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The extent to which the three-dimensional organization of the genome contributes to chromosomal translocations is an important question in cancer genomics. We generated a high-resolution Hi-C spatial organization map of the G1-arrested mouse pro-B cell genome and used high-throughput genome-wide translocation sequencing to map translocations from target DNA double-strand breaks (DSBs) within it. RAG endonuclease-cleaved antigen-receptor loci are dominant translocation partners for target DSBs regardless of genomic position, reflecting high-frequency DSBs at these loci and their colocalization in a fraction of cells. To directly assess spatial proximity contributions, we normalized genomic DSBs via ionizing radiation. Under these conditions, translocations were highly enriched in cis along single chromosomes containing target DSBs and within other chromosomes and subchromosomal domains in a manner directly related to pre-existing spatial proximity. By combining two high-throughput genomic methods in a genetically tractable system, we provide a new lens for viewing cancer genomes.
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Genoma , Neoplasias/genética , Translocación Genética , Animales , Roturas del ADN de Doble Cadena/efectos de la radiación , Fase G1 , Secuenciación de Nucleótidos de Alto Rendimiento , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos BALB C , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Células Precursoras de Linfocitos B/citología , Receptores de Antígenos/genéticaRESUMEN
Potassium ion (K+) plays a critical role as an essential electrolyte in all biological systems. Genetically-encoded fluorescent K+ biosensors are promising tools to further improve our understanding of K+-dependent processes under normal and pathological conditions. Here, we report the crystal structure of a previously reported genetically-encoded fluorescent K+ biosensor, GINKO1, in the K+-bound state. Using structure-guided optimization and directed evolution, we have engineered an improved K+ biosensor, designated GINKO2, with higher sensitivity and specificity. We have demonstrated the utility of GINKO2 for in vivo detection and imaging of K+ dynamics in multiple model organisms, including bacteria, plants, and mice.
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Técnicas Biosensibles , Transferencia Resonante de Energía de Fluorescencia , Animales , Técnicas Biosensibles/métodos , Transferencia Resonante de Energía de Fluorescencia/métodos , Iones , Ratones , PotasioRESUMEN
Although political violence has been perpetrated on behalf of a wide range of political ideologies, it is unclear whether there are systematic differences between ideologies in the use of violence to pursue a political cause. Prior research on this topic is scarce and mostly restricted to self-reported measures or less extreme forms of political aggression. Moreover, it has generally focused on respondents in Western countries and has been limited to either comparisons of the supporters of left-wing and right-wing causes or examinations of only Islamist extremism. In this research we address these gaps by comparing the use of political violence by left-wing, right-wing, and Islamist extremists in the United States and worldwide using two unique datasets that cover real-world examples of politically motivated, violent behaviors. Across both datasets, we find that radical acts perpetrated by individuals associated with left-wing causes are less likely to be violent. In the United States, we find no difference between the level of violence perpetrated by right-wing and Islamist extremists. However, differences in violence emerge on the global level, with Islamist extremists being more likely than right-wing extremists to engage in more violent acts.
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Islamismo , Política , Violencia , Conjuntos de Datos como Asunto , Humanos , Estados Unidos , Violencia/tendenciasRESUMEN
An ensemble of emitters can behave very differently from its individual constituents when they interact coherently via a common light field. After excitation of such an ensemble, collective coupling can give rise to a many-body quantum phenomenon that results in short, intense bursts of light-so-called superfluorescence1. Because this phenomenon requires a fine balance of interactions between the emitters and their decoupling from the environment, together with close identity of the individual emitters, superfluorescence has thus far been observed only in a limited number of systems, such as certain atomic and molecular gases and a few solid-state systems2-7. The generation of superfluorescent light in colloidal nanocrystals (which are bright photonic sources practically suited for optoelectronics8,9) has been precluded by inhomogeneous emission broadening, low oscillator strength, and fast exciton dephasing. Here we show that caesium lead halide (CsPbX3, X = Cl, Br) perovskite nanocrystals10-13 that are self-organized into highly ordered three-dimensional superlattices exhibit key signatures of superfluorescence. These are dynamically red-shifted emission with more than 20-fold accelerated radiative decay, extension of the first-order coherence time by more than a factor of four, photon bunching, and delayed emission pulses with Burnham-Chiao ringing behaviour14 at high excitation density. These mesoscopically extended coherent states could be used to boost the performance of opto-electronic devices15 and enable entangled multi-photon quantum light sources16,17.
