Proceedings of the National Academy of Sciences of the United States of America
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Proc. Natl. Acad. Sci. U.S.A. · Jun 2010
Complex I deficiency due to loss of Ndufs4 in the brain results in progressive encephalopathy resembling Leigh syndrome.
To explore the lethal, ataxic phenotype of complex I deficiency in Ndufs4 knockout (KO) mice, we inactivated Ndufs4 selectively in neurons and glia (NesKO mice). NesKO mice manifested the same symptoms as KO mice including retarded growth, loss of motor ability, breathing abnormalities, and death by approximately 7 wk. Progressive neuronal deterioration and gliosis in specific brain areas corresponded to behavioral changes as the disease advanced, with early involvement of the olfactory bulb, cerebellum, and vestibular nuclei. ⋯ Activation of caspase 8, but not caspase 9, in affected brain regions implicate the initiation of the extrinsic apoptotic pathway. Limited caspase 3 activation and the predominance of ultrastructural features of necrotic cell death suggest a switch from apoptosis to necrosis in affected neurons. These data suggest that dysfunctional complex I in specific brain regions results in progressive glial activation that promotes neuronal death that ultimately results in mortality.
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Proc. Natl. Acad. Sci. U.S.A. · Jun 2010
Tubulin polyglutamylation is essential for airway ciliary function through the regulation of beating asymmetry.
Airway epithelial cilia protect the mammalian respiratory system from harmful inhaled materials by providing the force necessary for effective mucociliary clearance. Ciliary beating is asymmetric, composed of clearly distinguished effective and recovery strokes. Neither the importance of nor the essential components responsible for the beating asymmetry has been directly elucidated. ⋯ The KO mice displayed a significant accumulation of mucus in the nasal cavity, and also emitted frequent coughing- or sneezing-like noises. Thus, the beating asymmetry is important for airway ciliary function. Our findings provide evidence that tubulin glutamylation is essential for ciliary function through the regulation of beating asymmetry, and provides insight into the molecular basis underlying the beating asymmetry.
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Proc. Natl. Acad. Sci. U.S.A. · Jun 2010
Telomere length is inherited with resetting of the telomere set-point.
We have studied models of telomerase haploinsufficiency in humans and mice to analyze regulation of telomere length and the significance of "set points" in inheritance of telomere length. In three families with clinical syndromes associated with short telomeres resulting from haploinsufficient mutations in TERT, the gene encoding telomerase reverse transcriptase, we asked whether restoration of normal genotypes in offspring of affected individuals would elongate inherited short telomeres. Telomeres were shorter than normal in some but not all genotypically normal offspring of telomerase-mutant parents or grandparents. ⋯ This breeding strategy therefore has established a mouse strain, B6. ST (short telomeres), with C57BL/6 genotype and stable short telomeres. These findings suggest that the set point of telomere lengths of offspring is determined by the telomere lengths of their parents in the presence of normal expression of telomerase.
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Proc. Natl. Acad. Sci. U.S.A. · Jun 2010
A snapshot of the age distribution of psychological well-being in the United States.
Psychological well-being (WB) includes a person's overall appraisal of his or her life (Global WB) and affective state (Hedonic WB), and it is considered a key aspect of the health of individuals and groups. Several cross-sectional studies have documented a relation between Global WB and age. Little is known, however, about the age distribution of Hedonic WB. ⋯ Unlike a prior study, men and women had very similar age profiles of WB. Several measures that could plausibly covary with the age-WB association (e.g., having children at home) did not alter the age-WB patterns. Global and Hedonic WB measures appear to index different aspects of WB over the lifespan, and the postmidlife increase in WB, especially in Hedonic WB, deserves continued exploration.