F5 and CNC2F3

Exploring the relationship between polygenic risk for cannabis use, peer cannabis use, and the longitudinal course of cannabis involvement

Background and aims: Few studies have explored how polygenic propensity to cannabis use unfolds across development, and no studies have yet examined this question in the context of environmental contributions such as peer cannabis use. Outlining the factors that contribute to progression from cannabis initiation to problem use over time may ultimately provide insights into mechanisms for targeted interventions. We sought to examine the relationships between polygenic liability for cannabis use, cannabis use trajectories across ages 12–30, and perceived peer cannabis use at ages 12–17. Design: Mixed effect logistic and linear regressions were used to examine associations between polygenic risk scores, cannabis use trajectory membership, and perceived peer cannabis use. Setting: USA Participants: From the Collaborative Study on the Genetics of Alcoholism (COGA) study, a cohort of 1,167 individuals aged 12–26 years at their baseline (i.e., first) interview. Measurements: Key measurements included lifetime cannabis use (yes/no), frequency of past 12-month cannabis use, maximum lifetime frequency of cannabis use, cannabis use disorder (using DSM-5 criteria), and perceived peer cannabis use. Polygenic risk scores (PRS) were created using summary statistics from a large (N = 162,082) genome-wide association study (GWAS) of cannabis use. Three trajectories reflecting no/low (n=844), moderate (n=137) and high (n=186) use were identified. PRS were significantly associated with trajectory membership (p=0.002 – 0.006, maximum conditional R2 = 0.014, ORs = 1.40 – 1.49). Individuals who reported that most/all of their best friends used cannabis had significantly higher PRS than those who reported that none of their friends were users (OR = 1.35, 95% C.I. = [1.04, 1.75], p = 0.023). Perceived peer use itself explained up to 11.3% of the variance in trajectory class membership (OR: 1.50 – 4.65). When peer cannabis use and the cannabis use PRS were entered into the model simultaneously, both the PRS and peer use continued to be significantly associated with class membership (p < 0.01). Conclusions: Genetic propensity to cannabis use derived from heterogeneous samples appears to correlate with longitudinal increases in cannabis use frequency in young adults

HSD3B1 genotype identifies glucocorticoid responsiveness in severe asthma

Asthma resistance to glucocorticoid treatment is a major health problem with unclear etiology. Glucocorticoids inhibit adrenal androgen production. However, androgens have potential benefits in asthma. HSD3B1 encodes for 3β-hydroxysteroid dehydrogenase-1 (3β-HSD1), which catalyzes peripheral conversion from adrenal dehydroepiandrosterone (DHEA) to potent androgens and has a germline missense-encoding polymorphism. The adrenal restrictive HSD3B1(1245A) allele limits conversion, whereas the adrenal permissive HSD3B1(1245C) allele increases DHEA metabolism to potent androgens. In the Severe Asthma Research Program (SARP) III cohort, we determined the association between DHEA-sulfate and percentage predicted forced expiratory volume in 1 s (FEV1PP). HSD3B1(1245) genotypes were assessed, and association between adrenal restrictive and adrenal permissive alleles and FEV1PP in patients with (GC) and without (noGC) daily oral glucocorticoid treatment was determined (n = 318). Validation was performed in a second cohort (SARP I&II; n = 184). DHEA-sulfate is associated with FEV1PP and is suppressed with GC treatment. GC patients homozygous for the adrenal restrictive genotype have lower FEV1PP compared with noGC patients (54.3% vs. 75.1%; P < 0.001). In patients with the homozygous adrenal permissive genotype, there was no FEV1PP difference in GC vs. noGC patients (73.4% vs. 78.9%; P = 0.39). Results were independently confirmed: FEV1PP for homozygous adrenal restrictive genotype in GC vs. noGC is 49.8 vs. 63.4 (P < 0.001), and for homozygous adrenal permissive genotype, it is 66.7 vs. 67.7 (P = 0.92). The adrenal restrictive HSD3B1(1245) genotype is associated with GC resistance. This effect appears to be driven by GC suppression of 3β-HSD1 substrate. Our results suggest opportunities for prediction of GC resistance and pharmacologic intervention

