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"Richard A. Stone"
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Project Mayflower : building and sailing a seventeenth-century replica
\"The never-before-told story of Project Mayflower--the building of the replica ship docked in Plymouth, Massachusetts--from the origins of the idea, through the financial and political influences that nearly scuttled her, the seven-week ocean voyage from England in the skilled hands of Alan Villiers, and finally her lasting impact on America. Today, the Mayflower II--the replica of the 1620 ship that brought the Pilgrims to America and launched a nation--is seen by some 2.6 million visitors to Plymouth annually and listed on the National Register of Historic Places. But there is much more to the replica's story than meets the eye. In fact, the origins of Project Mayflower began in the 1950s not with an American, but with a British World War II veteran named Warwick Charlton who had what seemed an impossible dream: build an historically accurate replica, sail her across the Atlantic, and present the finished product as a thank you to his country's wartime ally. What Charlton didn't know was that the son of a powerful New England financier had the same idea. Henry (\"Harry\") Hornblower II wanted a replica just as badly, though for a different reason: as a tourist attraction for a new museum he was building in Massachusetts, soon to be known as Plimoth Plantation, where the original Mayflower had landed centuries before. Despite different personal motives, Charlton and Hornblower agreed to join forces when they met by chance in 1955. Charlton would be responsible for financing, construction, and the vessel's safe passage across the Atlantic, while Hornblower promised mooring, maintenance, and exhibition. Neither man could imagine what would happen next. Project Mayflower recounts the never-before-told story of a grand adventure, from the origins of the idea, through the financial and political influences that nearly scuttled the ship, and the challenges of building an accurate replica based on a single known mention: William Bradford's reference in Of Plimoth Plantation describing his craft simply as \"180 tons of burden.\" From there, Stone traces the Mayflower II's dramatic seven-week ocean voyage from Plymouth, England, to Plymouth, Massachusetts, in the skilled hands of Alan Villiers and a crew of thirty-three bold men, and finishes by exploring the legacy of praise for the achievement, the skullduggery to tarnish the reputation of the project's creator, and finally the Mayflower II's lasting--and ongoing--impact on America.\"--Amazon.com.
BOOK
Meta-analysis of 542,934 subjects of European ancestry identifies new genes and mechanisms predisposing to refractive error and myopia
Refractive errors, in particular myopia, are a leading cause of morbidity and disability worldwide. Genetic investigation can improve understanding of the molecular mechanisms that underlie abnormal eye development and impaired vision. We conducted a meta-analysis of genome-wide association studies (GWAS) that involved 542,934 European participants and identified 336 novel genetic loci associated with refractive error. Collectively, all associated genetic variants explain 18.4% of heritability and improve the accuracy of myopia prediction (area under the curve (AUC) = 0.75). Our results suggest that refractive error is genetically heterogeneous, driven by genes that participate in the development of every anatomical component of the eye. In addition, our analyses suggest that genetic factors controlling circadian rhythm and pigmentation are also involved in the development of myopia and refractive error. These results may enable the prediction of refractive error and the development of personalized myopia prevention strategies in the future.
Meta-analysis of genome-wide association studies of 542,934 individuals identifies 336 novel loci associated with refractive error and implicates eye development, circadian rhythm and pigmentation pathways in controlling myopia.
Journal Article
Altered ocular parameters from circadian clock gene disruptions
The pathophysiology of refractive errors is poorly understood. Myopia (nearsightedness) in particular both blurs vision and predisposes the eye to many blinding diseases during adulthood. Based on past findings of diurnal variations in the dimensions of the eyes of humans and other vertebrates, altered diurnal rhythms of these ocular dimensions with experimentally induced myopia, and evolving evidence that ambient light exposures influence refractive development, we assessed whether disturbances in circadian signals might alter the refractive development of the eye. In mice, retinal-specific knockout of the clock gene Bmal1 induces myopia and elongates the vitreous chamber, the optical compartment separating the lens and the retina. These alterations simulate common ocular findings in clinical myopia. In Drosophila melanogaster, knockouts of the clock genes cycle or period lengthen the pseudocone, the optical component of the ommatidium that separates the facet lens from the photoreceptors. Disrupting circadian signaling thus alters optical development of the eye in widely separated species. We propose that mechanisms of myopia include circadian dysregulation, a frequent occurrence in modern societies where myopia also is both highly prevalent and increasing at alarming rates. Addressing circadian dysregulation may improve understanding of the pathogenesis of refractive errors and introduce novel therapeutic approaches to ameliorate myopia development in children.
