Strategies for identifying synthetic peptides to act as inhibitors of NADPH oxidases, or “All that you did and did not want to know about Nox inhibitory peptides”

Phagocytes utilize reactive oxygen species (ROS) to kill pathogenic microorganisms. The source of ROS is an enzymatic complex (the NADPH oxidase), comprising a membrane-associated heterodimer (flavocytochrome b (558)), consisting of subunits Nox2 and p22(phox), and four cytosolic components (p47(phox), p67(phox), p40(phox), and Rac). The primordial ROS (superoxide) is generated by the reduction of molecular oxygen by NADPH via redox centers located on Nox2. This process is activated by the translocation of the cytosolic components to the membrane and their assembly with Nox2. Membrane translocation is preceded by interactions among cytosolic components. A number of proteins structurally and functionally related to Nox2 have been discovered in many cells (the Nox family) and these have pleiotropic functions related to the production of ROS. An intense search is underway to design therapeutic means to modulate Nox-dependent overproduction of ROS, associated with diseases. Among drug candidates, a central position is held by synthetic peptides reflecting domains in oxidase components involved in NADPH oxidase assembly. Peptides, corresponding to domains in Nox2, p22(phox), p47(phox), and Rac, found to be oxidase activation inhibitory in vitro, are reviewed. Usually, peptides are inhibitory only when added preceding assembly of the complex. Although competition with intact components seems most likely, less obvious mechanisms are, sometimes, at work. The use of peptides as inhibitory drugs in vivo requires the development of methods to assure cell penetration, resistance to degradation, and avoidance of toxicity, and modest successes have been achieved. The greatest challenge remains the discovery of peptide inhibitors acting specifically on individual Nox isoforms.     

Why does the Chinese public accept evolution?

A substantial proportion of Chinese nationals seem to accept evolution, and the country is sometimes held up to show that the sorry state of evolution acceptance in the United States is not inevitable. Attempts to improve evolution acceptance generally focus on improving communication, curricular reform, and even identifying cognitive mechanisms that bias people against evolution. What is it that the Chinese scientific community did so well, and can it be generalized? This paper argues that evolution acceptance in China has a very specific history, one that other countries are very unlikely to emulate. We show that the interactions among science, education, mass media, social and political movements, and ideological arguments about evolution greatly influenced the Chinese public's understanding and acceptance of evolution. We find that it was not just formal education, but many more ideologically motivated methods of evolution exposure that contributed to the high rate of acceptance. But since the purpose of evolution dissemination has moved beyond merely teaching biology, the Chinese public persists with substantial misunderstandings of the theory. Thus, bottom line percentage of acceptance figures can be misleading; the details and the history really matter.     

Eulers “Harmony” Between the Principles of “Rest” and “Least Action”

In 1751, LEONHARD EULER established “harmony” between two principles that had been stated by PIERRE-LOUIS-MOREAU DE MAUPERTUIS a few years earlier. These principles are intended to be the foundations of Mechanics; they are the principle of rest and the principle of least action. My claim is that the way in which “harmony” is achieved sets the foundations of so called Analytical Mechanics: it discloses the physical bases of the general ideas, concepts, and motivations of the formalism. My paper intends to show what those physical bases are, and how a picture of the formalism issues from them. This picture is shown to be recast in JOSEPH-LOUIS LAGRANGES justification of the formalism, which strengthens my claim.     

“Agreement” in the IPCC Confidence measure

The Intergovernmental Panel on Climate Change (IPCC) has, in its most recent Assessment Report (AR5), articulated guidelines for evaluating and communicating uncertainty that include a qualitative scale of confidence. We examine one factor included in that scale: the “degree of agreement.” Some discussions of the degree of agreement in AR5 suggest that the IPCC is employing a consensus-oriented social epistemology. We consider the application of the degree of agreement factor in practice in AR5. Our findings, though based on a limited examination, suggest that agreement attributions do not so much track the overall consensus among investigators as the degree to which relevant research findings substantively converge in offering support for IPCC claims. We articulate a principle guiding confidence attributions in AR5 that centers not on consensus but on the notion of support. In concluding, we tentatively suggest a pluralist approach to the notion of support.     

