Understanding Racial Disparities in Exposure to Traffic-Related Air Pollution: Considering the Spatiotemporal Dynamics of Population Distribution

This study investigates the effect of spatiotemporal distributions of racial groups on disparities in exposure to traffic-related air pollution by considering people’s daily movement patterns. Due to human mobility, a residential neighborhood does not fully represent the true geographic context in which people experience racial segregation and unequal exposure to air pollution. Using travel-activity survey data containing individuals’ activity locations and time spent at each location, this study measures segregation levels that an individual might experience during the daytime and nighttime, estimates personal exposure by integrating hourly pollution maps and the survey data, and examines the association between daytime/nighttime segregation and exposure levels. The proximity of each activity location to major roads is also evaluated to further examine the unequal exposure. The results reveal that people are more integrated for work in high-traffic areas, which contributes to similarly high levels of exposure for all racial groups during the daytime. However, white people benefit from living in suburbs/exurbs away from busy roads. The finding suggests that policies for building an extensive and equitable public transit system should be implemented together with the policies for residential mixes among racial groups to reduce everyone’s exposure to traffic-related air pollution and achieve environmental justice

A comprehensive study of vector leptoquark with U(1)B3−L2U(1)_{B_3-L_2} on the BB-meson and Muon g-2 anomalies

Recently reported anomalies in various $B$ meson decays and also in the anomalous magnetic moment of muon $(g-2)_\mu$ motivate us to consider a particular extension of the standard model incorporating new interactions in lepton and quark sectors simultaneously. Our minimal choice would be leptoquark. In particular, we take vector leptoquark ($U_1$) and comprehensively study all related observables including ${(g-2)_{\mu}},\ R_{K^{(*)}},\ R_{D^{(*)}}$,$B \to (K) \ell \ell' $where$\ell\ell'$are various combinations of$\mu$and$\tau$, and also lepton flavor violation in the$\tau$decays. We find that a hybrid scenario with additional$U(1)_{B_3-L_2}$ gauge boson provides a common explanation of all these anomalies.Comment: 16 pages, 3 figure

Agonistic aptamer to the insulin receptor leads to biased signaling and functional selectivity through allosteric modulation

Due to their high affinity and specificity, aptamers have been widely used as effective inhibitors in clinical applications. However, the ability to activate protein function through aptamer-protein interaction has not been well-elucidated. To investigate their potential as target-specific agonists, we used SELEX to generate aptamers to the insulin receptor (IR) and identified an agonistic aptamer named IR-A48 that specifically binds to IR, but not to IGF-1 receptor. Despite its capacity to stimulate IR autophosphorylation, similar to insulin, we found that IR-A48 not only binds to an allosteric site distinct from the insulin binding site, but also preferentially induces Y1150 phosphorylation in the IR kinase domain. Moreover, Y1150-biased phosphorylation induced by IR-A48 selectively activates specific signaling pathways downstream of IR. In contrast to insulin-mediated activation of IR, IR-A48 binding has little effect on the MAPK pathway and proliferation of cancer cells. Instead, AKT S473 phosphorylation is highly stimulated by IR-A48, resulting in increased glucose uptake both in vitro and in vivo. Here, we present IR-A48 as a biased agonist able to selectively induce the metabolic activity of IR through allosteric binding. Furthermore, our study also suggests that aptamers can be a promising tool for developing artificial biased agonists to targeted receptors.111615Ysciescopu

Hypokalemia Promotes Late Phase 3 Early Afterdepolarization and Recurrent Ventricular Fibrillation During Isoproterenol Infusion in Langendorff Perfused Rabbit Ventricles

BACKGROUND Hypokalemia and sympathetic activation are commonly associated with electrical storm (ES) in normal and diseased hearts. The mechanisms remain unclear. OBJECTIVE To test the hypothesis that late phase 3 early afterdepolarization (EAD) induced by IKATP activation underlies the mechanisms of ES during isoproterenol infusion and hypokalemia. METHODS Intracellular calcium (Cai) and membrane voltage were optically mapped in 32 Langendorff-perfused normal rabbit hearts. RESULTS Repeated episodes of electrically-induced VF at baseline did not result in spontaneous VF (SVF). During isoproterenol infusion, SVF occurred in 1 of 15 hearts (7%) studied in normal extracellular potassium ([K+]o) (4.5 mmol/L), 3 of 8 hearts (38%) in 2.0 mmol/L [K+]o, 9 of 10 hearts (90%) in 1.5 mmol/L [K+]o, and 7 of 7 hearts (100%) in 1.0 mmol/L [K+]o (P<0.001). Optical mapping showed isoproterenol and hypokalemia enhanced Cai transient duration (CaiTD) and heterogeneously shortened action potential duration (APD) after defibrillation, leading to late phase 3 EAD and SVF. IKATP blocker (glibenclamide, 5 μmol/L) reversed the post-defibrillation APD shortening and suppressed recurrent SVF in all hearts studied despite no evidence of ischemia. Nifedipine reliably prevented recurrent VF when given before, but not after, the development of VF. IKr blocker (E-4031) and small conductance calcium activated potassium channel blocker (apamin) failed to prevent recurrent SVF. CONCLUSION Beta-adrenergic stimulation and concomitant hypokalemia could cause non-ischemic activation of IKATP, heterogeneous APD shortening and prolongation of CaiTD to provoke late phase 3 EAD, triggered activity and recurrent SVF. IKATP inhibition may be useful in managing ES during resistant hypokalemia

Par-4 Links Dopamine Signaling and Depression

SummaryProstate apoptosis response 4 (Par-4) is a leucine zipper containing protein that plays a role in apoptosis. Although Par-4 is expressed in neurons, its physiological role in the nervous system is unknown. Here we identify Par-4 as a regulatory component in dopamine signaling. Par-4 directly interacts with the dopamine D2 receptor (D2DR) via the calmodulin binding motif in the third cytoplasmic loop. Calmodulin can effectively compete with Par-4 binding in a Ca2+-dependent manner, providing a route for Ca2+-mediated downregulation of D2DR efficacy. To examine the importance of the Par-4/D2DR interaction in dopamine signaling in vivo, we used a mutant mouse lacking the D2DR interaction domain of Par-4, Par-4ΔLZ. Primary neurons from Par-4ΔLZ embryos exhibit an enhanced dopamine-cAMP-CREB signaling pathway, indicating an impairment in dopamine signaling in these cells. Remarkably, Par-4ΔLZ mice display significantly increased depression-like behaviors. Collectively, these results provide evidence that Par-4 constitutes a molecular link between impaired dopamine signaling and depression