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Nanostructured semiconductors emit light from electronic states known as excitons. For organic materials, Hund's rules state that the lowest-energy exciton is a poorly emitting triplet state. For inorganic semiconductors, similar rules predict an analogue of this triplet state known as the 'dark exciton'. Because dark excitons release photons slowly, hindering emission from inorganic nanostructures, materials that disobey these rules have been sought. However, despite considerable experimental and theoretical efforts, no inorganic semiconductors have been identified in which the lowest exciton is bright. Here we show that the lowest exciton in caesium lead halide perovskites (CsPbX3, with X = Cl, Br or I) involves a highly emissive triplet state. We first use an effective-mass model and group theory to demonstrate the possibility of such a state existing, which can occur when the strong spin-orbit coupling in the conduction band of a perovskite is combined with the Rashba effect. We then apply our model to CsPbX3 nanocrystals, and measure size- and composition-dependent fluorescence at the single-nanocrystal level. The bright triplet character of the lowest exciton explains the anomalous photon-emission rates of these materials, which emit about 20 and 1,000 times faster than any other semiconductor nanocrystal at room and cryogenic temperatures, respectively. The existence of this bright triplet exciton is further confirmed by analysis of the fine structure in low-temperature fluorescence spectra. For semiconductor nanocrystals, which are already used in lighting, lasers and displays, these excitons could lead to materials with brighter emission. More generally, our results provide criteria for identifying other semiconductors that exhibit bright excitons, with potential implications for optoelectronic devices.
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As Western societies become more ethnically and culturally diverse, understanding the acculturation of immigrant youth is essential for fostering social cohesion. How the cultural identity formation of ethnic minority adolescents relates to their academic, social, and psychological adjustment is an important and as yet unresolved research question. This study examined to what extent identifying with the heritage and/or host culture is an individual resource or risk factor for the adjustment of immigrant youth in Germany. A random sample of 15-17-year-olds (N = 1992; Mage_w1 = 15.3 years, SD = 0.64; 44.5% girls; 44.7% students with immigrant background) was assessed twice: at the end of 9th and 10th grade. Academic performance and three dimensions of social/psychological adjustment (school attachment, self-esteem, and life satisfaction) were examined. Results showed that biculturalism was the modal identification pattern. Contrary to expectations, cultural identification did not differ systematically with perceived distance from the majority culture. Multivariate structural equation modeling revealed that both heritage and host identification can be developmental resources, but that their effects are dependent on the dimension of adjustment; biculturalism only proved to be a cumulative resource for school attachment. The domain specificity of the findings challenges the generalization claims of predominant acculturation theories.
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Emigrantes e Inmigrantes , Ajuste Emocional , Femenino , Humanos , Adolescente , Masculino , Identificación Social , Etnicidad/psicología , Grupos Minoritarios , Emigración e Inmigración , Ajuste Social , AculturaciónRESUMEN
Research has shown that gender role attitudes develop during adolescence; however, the relevant predictors remain a matter of debate. In adolescence, the school environment gains in importance. Thus, the present study investigates how students' and especially teachers' culture and composition predict the development of gender role attitudes in young adolescents. The study addresses this question using a sample of 7360 Flemish students (44.8% girls), who were surveyed three times after entering secondary education between 2012 (Mage = 13.14, SD = 0.56) and 2014. Latent change models reveal that boys' initial gender role attitudes are associated with the students' gender role culture; however, boys with more traditional gender role attitudes do not develop in an even more traditional direction at the beginning of secondary education. In contexts with a more privileged student SES composition, boys develop less traditional attitudes, while a traditional gender role culture among teachers supports the development of more traditional gender role attitudes among boys. Girls with more traditional gender role attitudes find themselves within student contexts with a more traditional culture. However, the development does not vary with the students' gender role culture. Overall, boys seem more susceptible to students' cultural and compositional characteristics.