Is the classical limit “singular”?

We argue against claims that the classical ? → 0 limit is “singular” in a way that frustrates an eliminative reduction of classical to quantum physics. We show one precise sense in which quantum mechanics and scaling behavior can be used to recover classical mechanics exactly, without making prior reference to the classical theory. To do so, we use the tools of strict deformation quantization, which provides a rigorous way to capture the ? → 0 limit. We then use the tools of category theory to demonstrate one way that this reduction is explanatory: it illustrates a sense in which the structure of quantum mechanics determines that of classical mechanics.     

“Diabetes Renalis in Diabete Mellito” and the “Sugar-proof Kidney”

Résumé Nous appelons «concentration aglycosurique du sucre sanguin» (Ag) la concentration calculée limite au-dessus de laquelle le sucre dissous dans le plasme n'est plus résorbé mais s'élimine avec l'urine (Clearence). Lorsque le sucre sanguin augmente,Ag monte d'abord proportionnellement, puis la courbe s'applatit vers 350 mg%. Le compartement d'Ag a été étudié statistiquement. De cette façon on a obtenu une méthode qui donne de bons résultats pratiques pour reconnaître d'une part le diabète rénal compliqué de diabète mellitus et d'autre part un rein relativement étanche au sucre.     

Bolzano,Cauchy and the “new analysis” of the early nineteenth century

Summary In this paper I discuss the development of mathematical analysis during the second and third decades of the nineteenth century; and in particular I assert that the well-known correspondence of new ideas to be found in the writings of Bolzano and Cauchy is not a coincidence, but that Cauchy had read one particular paper of Bolzano and drew on its results without acknowledgement. The reasons for this conjecture involve not only the texts in question but also the state of development of mathematical analysis itself, Cauchy both as personality and as mathematician, and the rivalries which were prevalent in Paris at that time.     

Orally administered melatonin stimulates the 3α/β-hydroxysteroid oxidoreductase but not the 5α-reductase in the ventral prostate and seminal vesicles of pinealectomized rats

Summary Pinealectomized rats were treated orally with melatonin (MEL) for 14 days. Prostates and seminal vesicles were investigated for the activity of the 4-3-ketosteroid-5-oxidoreductase (5-R) and of the 3/-hydroxysteroid-oxidoreductase (3-HSO). The activity of the 3a-HSO was significantly stimulated (p<0.01, Friedman test) when compared to controls. The activity of the 5-R did not change significantly.This work was supported by the Deutsche Forschungsgemeinschaft, Sonderforschungsbereich 34 (Endokrinologie).     

“Local–Global”: the first twenty years

This paper investigates how and when pairs of terms such as “local–global” and “im Kleinen–im Grossen” began to be used by mathematicians as explicit reflexive categories. A first phase of automatic search led to the delineation of the relevant corpus, and to the identification of the period from 1898 to 1918 as that of emergence. The emergence appears to have been, from the very start, both transdisciplinary (function theory, calculus of variations, differential geometry) and international, although the AMS-Göttingen connection played a specific part. First used as an expository and didactic tool (e.g. by Osgood), it soon played a crucial part in the creation of new mathematical concepts (e.g. in Hahn’s work), in the shaping of research agendas (e.g. Blaschke’s global differential geometry), and in Weyl’s axiomatic foundation of the manifold concept. We finally turn to France, where in the 1910s, in the wake of Poincaré’s work, Hadamard began to promote a research agenda in terms of “passage du local au general.”     

The chemists go to war: The mobilization of civilian chemists and the british war effort, 1914–1918

The outbreak of war in 1914 found Britain unprepared for a lengthy conflict. British science and industry were particularly ill-prepared to meet the demands of static warfare. Within two years, however, mobilization had made appreciable strides, and, as Britain's munitions industries moved from crisis to confidence, Britain's chemical industry was transformed by an arsenal of ‘garrison chemists’, with skills either born of necessity or borrowed from overseas. At the same time, Britain's chemical leadership traced a path that led them from voluntarist to corporate methods, from private to public initiatives, and from individual to collective behaviours. This paper suggests four key stages in this mobilization, and hints at the significance of the war for the emergence of new sub-disciplines, for the careers of chemists, for academic-government relations in research, and for the image, status, and international position of British chemistry on the threshold of the postwar world.     

Protein folding revisited. A polypeptide chain at the folding – misfolding – nonfolding cross-roads: which way to go?

The structure-function paradigm claims that a specific function of a protein is determined by its unique and rigid three-dimensional (3D) structure. Thus, following its biosynthesis on the ribosome, a protein must fold to be functional. This idea represents one of the cornerstones of modern biology. Numerous cases when, due to the effect of environmental factors or because of genetic defects (mutations), a polypeptide chain has lost its capability to gain a proper functional 3D structure (i.e. became misfolded), seem to confirm this concept. Consequences of such misfolding are well known and represent lost of function, aggregation, development of conformational disorders and cell death. However, the recent revelation of countless examples of intrinsically disordered proteins has cast doubt on the general validity of the structure-function paradigm and revealed an intriguing route of functional disorder. Thus, in a living cell, a polypeptide chain chooses between three potential fates – functional folding, potentially deadly misfolding and mysterious nonfolding. This choice is dictated by the peculiarities of amino acid sequence and/or by the pressure of environmental factors. The aim of the present review is to outline some interesting features of these three routes.Received 5 March 2003; received after revision 28 March 2003; accepted 31 March 2003     

Protein folding and degradation in bacteria: to degrade or not to degrade? That is the question

In Escherichia coli protein quality control is carried out by a protein network, comprising chaperones and proteases. Central to this network are two protein families, the AAA+ and the Hsp70 family. The major Hsp70 chaperone, DnaK, efficiently prevents protein aggregation and supports the refolding of damaged proteins. In a special case, DnaK, together with the assistance of the AAA+ protein ClpB, can also refold aggregated proteins. Other Hsp70 systems have more specialized functions in the cell, for instance HscA appears to be involved in the assembly of Fe/S proteins. In contrast to ClpB, many AAA+ proteins associate with a peptidase to form proteolytic machines which remove irreversibly damaged proteins from the cellular pool. The AAA+ component of these proteolytic machines drives protein degradation. They are required not only for recognition of the substrate but also for substrate unfolding and translocation into the proteolytic chamber. In many cases, specific adaptor proteins modify the substrate binding properties of AAA+ proteins. While chaperones and proteases do not appear to directly cooperate with each other, both systems appear to be necessary for proper functioning of the cell and can, at least in part, substitute for one another. RID="*" ID="*"Corresponding author.     

Burnside’s engagement with the “modern theory of statistics”

The group theorist William Burnside devoted much of the last decade of his life to probability and statistics. The work led to contact with Ronald Fisher who was on his way to becoming the leading statistician of the age and with Karl Pearson, the man Fisher supplanted. Burnside corresponded with Fisher for nearly three years until their correspondence ended abruptly. This paper examines Burnside’s interactions with the statisticians and looks more generally at his work in probability and statistics. I am grateful to June Barrow-Green and Tony Mann for showing me important letters, to Susan Woodburn, Elise Bennetto and Jeniffer Beauchamps of the University of Adelaide for help with letters to Fisher and to Jonathan Harrison of St. John’s Cambridge for help with letters to Baker and White. Peter Neumann, the editor and a referee made helpful comments on an earlier draft.     

The “day of Brahman” in the work of Āryabhata

Summary In the astronomical treatise ryabhatya of ryabhata several verses are interpolated, namely all those verses in which either Brahman was mentioned or extremely large periods were introduced. The interpolator was known to AlBrn as ryabhata of Kusumapura, who belongs to the school of the elder ryabhata. The aim of the interpolator was to bring the teaching of the elder ryabhata into accordance with the revelation of Svayambh. Svayambh is another name for Brahm.