Quantitative correlation between promoter methylation and messenger RNA levels of the reduced folate carrier

<p>Abstract</p> <p>Background</p> <p>Methotrexate (MTX) uptake is mediated by the reduced folate carrier (RFC). Defective drug uptake in association with decreased RFC expression is a common mechanism of MTX resistance in many tumor types. Heavy promoter methylation was previously identified as a basis for the complete silencing of RFC in MDA-MB-231 breast cancer cells, its role and prevalence in RFC transcription regulation are, however, not widely studied.</p> <p>Methods</p> <p>In the current study, RFC promoter methylation was assessed using methylation specific PCR in a panel of malignant cell lines (n = 8), including MDA-MB-231, and M805, a MTX resistant cell line directly established from the specimen of a patient with malignant fibrohistocytoma, whom received multiple doses of MTX. A quantitative approach of real-time PCR for measuring the extent of RFC promoter methylation was developed, and was validated by direct bisulfite genomic sequencing. RFC mRNA levels were determined by quantitative real-time RT-PCR and were related to the extent of promoter methylation in these cell lines.</p> <p>Results</p> <p>A partial promoter methylation and RFC mRNA down-regulation were observed in M805. Using the quantitative approach, a reverse correlation (correlation coefficient = -0.59, <it>p </it>< 0.05) was identified between the promoter methylation and RFC mRNA levels in this a panel of malignant cell lines.</p> <p>Conclusion</p> <p>This study further suggests that promoter methylation is a potential basis for MTX resistance. The quantitative correlation identified in this study implies that promoter methylation is possibly a mechanism involved in the fine regulation of RFC transcription.</p

Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis

Allergic rhinitis is the most common clinical presentation of allergy, affecting 400 million people worldwide, with increasing incidence in westernized countries1,2. To elucidate the genetic architecture and understand the underlying disease mechanisms, we carried out a meta-analysis of allergic rhinitis in 59,762 cases and 152,358 controls of European ancestry and identified a total of 41 risk loci for allergic rhinitis, including 20 loci not previously associated with allergic rhinitis, which were confirmed in a replication phase of 60,720 cases and 618,527 controls. Functional annotation implicated genes involved in various immune pathways, and fine mapping of the HLA region suggested amino acid variants important for antigen binding. We further performed genome-wide association study (GWAS) analyses of allergic sensitization against inhalant allergens and nonallergic rhinitis, which suggested shared genetic mechanisms across rhinitis-related traits. Future studies of the identified loci and genes might identify novel targets for treatment and prevention of allergic rhinitis

Ecology and Transmission of Buruli Ulcer Disease: A Systematic Review

Buruli ulcer is a neglected emerging disease that has recently been reported in some countries as the second most frequent mycobacterial disease in humans after tuberculosis. Cases have been reported from at least 32 countries in Africa (mainly west), Australia, Southeast Asia, China, Central and South America, and the Western Pacific. Large lesions often result in scarring, contractual deformities, amputations, and disabilities, and in Africa, most cases of the disease occur in children between the ages of 4–15 years. This environmental mycobacterium, Mycobacterium ulcerans, is found in communities associated with rivers, swamps, wetlands, and human-linked changes in the aquatic environment, particularly those created as a result of environmental disturbance such as deforestation, dam construction, and agriculture. Buruli ulcer disease is often referred to as the “mysterious disease” because the mode of transmission remains unclear, although several hypotheses have been proposed. The above review reveals that various routes of transmission may occur, varying amongst epidemiological setting and geographic region, and that there may be some role for living agents as reservoirs and as vectors of M. ulcerans, in particular aquatic insects, adult mosquitoes or other biting arthropods. We discuss traditional and non-traditional methods for indicting the roles of living agents as biologically significant reservoirs and/or vectors of pathogens, and suggest an intellectual framework for establishing criteria for transmission. The application of these criteria to the transmission of M. ulcerans presents a significant challenge

