172 research outputs found
Model Systems to Define Remyelination Therapies
Demyelinating diseases of the central nervous system (CNS), such as multiple sclerosis (MS), are characterized by multiple focal demyelinating lesions, resulting in various functional deficits. The pathology of MS is defined by local loss of myelin sheaths in the brain and spinal cord associated with infiltration of peripheral immune cells. Classically, MS starts with a series of relapses and remissions, followed several years later by a more progressive form of the disease and a steady functional decline. Although the mechanism of disease initiation is poorly understood, disease progression is associated with immune system activation toward CNS antigens including myelin proteins. Animal models of MS have been critical in the development of MS therapies, with experimental allergic encephalitis (EAE) being the most common. This model has been instrumental in defining the role of T cells in disease progression and in the development of targeted therapies. Understanding the biology of myelin repair has, however, largely come from other model systems including local targeted demyelination in vivo, slice preparations, and in vitro. This has led to the identification of a diverse array of potential new targets to modulate disease progression. Development of these new avenues is the target of intensive ongoing research
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Broad-Scale Recombination Patterns Underlying Proper Disjunction in Humans
Although recombination is essential to the successful completion of human meiosis, it remains unclear how tightly the process is regulated and over what scale. To assess the nature and stringency of constraints on human recombination, we examined crossover patterns in transmissions to viable, non-trisomic offspring, using dense genotyping data collected in a large set of pedigrees. Our analysis supports a requirement for one chiasma per chromosome rather than per arm to ensure proper disjunction, with additional chiasmata occurring in proportion to physical length. The requirement is not absolute, however, as chromosome 21 seems to be frequently transmitted properly in the absence of a chiasma in females, a finding that raises the possibility of a back-up mechanism aiding in its correct segregation. We also found a set of double crossovers in surprisingly close proximity, as expected from a second pathway that is not subject to crossover interference. These findings point to multiple mechanisms that shape the distribution of crossovers, influencing proper disjunction in humans.</p
Developmental expression and differentiation-related neuron-specific splicing of metastasis suppressor 1 (Mtss1) in normal and transformed cerebellar cells
Background:
Mtss1 encodes an actin-binding protein, dysregulated in a variety of tumors, that interacts with sonic hedgehog/Gli signaling in epidermal cells. Given the prime importance of this pathway for cerebellar development and tumorigenesis, we assessed expression of Mtss1 in the developing murine cerebellum and human medulloblastoma specimens.
Results:
During development, Mtss1 is transiently expressed in granule cells, from the time point they cease to proliferate to their synaptic integration. It is also expressed by granule cell precursor-derived medulloblastomas. In the adult CNS, Mtss1 is found exclusively in cerebellar Purkinje cells. Neuronal differentiation is accompanied by a switch in Mtss1 splicing. Whereas immature granule cells express a Mtss1 variant observed also in peripheral tissues and comprising exon 12, this exon is replaced by a CNS-specific exon, 12a, in more mature granule cells and in adult Purkinje cells. Bioinformatic analysis of Mtss1 suggests that differential exon usage may affect interaction with Fyn and Src, two tyrosine kinases previously recognized as critical for cerebellar cell migration and histogenesis. Further, this approach led to the identification of two evolutionary conserved nuclear localization sequences. These overlap with the actin filament binding site of Mtss1, and one also harbors a potential PKA and PKC phosphorylation site.
Conclusion:
Both the pattern of expression and splicing of Mtss1 is developmentally regulated in the murine cerebellum. These findings are discussed with a view on the potential role of Mtss1 for cytoskeletal dynamics in developing and mature cerebellar neurons
Veterans and Agent Orange: Update 11 (2018) (2018)
Contents
ACRONYMS AND ABBREVIATIONS xvii
SUMMARY 1
1 INTRODUCTION 17
Previous Veterans and Agent Orange Reports, 18
Charge to the Committee, 19
Information Gathering, 20
Organization of the Report, 21
2 BACKGROUND 25
The Current Population of Vietnam Veterans,25
Military Use of Herbicides in Vietnam, 27
Exposure of Different Groups of Vietnam Veterans, 30
Characterizing Exposure, 38
Determining Increased Risk in Vietnam Veterans, 4
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Reference-free deconvolution of DNA methylation data and mediation by cell composition effects
Background: Recent interest in reference-free deconvolution of DNA methylation data has led to several supervised methods, but these methods do not easily permit the interpretation of underlying cell types.
