Patients with naproxen-induced liver injury display T-cell memory responses toward an oxidative (S)-O-Desmethyl Naproxen metabolite but not the acyl glucuronide

Background Exposure to nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen (IBU) and naproxen (NAP) is associated with idiosyncratic drug-induced liver injury (DILI). Carboxylate bioactivation into reactive metabolites (e.g., acyl glucuronides, AG) and resulting T-cell activation is hypothesized as causal for this adverse event. However, conclusive evidence supporting this is lacking. Methods In this work, we identify CD4+ and CD8+ T-cell hepatic infiltration in a biopsy from an IBU DILI patient. Lymphocyte transformation test and IFN-γ ELIspot, conducted on peripheral blood mononuclear cells (PBMCs) of patients with NAP-DILI, were used to explore drug-specific T-cell activation. T-cell clones (TCC) were generated and tested for drug specificity, phenotype/function, and pathways of T-cell activation. Cells were exposed to NAP, its oxidative metabolite 6-O-desmethyl NAP (DM-NAP), its AG or synthesized NAP-AG human-serum albumin adducts (NAP-AG adduct). Results CD4+ and CD8+ T-cells from patients expressing a range of different Vβ receptors were stimulated to proliferate and secrete IFN-γ and IL-22 when exposed to DM-NAP, but not NAP, NAP-AG or the NAP-AG adduct. Activation of the CD4+ TCC was HLA-DQ-restricted and dependent on antigen presenting cells (APC); most TCC were activated with DM-NAP-pulsed APC, while fixation of APC blocked the T-cell response. Cross-reactivity was not observed with structurally-related drugs. Conclusion Our results confirm hepatic T-cell infiltrations in NSAID-induced DILI, and show a T-cell memory response toward DM-NAP indicating an immune-mediated basis for the adverse event. Whilst bioactivation at the carboxylate group is widely hypothesized to be pathogenic for NSAID associated DILI, we found no evidence of this with NAP

Design and sensitivity of a 6-axis seismometer for gravitational wave observatories

We present the design, control system, and noise analysis of a 6-axis seismometer comprising a mass suspended by a single fused silica fiber. We utilize custom-made, compact Michelson interferometers for the readout of the mass motion relative to the table and successfully overcome the sensitivity of existing commercial seismometers by over an order of magnitude in the angular degrees of freedom. We develop the sensor for gravitational-wave observatories, such as LIGO, Virgo, and KAGRA, to help them observe intermediate-mass black holes, increase their duty cycle, and improve localization of sources. Our control system and its achieved sensitivity makes the sensor suitable for other fundamental physics experiments, such as tests of semiclassical gravity, searches for bosonic dark matter, and studies of the Casimir force

Design and sensitivity of a 6-axis seismometer for gravitational wave observatories

We present the design, control system, and noise analysis of a 6-axis seismometer comprising a mass suspended by a single fused silica fiber. We utilize custom-made, compact Michelson interferometers for the readout of the mass motion relative to the table and successfully overcome the sensitivity of existing commercial seismometers by over an order of magnitude in the angular degrees of freedom. We develop the sensor for gravitational-wave observatories, such as LIGO, Virgo, and KAGRA, to help them observe intermediate-mass black holes, increase their duty cycle, and improve localization of sources. Our control system and its achieved sensitivity makes the sensor suitable for other fundamental physics experiments, such as tests of semiclassical gravity, searches for bosonic dark matter, and studies of the Casimir force

Design and sensitivity of a 6-axis seismometer for gravitational wave observatories

We present the design, control system, and noise analysis of a 6-axis seismometer comprising a mass suspended by a single fused silica fibre. We utilise custom-made, compact Michelson interferometers for the readout of the mass motion relative to the table and successfully overcome the sensitivity of existing commercial seismometers by over an order of magnitude in the angular degrees of freedom. We develop the sensor for gravitational-wave observatories, such as LIGO, Virgo, and KAGRA, to help them observe intermediate-mass black holes, increase their duty cycle, and improve localisation of sources. Our control system and its achieved sensitivity makes the sensor suitable for other fundamental physics experiments, such as tests of semiclassical gravity, searches for bosonic dark matter, and studies of the Casimir force