High Polygenic Risk Scores Are Associated With Early Age of Onset of Alcohol Use Disorder in Adolescents and Young Adults at Risk

Background Genome-wide association studies have been conducted in alcohol use disorder (AUD), and they permit the use of polygenic risk scores (PRSs), in combination with clinical variables, to predict the onset of AUD in vulnerable populations. Methods A total of 2794 adolescent/young adult subjects from the Collaborative Study on the Genetics of Alcoholism were followed, with clinical assessments every 2 years. Subjects were genotyped using a genome-wide chip. Separate PRS analyses were performed for subjects of European ancestry and African ancestry. Age of onset of DSM-5 AUD was evaluated using the Cox proportional hazard model. Predictive power was assessed using receiver operating characteristic curves and by analysis of the distribution of PRS. Results European ancestry subjects with higher than median PRSs were at greater risk for onset of AUD than subjects with lower than median PRSs (p = 3 × 10–7). Area under the curve for the receiver operating characteristic analysis peaked at 0.88 to 0.95 using PRS plus sex, family history, comorbid disorders, age at first drink, and peer drinking; predictive power was primarily driven by clinical variables. In this high-risk sample, European ancestry subjects with a PRS score in the highest quartile showed a 72% risk for developing AUD and a 35% risk of developing severe AUD (compared with risks of 54% and 16%, respectively, in the lowest quartile). Conclusions Predictive power for PRSs in the extremes of the distribution suggests that these may have future clinical utility. Uncertainties in interpretation at the individual level still preclude current application

Global collision-risk hotspots of marine traffic and the world’s largest fish, the whale shark

