Genetic ablation of smooth muscle KIR2.1 is inconsequential to the function of mouse cerebral arteries

Cerebral blood flow is a finely tuned process dependent on coordinated changes in arterial tone. These changes are strongly tied to smooth muscle membrane potential and inwardly rectifying K⁺ (K_IR) channels are thought to be a key determinant. To elucidate the role of K_IR2.1 in cerebral arterial tone development, this study examined the electrical and functional properties of cells, vessels and living tissue from tamoxifen-induced smooth muscle cell (SMC)-specific K_IR2.1 knockout mice. Patch-clamp electrophysiology revealed a robust Ba²⁺-sensitive inwardly rectifying K⁺ current in cerebral arterial myocytes irrespective of K_IR2.1 knockout. Immunolabeling clarified that K_IR2.1 expression was low in SMCs while K_IR2.2 labeling was remarkably abundant at the membrane. In alignment with these observations, pressure myography revealed that the myogenic response and K⁺-induced dilation were intact in cerebral arteries post knockout. At the whole organ level, this translated to a maintenance of brain perfusion in SMC K_IR2.1^−/− mice, as assessed with arterial spin-labeling MRI. We confirmed these findings in superior epigastric arteries and implicated K_IR2.2 as more functionally relevant in SMCs. Together, these results suggest that subunits other than K_IR2.1 play a significant role in setting native current in SMCs and driving arterial tone.     

Educating and Training a Workforce for Nutrition in a Post-2015 World

Nearly all countries in the world today are burdened with malnutrition, manifesting as undernutrition, micronutrient deficiencies, and/or overweight and obesity. Despite some progress, efforts to alleviate malnutrition are hampered by a shortage in number, skills, and geographic coverage, of a workforce for nutrition. Here, we report the findings of the Castel Gandolfo workshop, a convening of experts from diverse fields in March 2014 to consider how to develop the capacity of a global cadre of nutrition professionals for the post-2015 development era. Workshop participants identified several requirements for developing a workforce for nutrition, including an ability to work as part of a multisectoral team; communication, advocacy, and leadership skills to engage decision makers; and a set of technical skills to address future challenges for nutrition. Other opportunities were highlighted that could immediately contribute to capacity development, including the creation of a consortium to link global North and South universities, online training modules for middle managers, and practical, hands-on experiences for frontline nutrition workers. Institutional and organizational support is needed to enable workshop recommendations on education and training to be effectively implemented and sustained. The findings from the Castel Gandolfo workshop can contribute to the delivery of successful nutrition-relevant actions in the face of mounting external pressures and informing and attaining the forthcoming Sustainable Development Goals.     

Detection of genomic deletions of PKP2 in arrhythmogenic right ventricular cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited myocardial disease that predominantly affects the right ventricle and is associated with ventricular arrhythmias that may lead to sudden cardiac death. Mutations within at least seven separate genes have been identified to cause ARVC, however a genetic culprit remains elusive in approximately 50% of cases. Although negative genetic testing may be secondary to pathogenic mutations within undiscovered genes, an alternative explanation may be the presence of large deletions or duplications involving known genes. These large copy number variants may not be detected with standard clinical genetic testing which is presently limited to direct DNA sequencing. We describe two cases of ARVC possessing large deletions involving plakophilin‐2 (PKP2) identified with microarray analysis and/or multiplex ligation‐dependent probe amplification (MLPA) that would have been classified as genotype negative with standard clinical genetic testing. A deletion of the entire coding region of PKP2 excluding exon 1 was identified in patient 1 and his son. In patient 2, MLPA analysis of PKP2 revealed deletion of the entire gene with subsequent microarray analysis demonstrating a de novo 7.9 Mb deletion of chromosome 12p12.1p11.1. These findings support screening for large copy number variants in clinically suspected ARVC cases without clear disease causing mutations following initial sequencing analysis.