Showing papers by "Christopher A. Walsh published in 1999"

Differences in the gyral pattern distinguish chromosome 17–linked and X-linked lissencephaly

Abstract: Background: Classical lissencephaly or “smooth brain” is a human brain malformation that consists of diffuse agyria and pachygyria. Two genes associated with classical lissencephaly have recently been cloned— LIS1 from chromosome 17p13.3 and XLIS (also called DCX ) from Xq22.3-q23. Objective: We performed genotype-phenotype analysis in children with lissencephaly associated with mutations of different genes. Methods: We compared the phenotype, especially brain imaging studies, in a series of 48 children with lissencephaly, including 12 with Miller-Dieker syndrome (MDS), which is associated with large deletions of LIS1 and other genes in the region, 24 with isolated lissencephaly sequence caused by smaller LIS1 deletions or mutations, and 12 with isolated lissencephaly sequence caused by XLIS mutations. Results: We found consistent differences in the gyral patterns, with the malformation more severe posteriorly in individuals with LIS1 mutations and more severe anteriorly in individuals with XLIS mutations. Thus, mutations of LIS1 are associated with a posterior-to-anterior gradient of lissencephaly, whereas mutations of XLIS are associated with an anterior-to-posterior gradient. We also confirmed differences in severity between MDS and ILS17. Hypoplasia of the cerebellar vermis proved to be more common with XLIS mutations. Conclusion: It is often possible to predict the gene mutation from careful review of brain imaging studies.

Characterization of mutations in the gene doublecortin in patients with double cortex syndrome.

Abstract: Mutations in the X-linked gene doublecortin, which encodes a protein with no dear structural homologues, are found in pedigrees in which affected females show "double cortex" syndrome (DC; also known as subcortical band heterotopia or laminar heterotopia) and affected males show X-linked lissencephaly. Mutations in doublecortin also cause sporadic DC in females. To determine the incidence of doublecortin mutations in DC, we investigated a cohort of eight pedigrees and 47 sporadic patients with DC for mutations in the doublecortin open reading frame as assessed by single-stranded conformational polymorphism analysis. Mutations were identified in each of the eight DC pedigrees (100%), and in 18 of the 47 sporadic DC patients (38%). Identified mutations were of two types, protein truncation mutations and single amino acid substitution mutations. However, pedigrees with DC displayed almost exclusively single amino acid substitution mutations, suggesting that patients with these mutations may have less of a reproductive disadvantage versus those patients with protein truncation mutations. Single amino acid substitution mutations were tightly clustered in two regions of the open reading frame, suggesting that these two regions are critical for the function of the Doublecortin protein.

Coexistence of widespread clones and large radial clones in early embryonic ferret cortex.

Abstract: Cell lineage analysis in rodents has shown that the cerebral cortex is formed from both widespread and large radial clustered clones representing partly distinct lineages and producing differing cell types Since previous cell lineage analysis of the ferret cortex using retroviral libraries showed that most neurons labeled at E33-E35 formed widespread clones, we determined whether clones labeled earlier in neurogenesis showed a greater tendency to form coherent radial clones Clones labeled at E27-E29 occasionally consisted of widespread multineuron clones (13% of PCR-defined clones), but commonly consisted of small clusters of two to four neurons (65%) Moreover, 6/21 hemispheres contained a single, much larger (6-150 cells) radial cluster Although large clusters were observed in 28% of experiments, they contained many neurons, accounting for 38% of retrovirally labeled cells The large clusters showed at most few widely scattered sibling cells, either by histological analysis or by PCR analysis, suggesting that radial and widespread clones coexist but are lineally separate at early stages of corticogenesis Coexistence of large radial and widespread neuronal clones appears to be an evolutionarily conserved mechanism for cortical neurogenesis

Periventricular heterotopia and the genetics of neuronal migration in the cerebral cortex.

Abstract: In recent years, remarkable contributions to our understanding of how the brain develops have come from the field of genetics. The study of brain development is important, not only to further our understanding of this complex phenomenon, but because gross brain malformations are now recognized to cause significant proportions of cognitive and neurologic disorders. When the cerebral cortex fails to form properly, the result is often severe mental retardation. Even mild dysgenesis of the cortex is frequently associated with epilepsy.

Clonal mixing, clonal restriction, and specification of cell types in the developing rat olfactory bulb.

Abstract: To understand the clonal relationship of various olfactory bulb (OB) cell types, OB progenitor cells were infected at embryonic day (E) 14, E15, and E17 with retroviral libraries encoding alkaline phosphatase or beta-galactosidase. After survival to postnatal day 10-15, sibling relationships were identified by polymerase chain reaction DNA amplification of distinct sequences in the retroviral constructs. Within the OB, clonal progeny dispersed widely in all directions. In sharp contrast, however, clonal dispersion between the OB and neocortex was not observed, although occasional clonal dispersion between the OB and pyriform and hippocampal regions could not be excluded. Most clones (84%) contained a single cell type, especially after E17 injections, suggesting the existence of either restricted precursors, or multipotential progenitors instructed by a restricted cellular environment. Mixed OB clones (16%) contained multiple cell types in the OB, or occasionally glial or neuronal cells outside the OB, demonstrating the existence of multipotential OB progenitors, likely at a stage before formation of the olfactory rostral migratory stream. Surprisingly, OB glial cells were not labeled, suggesting distinct lineages or perhaps distinct migratory paths for glia and neurons into the OB. A hierarchical cell lineage is proposed that involves a multipotential progenitor that gives rise to potentially more limited progenitors.

