Systematic documentation and analysis of human genetic variation in hemoglobinopathies using the microattribution approach

We developed a series of interrelated locus-specific databases to store all published and unpublished genetic variation related to hemoglobinopathies and thalassemia and implemented microattribution to encourage submission of unpublished observations of genetic variation to these public repositories. A total of 1,941 unique genetic variants in 37 genes, encoding globins and other erythroid proteins, are currently documented in these databases, with reciprocal attribution of microcitations to data contributors. Our project provides the first example of implementing microattribution to incentivise submission of all known genetic variation in a defined system. It has demonstrably increased the reporting of human variants, leading to a comprehensive online resource for systematically describing human genetic variation in the globin genes and other genes contributing to hemoglobinopathies and thalassemias. The principles established here will serve as a model for other systems and for the analysis of other common and/or complex human genetic diseases.     

‘Good Sense’ in context: A response to Kidd

In his response to my (2010), Ian Kidd claims that my argument against Stump’s interpretation of Duhem’s concept of ‘good sense’ is unsound because it ignores an important distinction within virtue epistemology. In light of the distinction between reliabilist and responsibilist virtue epistemology, Kidd argues that Duhem can be seen as supporting the latter, which he further illustrates with a discussion of Duhem’s argument against ‘perfect theory’. I argue that no substantive argument is offered to show that the distinction is relevant and can establish that Duhem’s ‘good sense’ can be understood within responsibilist virtue epistemology. I furthermore demonstrate that Kidd’s attempt to support his contention relies on a crucial misreading of Duhem’s general philosophy of science, and in doing so highlight the importance of understanding ‘good sense’ in its original context, that of theory choice.     

Metagenomic and functional analysis of hindgut microbiota of a wood-feeding higher termite

From the standpoints of both basic research and biotechnology, there is considerable interest in reaching a clearer understanding of the diversity of biological mechanisms employed during lignocellulose degradation. Globally, termites are an extremely successful group of wood-degrading organisms and are therefore important both for their roles in carbon turnover in the environment and as potential sources of biochemical catalysts for efforts aimed at converting wood into biofuels. Only recently have data supported any direct role for the symbiotic bacteria in the gut of the termite in cellulose and xylan hydrolysis. Here we use a metagenomic analysis of the bacterial community resident in the hindgut paunch of a wood-feeding 'higher' Nasutitermes species (which do not contain cellulose-fermenting protozoa) to show the presence of a large, diverse set of bacterial genes for cellulose and xylan hydrolysis. Many of these genes were expressed in vivo or had cellulase activity in vitro, and further analyses implicate spirochete and fibrobacter species in gut lignocellulose degradation. New insights into other important symbiotic functions including H2 metabolism, CO2-reductive acetogenesis and N2 fixation are also provided by this first system-wide gene analysis of a microbial community specialized towards plant lignocellulose degradation. Our results underscore how complex even a 1-microl environment can be.     

An ‘Ultra’ rapid Golgi method for vertebrate neuroanatomy

Summary A modification of the hardening solution of the rapid Golgi method permits constant successful impregnations of the brain of several vertebrate representatives in only 24 hours.Acknowledgment. Thanks are due to Mr.V. Guglielmotti and Mr.E. Casale for technical assistance.     

Crumbs, the Drosophila homologue of human CRB1/RP12, is essential for photoreceptor morphogenesis

The apical transmembrane protein Crumbs is a central regulator of epithelial apical-basal polarity in Drosophila. Loss-of-function mutations in the human homologue of Crumbs, CRB1 (RP12), cause recessive retinal dystrophies, including retinitis pigmentosa. Here we show that Crumbs and CRB1 localize to corresponding subdomains of the photoreceptor apical plasma membrane: the stalk of the Drosophila photoreceptor and the inner segment of mammalian photoreceptors. These subdomains support the morphogenesis and orientation of the photosensitive membrane organelles: rhabdomeres and outer segments, respectively. Drosophila Crumbs is required to maintain zonula adherens integrity during the rapid apical membrane expansion that builds the rhabdomere. Crumbs also regulates stalk development by stabilizing the membrane-associated spectrin cytoskeleton, a function mechanistically distinct from its role in epithelial apical-basal polarity. We propose that Crumbs is a central component of a molecular scaffold that controls zonula adherens assembly and defines the stalk as an apical membrane subdomain. Defects in such scaffolds may contribute to human CRB1-related retinal dystrophies.     

Pierre Duhem’s good sense as a guide to theory choice

This paper examines Duhem’s concept of good sense as an attempt to support a non rule-governed account of rationality in theory choice. Faced with the underdetermination of theory by evidence thesis and the continuity thesis, Duhem tried to account for the ability of scientists to choose theories that continuously grow to a natural classification. I will examine the concept of good sense and the problems that stem from it. I will also present a recent attempt by David Stump to link good sense to virtue epistemology. I will argue that even though this approach can be useful for the better comprehension of the concept of good sense, there are some substantial differences between virtue epistemologists and Duhem. In the light of this reconstruction of good sense, I will propose a possible way to interpret the concept of good sense, which overcomes the noted problems and fits better with Duhem’s views on scientific method and motivation in developing the concept of good sense.     

Cytokinesis failure generating tetraploids promotes tumorigenesis in p53-null cells

A long-standing hypothesis on tumorigenesis is that cell division failure, generating genetically unstable tetraploid cells, facilitates the development of aneuploid malignancies. Here we test this idea by transiently blocking cytokinesis in p53-null (p53-/-) mouse mammary epithelial cells (MMECs), enabling the isolation of diploid and tetraploid cultures. The tetraploid cells had an increase in the frequency of whole-chromosome mis-segregation and chromosomal rearrangements. Only the tetraploid cells were transformed in vitro after exposure to a carcinogen. Furthermore, in the absence of carcinogen, only the tetraploid cells gave rise to malignant mammary epithelial cancers when transplanted subcutaneously into nude mice. These tumours all contained numerous non-reciprocal translocations and an 8-30-fold amplification of a chromosomal region containing a cluster of matrix metalloproteinase (MMP) genes. MMP overexpression is linked to mammary tumours in humans and animal models. Thus, tetraploidy enhances the frequency of chromosomal alterations and promotes tumour development in p53-/- MMECs.     

Muscular respiratory receptors in self-regulation of normal breathing in man.

In man, in the process of evolution the proprioceptive reflexes from the chest muscle during apnea become weak. Probably the impulses from the respiratory stretch receptors do not take part in self-regulation of eupnea.