Screen for Small-Molecule Modulators of Circadian Rhythms Reveals Phenazine as a Redox-State Modifying Clockwork Tuner.

A high-throughput cell-based screen identified redox-active small molecules that produce a period lengthening of the circadian rhythm. The strongest period lengthening phenotype was induced by a phenazine carboxamide (VU661). Comparison to two isomeric benzquinoline carboxamides (VU673 and VU164) shows the activity is associated with the redox modulating phenazine functionality. Furthermore, ex vivo cell analysis using optical redox ratio measurements shows the period lengthening phenotype to be associated with a shift to the NAD/FAD oxidation state of nicotinamide and flavine coenzymes.

Distribución del riesgo cardiovascular en la Argentina en 2018 / Cardiovascular Risk Distribution in Argentina in 2018

RESUMEN Introducción: Las enfermedades cardiovasculares son la principal causa de discapacidad y muerte a nivel global. El riesgo cardiovascular (RC) total es la probabilidad de tener un evento cardiovascular en un período definido y está determinado por el efecto combinado de los factores de riesgo. Objetivos: Estimar el RC y describir su distribución en la Argentina en 2018. Materiales y métodos: Se analizaron 11 450 individuos mayores de 30 años provenientes de la 4° ENFR. Se realizó la estimación y calibración del RC global bajo las ecuaciones del estudio Framingham y se clasificó a los individuos en los siguientes tres grupos: RC óptimo (<5,9%), RC moderado (6 a 19,9%) y RC alto (>20%). Se estimaron prevalencias e intervalos de credibilidad bayesianos (ICB) bajo distribución beta prior no informativa. Resultados: A nivel nacional, el 60,6% de los individuos presentaron RC moderado/alto. El RC moderado por región se distribuyó de manera homogénea. Al analizar los RC extremos, las regiones metropolitana (47,6%) y pampeana (28,6%) presentaron las prevalencias más elevadas de RC alto. La mayor prevalencia del RC óptimo se encontró en la región Patagonia, seguido del Noroeste, Noreste y Cuyo, todas estas fueron superiores al 40%. Por provincia, las prevalencias más elevadas de RC alto se presentaron en Buenos Aires (49,9%) y CABA (45,7%). En todos los niveles, las prevalencias de RC moderado/alto son muy superiores en varones, con excepción de la región metropolitana. Conclusiones: Las diferencias geográficas posicionan a la región metropolitana como la de mayor RC debido a la alta prevalencia de RC alto y moderado. Los hombres presentaron una prevalencia de RC alto hasta 4 veces superior a la registrada en mujeres.

ABSTRACT Background: Cardiovascular diseases are the main cause of disability and death globally. Total cardiovascular risk (CR) is the probability of having a cardiovascular event in a defined period and is determined by the combined effect of risk factors. Objectives: The aim of this study was to estimate CR and describe its distribution in Argentina in 2018. Methods: Cardiovascular risk was analyzed in 11,450 individuals over 30 years of age from the 4th National Risk Factor Survey (NRFS). The Framingham risk equations used to estimate and calibrate global CR classified the individuals into the following three groups: optimum CR (<5.9%), moderate CR (6 to 19.9%) and high CR (>20%). Bayesian prevalence and credibility intervals (BCI) were estimated under the non-informative beta prior distribution. Results: Nationally, 60.6% of the individuals presented moderate/high CR. Moderate CR by region was distributed homogeneously. When analyzing extreme CRs, the metropolitan (47.6%) and Pampean (28.6%) regions presented the greatest incidence of high CR. The highest prevalence of optimum CR was found in the Patagonian region, followed by the Northwest, Northeast and Cuyo, all above 40%. The analysis by province showed that the greatest incidence of high CR was found in Buenos Aires (49.9%) and CABA (45.7%). At all levels, the prevalence of moderate/high CR is much higher in men, with the exception of the metropolitan region. Conclusions: Geographical differences position the metropolitan region as the one with maximum CR due to the great incidence of high and moderate CR. Prevalence of high CR in men is almost 4 times greater than that registered in women.

Shift work in nurses: contribution of phenotypes and genotypes to adaptation.

BACKGROUND: Daily cycles of sleep/wake, hormones, and physiological processes are often misaligned with behavioral patterns during shift work, leading to an increased risk of developing cardiovascular/metabolic/gastrointestinal disorders, some types of cancer, and mental disorders including depression and anxiety. It is unclear how sleep timing, chronotype, and circadian clock gene variation contribute to adaptation to shift work. METHODS: Newly defined sleep strategies, chronotype, and genotype for polymorphisms in circadian clock genes were assessed in 388 hospital day- and night-shift nurses. RESULTS: Night-shift nurses who used sleep deprivation as a means to switch to and from diurnal sleep on work days (∼25%) were the most poorly adapted to their work schedule. Chronotype also influenced efficacy of adaptation. In addition, polymorphisms in CLOCK, NPAS2, PER2, and PER3 were significantly associated with outcomes such as alcohol/caffeine consumption and sleepiness, as well as sleep phase, inertia and duration in both single- and multi-locus models. Many of these results were specific to shift type suggesting an interaction between genotype and environment (in this case, shift work). CONCLUSIONS: Sleep strategy, chronotype, and genotype contribute to the adaptation of the circadian system to an environment that switches frequently and/or irregularly between different schedules of the light-dark cycle and social/workplace time. This study of shift work nurses illustrates how an environmental "stress" to the temporal organization of physiology and metabolism can have behavioral and health-related consequences. Because nurses are a key component of health care, these findings could have important implications for health-care policy.