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Rol de Género , Estudiantes , Masculino , Femenino , Humanos , Adolescente , Actitud , Encuestas y Cuestionarios , MaestrosRESUMEN
The GeneXpert® Xpert® Xpress SARS-CoV-2/Flu/RSV PLUS combination test (PLUS assay) received Health Canada approval in January 2022. The PLUS assay is similar to the SARS-CoV-2/Flu/RSV combination test, with modifications to improve assay robustness against circulating and emerging variants. The performance characteristics of the PLUS assay were assessed at the Lakeridge Health Oshawa Hospital Centre and the National Microbiology Laboratory of Canada. The PLUS assay was directly compared to the SARS-CoV-2/Flu/RSV combination test using SARS-CoV-2 culture from five variants and remnant clinical specimens collected across the coronavirus disease 2019 pandemic. This included 50 clinical specimens negative for all pathogens, 110 clinical specimens positive for SARS-CoV-2, influenza A, influenza B, RSVA, and(or) RSVB and an additional 11 mixed samples to screen for target interactions. The PLUS assay showed a high % agreement with the widely used SARS-CoV-2/Flu/RSV combination test. Based on these findings, the PLUS assay and the Xpert SARS-CoV-2/Flu/RSV combination test results are largely consistent with no observed difference in sensitivity, specificity, or time to result when challenged with various SARS-CoV-2 variants. The reported cycle threshold (Ct) values provided by the new PLUS assay were also unchanged, with the exception of a possible 1-2 decrease reported in Ct for RSVA across a limited sample size.
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COVID-19 , Virus de la Influenza A , Gripe Humana , Humanos , Gripe Humana/diagnóstico , SARS-CoV-2/genética , COVID-19/diagnóstico , Virus de la Influenza B/genética , Nasofaringe , Técnicas de Diagnóstico Molecular/métodos , Virus de la Influenza A/genética , Sensibilidad y EspecificidadRESUMEN
INTRODUCTION: Complex chromosomal rearrangements (CCRs) involve two or more chromosomes and at least three breakpoints. Due to their complexity, they are associated with a high number of unbalanced gametes, whose fertilization is often incompatible with viable fetal development. Preimplantation genetic diagnosis (PGD) is usually offered to those patients and typically shows modest results considering the high number of unbalanced embryos. We previously showed that a sperm selection process using the hypo-osmotic swelling test (HOST) allows for an 83% reduction in the proportion of unbalanced spermatozoa (US) in male rearrangements carriers. This is the first report of the use of this procedure in a CCR carrier. CASE DESCRIPTION: We report on the case of a 36-year-old male t(4;7;14)(q12;p21;q11.2) carrier who presented to our center for infertility. Sperm fluorescent in situ hybridization showed an 88% proportion of unbalanced spermatozoa. After hypo-osmotic incubation and selection of spermatozoa with a specific flagellar conformation, the proportion of unbalanced spermatozoa dropped to 15%. DISCUSSION: In the present case, we show that it is possible to select chromosomally balanced prior to in vitro fertilization in male CCR carriers. This technique has the potential of increasing the proportion of euploid embryos and therefore the chances of healthy pregnancy and birth.
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Diagnóstico Preimplantación , Semen , Embarazo , Femenino , Humanos , Masculino , Adulto , Hibridación Fluorescente in Situ/métodos , Translocación Genética/genética , Espermatozoides , Aberraciones Cromosómicas , Diagnóstico Preimplantación/métodos , Segregación Cromosómica/genéticaRESUMEN
The transition to secondary school may negatively impact adolescents' psychosocial and subjective well-being development. However, how subjective well-being develops during secondary school and how school contextual factors, including aspects of ability grouping and achievement composition, are associated with the development of subjective well-being still require clarification. This study examined two measures of subjective well-being, life satisfaction and school satisfaction, to investigate the development of subjective well-being during secondary school. Moreover, school context variations in the form of school tracks and school-level achievement were analyzed to examine the extent to which ability grouping and achievement composition were associated with the development of subjective well-being. A large-scale longitudinal German dataset with four measurement points from grades 6 to 10 was analyzed (Time 1: N = 1,841; Mage = 12.20, SD = 0.81; 48.4% female; 45.3% immigrant students). The latent growth model revealed that life satisfaction and school satisfaction decreased statistically significantly during secondary school, yet school satisfaction showed a temporary increase between the end of primary school and right after the transition to secondary school. School tracks did not statistically significantly predict the magnitude of the decline in life satisfaction or school satisfaction. Only school-level achievement composition significantly negatively predicted the decline in life satisfaction, suggesting that students in schools with higher levels of achievement composition had a greater decrease in life satisfaction than their counterparts in schools with lower levels of achievement composition. Taken together, these findings contribute to the knowledge of how life and school satisfaction develop during secondary school and the long-term associations between subjective well-being and school context factors.
