Journal de la Societe de biologie最新文献

This paper reviews the process used in the pharmaceutical industry to discover new innovative drugs originating from medicinal chemistry or biotherapeutics. After a rapid description of the global Research and Development process (preclinical and clinical studies), the different steps involved specifically in the Discovery Research phase (from the initiation of the research program to the proposal of a candidate for development) are analysed in detail. As far as compounds originating from medicinal chemistry are concerned, we discuss the choice of the biological target (molecular or cellular) and its functional validation, the process used for the screening of chemical libraries and the generation of chemical hits, the hit-to-lead process and finally the chemical optimisation of the leads into drug candidates which will be proposed for preclinical and clinical development. As far as biotherapeutics are concerned, the process used for the generation and manufacturing of humanized naked or conjugated monoclonal antibodies and recombinant therapeutic proteins is discussed in detail.

Closing this symposium, André Calas remembers his teachers, his past and present collaborators, his students, his teaching and research itineraries and enlarges on the problems of public policy concerning these areas in France.

Reproduction in mammals is directly controlled by GnRH neurons. These neurons are regulated by many external and internal factors, among which sexual steroids, in particular oestradiol, play an important part. However the mechanisms through which these steroids regulate GnRH secretion are largely unappreciated, and the neurochemical identity of central neurons liable to transmit the steroidal information to GnRH neurons is not completely clarified. Many functional neuroanatomy studies have been carried out on the ovine model, which is particularly favorable to understand the neuroendocrine mechanisms controlling reproduction. These studies have brought about the identification of some of the potential actors in this regulation. The present review reports the major results concerning two recently discovered neuropeptides, galanin and kisspeptin, which appear to be major actors in integration of signals regulating reproduction, among which steroids. These results have revealed the major interaction sites between neurons expressing these neuropeptides and GnRH neurons.

The mammalian circadian clock, whose central component is located in the suprachiasmatic nucleus of the hypothalamus (SCN), orchestrates rhythmic events in metabolism, physiology and behavior. Adaptation of the organism to its environment requires precise adjustment of the clock to the 24 h astronomical time, primarily by the light/dark cycle. Photic synchronization acts on both the molecular loops which trigger circadian oscillations and the phasing of the multiple SCN cellular oscillators whose coordination permits elaboration of the rhythmic message that will be distributed throughout the organism. It is concomitant with structural plastic events characterized by day/night rearrangements of the SCN neuronal-glial network. The two main sources of SCN efferents, namely the VIP (vasoactive intestinal peptide)-synthesizing neurons which are major integrators of photic signals and the AVP (arginine-vasopressin)-synthesizing neurons which are known to importantly contribute to conveying rhythmic messages to brain targets, are involved in these mechanisms. Over the light/dark cycle, they indeed undergo ultrastructural changes in the extent of their membrane coverage by glial, axon terminal and/or somato-dendritic elements. These structural rearrangements appear to be dependent on light entrainment, as the rhythmic expression in SCN of glial fibrillary acidic protein (GFAP), a marker for brain astrocytes whose changing expression has proved to be a reliable index of neuronal-glial plasticity, is disrupted under constant darkness. Glucocorticoid hormones, which are known as important endocrine outputs of the clock, are required to maintain amplitude of the SCN GFAP rhythm to normal values, indicating that they modulate astrocytic plasticity within the SCN and, therefore, nycthemeral changes of the configuration of its neuronal-glial network. The view that such plastic events may subserve synchronization of the clock to the light-dark cycle is reinforced by other data showing that the daily fluctuations of circulating glucocorticoids actually are involved in modulation of light effects, contributing to the resistance of the circadian timing system to variations of the photoperiod. It is thus proposed that the capacity of the clock to integrate cyclic variations of the environment rely on the inherent capacity of the SCN to undergo neuronal-glial plasticity.

Claude Bernard created controversy because of his originality of thought, his rejection of dogma and lack of respect for tradition. Some of his controversies resulted in unjustifiable personal and scientific attacks by others which probably affected both his morale and his health. In addition, he was undoubtedly envied for his success and the firmness with which he supported his results and conclusions. The counterattacks which he directed towards others were also not always justified, and sometimes displayed disdain for his adversaries' method and results - without having the strength to admit his own rare errors. None of this detracted from his status as the most eminent of scientists of his era.

The Angiotensin-Converting Enzyme (ACE) is crucial for vascular homeostasis in mammals. Three isoforms are present in the human. the somatic ACE (sACE) generates the vasoactive angiotensin II. The testicular isoform (tACE) is required for male fertility. ACE2 was cloned from another gene and displays an antagonistic role. Several ACEs were cloned from insects, despite their lack of a closed circulatory system. Insect isoforms are implied in reproduction and development. No sequence in the C. elegans genome is able to encode a functional enzyme. Nevertheless, an active ACE was characterized in an even more distant organism, the leech, in which the enzyme is mainly expressed within the digestive tract. The presence of ACE is lophotrochozoans raises questions about the appearance and original functions of the enzyme. Besides, the recent availability of genomic data unraveled the putative presence of orthologues in even more distant phyla such as cnidaria, placozoa and even many procaryotes. Moreover, the characterization of an active ACE in a proteobacteria indicates that the ancestor isoform was already functional. Thus, ACE is present from bacteria to mammals and exhibits incredibly conserved molecular, biochemical as well as structural features. The absence of ACE in all eucaryotic bicounts could thus result from a secondary loss. Taken together, these data suggest that ACE appeared early during the course of evolution. Mammalian ACE features could thus be a result of the long evolutive specialization of an ancient protease whose physiological functions remain to be elucidated.

Transgenic plant varieties are grown since 1996 on surfaces increasing each year. They covered 114 million hectares worldwide in 2007, which shows their success among the farmers in developed as well as developing countries, despite the propaganda campaigns of the environmental movements and advocates of decline. The first transgenic crops (soybean, corn, coton and rapeseed) offer benefits in terms of health, economy and environment. Europe and especially France, which reject this technology, sentence their research to death and penalize their agriculture.

Developmental genetics of congenital heart diseases have evolved from analysis of embryonic hearts towards molecular genetics of cardiac morphogenesis with a dynamic view of cardiac development. Ablation techniques, transgenic animal models and clonal analysis of the developing heart led to identification of different cardiac lineages and their respective roles. The mechanistic approach for great arteries anomalies has led to emerging concepts such as common embryological origin of anatomically different cardiac defects, phenotypic continuum of left heart obstructive defects, or developmental algorithms for cardiac isomerisms. Recent experiments that demonstrated the myocardial rotation of the outflow tract in mouse embryos led to a better understanding of the origin of transposition of the large arteries. This has also raised the hypothesis of a new group of congenital heart anomalies defined as laterality defects limited to a segment of the embryonic heart. These results confirm that genetic heterogeneity of congenital heart defects is related to the heterogeneity of the mechanisms that finally produce the same phenotype.

In vertebrates, the active form of thyroid hormone (T3) acts directly on transcription by changing the conformation of the TR nuclear receptors (TR alpha 1, TR beta 1 et TR beta 2) which are encoded by the THRA and THRB genes. These receptors are bound to DNA at specific response elements in a ligand independent manner. Mouse genetics have clarified the respective function of each receptor isoform, mainly reflecting THRA and THRB expression patterns. It also revealed the importance of negative regulation by unliganded receptors not only in pathological but also in physiological situations.