The Experts below are selected from a list of 306 Experts worldwide ranked by ideXlab platform
Karl Skorecki - One of the best experts on this subject based on the ideXlab platform.
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apol1 nephropathy a population genetics and evolutionary medicine Detective Story
Seminars in Nephrology, 2017Co-Authors: Etty Kruzeldavila, Walter G Wasser, Karl SkoreckiAbstract:Summary: Common DNA sequence variants rarely have a high-risk association with a common disease. When such associations do occur, evolutionary forces must be sought, such as in the association of apolipoprotein L1 (APOL1) gene risk variants with nondiabetic kidney diseases in populations of African ancestry. The variants originated in West Africa and provided pathogenic resistance in the heterozygous state that led to high allele frequencies owing to an adaptive evolutionary selective sweep. However, the homozygous state is disadvantageous and is associated with a markedly increased risk of a spectrum of kidney diseases encompassing hypertension-attributed kidney disease, focal segmental glomerulosclerosis, human immunodeficiency virus nephropathy, sickle cell nephropathy, and progressive lupus nephritis. This scientific success Story emerged with the help of the tools developed over the past 2 decades in human genome sequencing and population genomic databases. In this introductory article to a timely issue dedicated to illuminating progress in this area, we describe this unique population genetics and evolutionary medicine Detective Story. We emphasize the paradox of the inheritance mode, the missing heritability, and unresolved associations, including cardiovascular risk and diabetic nephropathy. We also highlight how genetic epidemiology elucidates mechanisms and how the principles of evolution can be used to unravel conserved pathways affected by APOL1 that may lead to novel therapies. The APOL1 gene provides a compelling example of a common variant association with common forms of nondiabetic kidney disease occurring in a continental population isolate with subsequent global admixture. Scientific collaboration using multiple experimental model systems and approaches should further clarify pathomechanisms further, leading to novel therapies.
Christopher Wills - One of the best experts on this subject based on the ideXlab platform.
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when did eve live an evolutionary Detective Story
Evolution, 1995Co-Authors: Christopher WillsAbstract:Various estimates of the time at which the human mitochondrial Eve lived have ranged from as little as 60,000 yr to more than 500,000 yr ago. Because of this immense range, it is impossible to distinguish between single- origin and multiple-origins hypotheses for the evolution of our species. In an attempt to reduce the uncertainty, I have examined the largest available body of sequence information, comprising the mitochondrial control region, for clues to how the observed diversity arose. In this region it is possible to show, by examining the distribution of polymorphic sites, that transitions have occurred at some sites at a much higher rate than at others. Computer simulations can, when two rates for transitions are postulated, provide close approximations to the distribution of substitutions seen in the actual data. The "best fit" was obtained when the rate at 3/4 of the sites was 4 times the transversion rate, and the rate at the remainder 160 times the transversion rate. The likelihood of such a high rate at some sites helps to explain why tree-building methods employing these data have provided so little phylogenetic information. Furthermore, it is possible to show that transversions do not appear to occur preferentially at these transition "hot-spot" sites and that such huge differences in substitution rates are not seen for transversions, suggesting that the rules governing the mutation and acceptance or rejection of transversions are different from those governing transitions. The great majority of transversions appear to occur at a low rate throughout the region. Thus, methods for determining the age of Eve that are based on recent divergence in human populations, or on applying a mutation probability matrix based on an assumption of uniform mutation rates, are likely to result in underestimates. The rate of accumulation of transversions is shown to be a more accurate estimator. of the age of Eve. The conclusion is reached that Eve probably lived (depending on when the ancestors of humans and chimpanzees diverged) between 436,000 and 806,000 yr ago.
Egisto Boschetti - One of the best experts on this subject based on the ideXlab platform.
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Sherlock Holmes and the proteome--a Detective Story.
The FEBS journal, 2007Co-Authors: Pier Giorgio Righetti, Egisto BoschettiAbstract:The performance of a hexapeptide ligand library in capturing the 'hidden proteome' is illustrated and evaluated. This library, insolubilized on an organic polymer and available under the trade name 'Equalizer Bead Technology', acts by capturing all components of a given proteome, by concentrating rare and very rare proteins, and simultaneously diluting the abundant ones. This results in a proteome of 'normalized' relative abundances, amenable to analysis by MS and any other analytical tool. Examples are given of analysis of human urine and serum, as well as cell and tissue lysates, such as Escherichia coli and Saccharomyces cerevisiae extracts. Another important application is impurity tracking and polishing of recombinant DNA products, especially biopharmaceuticals meant for human consumption.
Susan Elizabeth Sweeney - One of the best experts on this subject based on the ideXlab platform.
