The Rhesus Factor and Disease Prevention

First published by the Wellcome Trust Centre for the History of Medicine at UCL, 2004. ©The Trustee of the Wellcome Trust, London, 2004. All volumes are freely available online at: www.history.qmul.ac.uk/research/modbiomed/wellcome_witnesses/Annotated and edited transcript of a Witness Seminar held on 3 June 2003. Introduction by Professor Doris T Zallen.Annotated and edited transcript of a Witness Seminar held on 3 June 2003. Introduction by Professor Doris T Zallen.Annotated and edited transcript of a Witness Seminar held on 3 June 2003. Introduction by Professor Doris T Zallen.Annotated and edited transcript of a Witness Seminar held on 3 June 2003. Introduction by Professor Doris T Zallen.Annotated and edited transcript of a Witness Seminar held on 3 June 2003. Introduction by Professor Doris T Zallen.Annotated and edited transcript of a Witness Seminar held on 3 June 2003. Introduction by Professor Doris T Zallen.Consists of the edited transcripts of Witness SeThe prevention of rhesus disease of the newborn is a stunning medical success story. This disease afflicted thousands of newborns each year, causing serious health problems, even death. Yet from the early 1940s to the 1970s – British and American researchers uncovered the basis of the disease and developed the medical intervention that could prevent its occurrence. Many of the key steps leading to this remarkable achievement took place at the University of Liverpool School of Medicine. Chaired by Professor Sir David Weatherall, this Witness Seminar examines the factors that triggered these studies and the challenges that confronted scientists and clinicians; the intellectual, institutional, and social factors that guided the work; the crucial insights; and the vistas that the prevention of rhesus disease has opened in fetal medicine. Participants include Professor Robin Coombs, the late Professor Ronald Finn, Dr Nevin Hughes-Jones, Professor Patrick Mollison, Dr Archie Norman, Dr Derrick Tovey, Professor Charles Whitfield, Professor John Woodrow and Professor Doris Zallen. Zallen, D T, Christie D A, Tansey E M. (eds) (2004) The Rhesus factor and disease prevention, Wellcome Witnesses to Twentieth Century Medicine, vol. 22. London: The Wellcome Trust Centre for the History of Medicine at UCL. ISBN 978 0 85484 099 1minars organized by the History of Twentieth Century Medicine Group and held at the Wellcome Institute for the History of Medicine.The Wellcome Trust Centre for the History of Medicine at University College London is funded by the Wellcome Trust,which is a registered charity, no. 210183

Cost-Effectiveness of Risk-Stratified Colorectal Cancer Screening Based on Polygenic Risk: Current Status and Future Potential

Background: Although uniform colonoscopy screening reduces colorectal cancer (CRC) mortality, risk-based screening may be more efficient. We investigated whether CRC screening based on polygenic risk is a cost-effective alternative to current uniform screening, and if not, under what conditions it would be. Methods: The MISCAN-Colon model was used to simulate a hypothetical cohort of US 40-year-olds. Uniform screening was modeled as colonoscopy screening at ages 50, 60, and 70 years. For risk-stratified screening, individuals underwent polygenic testing with current and potential future discriminatory performance (area under the receiveroperating curve [AUC] of 0.60 and 0.65–0.80, respectively). Polygenic testing results were used to create risk groups, for which colonoscopy screening was optimized by varying the start age (40–60 years), en

A Modifier Screen for Bazooka/PAR-3 Interacting Genes in the Drosophila Embryo Epithelium

The development and homeostasis of multicellular organisms depends on sheets of epithelial cells. Bazooka (Baz; PAR-3) localizes to the apical circumference of epithelial cells and is a key hub in the protein interaction network regulating epithelial structure. We sought to identify additional proteins that function with Baz to regulate epithelial structure in the Drosophila embryo.The baz zygotic mutant cuticle phenotype could be dominantly enhanced by loss of known interaction partners. To identify additional enhancers, we screened molecularly defined chromosome 2 and 3 deficiencies. 37 deficiencies acted as strong dominant enhancers. Using deficiency mapping, bioinformatics, and available single gene mutations, we identified 17 interacting genes encoding known and predicted polarity, cytoskeletal, transmembrane, trafficking and signaling proteins. For each gene, their loss of function enhanced adherens junction defects in zygotic baz mutants during early embryogenesis. To further evaluate involvement in epithelial polarity, we generated GFP fusion proteins for 15 of the genes which had not been found to localize to the apical domain previously. We found that GFP fusion proteins for Drosophila ASAP, Arf79F, CG11210, Septin 5 and Sds22 could be recruited to the apical circumference of epithelial cells. Nine of the other proteins showed various intracellular distributions, and one was not detected.Our enhancer screen identified 17 genes that function with Baz to regulate epithelial structure in the Drosophila embryo. Our secondary localization screen indicated that some of the proteins may affect epithelial cell polarity by acting at the apical cell cortex while others may act through intracellular processes. For 13 of the 17 genes, this is the first report of a link to baz or the regulation of epithelial structure