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Éxito Académico , Instituciones Académicas , Humanos , Adolescente , Femenino , Niño , Masculino , Estudios Longitudinales , Estudiantes/psicología , Satisfacción PersonalRESUMEN
Algorithms and procedures to fully automate retuning of synchrotron radiation beamlines over wide energy ranges are discussed. The discussion is based on the implementation at the National Institute of General Medical Sciences and the National Cancer Institute Structural Biology Facility at the Advanced Photon Source. When a user selects a new beamline energy, software synchronously controls the beamline monochromator and undulator to maintain the X-ray beam flux after the monochromator, preserves beam attenuation by determining a new set of attenuator foils, changes, as needed, mirror reflecting stripes and the undulator harmonic, preserves beam focal distance of compound refractive lens focusing by changing the In/Out combination of lenses in the transfocator, and, finally, restores beam position at the sample by on-the-fly scanning of either the Kirkpatrick-Baez mirror angles or the transfocator up/down and inboard/outboard positions. The sample is protected from radiation damage by automatically moving it out of the beam during the energy change and optimization.
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Lentes , Sincrotrones , Fotones , Programas Informáticos , Rayos XRESUMEN
Throughout the coronavirus disease 2019 (COVID-19) pandemic, wastewater surveillance has been used to monitor trends in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) prevalence in the community. A major challenge in establishing wastewater surveillance programs, especially in remote areas, is the need for a well-equipped laboratory for sample analysis. Currently, no options exist for rapid, sensitive, mobile, and easy-to-use wastewater tests for SARS-CoV-2. The performance of the GeneXpert system, which offers cartridge-based, rapid molecular clinical testing for SARS-CoV-2 in a portable platform, was evaluated using wastewater as the input. The GeneXpert demonstrated a SARS-CoV-2 limit of detection in wastewater below 32 copies/mL with a sample processing time of less than an hour. Using wastewater samples collected from multiple sites across Canada during February and March 2021, a high overall agreement (97.8%) was observed between the GeneXpert assay and laboratory-developed tests regarding the presence or absence of SARS-CoV-2. Additionally, with the use of centrifugal filters, the detection threshold of the GeneXpert system was improved to <10 copies/mL in wastewater. Finally, to support on-site wastewater surveillance, GeneXpert testing was implemented in Yellowknife, a remote community in Northern Canada, where its use successfully alerted public health authorities to undetected transmission of COVID-19. The identification of SARS-CoV-2 in wastewater triggered clinical testing of recent travelers and identification of new COVID-19 cases/clusters. Taken together, these results suggest that GeneXpert is a viable option for surveillance of SARS-CoV-2 in wastewater in locations that do not have access to established testing laboratories. IMPORTANCE Wastewater-based surveillance is a powerful tool that provides an unbiased measure of COVID-19 prevalence in a community. This work describes a sensitive wastewater rapid test for SARS-CoV-2 based on a widely distributed technology, the GeneXpert. The advantages of an easy-to-use wastewater test for SARS-CoV-2 are clear: it supports surveillance in remote communities, improves access to testing, and provides faster results allowing for an immediate public health response. The application of wastewater rapid testing in a remote community facilitated the detection of a COVID-19 cluster and triggered public health action, clearly demonstrating the utility of this technology. Wastewater surveillance will become increasingly important in the postvaccination pandemic landscape as individuals with asymptomatic/mild infections continue transmitting SARS-CoV-2 but are unlikely to be tested.
