Identification of a common polymorphism in COQ8B acting as a modifier of thoracic aortic aneurysm severity

Thoracic aortic aneurysm (TAA) predisposes to sudden, life-threatening aortic dissection. The factors that regulate interindividual variability in TAA severity are not well understood. Identifying a molecular basis for this variability has the potential to improve clinical risk stratification and advance mechanistic insight. We previously identified COQ8B, a gene important for biosynthesis of coenzyme Q, as a candidate genetic modifier of TAA severity. Here, we investigated the physiological role of COQ8B in human aortic smooth muscle cells (SMCs) and further tested its genetic association with TAA severity. We find COQ8B protein localizes to mitochondria in SMCs, and loss of mitochondrial COQ8B leads to increased oxidative stress, decreased mitochondrial respiration, and altered expression of SMC contractile genes. Oxidative stress and mitochondrial cristae defects were prevalent in the medial layer of human proximal aortic tissues in patients with TAA, and COQ8B expression was decreased in TAA SMCs compared with controls. A common single nucleotide polymorphism (SNP) rs3865452 in COQ8B (c.521A>G, p.H174R) was associated with decreased rate of aortic root dilation in young patients with TAA. In addition, the SNP was less frequent in a second cohort of early-onset thoracic aortic dissection cases compared with controls. COQ8B protein levels in aortic SMCs were increased in TAA patients homozygous for rs3865452 compared with those homozygous for the reference allele. Thus, COQ8B is important for aortic SMC metabolism, which is dysregulated in TAA, and rs3865452 may decrease TAA severity by increasing COQ8B level. Genotyping rs3865452 may be useful for clinical risk stratification and tailored aortopathy management

Experience-Driven Axon Retraction in the Pharmacologically Inactivated Visual Cortex Does Not Require Synaptic Transmission

BACKGROUND: Experience during early postnatal development plays an important role in the refinement of specific neural connections in the brain. In the mammalian visual system, altered visual experiences induce plastic adaptation of visual cortical responses and guide rearrangements of afferent axons from the lateral geniculate nucleus. Previous studies using visual deprivation demonstrated that the afferents serving an open eye significantly retract when cortical neurons are pharmacologically inhibited by applying a gamma-aminobutyric acid type A receptor agonist, muscimol, whereas those serving a deprived eye are rescued from retraction, suggesting that presynaptic activity can lead to the retraction of geniculocortical axons in the absence of postsynaptic activity. Because muscimol application suppresses the spike activity of cortical neurons leaving transmitter release intact at geniculocortical synapses, local synaptic interaction may underlie the retraction of active axons in the inhibited cortex. METHOD AND FINDINGS: New studies reported here determined whether experience-driven axon retraction can occur in the visual cortex inactivated by blocking synaptic inputs. We inactivated the primary visual cortex of kittens by suppressing synaptic transmission with cortical injections of botulinum neurotoxin type E, which cleaves a synaptic protein, SNAP-25, and blocks transmitter release, and examined the geniculocortical axon morphology in the animals with normal vision and those deprived of vision binocularly. We found that afferent axons in the animals with normal vision showed a significant retraction in the inactivated cortex, as similarly observed in the muscimol-treated cortex, whereas the axons in the binocularly deprived animals were preserved. CONCLUSIONS: Therefore, the experience-driven axon retraction in the inactivated cortex can proceed in the absence of synaptic transmission. These results suggest that presynaptic mechanisms play an important role in the experience-driven refinement of geniculocortical axons

US employment inequality in the Great Recession and the COVID-19 pandemic

This article compares inequality in employment across demographic groups in the Great Recession and the COVID-19 pandemic. We develop a measure to capture both how much employment declines during a recession and the persistence of employment losses. Results show a significant shift of job loss from men in the Great Recession to women in the COVID-19 lockdown. White workers fare better than other racial/ethnic groups in both recessions. Black and Hispanic women are hit especially hard in the COVID-19 pandemic. With our job-loss measure, less-educated workers had modestly worse outcomes in the Great Recession. However, during COVID-19, less-educated workers suffer much more severe employment consequences than more-educated groups. We discuss long-term effects of employment inequality and how these findings are relevant to debates about policy responses