BACKGROUND AND PURPOSETransient receptor potential melastatin 7 (TRPM7) is a unique channel kinase which is crucial for various physiological functions. However, the mechanism by which TRPM7 is gated and modulated is not fully understood. To better understand how modulation of TRPM7 may impact biological processes, we investigated if TRPM7 can be regulated by the phospholipids sphingosine (SPH) and sphingosine-1-phosphate (S1P), two potent bioactive sphingolipids that mediate a variety of physiological functions. Moreover, we also tested the effects of the structural analogues of SPH, N,N-dimethyl-D-erythrosphingosine (DMS), ceramides and FTY720 on TRPM7. EXPERIMENTAL APPROACHHEK293 cells stably expressing TRPM7 were used for whole-cell, single-channel and macropatch current recordings. Cardiac fibroblasts were used for native TRPM7 current recording. KEY RESULTSSPH potently inhibited TRPM7 in a concentration-dependent manner, whereas S1P and other ceramides did not produce noticeable effects. DMS also markedly inhibited TRPM7. Moreover, FTY720, an immunosuppressant and the first oral drug for treatment of multiple sclerosis, inhibited TRPM7 with a similar potency to that of SPH. In contrast, FTY720-P has no effect on TRPM7. It appears that SPH and FTY720 inhibit TRPM7 by reducing channel open probability. Furthermore, endogenous TRPM7 in cardiac fibroblasts was markedly inhibited by SPH, DMS and FTY720. CONCLUSIONS AND IMPLICATIONSThis is the first study demonstrating that SPH and FTY720 are potent inhibitors of TRPM7. Our results not only provide a new modulation mechanism of TRPM7, but also suggest that TRPM7 may serve as a direct target of SPH and FTY720, thereby mediating S1P-independent physiological/pathological functions of SPH and FTY720. LINKED ARTICLEThis article is commented on by Rohacs, pp. 1291-1293 of this issue. To view this commentary visit http://dx.doi.org/10.1111/bph.12070 Abbreviations FTY720, fingolimod, 2-amino-2-propane-1,3-diol hydrochloride; FTY720-P, FTY720-phosphate; S1P, sphingosine-1-phosphate; SPH, sphingosine; TRPM7, transient receptor potential melastatin 7

Background Anger and extreme stress can trigger potentially fatal cardiovascular events in susceptible people. Political elections, such as the 2016 US presidential election, are significant stressors. Whether they can trigger cardiac arrhythmias is unknown. Methods and Results In this retrospective case‐crossover study, we linked cardiac device data, electronic health records, and historic voter registration records from 2436 patients with implanted cardiac devices. The incidence of arrhythmias during the election was compared with a control period with Poisson regression. We also tested for effect modification by demographics, comorbidities, political affiliation, and whether an individual's political affiliation was concordant with county‐level election results. Overall, 2592 arrhythmic events occurred in 655 patients during the hazard period compared with 1533 events in 472 patients during the control period. There was a significant increase in the incidence of composite outcomes for any arrhythmia (incidence rate ratio [IRR], 1.77 [95% CI, 1.42–2.21]), supraventricular arrhythmia (IRR, 1.82 [95% CI, 1.36–2.43]), and ventricular arrhythmia (IRR, 1.60 [95% CI, 1.22–2.10]) during the election relative to the control period. There was also an increase in specific types of arrhythmia, including atrial fibrillation (IRR, 1.50 [95% CI, 1.06–2.11]), supraventricular tachycardia (IRR, 3.7 [95% CI, 2.2–6.2]), nonsustained ventricular tachycardia (IRR, 1.7 [95% CI, 1.3–2.2]), and daily atrial fibrillation burden ( P <0.001). No significant interaction was found for sex, race/ethnicity, device type, age ≥65 years, hypertension, coronary artery disease, heart failure, political affiliation, or concordance between individual political affiliation and county‐level election results. Conclusions There was a significant increase in cardiac arrhythmias during the 2016 US presidential election. These findings suggest that exposure to stressful sociopolitical events may trigger arrhythmogenesis in susceptible people.

This paper examines the energy–poverty nexus in Pakistan at the national and provincial level, using the multidimensional energy poverty index. Based on data from the Pakistan Social and Living Standards Measurement Survey for 2010/11, we find that the average household in Pakistan is 26.4 percent energy-poor. The study shows that the incidence of energy poverty is higher in rural areas than in urban areas, with a similar trend at the provincial level. A comparison with findings based on data from 2008/09 shows a slight decrease in energy poverty at the national level.

By facilitating the flow of information in society, communications technology (CT; e.g., newspapers, radio, television, the Internet) can help terrorists to (i) spread their message, (ii) recruit followers, and (iii) coordinate among group members. However, CT also facilitates monitoring and arresting terrorists. This article formulates the hypothesis that a society’s level of CT is systematically related to terrorism. We introduce a simple theoretical framework, suggesting that terrorism first becomes more attractive with a rise in CT, but then decreases, following an inverted U shape. Accessing data for 199 countries from 1970 to 2014, we find evidence consistent with these predictions: terrorism peaks at intermediate ranges of CT and corresponding magnitudes are sizable. Our estimations control for a range of potentially confounding factors, as well as country fixed effects and year fixed effects. Results are robust to a battery of alternative specifications and placebo regressions. We find no evidence of a potential reporting bias explaining our findings.