Journal Article
Diurnal gene expression patterns in retina and choroid distinguish myopia progression from myopia onset
The world-wide prevalence of myopia (nearsightedness) is increasing, but its pathogenesis is incompletely understood. Among many putative mechanisms, laboratory and clinical findings have implicated circadian biology in the etiology of myopia. Consistent with a circadian hypothesis, we recently reported a marked variability in diurnal patterns of gene expression in two crucial tissues controlling post-natal refractive development ‐ the retina and choroid–at the onset of form-deprivation myopia in chick, a widely studied and validated model. To extend these observations, we assayed gene expression by RNA-Seq in retina and choroid during the progression of established unilateral form-deprivation myopia of chick. We assayed gene expression every 4 hours during a single day from myopic and contralateral control eyes. Retinal and choroidal gene expression in myopic vs. control eyes during myopia progression differed strikingly at discrete times during the day. Very few differentially expressed genes occurred at more than one time in either tissue during progressing myopia. Similarly, Gene Set Enrichment Analysis pathways varied markedly by time during the day. Some of the differentially expressed genes in progressing myopia coincided with candidate genes for human myopia, but only partially corresponded with genes previously identified at myopia onset. Considering other laboratory findings and human genetics and epidemiology, these results further link circadian biology to the pathogenesis of myopia; but they also point to important mechanistic differences between the onset of myopia and the progression of established myopia. Future laboratory and clinical investigations should systematically incorporate circadian mechanisms in studying the etiology of myopia and in seeking more effective treatments to normalize eye growth in children.
Journal Article
Diurnal retinal and choroidal gene expression patterns support a role for circadian biology in myopia pathogenesis
The prevalence of myopia (nearsightedness) is increasing to alarming levels, but its etiology remains poorly understood. Because both laboratory and clinical findings suggest an etiologic role for circadian rhythms in myopia development, we assayed gene expression by RNA-Seq in retina and choroid at the onset of unilateral experimental myopia in chick, isolating tissues every 4 h during a single 24-h period from myopic and contralateral control eyes. Occluded versus open eye gene expression differences varied considerably over the 24-h sampling period, with some occurring at multiple times of day but with others showing differences at only a single investigated timepoint. Some of the genes identified in retina or choroid of chick myopia were previously identified as candidate genes for common human myopia. Like differentially expressed genes, pathways identified by Gene Set Enrichment Analysis also varied dramatically by sampling time. Considered with other laboratory data, human genetic and epidemiology data, these findings further implicate circadian events in myopia pathogenesis. The present results emphasize a need to include time of day in mechanistic studies of myopia and to assess circadian biology directly in trying to understand better the origin of myopia and to develop more effective therapies.
Journal Article
A1‐, A2A‐ and A3‐subtype adenosine receptors modulate intraocular pressure in the mouse
Despite the potential importance of the mouse in studying the pharmacology of aqueous dynamics, measurement of intraocular pressure (IOP) in its very small eye has been problematic. Utilizing a novel servo‐null electrophysiologic approach recently applied to the mouse, we have identified a diversity of adenosine‐receptor mechanisms in modulating IOP in this species. We report the first evidence that A3 receptors increase IOP in any species, and verify in the mouse reports with larger mammals that A1 receptors lower and A2A receptors increase IOP. British Journal of Pharmacology (2001) 134, 241–245; doi:10.1038/sj.bjp.0704267
Journal Article
A Release Mechanism for Stored ATP in Ocular Ciliary Epithelial Cells
Purines can modify ciliary epithelial secretion of aqueous humor into the eye. The source of the purinergic agonists acting in the ciliary epithelium, as in many epithelial tissues, is unknown. We found that the fluorescent ATP marker quinacrine stained rabbit and bovine ciliary epithelia but not the nerve fibers in the ciliary bodies. Cultured bovine pigmented and nonpigmented ciliary epithelial cells also stained intensely when incubated with quinacrine. Hypotonic stimulation of cultured epithelial cells increased the extracellular ATP concentration by 3-fold; this measurement underestimates actual release as the cells also displayed ecto-ATPase activity. The hypotonically triggered increase in ATP was inhibited by the Cl--channel blocker 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB) in both cell types. In contrast, the P-glycoprotein inhibitors tamoxifen and verapamil and the cystic fibrosis transmembrane conductance regulator (CFTR) blockers glybenclamide and diphenylamine-2-carboxylate did not affect ATP release from either cell type. This pharmacological profile suggests that ATP release is not restricted to P-glycoprotein or the cystic fibrosis transmembrane conductance regulator, but can proceed through a route sensitive to NPPB. ATP release also was triggered by ionomycin through a different NPPB-insensitive mechanism, inhibitable by the calcium/calmodulin-activated kinase II inhibitor KN-62. Thus, both layers of the ciliary epithelium store and release ATP, and purines likely modulate aqueous humor flow by paracrine and/or autocrine mechanisms within the two cell layers of this epithelium.
Journal Article
Myopia and ambient lighting at night
Myopia, or short-sightedness, occurs when the image of distant objects, focused by the cornea and lens, falls in front of the retina. It commonly arises from excessive postnatal eye growth, particularly in the vitreous cavity. Its prevalence is increasing and now reaches 70-90% in some Asian populations
1
,
2
. As well as requiring optical correction, myopia is a leading risk factor for acquired blindness in adults because it predisposes individuals to retinal detachment, retinal degeneration and glaucoma. It typically develops in the early school years but can manifest into early adulthood
2
. Its aetiology is poorly understood but may involve genetic and environmental factors
1
,
2
, such as viewing close objects, although how this stimulates eye growth is not known
3
. We have looked at the effects of light exposure on vision, and find a strong association between myopia and night-time ambient light exposure during sleep in children before they reach two years of age.
Journal Article