Proceedings of the National Academy of Sciences of the United States of America
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Proc. Natl. Acad. Sci. U.S.A. · Jan 2015
Genomic responses in mouse models greatly mimic human inflammatory diseases.
The use of mice as animal models has long been considered essential in modern biomedical research, but the role of mouse models in research was challenged by a recent report that genomic responses in mouse models poorly mimic human inflammatory diseases. Here we reevaluated the same gene expression datasets used in the previous study by focusing on genes whose expression levels were significantly changed in both humans and mice. ⋯ Moreover, meta-analysis of those datasets revealed a number of pathways/biogroups commonly regulated by multiple conditions in humans and mice. These findings demonstrate that gene expression patterns in mouse models closely recapitulate those in human inflammatory conditions and strongly argue for the utility of mice as animal models of human disorders.
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Proc. Natl. Acad. Sci. U.S.A. · Jan 2015
Clinical TrialEvening use of light-emitting eReaders negatively affects sleep, circadian timing, and next-morning alertness.
In the past 50 y, there has been a decline in average sleep duration and quality, with adverse consequences on general health. A representative survey of 1,508 American adults recently revealed that 90% of Americans used some type of electronics at least a few nights per week within 1 h before bedtime. Mounting evidence from countries around the world shows the negative impact of such technology use on sleep. ⋯ Here we compare the biological effects of reading an electronic book on a light-emitting device (LE-eBook) with reading a printed book in the hours before bedtime. Participants reading an LE-eBook took longer to fall asleep and had reduced evening sleepiness, reduced melatonin secretion, later timing of their circadian clock, and reduced next-morning alertness than when reading a printed book. These results demonstrate that evening exposure to an LE-eBook phase-delays the circadian clock, acutely suppresses melatonin, and has important implications for understanding the impact of such technologies on sleep, performance, health, and safety.
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Proc. Natl. Acad. Sci. U.S.A. · Jan 2015
Clinical TrialHaptoglobin phenotype predicts the development of focal and global cerebral vasospasm and may influence outcomes after aneurysmal subarachnoid hemorrhage.
Cerebral vasospasm (CV) and the resulting delayed cerebral ischemia (DCI) significantly contribute to poor outcomes following aneurysmal subarachnoid hemorrhage (aSAH). Free hemoglobin (Hb) within the subarachnoid space has been implicated in the pathogenesis of CV. Haptoglobin (Hp) binds free pro-oxidant Hb, thereby modulating its harmful effects. ⋯ Strong trends toward increased mortality (P = 0.079) and worse functional outcomes were seen for the Hp2-2 patients with modified Rankin scale at 6 wk (P = 0.076) and at 1 y (P = 0.051) and with Glasgow Outcome Scale Extended at discharge (P = 0.091) and at 1 y (P = 0.055). In conclusion, Hp2-2 phenotype is an independent risk factor for the development of both focal and global CV and also predicts poor functional outcomes and mortality after aSAH. Hp phenotyping may serve as a clinically useful tool in the critical care management of aSAH patients by allowing for early prediction of those patients who require increased vigilance due to their inherent genetic risk for the development of CV and resulting DCI and poor outcomes.
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Proc. Natl. Acad. Sci. U.S.A. · Jan 2015
Signature of consciousness in the dynamics of resting-state brain activity.
At rest, the brain is traversed by spontaneous functional connectivity patterns. Two hypotheses have been proposed for their origins: they may reflect a continuous stream of ongoing cognitive processes as well as random fluctuations shaped by a fixed anatomical connectivity matrix. Here we show that both sources contribute to the shaping of resting-state networks, yet with distinct contributions during consciousness and anesthesia. ⋯ Under anesthesia, the more frequent functional connectivity patterns inherit the structure of anatomical connectivity, exhibit fewer small-world properties, and lack negative correlations. Conversely, wakefulness is characterized by the sequential exploration of a richer repertoire of functional configurations, often dissimilar to anatomical structure, and comprising positive and negative correlations among brain regions. These results reconcile theories of consciousness with observations of long-range correlation in the anesthetized brain and show that a rich functional dynamics might constitute a signature of consciousness, with potential clinical implications for the detection of awareness in anesthesia and brain-lesioned patients.
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Proc. Natl. Acad. Sci. U.S.A. · Jan 2015
Single cell-derived clonal analysis of human glioblastoma links functional and genomic heterogeneity.
Glioblastoma (GBM) is a cancer comprised of morphologically, genetically, and phenotypically diverse cells. However, an understanding of the functional significance of intratumoral heterogeneity is lacking. We devised a method to isolate and functionally profile tumorigenic clones from patient glioblastoma samples. ⋯ Further, candidate therapies for resistant clones were detected with clone-specific drug screening. Genomic analyses revealed genes and pathways that associate with specific functional behavior of single clones. Our results suggest that functional clonal profiling used to identify tumorigenic and drug-resistant tumor clones will lead to the discovery of new GBM clone-specific treatment strategies.