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COVID-19 , SARS-CoV-2 , COVID-19/diagnóstico , COVID-19/epidemiología , Humanos , Pandemias , Aguas Residuales , Monitoreo Epidemiológico Basado en Aguas ResidualesRESUMEN
White mold is caused by the fungal pathogen Sclerotinia sclerotiorum and leads to rapid and significant loss in plant yield. Among its many brassicaceous hosts, including Brassica napus (canola) and Arabidopsis, the response of individual tissue layers directly at the site of infection has yet to be explored. Using laser microdissection coupled with RNA sequencing, we profiled the epidermis, mesophyll, and vascular leaf tissue layers of B. napus in response to S. sclerotiorum. High-throughput tissue-specific mRNA sequencing increased the total number of detected transcripts compared with whole-leaf assessments and provided novel insight into the conserved and specific roles of ontogenetically distinct leaf tissue layers in response to infection. When subjected to pathogen infection, the epidermis, mesophyll, and vasculature activate both specific and shared gene sets. Putative defense genes identified through transcription factor network analysis were then screened for susceptibility against necrotrophic, hemi-biotrophic, and biotrophic pathogens. Arabidopsis deficient in PR5-like RECEPTOR KINASE (PR5K) mRNA levels were universally susceptible to all pathogens tested and were further characterized to identify putative interacting partners involved in the PR5K signaling pathway. Together, these data provide insight into the complexity of the plant defense response directly at the site of infection.
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Arabidopsis , Brassica napus , Brassica napus/metabolismo , Arabidopsis/genética , Enfermedades de las Plantas/microbiología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Inmunidad de la Planta/genéticaRESUMEN
BACKGROUND: Polypharmacy is common among patients with CKD, but little is known about the urinary excretion of many drugs and their metabolites among patients with CKD. METHODS: To evaluate self-reported medication use in relation to urine drug metabolite levels in a large cohort of patients with CKD, the German Chronic Kidney Disease study, we ascertained self-reported use of 158 substances and 41 medication groups, and coded active ingredients according to the Anatomical Therapeutic Chemical Classification System. We used a nontargeted mass spectrometry-based approach to quantify metabolites in urine; calculated specificity, sensitivity, and accuracy of medication use and corresponding metabolite measurements; and used multivariable regression models to evaluate associations and prescription patterns. RESULTS: Among 4885 participants, there were 108 medication-drug metabolite pairs on the basis of reported medication use and 78 drug metabolites. Accuracy was excellent for measurements of 36 individual substances in which the unchanged drug was measured in urine (median, 98.5%; range, 61.1%-100%). For 66 pairs of substances and their related drug metabolites, median measurement-based specificity and sensitivity were 99.2% (range, 84.0%-100%) and 71.7% (range, 1.2%-100%), respectively. Commonly prescribed medications for hypertension and cardiovascular risk reduction-including angiotensin II receptor blockers, calcium channel blockers, and metoprolol-showed high sensitivity and specificity. Although self-reported use of prescribed analgesics (acetaminophen, ibuprofen) was <3% each, drug metabolite levels indicated higher usage (acetaminophen, 10%-26%; ibuprofen, 10%-18%). CONCLUSIONS: This comprehensive screen of associations between urine drug metabolite levels and self-reported medication use supports the use of pharmacometabolomics to assess medication adherence and prescription patterns in persons with CKD, and indicates under-reported use of medications available over the counter, such as analgesics.