Identification of a candidate gene for astigmatism

PURPOSE. Astigmatism is a common refractive error that reduces vision, where the curvature and refractive power of the cornea in one meridian are less than those of the perpendicular axis. It is a complex trait likely to be influenced by both genetic and environmental factors. Twin studies of astigmatism have found approximately 60% of phenotypic variance is explained by genetic factors. This study aimed to identify susceptibility loci for astigmatism

Why Tenth Graders Fail to Finish High School: A Dropout Typology Latent Class Analysis

A large percentage of the students who drop out of K-12 schools in the United States do so at the end of high school, at some point after grade 10. Yet we know little about the differences between different types of students who drop out of the end of high school. The purpose of this study is to examine a typology of high school dropouts from a large nationally representative dataset (ELS:2002) using latent class analysis (LCA). We found three significantly different types of dropouts; Quiet, Jaded, and Involved. Based on this typology of three subgroups, we discuss implications for future dropout intervention research, policy, and practice

Author Correction: Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases.

Emmanuelle Souzeau, who contributed to analysis of data, was inadvertently omitted from the author list in the originally published version of this Article. This has now been corrected in both the PDF and HTML versions of the Article

Time spent outdoors in childhood is associated with reduced risk of myopia as an adult

Myopia (near-sightedness) is an important public health issue. Spending more time outdoors can prevent myopia but the long-term association between this exposure and myopia has not been well characterised. We investigated the relationship between time spent outdoors in childhood, adolescence and young adulthood and risk of myopia in young adulthood. The Kidskin Young Adult Myopia Study (KYAMS) was a follow-up of the Kidskin Study, a sun exposure-intervention study of 1776 children aged 6–12 years. Myopia status was assessed in 303 (17.6%) KYAMS participants (aged 25–30 years) and several subjective and objective measures of time spent outdoors were collected in childhood (8–12 years) and adulthood. Index measures of total, childhood and recent time spent outdoors were developed using confirmatory factor analysis. Logistic regression was used to assess the association between a 0.1-unit change in the time outdoor indices and risk of myopia after adjusting for sex, education, outdoor occupation, parental myopia, parental education, ancestry and Kidskin Study intervention group. Spending more time outdoors during childhood was associated with reduced risk of myopia in young adulthood (multivariable odds ratio [OR] 0.82, 95% confidence interval [CI] 0.69, 0.98). Spending more time outdoors in later adolescence and young adulthood was associated with reduced risk of late-onset myopia (≥ 15 years of age, multivariable OR 0.79, 95% CI 0.64, 0.98). Spending more time outdoors in both childhood and adolescence was associated with less myopia in young adulthood.Te authors thank the participants of the Kidskin Study and their families. Te Kidskin Young Adult Myopia Study was supported by Perpetual Impact Philanthropy (IPAP2015/0230) and the National Health and Medical Research Council (1121979). Te Kidskin Study was supported by the National Health and Medical Research Council (954601, 110221, 209057) and by the Cancer Foundation of Western Australia. GL receives fnancial support through an Australian Government Research Training Program Scholarship

Meta-analysis of 542,934 subjects of European ancestry identifies new genes and mechanisms predisposing to refractive error and myopia.

Refractive errors, in particular myopia, are a leading cause of morbidity and disability worldwide. Genetic investigation can improve understanding of the molecular mechanisms that underlie abnormal eye development and impaired vision. We conducted a meta-analysis of genome-wide association studies (GWAS) that involved 542,934 European participants and identified 336 novel genetic loci associated with refractive error. Collectively, all associated genetic variants explain 18.4% of heritability and improve the accuracy of myopia prediction (area under the curve (AUC) = 0.75). Our results suggest that refractive error is genetically heterogeneous, driven by genes that participate in the development of every anatomical component of the eye. In addition, our analyses suggest that genetic factors controlling circadian rhythm and pigmentation are also involved in the development of myopia and refractive error. These results may enable the prediction of refractive error and the development of personalized myopia prevention strategies in the future

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes