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"Stone, Richard"
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Hidden stories of the Stephen Lawrence inquiry : personal reflections
This book provides an insight into what happened inside the Stephen Lawrence Inquiry. It details key incidents, presenting hitherto unseen information, and interprets the challenges faced by Sir William Macpherson and his panel.
Book
Dam-building threatens Mekong fisheries
With scores of dams planned, scientists debate measures to soften the impact. Laos and its neighbors hungry for electric power are embarking on a dam-building spree on the Mekong River and on major tributaries that threatens to trigger a food security crisis. By blocking migration routes and cutting sediment flow to the Mekong delta, the projects could wipe out more than a third of the lower Mekong Basin's annual haul of river fish—a serious blow to the region's 60 million people. Hoping to forestall catastrophe, environmentalists and scientists are pressing the hydropower companies to incorporate \"fish-friendly\" turbines, ladders, and locks for migratory fish into their dam designs. At a meeting last month in Vientiane to discuss fish-passage approaches, some scientists saw reason for optimism. But others scoffed at the mitigation plans and believe that the only way to spare the fisheries is to drop some of the projects.
Journal Article
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
Introducing a Remote Patient Monitoring Usability Impact Model to Overcome Challenges
Telehealth and remote patient monitoring (RPM), in particular, have been through a massive surge of adoption since 2020. This initiative has proven potential for the patient and the healthcare provider in areas such as reductions in the cost of care. While home-use medical devices or wearables have been shown to be beneficial, a literature review illustrates challenges with the data generated, driven by limited device usability. This could lead to inaccurate data when an exam is completed without clinical supervision, with the consequence that incorrect data lead to improper treatment. Upon further analysis of the existing literature, the RPM Usability Impact model is introduced. The goal is to guide researchers and device manufacturers to increase the usability of wearable and home-use medical devices in the future. The importance of this model is highlighted when the user-centered design process is integrated, which is needed to develop these types of devices to provide the proper user experience.
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
MEN1 mutations mediate clinical resistance to menin inhibition
Chromatin-binding proteins are critical regulators of cell state in haematopoiesis
1
,
2
. Acute leukaemias driven by rearrangement of the mixed lineage leukaemia 1 gene (
KMT2A
r) or mutation of the nucleophosmin gene (
NPM1
) require the chromatin adapter protein menin, encoded by the
MEN1
gene, to sustain aberrant leukaemogenic gene expression programs
3
–
5
. In a phase 1 first-in-human clinical trial, the menin inhibitor revumenib, which is designed to disrupt the menin–MLL1 interaction, induced clinical responses in patients with leukaemia with
KMT2A
r or mutated
NPM1
(ref.
6
). Here we identified somatic mutations in
MEN1
at the revumenib–menin interface in patients with acquired resistance to menin inhibition. Consistent with the genetic data in patients, inhibitor–menin interface mutations represent a conserved mechanism of therapeutic resistance in xenograft models and in an unbiased base-editor screen. These mutants attenuate drug–target binding by generating structural perturbations that impact small-molecule binding but not the interaction with the natural ligand MLL1, and prevent inhibitor-induced eviction of menin and MLL1 from chromatin. To our knowledge, this study is the first to demonstrate that a chromatin-targeting therapeutic drug exerts sufficient selection pressure in patients to drive the evolution of escape mutants that lead to sustained chromatin occupancy, suggesting a common mechanism of therapeutic resistance.
Somatic mutations in
MEN1
are identified in patients with leukaemia treated with a novel chromatin-targeting therapy, and the mechanism by which these mutations mediate therapeutic resistance is characterized.
Journal Article
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
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