Cranking It Up a Notch

Abstract: Neurons in the cerebral cortex grow by extending neurites (axons and dendrites) and making connections with their neighbors. It now transpires, as Chenn and Walsh discuss in their Perspective, that the Notch receptor and its ligands control the process of neurite extension ( estan et al.). When neurons are bunched close together and their neurites are touching each other, the Notch receptor is activated and neurites retract. But if neurons are spaced too widely apart, the Notch receptor is not activated and neurites continue to grow and extend until they connect with the neurites of their neighbors.

The Practice of Reading: Interpreting the Novel

Abstract: Preface Acknowledgements List of Editions Used Reading and Interpretation The Role of the Reader: Tristram Shandy The Process of Reading: Pride and Prejudice The Experience of Reading: Great Expectations Deconstruction and Reading: Daniel Deronda Reading as Revelation: A Portrait of the Artist as a Young Man Reading the Self: Beckett's Trilogy - Molloy Malone Dies The Unnamable Postmodernist Readings: Possession Conclusion Notes Select Bibliography Index

Reading and Interpretation

Abstract: What happens when someone reads a novel? What do novel-readers actually do? Is it really possible to generalize about ‘the role of the reader’ and ‘the experience of reading’? How is meaning produced? How far does meaning depend on the reader, and how far on the text of the novel itself? To what extent — if any — should the novelist’s stated intentions be taken into account in discussing the process of reading? How important are language and context to reading practices? How significant are various modern developments in literary theory and criticism for our understanding of what is involved in the process of reading novels?

Studies of the candidate genes in X-linked congenital cerebellar hypoplasia.

Abstract: A gene for X-linked congenital cerebellar hypoplasia was recently localized to chromosome Xp11.21-q24. This region comprises several brain-specific genes responsible for various neurological disorders, including the proteolipid protein (PLP), doublecortin, and PAK3 genes. We screened these genes for mutations in patients with X-linked congenital cerebellar hypoplasia and found no pathogenic nucleotide changes or gene dose alterations. These findings allow the ruling out of PLP, doublecortin, and PAK3 as the disease-causing genes in this hereditary neurological syndrome.

Cell Fate and Cell Migration in the Developing Cerebral Cortex

Abstract: Publisher Summary The mammalian cerebral cortex is composed of the neural networks responsible for the behavioral diversity of mammals and intellectual life of humans. The formation of the neural networks that perform these tasks requires the creation, migration, and proper connections of neurons of different physiological types. In addition to the neurons of these networks, there are a number of other cell types required for the creation of a functional cerebral cortex. These include cells that support the function of neurons in the adult, such as astrocytes and oligodendrocytes, and cells that are required only during development, such as radial glia. The adult cerebral cortex is organized horizontally into functional areas and vertically into cortical layers, or lamina. Vertically, each layer consists of different neuronal types that make characteristic connections to other neurons locally within the cortex, to distant sites within the cortex, and/or to sites outside the cerebral cortex. Different functional areas of the cortex have the same basic laminar structure, but differ in the number of neurons within each layer and thickness of each layer. Also, neurons in different functional areas make connections that reflect their functional specification.

Reading the Self: Beckett’s Trilogy — Molloy; Malone Dies; The Unnamable

Abstract: Reading Beckett’s novels is not easy. In part, this is because syntax, in Beckett, collapses under the pressure of the unsayable. For the ‘Unnamable’ narrator of the third part of Beckett’s Trilogy (1959), most obviously unsayable is the nature of the self that cannot be named. We have seen Tristram Shandy, too, lose track of his ostensible subject — himself, his life and opinions — apparently the victim of association and contingency. We have also seen him lose his way with a sentence, forget where it was leading, and have to begin it again. But in Sterne’s novel, digression from self and the syntactic convolutions that go with it have an essentially narrative reference. Tristram’s loss of way is not seen to present a crisis of identity: the questioning of self is itself only part of the narrative humour which makes it impossible for Tristram to get on with his account: —— My good friend, quoth I —— as sure as I am I —— and you are you —— —— And who are you? said he. —— Don’t puzzle me; said I. (Tristram Shandy, p. 434)

NEUROGENETICS '99 Periventricular Heterotopia and the Genetics of Neuronal Migration in the Cerebral Cortex