© The Author(s), 2022. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Womersley, F. C., Humphries, N. E., Queiroz, N., Vedor, M., da Costa, I., Furtado, M., Tyminski, J. P., Abrantes, K., Araujo, G., Bach, S. S., Barnett, A., Berumen, M. L., Bessudo Lion, S., Braun, C. D., Clingham, E., Cochran, J. E. M., de la Parra, R., Diamant, S., Dove, A. D. M., Dudgeon, C. L., Erdmann, M. V., Espinoza, E., Fitzpatrick, R., González Cano, J., Green, J. R., Guzman, H. M., Hardenstine, R., Hasan, A., Hazin, F. H. V., Hearn, A. R., Hueter, R. E., Jaidah, M. Y., Labaja, J., Ladinol, F., Macena, B. C. L., Morris Jr., J. J., Norman, B. M., Peñaherrera-Palmav, C., Pierce, S. J., Quintero, L. M., Ramırez-Macías, D., Reynolds, S. D., Richardson, A. J., Robinson, D. P., Rohner, C. A., Rowat, D. R. L., Sheaves, M., Shivji, M. S., Sianipar, A. B., Skomal, G. B., Soler, G., Syakurachman, I., Thorrold, S. R., Webb, D. H., Wetherbee, B. M., White, T. D., Clavelle, T., Kroodsma, D. A., Thums, M., Ferreira, L. C., Meekan, M. G., Arrowsmith, L. M., Lester, E. K., Meyers, M. M., Peel, L. R., Sequeira, A. M. M., Eguıluz, V. M., Duarte, C. M., & Sims, D. W. Global collision-risk hotspots of marine traffic and the world’s largest fish, the whale shark. Proceedings of the National Academy of Sciences of the United States of America, 119(20), (2022): e2117440119, https://doi.org/10.1073/pnas.2117440119.Marine traffic is increasing globally yet collisions with endangered megafauna such as whales, sea turtles, and planktivorous sharks go largely undetected or unreported. Collisions leading to mortality can have population-level consequences for endangered species. Hence, identifying simultaneous space use of megafauna and shipping throughout ranges may reveal as-yet-unknown spatial targets requiring conservation. However, global studies tracking megafauna and shipping occurrences are lacking. Here we combine satellite-tracked movements of the whale shark, Rhincodon typus, and vessel activity to show that 92% of sharks’ horizontal space use and nearly 50% of vertical space use overlap with persistent large vessel (>300 gross tons) traffic. Collision-risk estimates correlated with reported whale shark mortality from ship strikes, indicating higher mortality in areas with greatest overlap. Hotspots of potential collision risk were evident in all major oceans, predominantly from overlap with cargo and tanker vessels, and were concentrated in gulf regions, where dense traffic co-occurred with seasonal shark movements. Nearly a third of whale shark hotspots overlapped with the highest collision-risk areas, with the last known locations of tracked sharks coinciding with busier shipping routes more often than expected. Depth-recording tags provided evidence for sinking, likely dead, whale sharks, suggesting substantial “cryptic” lethal ship strikes are possible, which could explain why whale shark population declines continue despite international protection and low fishing-induced mortality. Mitigation measures to reduce ship-strike risk should be considered to conserve this species and other ocean giants that are likely experiencing similar impacts from growing global vessel traffic.Funding for data analysis was provided by the UK Natural Environment Research Council (NERC) through a University of Southampton INSPIRE DTP PhD Studentship to F.C.W. Additional funding for data analysis was provided by NERC Discovery Science (NE/R00997/X/1) and the European Research Council (ERC-AdG-2019 883583 OCEAN DEOXYFISH) to D.W.S., Fundação para a Ciência e a Tecnologia (FCT) under PTDC/BIA/28855/2017 and COMPETE POCI-01–0145-FEDER-028855, and MARINFO–NORTE-01–0145-FEDER-000031 (funded by Norte Portugal Regional Operational Program [NORTE2020] under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund–ERDF) to N.Q. FCT also supported N.Q. (CEECIND/02857/2018) and M.V. (PTDC/BIA-COM/28855/2017). D.W.S. was supported by a Marine Biological Association Senior Research Fellowship. All tagging procedures were approved by institutional ethical review bodies and complied with all relevant ethical regulations in the jurisdictions in which they were performed. Details for individual research teams are given in SI Appendix, section 8. Full acknowledgments for tagging and field research are given in SI Appendix, section 7. This research is part of the Global Shark Movement Project (https://www.globalsharkmovement.org)

蓮華寺池と西湖 : 石野雲嶺の風景

The potential for increased drought frequency and severity linked to anthropogenic climate change in the semi-arid regions of the southwestern United States (US) is a serious concern1. Multi-year droughts during the instrumental period2 and decadal-length droughts of the past two millennia1, 3 were shorter and climatically different from the future permanent, ‘dust-bowl-like’ megadrought conditions, lasting decades to a century, that are predicted as a consequence of warming4. So far, it has been unclear whether or not such megadroughts occurred in the southwestern US, and, if so, with what regularity and intensity. Here we show that periods of aridity lasting centuries to millennia occurred in the southwestern US during mid-Pleistocene interglacials. Using molecular palaeotemperature proxies5 to reconstruct the mean annual temperature (MAT) in mid-Pleistocene lacustrine sediment from the Valles Caldera, New Mexico, we found that the driest conditions occurred during the warmest phases of interglacials, when the MAT was comparable to or higher than the modern MAT. A collapse of drought-tolerant C4 plant communities during these warm, dry intervals indicates a significant reduction in summer precipitation, possibly in response to a poleward migration of the subtropical dry zone. Three MAT cycles ~2 °C in amplitude occurred within Marine Isotope Stage (MIS) 11 and seem to correspond to the muted precessional cycles within this interglacial. In comparison with MIS 11, MIS 13 experienced higher precessional-cycle amplitudes, larger variations in MAT (4–6 °C) and a longer period of extended warmth, suggesting that local insolation variations were important to interglacial climatic variability in the southwestern US. Comparison of the early MIS 11 climate record with the Holocene record shows many similarities and implies that, in the absence of anthropogenic forcing, the region should be entering a cooler and wetter phase