Amyloid fibrils from the viewpoint of protein folding

In amyloid related diseases, proteins form fibrillar aggregates with highly ordered -sheet structure regardless of their native conformations. Formation of such amyloid fibrils can be reproducible in vitro using isolated proteins/peptides, suggesting that amyloid fibril formation takes place as a result of protein conformational change. In vitro studies revealed that perturbation of the native structure is important for the fibril formation, and it is suggested that the mechanisms of amyloid fibril formation share the mechanisms of protein folding. In particular, amyloid fibril formation is similar to one of the common features of proteins, i.e. amorphous aggregation upon partial unfolding, which is likely driven by hydrophobic interactions through exposed protein interior. However, these molecular associations are distinct phenomena, and identifying factors that lead to amyloid fibril formation would precede our understanding of the mechanisms of amyloid fibrillization. The necessity of understanding the nature of protein denatured states is also suggested.Received 6 July 2003; accepted 19 August 2003     

Beyond Mendelism and Biometry

Historiographical analyses of the development of genetics in the first decade of the 20th century have been to a great extent framed in the context of the Mendelian-Biometrician controversy. Much has been discussed on the nature, origin, development, and legacy of the controversy. However, such a framework is becoming less useful and fruitful. This paper challenges the traditional historiography framed by the Mendelian-Biometrician distinction. It argues that the Mendelian-Biometrician distinction fails to reflect the theoretical and methodological diversity in the controversy. It also argues that the Mendelian-Biometrician distinction is not helpful to make a full understanding of the development of genetics in the first decade of the twentieth century.     

Philosophy and history of science: Beyond the Kuhnian paradigm

At issue in this paper is the question of the appropriate relationship between the philosophy and history of science. The discussion starts with a brief sketch of Kuhn's approach, followed by an analysis of the so-called ‘testing-theories-of-scientific-change programme’. This programme is an attempt at a more rigorous approach to the historical philosophy of science. Since my conclusion is that, by and large, this attempt has failed, I proceed to examine some more promising approaches. First, I deal with Hacking's recent views on the issues in question, particularly his notion of a ‘style of reasoning’. Next, Nickles's reconstructionist interpretation of the development of science and his views on Whig history are addressed. Finally, I propose an account of philosophy as a theoretical, an interpretative and explanatory, enterprise. Thus, three alternatives to the Kuhnian paradigm are discussed, alternatives that share a recognition of the relative autonomy of philosophy from history. Hence, they assume a less tight relationship between philosophy and history of science than is the case within the Kuhnian paradigm.     

Beyond blood pressure: new roles for angiotensin II

Since the discovery 100 years ago by Tigerstedt and Bergman of renin, an acid protease generating angiotensin peptide, numerous discoveries have advanced our understanding of the renin-angiotensin system (RAS). The recent cloning of angiotensin receptors and the availability of specific receptor ligands have allowed characterization of angiotensin-receptor-mediated actions, and an increasing number of studies using biochemical, pharmacological and molecular biological methods has focused on the many different physiological actions of the RAS in various tissues. Angiotensin II, the main effector peptide of the RAS, exerts most of its known actions in blood pressure control and body fluid homeostasis via the AT, receptor. AT, receptors not only play a role in growth control and cell differentiation but have been implicated in apoptosis and tissue regeneration. This review focuses on the extrarenal functions of angiotensin, especially in neuronal cells and the nervous system, and on recent advances in angiotensin receptor research.     

Beyond natural antimicrobial peptides: multimeric peptides and other peptidomimetic approaches

Naturally occurring antimicrobial peptides (AMPs) present several drawbacks that strongly limit their development into therapeutically valuable antibiotics. These include susceptibility to protease degradation and high costs of manufacture. To overcome these problems, researchers have tried to develop mimics or peptidomimetics endowed with better properties, while retaining the basic features of membrane-active natural AMPs such as cationic charge and amphipathic design. Protein epitope mimetics, multimeric (dendrimeric) peptides, oligoacyllysines, ceragenins, synthetic lipidated peptides, peptoids and other foldamers are some of the routes explored so far. The synthetic approach has led to compounds that have already entered clinical evaluation for the treatment of specific conditions, such as Staphylococcus (MRSA) infections. Should these trials be successful, an important proof-of-concept would be established, showing that synthetic oligomers rather than naturally occurring molecules could bring peptide-based antibiotics to clinical practice and the drug market for local and systemic treatment of medical conditions associated with multi-drug resistant pathogens.     

Beyond heuristics and biases: A contingency model of judgemental forecasting

The conflicting viewpoints about the quality of judgemental forecasts are examined and a model is proposed that attempts to resolve the conflict. The model sees forecasts as contingent upon the repertory of forecasting strategies that the forecaster brings to the forecasting task, the strategy that he or she selects as a function of the characteristics of the task, and the rigour with which he or she applies the strategy as a function of the motivating characteristics of the environment in which the task is encountered. The implications of differences in subjects' and experimenters' assumptions about which strategies are appropriate in experimental studies are examined, as are the implications of the differences between the motivating aspects of experimental and applied settings on both performance and on the generatizability of the results of experiments to applied judgemental forecasting.     

Statistical analysis of the relation between the length of the genoma and the diploid number of the chromosomes inCercopithecus

Riassunto Utilizzando metodiche statistiche è stato analizzato l'incremento della lunghezza totale del genoma rispetto al numero dei cromosomi in piastre a diversa ploidia nel genereCercopithecus. È stato riscontrato che la relazione numero dei cromosomi e lunghezza del genoma è significativamente lineare. È supposto un meccanismo adittivo per interpretare l'incremento del numero dei cromosomi.