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detecting texts the metaphysical Detective Story from poe to postmodernism
South Central Review, 1999Co-Authors: Patricia Merivale, Susan Elizabeth SweeneyAbstract:Although readers of Detective fiction ordinarily expect to learn the mystery's solution at the end, there is another kind of Detective Story -- whose hiStory encompasses writers as diverse as Poe, Borges, Robbe-Grillet, Auster, and Stephen King -- that ends with a question rather than an answer. The Detective not only fails to solve the crime, but also confronts insoluble mysteries of interpretation and identity. As the contributors to Detecting Texts contend, such stories belong to a distinct genre, the metaphysical Detective Story, in which the Detective hero's inability to interpret the mystery inevitably casts doubt on the reader's similar attempt to make sense of the text and the world.
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Detecting Texts: The Metaphysical Detective Story from Poe to Postmodernism - Detecting Texts: The Metaphysical Detective Story from Poe to Postmodernism
1999Co-Authors: Patricia Merivale, Susan Elizabeth SweeneyAbstract:Although readers of Detective fiction ordinarily expect to learn the mystery's solution at the end, there is another kind of Detective Story -- whose hiStory encompasses writers as diverse as Poe, Borges, Robbe-Grillet, Auster, and Stephen King -- that ends with a question rather than an answer. The Detective not only fails to solve the crime, but also confronts insoluble mysteries of interpretation and identity. As the contributors to Detecting Texts contend, such stories belong to a distinct genre, the metaphysical Detective Story, in which the Detective hero's inability to interpret the mystery inevitably casts doubt on the reader's similar attempt to make sense of the text and the world.
Michael Cook - One of the best experts on this subject based on the ideXlab platform.
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Tony Hillerman’s Cultural Metaphysics
Detective Fiction and the Ghost Story, 2014Co-Authors: Michael CookAbstract:Tony Hiller man’s novels embody much that has changed in the Detective fiction of the last thirty years. Since the re-emergence and development of metaphysical ideas in the Detective Story, a phenomenon which heralded, in part, a reconnection with some of the founding principles exhibited by Poe, the genre has broadened its thematic horizons considerably. These innovations have seen the Detective Story become infinitely more inclusive of different cultures away from the traditional representation of western values towards an increasing body of work on gender and racial politics, cultural diversity and, importantly for these pages, an acceptance of the supernatural. For many of these reasons, Hillerman’s Joe Leaphorn/ Jim Shee series of Detective novels are pointers into a future where supernatural ideas can find new and enriching ways to co-exist with the conventions of the genre. They are texts, too, which frequent the borders of interpretation; all of them may be read as conventional Detective stories while simultaneously embracing metaphysical ideas that draw attention to the profound nature of spiritual belief and its relationship with the natural world.1 They posit, too, the tensions between two very different cultures, the mystical traditions of the Navajo way of life and that of the crime Story and its investigation.
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The Question is the Writer Himself: Paul Auster’s Locked Room in City of Glass
Narratives of Enclosure in Detective Fiction, 2011Co-Authors: Michael CookAbstract:Paul Auster’s The New York Trilogy — originally published as three separate novels, City of Glass (1985), Ghosts (1986) and The Locked Room (1986) — are works where the ultimate nightmares for Detective fiction come true. These are stories where unexplained absences and strange disappearances are the norm and where the generic conventions dissolve into an endless pursuit of an unspecified mystery. In the post-Second World War period, since the appearance of Borges’s three Detective stories, two distinct forms of the ratiocinative Detective Story emerged. The conventional Detective tale with its formulaic narrative of enclosure now found itself running parallel with a new form, the metaphysical Detective Story.1 Successive novels by writers such as Nabokov, Robbe-Grillet, Durrenmatt and Pynchon, amongst others, have all augmented this growing body of work.2
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Edgar Allan Poe and the Detective Story Narrative
Narratives of Enclosure in Detective Fiction, 2011Co-Authors: Michael CookAbstract:One of the more remarkable facts about Detective fiction, a genre which has now assumed epic proportions, is its foundation of just three short stories, an experiment to be abandoned by its creator almost as quickly as it appeared. For Edgar Allan Poe, the publication of ‘The Murders in the Rue Morgue’ in 1841, followed by ‘The Mystery of Marie Roget’ (1842–3) and ‘The Purloined Letter’ (1844), was to represent the extent of his output in this field. Although he always seemed diffident about his foray into Detective fiction, being ‘conscious of the inherent gimmickry’ of the tales, he nevertheless realized that he was in uncharted literary territory.3 In a letter to a friend, he wrote, ‘these tales of ratiocination owe most of their popularity to being something in a new key’.4 This ‘new key’ was characterized by the representation of crime as an intellectual puzzle, invoking the practice of scientism in clue solving and heralding the Detective as a major literary figure. So complete was Poe’s innovation that the narrative structure he composed for these tales was to become a blueprint for all subsequent Detective stories. Thus the locked room of ‘The Murders in the Rue Morgue’, as a prototype for Detective fiction with its accent on enclosures, death and references to sequestered lives, not only became a paradigm for the way in which the genre would function structurally, but carried with it an idea central to Poe’s Gothic texts.