CaMKII (Ca2+/Calmodulin-Dependent Kinase II) in Mitochondria of Smooth Muscle Cells Controls Mitochondrial Mobility, Migration, and Neointima Formation.

OBJECTIVE: The main objective of this study is to define the mechanisms by which mitochondria control vascular smooth muscle cell (VSMC) migration and impact neointimal hyperplasia. APPROACH AND RESULTS: The multifunctional CaMKII (Ca2+/calmodulin-dependent kinase II) in the mitochondrial matrix of VSMC drove a feed-forward circuit with the mitochondrial Ca2+ uniporter (MCU) to promote matrix Ca2+ influx. MCU was necessary for the activation of mitochondrial CaMKII (mtCaMKII), whereas mtCaMKII phosphorylated MCU at the regulatory site S92 that promotes Ca2+ entry. mtCaMKII was necessary and sufficient for platelet-derived growth factor-induced mitochondrial Ca2+ uptake. This effect was dependent on MCU. mtCaMKII and MCU inhibition abrogated VSMC migration and mitochondrial translocation to the leading edge. Overexpression of wild-type MCU, but not MCU S92A, mutant in MCU-/- VSMC rescued migration and mitochondrial mobility. Inhibition of microtubule, but not of actin assembly, blocked mitochondrial mobility. The outer mitochondrial membrane GTPase Miro-1 promotes mitochondrial mobility via microtubule transport but arrests it in subcellular domains of high Ca2+ concentrations. In Miro-1-/- VSMC, mitochondrial mobility and VSMC migration were abolished, and overexpression of mtCaMKII or a CaMKII inhibitory peptide in mitochondria (mtCaMKIIN) had no effect. Consistently, inhibition of mtCaMKII increased and prolonged cytosolic Ca2+ transients. mtCaMKII inhibition diminished phosphorylation of focal adhesion kinase and myosin light chain, leading to reduced focal adhesion turnover and cytoskeletal remodeling. In a transgenic model of selective mitochondrial CaMKII inhibition in VSMC, neointimal hyperplasia was significantly reduced after vascular injury. CONCLUSIONS: These findings identify mitochondrial CaMKII as a key regulator of mitochondrial Ca2+ uptake via MCU, thereby controlling mitochondrial translocation and VSMC migration after vascular injury.

Factors Predictive of Refractive Error After Toric Lens Implantation.

Purpose: To identify factors related to suboptimal refractive outcomes after toric intraocular lens implantation. Patients and Methods: A retrospective case-control chart review of 446 eyes with toric lens insertion by the same surgeon at a university hospital from 2016 to 2020 was conducted. Pre-operative exam findings, biometry, and one month and three month post-operative vision and refraction were noted. Reviewed charts were considered cases if uncorrected distance visual acuity (UDVA) was worse than 20/40, spherical equivalent (SE) >1 diopter (D) off target, or cylinder >1 D off target. Results: Overall, 93.7% (n = 343) of eyes achieved UDVA of 20/40 or better, 92.7% (n = 306) were within 1 D of target SE, and 90.9% (n = 300) were within 1 D of target cylinder. UDVA cases had more eyes with prior LASIK (21.7% vs 7.0%, p = 0.01) and keratoconus (8.7% vs 0.6%, p < 0.001) than controls. More SE cases had prior radial keratotomy (RK) (8.3% vs 0%, p < 0.001) and keratoconus (12.5% vs 0%, p < 0.001) than controls. More cylinder cases had prior LASIK (30.0% vs 8.7%, p < 0.001) and higher mean astigmatism (2.3 vs 1.5 D, p = 0.02) than controls. More cases in all three analyses had higher toric cylinder power (T5-T9) than controls. Age, sex, eye laterality, axial length, anterior chamber depth, lens power, dry eye, anterior basement membrane dystrophy, and Fuchs' endothelial dystrophy differences were not significant. Conclusion: Prior LASIK or RK, keratoconus, and higher astigmatism may increase the chance of a suboptimal outcome.

NIH funding trends to US medical schools from 2009 to 2018.

Total NIH funding dollars have increased from 2009-2018. We questioned whether this growth has occurred proportionately around the country and throughout allopathic medical schools. Therefore, we compared the trend in NIH grant funding from 2009 to 2018 for United States allopathic medical schools among historically top-funded schools, private and public schools, and by region of the country. Changes in both unadjusted and real funding dollars over time revealed a significant difference. Region was the only significant factor for mean percent change in funding from 2009-2018, with the Western region showing a 33.79% increase in purchasing power. The Northeastern region showed a -6.64% decrease in purchasing power while the Central and Southern regions reported changes of 2.46% and -6.08%, respectively. The mean percent increases were more proportional and nonsignificant in the public vs. private institutions comparison, at -3.41% and 4.75%, respectively. Likewise, the top-funded institutions vs. other institutions comparisons demonstrated modest, nonsignificant differences. However, although the relative changes might be proportional, the absolute increases evidence a pattern of growing cumulative advantage that favor the highest-funded institutions and private institutions. The potential consequences of this disproportionate increase include health science education, biomedical research, and patient access disparities in large parts of the country. The NIH and the scientific community should explore potential solutions in its funding models.