Abstract: In recent years, remarkable contributions to our understanding of how the brain develops have come from the field of genetics. The study of brain development is important, not only to further our understanding of this complex phenomenon, but because gross brain malformations are now recognized to cause significant proportions of cognitive and neurologic disorders. When the cerebral cortex fails to form properly, the result is often severe mental retardation. Even mild dysgenesis of the cortex is frequently associated with epilepsy.Modern genetics affords us the opportunity to explain these developmental mishaps at a molecular level and provides critical insight into nature’s program for brain development, adding an important new dimension to the extensive neuroanatomic work of the last 100 years. Neurons that populate the adult cortex are not born in place. Instead, they are born deep within the brain, in the germinal layer of the ventricular zone, which develops from the lining of the lumen of the neural tube. To get to their proper adult location, most cerebral cortical neurons migrate hundreds to thousands of cellbody lengths along tracks of radially oriented glial cells,which stretch from the ventricular zone to the outer, pial surface. These cortical neurons migrate in waves to build layers in the cortex, with each successive wave migrating past earlier-born neurons to add a more superficial layer (fig. 1A). This migration pattern is referred to as “inside out” and must be faithfully executed for the adult cortex to form and function properly. When migration is complete, the cortex is a six-layered structure (fig. 1B), with each layer comprising different types of neurons that form discrete connections within the CNS and perform distinct functions.

The Role of the Reader: Tristram Shandy

Abstract: There can be few other novels that so comprehensively evoke and explore the central importance of the reader’s response than Laurence Sterne’s The Life and Opinions of Tristram Shandy, Gentleman (1759–67). A novel which makes use of every conceivable kind of vacancy (including missing pages, blank pages, misplaced chapters, empty chapters) and, in place of words, gives rows of asterisks, squiggles, and black and marbled pages, offers an abundance of easy material for those who wish to stress the crucial productive involvement of the reader’s imagination in the generation of meaning. Equally helpful are Tristram’s and Sterne’s explicit statements concerning the creative and active participation of the reader. Here is Tristram’s colloquial analogy, which gives the idea of a ‘mediated’ response in its etymological sense (from the Latin mediāre, meaning to halve or be in the middle): WRiting, when properly managed, (as you may be sure I think mine is) is but a different name for conversation: As no one, who knows what he is about in good company, would venture to talk all; — so no author, who understands the just boundaries of decorum and good breeding, would presume to think all: The truest respect which you can pay to the reader’s understanding, is to halve this matter amicably, and leave him something to imagine, in his turn, as well as yourself. (p. 88) In that such a comment explicitly acknowledges the importance of an ‘interaction’ between novel (or fictional autobiography) and reader, it is hardly surprising that Wolfgang Iser, whose theory of response is based on such an idea, should want to quote this passage in his volume on Tristram Shandy.1 Tristram’s sentence even anticipates the terms of Iser’s debate.

The Experience of Reading: Great Expectations

Abstract: Although ‘reading’ and ‘interpretation’ are not exact synonyms, each activity may obviously be said to overlap with the other to a very considerable extent. Indeed, the fourth definition of ‘read’ in the OED is ‘the act of interpreting or expounding’, and etymologically the word ‘read’ derives from the Old English rāedan — advise, consider, discern. The process of considering or deliberating sometimes entails ‘putting to the test’ or ‘an experiment’ (part of the first OED definition of ‘experience’). But, as the OED’s definitions indicate, ‘experience’, like ‘expectation’, has a personal, subjective dimension to it (‘being consciously affected by an event’) as well as an impersonal, objective dimension (‘actual observation of fact or event’). To read, to interpret, to experience, — these are all ‘acts’ (or ‘actions’) performed by individual human beings, whether alone or with others. ‘Acts’ suggests ‘acting’, and ‘active’, and yet there is clearly a ‘re-active’ (if not passive, exactly) aspect to reading, interpretation, and experience. Something is being read, interpreted, experienced. Repeated acts become a ‘practice’, the second OED definition of which word reads: the habitual doing or carrying on of something; usual, customary or constant action; action as distinguishable from profession, theory, knowledge, etc.; conduct …

Deconstruction and Reading: Daniel Deronda

Abstract: For good and for ill, the fortunes of deconstruction from the late 1980s through the 1990s were mixed. Certainly, by 1989, when revelations about the late Paul de Man’s allegedly pro-Nazi past broke upon the critical scene, the concept had already been under attack from two opposite, if not equal, camps. On the one hand, entrenched conservatives continued to pour scorn on what they considered to be an absurd, self-refuting, even nihilistic approach to reading and criticism.1 On the other hand, born-again historicists and cultural materialists were beginning to react vigorously against the emergence of what they saw as a disturbingly ahistorical, apolitical critical wisdom.2 The rearguard actions fought since then by some of deconstruction’s proponents and exemplars, however, have varied enormously in terms of their effectiveness, ranging from the embarrassingly inept to the impressively astute.3 And battle is still joined, despite apocalyptic predictions of literary theory’s imminent demise.4 Reports of the death of deconstruction, at any rate, would appear to have been somewhat exaggerated.