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Cumplimiento de la Medicación , Preparaciones Farmacéuticas/orina , Polifarmacia , Insuficiencia Renal Crónica/orina , Autoinforme , Anciano , Estudios de Cohortes , Femenino , Alemania , Humanos , Masculino , Espectrometría de Masas , Persona de Mediana Edad , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/terapia , Sensibilidad y Especificidad , Orina/químicaRESUMEN
Methylphenidate (MPH) is an indirect-acting sympathomimetic drug and structurally related to amphetamine. It is widely used to treat children aged 6 years and older, as well as adolescents who have attention-deficit/hyperactivity disorder (ADHD). We report on a 6-year-old boy who presented with typical angina symptoms occurring several hours after intake of an increased dose of MPH, which had been initiated for ADHD treatment 2 days earlier. Despite typical angina symptoms, the diagnosis of myocardial infarction due to spontaneous coronary artery dissection of the right coronary artery was delayed. Most epidemiological studies could not detect an increased risk for cardiovascular events in association with ADHD medications. However, the direct temporal relationship in our case indicates the possibility that MPH may trigger spontaneous coronary artery dissection in predisposed patients. Since myocardial infarction in children is rare but comprises various etiologies, awareness of this possible catastrophic event among medical staff may be lower and may delay immediate life-saving diagnostic and therapeutic measures.
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Trastorno por Déficit de Atención con Hiperactividad , Estimulantes del Sistema Nervioso Central , Metilfenidato , Infarto del Miocardio , Trastorno por Déficit de Atención con Hiperactividad/complicaciones , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Estimulantes del Sistema Nervioso Central/efectos adversos , Niño , Vasos Coronarios , Preparaciones de Acción Retardada/uso terapéutico , Humanos , Masculino , Metilfenidato/efectos adversos , Infarto del Miocardio/inducido químicamente , Infarto del Miocardio/tratamiento farmacológico , Resultado del TratamientoRESUMEN
AIM: This study investigated the impact of an interprofessional mock code on students' comfort and competency related to Parkinson's disease (PD) medication administration during care transitions. BACKGROUD: Patients with PD are at increased risk for medication errors during hospitalization. Individualization of PD medication creates vulnerability during care transitions. METHOD: Four interprofessional groups took part in this study: baccalaureate degree senior nursing students (n = 113), master's level nurse anesthesia students (n = 35), doctor of osteopathic medicine fourth-year students (n = 32), and doctor of clinical psychology fourth-year students (n = 22). Groups participated in an unfolding case study simulation involving a mock code with a focus on the omission of time-sensitive PD medication. Pre- and postsimulation test results were compared. RESULTS: Findings indicated an increased understanding among three of the four groups relating to medication timing during care transitions. CONCLUSION: All groups improved with respect to perceived comfort and competency.
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Bachillerato en Enfermería , Enfermedad de Parkinson , Estudiantes de Enfermería , Simulación por Computador , Bachillerato en Enfermería/métodos , Humanos , Relaciones Interprofesionales , Enfermedad de Parkinson/tratamiento farmacológico , Transferencia de Pacientes , Estudiantes de Enfermería/psicologíaRESUMEN
How gender role attitudes develop during adolescence, and how biological, social, and cognitive factors predict this development, remains a matter of debate. This study examines the development of gender role attitudes from early adolescence to emerging adulthood and investigates how the developmental trajectory is affected by sex, socioeconomic status, and cognitive abilities (intelligence). Four waves of the large-scale longitudinal German dataset BIJU between 1991 (grade 7; N = 3828, Mage = 13, SD = 0.61, 53.1% female, 96.4% German nationality), 1995 (grade 10, Mage = 17), 1997 (grade 12, Mage = 19) and 2001/2002 (university/career entry, Mage = 24) were used. Measurement invariance was examined across waves and gender. Latent growth curve models showed that adolescents developed more egalitarian gender role attitudes. Differences between the sexes decreased over time but remained significant. Socioeconomic status seemed less relevant, while adolescents, especially those with lower intelligence scores, developed more egalitarian gender role attitudes during adolescence. The results showed that teenagers developed more open and egalitarian attitudes during adolescence, and that the development trajectories of female and male adolescents converge.
