RESUMEN
Electronic nicotine delivery systems (ENDS) are a potentially lower-risk tobacco product which could help smokers switch completely away from cigarettes. However, the lack of strong evidence to date of a measurable, population-level effect on reducing smoking has generated skepticism about ENDS' potential benefits. This study examines whether increased US ENDS sales have been associated with reduced cigarette sales. Retail data on weekly per-capita cigarette and ENDS purchases in the USA during 2014-2019 were obtained from a national sample of brick-and-mortar retail outlets. Trends in cigarette sales were modeled before (2014-2016) ENDS had a substantial market share, and, after adjusting for macroeconomic factors, projected into the post-period (2017-2019). Actual cigarette sales were lower than projected sales (by up to 16% across the post-period), indicating a substantial "cigarette shortfall" in the post-period. To explore whether general (i.e., inclusive of potentially many mechanisms) substitution by ENDS can explain the cigarette shortfall, its association with per-capita ENDS volume sales was examined. Higher ENDS sales were significantly associated with a greater cigarette shortfall: for every additional per-capita ENDS unit, cigarette sales were 1.4 packs-per-capita lower than expected (B = 1.4, p < .0001). Error correction models which account for spurious correlation yielded similar results. These findings support ENDS serving as a substitute for cigarettes (through potentially many mechanisms including cigarette price), causing cigarette consumption to decline. Since ENDS potentially pose lower risk than cigarettes, this general substitution effect suggests that risk-proportionate tobacco regulation could mitigate the tobacco-related health burden. Supplementary Information: The online version contains supplementary material available at 10.1007/s10603-022-09533-4.
RESUMEN
Multiple-mouse magnetic resonance imaging (MRI) increases scan throughput by imaging several mice simultaneously in the same magnet bore, enabling multiple images to be obtained in the same time as a single scan. This increase in throughput enables larger studies than otherwise feasible and is particularly advantageous in longitudinal study designs where frequent imaging time points result in high demand for MRI resources. Cryogenically-cooled radiofrequency probes (CryoProbes) have been demonstrated to have significant signal-to-noise ratio benefits over comparable room temperature coils for in vivo mouse imaging. In this work, we demonstrate implementation of a multiple-mouse MRI system using CryoProbes, achieved by mounting four such coils in a 30-cm, 7-Tesla magnet bore. The approach is demonstrated for longitudinal quantification of brain structure from infancy to early adulthood in a mouse model of Sanfilippo syndrome (mucopolysaccharidosis type III), generated by knockout of the Hgsnat gene. We find that Hgsnat-/- mice have regionally increased growth rates compared to Hgsnat+/+ mice in a number of brain regions, notably including the ventricles, amygdala and superior colliculus. A strong sex dependence was also noted, with the lateral ventricle volume growing at an accelerated rate in males, but several structures in the brain parenchyma growing faster in females. This approach is broadly applicable to other mouse models of human disease and the increased throughput may be particularly beneficial in studying mouse models of neurodevelopmental disorders.
Asunto(s)
Imagen por Resonancia Magnética , Ondas de Radio , Acetiltransferasas , Adulto , Animales , Encéfalo/diagnóstico por imagen , Femenino , Humanos , Estudios Longitudinales , Imagen por Resonancia Magnética/métodos , Masculino , Ratones , Relación Señal-RuidoRESUMEN
The auxiliary beta-subunit KCNMB2 (beta(2)) endows the non-inactivating large conductance Ca(2+)- and voltage-dependent potassium (BK) channel with fast inactivation. This process is mediated by the N terminus of KCNMB2 and closely resembles the "ball-and-chain"-type inactivation observed in voltage-gated potassium channels. Here we investigated the solution structure and function of the KCNMB2 N terminus (amino acids 1-45, BKbeta(2)N) using NMR spectroscopy and patch clamp recordings. BKbeta(2)N completely inactivated BK channels when applied to the cytoplasmic side; its interaction with the BK alpha-subunit is characterized by a particularly slow dissociation rate and an affinity in the upper nanomolar range. The BKbeta(2)N structure comprises two domains connected by a flexible linker: the pore-blocking "ball domain" (formed by residues 1-17) and the "chain domain" (between residues 20-45) linking it to the membrane segment of KCNMB2. The ball domain is made up of a flexible N terminus anchored at a well ordered loop-helix motif. The chain domain consists of a 4-turn helix with an unfolded linker at its C terminus. These structural properties explain the functional characteristics of BKbeta(2)N-mediated inactivation.
Asunto(s)
Canales de Potasio Calcio-Activados , Canales de Potasio/química , Secuencia de Aminoácidos , Animales , Femenino , Subunidades alfa de los Canales de Potasio de Gran Conductancia Activados por Calcio , Subunidades beta de los Canales de Potasio de Gran Conductancia Activados por el Calcio , Canales de Potasio de Gran Conductancia Activados por el Calcio , Espectroscopía de Resonancia Magnética , Datos de Secuencia Molecular , Canales de Potasio/fisiología , Estructura Secundaria de Proteína , Subunidades de Proteína , XenopusRESUMEN
Rapid N-type inactivation of voltage-dependent potassium (Kv) channels controls membrane excitability and signal propagation in central neurons and is mediated by protein domains (inactivation gates) occluding the open channel pore from the cytoplasmic side. Inactivation domains (ID) are donated either by the pore-forming alpha-subunit or certain auxiliary beta-subunits. Upon coexpression, Kvbeta1.1 was found to endow non-inactivating members of the Kv1alpha family with fast inactivation via its unique N terminus. Here we investigated structure and functional properties of the Kvbeta1.1 N terminus (amino acids 1-62, betaN-(1-62)) using NMR spectroscopy and patch clamp recordings. betaN-(1-62) showed all hallmarks of N-type inactivation: it inactivated non-inactivating Kv1.1 channels when applied to the cytoplasmic side as a synthetic peptide, and its interaction with the alpha-subunit was competed with tetraethylammonium and displayed an affinity in the lower micromolar range. In aequous and physiological salt solution, betaN-(1-62) showed no well defined three-dimensional structure, it rather existed in a fast equilibrium of multiple weakly structured states. These structural and functional properties of betaN-(1-62) closely resemble those of the "unstructured" ID from Shaker B, but differ markedly from those of the compactly folded ID of the Kv3.4 alpha-subunit.