Results: We propose a simple method for reference-free deconvolution that provides both proportions of putative cell types defined by their underlying methylomes, the number of these constituent cell types, as well as a method for evaluating the extent to which the underlying methylomes reflect specific types of cells. We demonstrate these methods in an analysis of 23 Infinium data sets from 13 distinct data collection efforts; these empirical evaluations show that our algorithm can reasonably estimate the number of constituent types, return cell proportion estimates that demonstrate anticipated associations with underlying phenotypic data; and methylomes that reflect the underlying biology of constituent cell types.
Conclusions: Our methodology permits an explicit quantitation of the mediation of phenotypic associations with DNA methylation by cell composition effects. Although more work is needed to investigate functional information related to estimated methylomes, our proposed method provides a novel and useful foundation for conducting DNA methylation studies on heterogeneous tissues lacking reference data.Keywords: Non-negative matrix factorization, DNA methylation, Deconvolution, Epigenetic
Reading Across Cultures: Global Narratives, Hotels and Railway Stations
This is the final version of the article. Available from Springer Verlag via the DOI in this record.This article takes its cue from the English critic, novelist and painter John Berger. He argues that what we know determines what we see. Hotels and railway stations, though they differ in size, design and appearance, are places of temporary national and international congress that are recognized by everyone. They become visible or even iconic once their history or their role is turned into at least part of a wider narrative—in literature, film or in other arts. This provides a representative focus by which we may read a city’s or a nation’s past. In exemplifying such connections I focus first on the long-term history of Friedrichstraße station and some of the surrounding hotels in the context of the history of Berlin, situating them within the national and, by implication, also the international context. Secondly, I will consider the outbreak of the First World War in 1914 as an event in which the role of railway stations generated both personal and collective memories across cultures and over several decades
Broad-Scale Recombination Patterns Underlying Proper Disjunction in Humans
Although recombination is essential to the successful completion of human meiosis, it remains unclear how tightly the process is regulated and over what scale. To assess the nature and stringency of constraints on human recombination, we examined crossover patterns in transmissions to viable, non-trisomic offspring, using dense genotyping data collected in a large set of pedigrees. Our analysis supports a requirement for one chiasma per chromosome rather than per arm to ensure proper disjunction, with additional chiasmata occurring in proportion to physical length. The requirement is not absolute, however, as chromosome 21 seems to be frequently transmitted properly in the absence of a chiasma in females, a finding that raises the possibility of a back-up mechanism aiding in its correct segregation. We also found a set of double crossovers in surprisingly close proximity, as expected from a second pathway that is not subject to crossover interference. These findings point to multiple mechanisms that shape the distribution of crossovers, influencing proper disjunction in humans
Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma
Genome-wide association studies (GWAS) have transformed our understanding of susceptibility to multiple myeloma (MM), but much of the heritability remains unexplained. We report a new GWAS, a meta-analysis with previous GWAS and a replication series, totalling 9974 MM cases and 247,556 controls of European ancestry. Collectively, these data provide evidence for six new MM risk loci, bringing the total number to 23. Integration of information from gene expression, epigenetic profiling and in situ Hi-C data for the 23 risk loci implicate disruption of developmental transcriptional regulators as a basis of MM susceptibility, compatible with altered B-cell differentiation as a key mechanism. Dysregulation of autophagy/apoptosis and cell cycle signalling feature as recurrently perturbed pathways. Our findings provide further insight into the biological basis of MM.</p
Girls and Boys Born before 28Â Weeks Gestation: Risks of Cognitive, Behavioral, and Neurologic Outcomes at Age 10Â Years
To compare the prevalence of cognitive, neurological, and behavioral outcomes at 10 years of age in 428 girls and 446 boys who were born extremely preterm (EP)
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