A GRFa2/Prop1/Stem (GPS) Cell Niche in the Pituitary

BACKGROUND: The adult endocrine pituitary is known to host several hormone-producing cells regulating major physiological processes during life. Some candidates to progenitor/stem cells have been proposed. However, not much is known about pituitary cell renewal throughout life and its homeostatic regulation during specific physiological changes, such as puberty or pregnancy, or in pathological conditions such as tumor development. PRINCIPAL FINDINGS: We have identified in rodents and humans a niche of non-endocrine cells characterized by the expression of GFRa2, a Ret co-receptor for Neurturin. These cells also express b-Catenin and E-cadherin in an oriented manner suggesting a planar polarity organization for the niche. In addition, cells in the niche uniquely express the pituitary-specific transcription factor Prop1, as well as known progenitor/stem markers such as Sox2, Sox9 and Oct4. Half of these GPS (GFRa2/Prop1/Stem) cells express S-100 whereas surrounding elongated cells in contact with GPS cells express Vimentin. GFRa2+-cells form non-endocrine spheroids in culture. These spheroids can be differentiated to hormone-producing cells or neurons outlining the neuroectoderm potential of these progenitors. In vivo, GPSs cells display slow proliferation after birth, retain BrdU label and show long telomeres in its nuclei, indicating progenitor/stem cell properties in vivo. SIGNIFICANCE: Our results suggest the presence in the adult pituitary of a specific niche of cells characterized by the expression of GFRa2, the pituitary-specific protein Prop1 and stem cell markers. These GPS cells are able to produce different hormone-producing and neuron-like cells and they may therefore contribute to postnatal pituitary homeostasis. Indeed, the relative abundance of GPS numbers is altered in Cdk4-deficient mice, a model of hypopituitarism induced by the lack of this cyclin-dependent kinase. Thus, GPS cells may display functional relevance in the physiological expansion of the pituitary gland throughout life as well as protection from pituitary disease

Using C. elegans to decipher the cellular and molecular mechanisms underlying neurodevelopmental disorders

Prova tipográfica (uncorrected proof)Neurodevelopmental disorders such as epilepsy, intellectual disability (ID), and autism spectrum disorders (ASDs) occur in over 2 % of the population, as the result of genetic mutations, environmental factors, or combination of both. In the last years, use of large-scale genomic techniques allowed important advances in the identification of genes/loci associated with these disorders. Nevertheless, following association of novel genes with a given disease, interpretation of findings is often difficult due to lack of information on gene function and effect of a given mutation in the corresponding protein. This brings the need to validate genetic associations from a functional perspective in model systems in a relatively fast but effective manner. In this context, the small nematode, Caenorhabditis elegans, presents a good compromise between the simplicity of cell models and the complexity of rodent nervous systems. In this article, we review the features that make C. elegans a good model for the study of neurodevelopmental diseases. We discuss its nervous system architecture and function as well as the molecular basis of behaviors that seem important in the context of different neurodevelopmental disorders. We review methodologies used to assess memory, learning, and social behavior as well as susceptibility to seizures in this organism. We will also discuss technological progresses applied in C. elegans neurobiology research, such as use of microfluidics and optogenetic tools. Finally, we will present some interesting examples of the functional analysis of genes associated with human neurodevelopmental disorders and how we can move from genes to therapies using this simple model organism.The authors would like to acknowledge Fundação para a Ciência e Tecnologia (FCT) (PTDC/SAU-GMG/112577/2009). AJR and CB are recipients of FCT fellowships: SFRH/BPD/33611/2009 and SFRH/BPD/74452/2010, respectively

Organisms in experimental research

Rachel A. Ankeny and Sabina Leonell

National Traditions and the Emergence of Genetics: The French Example

International audienceAfter the 'rediscovery' of Mendel in 1900, Mendelian approaches to heredity were controversial. In France, however, resistance to Mendelism was especially strong and genetics only began to be institutionalized there after 1945. Nonetheless, extra-university research programmes in population and physiological genetics, which began after 1930, led to the rapid growth of genetic research after the Second World War, especially in regulatory genetics. We show that this rapid, but delayed, growth of genetic research was based on distinctively French traditions