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Actitud , Rol de Género , Adolescente , Adulto , Cognición , Femenino , Humanos , Estudios Longitudinales , Masculino , Factores Sexuales , Clase Social , Adulto JovenRESUMEN
BACKGROUND: Cardiovascular risk is increased in patients with gout. We compared cardiovascular outcomes associated with febuxostat, a nonpurine xanthine oxidase inhibitor, with those associated with allopurinol, a purine base analogue xanthine oxidase inhibitor, in patients with gout and cardiovascular disease. METHODS: We conducted a multicenter, double-blind, noninferiority trial involving patients with gout and cardiovascular disease; patients were randomly assigned to receive febuxostat or allopurinol and were stratified according to kidney function. The trial had a prespecified noninferiority margin of 1.3 for the hazard ratio for the primary end point (a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or unstable angina with urgent revascularization). RESULTS: In total, 6190 patients underwent randomization, received febuxostat or allopurinol, and were followed for a median of 32 months (maximum, 85 months). The trial regimen was discontinued in 56.6% of patients, and 45.0% discontinued follow-up. In the modified intention-to-treat analysis, a primary end-point event occurred in 335 patients (10.8%) in the febuxostat group and in 321 patients (10.4%) in the allopurinol group (hazard ratio, 1.03; upper limit of the one-sided 98.5% confidence interval [CI], 1.23; P=0.002 for noninferiority). All-cause and cardiovascular mortality were higher in the febuxostat group than in the allopurinol group (hazard ratio for death from any cause, 1.22 [95% CI, 1.01 to 1.47]; hazard ratio for cardiovascular death, 1.34 [95% CI, 1.03 to 1.73]). The results with regard to the primary end point and all-cause and cardiovascular mortality in the analysis of events that occurred while patients were being treated were similar to the results in the modified intention-to-treat analysis. CONCLUSIONS: In patients with gout and major cardiovascular coexisting conditions, febuxostat was noninferior to allopurinol with respect to rates of adverse cardiovascular events. All-cause mortality and cardiovascular mortality were higher with febuxostat than with allopurinol. (Funded by Takeda Development Center Americas; CARES ClinicalTrials.gov number, NCT01101035 .).
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Alopurinol/efectos adversos , Enfermedades Cardiovasculares/inducido químicamente , Febuxostat/efectos adversos , Supresores de la Gota/efectos adversos , Gota/tratamiento farmacológico , Anciano , Alopurinol/uso terapéutico , Enfermedades Cardiovasculares/complicaciones , Enfermedades Cardiovasculares/mortalidad , Causas de Muerte , Método Doble Ciego , Febuxostat/uso terapéutico , Femenino , Gota/complicaciones , Supresores de la Gota/uso terapéutico , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Autotaxin (ATX) plays an important role in (patho-)physiological lysophosphatidic acid (LPA) signaling. Here we describe the establishment of novel cell-based ATX assay formats. ATX-mediated LPA generation is detected by using a stable LPA receptor reporter cell line. In a first assay variant, ATX-mediated LPA generation is started in the absence of cells and the reaction mix is transferred to the reporter cells after stopping the reaction (two-tube assay). In a second assay variant, ATX is added to the reporter cells expressing the known autotaxin binding partners integrin ß1, integrin ß3 and the LPA receptor 1. LPA generation is started in the presence of cells and is detected in real-time (one-tube assay). Structurally diverse ATX inhibitors with different binding modes were characterized in both cell-based assay variants and were also tested in the well-established biochemical choline release assay. ATX inhibitors displayed similar potencies, regardless if the assay was performed in the absence or presence of cells, and comparable results were obtained in all three assay formats. In summary, our novel cell-based ATX assay formats are well-suited for sensitive detection of enzyme activity as well as for the characterization of ATX inhibitors in the presence and absence of cells.
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Hidrolasas Diéster Fosfóricas/análisis , Células Cultivadas , Humanos , Lisofosfolípidos/química , Lisofosfolípidos/metabolismo , Modelos Moleculares , Hidrolasas Diéster Fosfóricas/metabolismoRESUMEN
The current National Institutes of Health (NIH) consensus paper excluded "white hyperkeratotic plaque" from the diagnostic criteria for oral chronic graft-versus-host disease (cGVHD) in order to ensure malignant transformation is not overlooked. Therefore, an isolated oral white plaque is recommended to be subjected to biopsy and pathologic examination. The cases described in this paper shed a new light on the clinical approach to oral white plaque post-hematopoietic stem cell transplantation. The objectives of this article are to demonstrate that a white plaque does not contradict a diagnosis of oral cGVHD, and to highlight the clinical considerations for taking a biopsy.