An 8-bp deletion in mNOTCH4 intron 10 leads to its retention in mRNA and to synthesis of a truncated protein

Notch signaling participates in the development of multicellular organisms by maintaining self-renewal potential or inducing differentiation of numerous tissues. In this study, we characterized Notch4, the evolutionary most distant and least studied Notch family member. We identified a Notch4 inter-strain polymorphism with a previously undescribed mRNA variant. This longer Notch4 mRNA, which represented up to one-third of total Notch4 mRNA, resulted from intron 10 retention. Analysis of Notch4 intron 10 revealed that an 8-bp deletion, reducing its length from 68 to 60 bp, strictly correlated with its retention. Further experiments demonstrated that intron length was the only cause of the mis-splicing. Moreover, this mRNA variant resulted in a truncated protein containing half the extracellular domain of Notch4, including the ligand-binding domain.     

Defining Life: Synthesis and Conclusions

The first part of the paper offers philosophical landmarks on the general issue of defining life. §1 defends that the recognition of “life” has always been and remains primarily an intuitive process, for the scientist as for the layperson. However we should not expect, then, to be able to draw a definition from this original experience, because our cognitive apparatus has not been primarily designed for this. §2 is about definitions in general. Two kinds of definition should be carefully distinguished: lexical definitions (based upon current uses of a word), and stipulative or legislative definitions, which deliberately assign a meaning to a word, for the purpose of clarifying scientific or philosophical arguments. The present volume provides examples of these two kinds of definitions. §3 examines three traditional philosophical definitions of life, all of which have been elaborated prior to the emergence of biology as a specific scientific discipline: life as animation (Aristotle), life as mechanism, and life as organization (Kant). All three concepts constitute a common heritage that structures in depth a good deal of our cultural intuitions and vocabulary any time we try to think about “life”. The present volume offers examples of these three concepts in contemporary scientific discourse. The second part of the paper proposes a synthesis of the major debates developed in this volume. Three major questions have been discussed. A first issue (§4) is whether we should define life or not, and why. Most authors are skeptical about the possibility of defining life in a strong way, although all admit that criteria are useful in contexts such as exobiology, artificial life and the origins of life. §5 examines the possible kinds of definitions of life presented in the volume. Those authors who have explicitly defended that a definition of life is needed, can be classified into two categories. The first category (or standard view) refers to two conditions: individual self-maintenance and the open-ended evolution of a collection of similar entities. The other category refuse to include reproduction and evolution, and take a sort of psychic view of the living. §6 examines the relationship between the question of the definition of life and that of the origins of life. There is a close parallel between the general conceptions of the origins of life and the definitions of life.     

Chance, explanation, and causation in evolutionary theory

Chance comes into plays at many levels of the explanation of the evolutionary process; but the unity of sense of this category is problematic. The purpose of this talk is to clarify the meaning of chance at various levels in evolutionary theory: mutations, genetic drift, genetic revolutions, ecosystems, macroevolution. Three main concepts of chance are found at these various levels: luck (popular concept), randomness (probabilistic concept), and contingency relative to a given theoretical system (epistemological concept). After identifying which concept(s) of chance fit(s) with these levels, the question is raised whether these concepts can be reduced to a smaller number, and whether chance in evolutionary theory has a subjective or an objective sense.     

The Contributions – and Collapse – of Lamarckian Heredity in Pasteurian Molecular Biology: 1. Lysogeny, 1900–1960

This article shows how Lamarckism was essential in the birth of the French school of molecular biology. We argue that the concept of inheritance of acquired characters positively shaped debates surrounding bacteriophagy and lysogeny in the Pasteurian tradition during the interwar period. During this period the typical Lamarckian account of heredity treated it as the continuation of protoplasmic physiology in daughter cells. Félix d’Hérelle applied this conception to argue that there was only one species of bacteriophage and Jules Bordet applied it to develop an account of bacteriophagy as a transmissible form of autolysis and to analyze the new phenomenon of lysogeny. In a long-standing controversy with Bordet, Eugène Wollman deployed a more morphological understanding of the inheritance of acquired characters, yielding a particulate, but still Lamarckian, account of lysogeny. We then turn to André Lwoff who, with several colleagues, completed Wollman’s research program from 1949 to 1953. We examine how he gradually set aside the Lamarckian background, finally removing inheritance of acquired characters from the resulting account of bacteriophagy and lysogeny. In the conclusion, we emphasize the complex dual role of Lamarckism as it moved from an assumed explanatory framework to a challenge that the nascent molecular biology had to overcome.     

Genetics: still a discipline?

In the institutional sense of the term "discipline" (laboratories, societies, congresses, curricula, etc.), genetics remains a discipline. In the intellectual sense of the term (consensus on a definite array of concepts, methods and theoretical purposes), it is doubtful that genetics is still a discipline. At first, molecular biology seemed to have introduced an unequivocal structural (or molecular) definition of the gene: a definite sequence of nucleotides that code for a protein. In fact, as it appears in retrospect, this was not the case. Even in 1961, when Jacob and Monod proposed their first model of genetic regulation in bacteria, there was no possibility of constructing a non equivocal concept of the gene. More recent developments in molecular genetics have made this situation worse. There is no possible definition of the gene as a general category. The reasons why biologists keep the word are pragmatic rather than theoretical: communication among scientists, economic interests and ideology.     

Endothelial cell phenotypes in the rheumatoid synovium: activated,angiogenic, apoptotic and leaky

Endothelial cells are active participants in chronic inflammatory diseases. These cells undergo phenotypic changes that can be characterised as activated, angiogenic, apoptotic and leaky. In the present review, these phenotypes are described in the context of human rheumatoid arthritis as the disease example. Endothelial cells become activated in rheumatoid arthritis pathophysiology, expressing adhesion molecules and presenting chemokines, leading to leukocyte migration from the blood into the tissue. Endothelial cell permeability increases, leading to oedema formation and swelling of the joints. These cells proliferate as part of the angiogenic response and there is also a net increase in the turnover of endothelial cells since the number of apoptotic endothelial cells increases. The endothelium expresses various cytokines, cytokine receptors and proteases that are involved in angiogenesis, proliferation and tissue degradation. Associated with these mechanisms is a change in the spectrum of genes expressed, some of which are relatively endothelial specific and others are widely expressed by other cells in the synovium. Better knowledge of molecular and functional changes occurring in endothelial cells during chronic inflammation may lead to the development of endothelium-targeted therapies for rheumatoid arthritis and other chronic inflammatory diseases.