Developmental regulation of p70 S6 kinase by a G protein-coupled receptor dynamically modelized in primary cells

The mechanisms whereby G protein-coupled receptors (GPCR) activate signalling pathways involved in mRNA translation are ill-defined, in contrast to tyrosine kinase receptors (TKR). We compared a GPCR and a TKR, both endogenously expressed, for their ability to mediate phosphorylation of 70-kDa ribosomal S6 kinase p70S6K in primary rat Sertoli cells at two developmental stages. In proliferating cells stimulated with follicle-stimulating hormone (FSH), active p70S6K was phosphorylated on T389 and T421/S424, through cAMP-dependent kinase (PKA) and phosphatidyl-inositide-3 kinase (PI3K) antagonizing actions. In FSH-stimulated differentiating cells, active p70S6K was phosphorylated solely on T389, PKA and PI3K independently enhancing its activity. At both developmental stages, insulin-induced p70S6K regulation was consistent with reported data. Therefore, TKR and GPCR trigger distinct p70S6K active conformations. p70S6K developmental regulation was formalized in a dynamic mathematical model fitting the data, which led to experimentally inaccessible predictions on p70S6K phosphorylation rate.     

The correspondence between James Hutton (1726–1797) and James Watt (1736–1819) with two letters from Hutton to George Clerk-Maxwell (1715–1784): Part I

In the collection of Watt's papers at Doldowlod, home of Lord Gibson-Watt, there are seven previously unpublished letters from James Hutton to James Watt, and four letters from Watt to Hutton, also unpublished. The letters were written between 1774 and 1795. Very little of Hutton's other correspondence survives, so these letters add significantly to our knowledge. The earliest letters, together with two letters to George Clerk-Maxwell (in the Scottish Record Office), describe geological tours that Hutton made through Wales, the Midlands, and the south-west of England in 1774. The correspondence after 1774, which will appear in a later edition of Annals of Science, reveals Watt's expertise in geology, and also discusses meteorology, varnish making, Symington's steam engines, the first experiments with steam navigation, pneumatic medicine, and other topics.     

Newtonian Emanation, Spinozism, Measurement and the Baconian Origins of the Laws of Nature

The first two sections of this paper investigate what Newton could have meant in a now famous passage from “De Graviatione” (hereafter “DeGrav”) that “space is as it were an emanative effect of God.” First it offers a careful examination of the four key passages within DeGrav that bear on this. The paper shows that the internal logic of Newton’s argument permits several interpretations. In doing so, the paper calls attention to a Spinozistic strain in Newton’s thought. Second it sketches four interpretive options: (i) one approach is generic neo-Platonic; (ii) another approach is associated with the Cambridge Platonist, Henry More; a variant on this (ii*) emphasizes that Newton mixes Platonist and Epicurean themes; (iii) a necessitarian approach; (iv) an approach connected with Bacon’s efforts to reformulate a useful notion of form and laws of nature. Hitherto only the second and third options have received scholarly attention in scholarship on DeGrav. The paper offers new arguments to treat Newtonian emanation as a species of Baconian formal causation as articulated, especially, in the first few aphorisms of part two of Bacon’s New Organon. If we treat Newtonian emanation as a species of formal causation then the necessitarian reading can be combined with most of the Platonist elements that others have discerned in DeGrav, especially Newton’s commitment to doctrines of different degrees of reality as well as the manner in which the first existing being ‘transfers’ its qualities to space (as a kind of causa-sui). This can clarify the conceptual relationship between space and its formal cause in Newton as well as Newton’s commitment to the spatial extended-ness of all existing beings. While the first two sections of this paper engage with existing scholarly controversies, in the final section the paper argues that the recent focus on emanation has obscured the importance of Newton’s very interesting claims about existence and measurement in “DeGrav”. The paper argues that according to Newton God and other entities have the same kind of quantities of existence; Newton is concerned with how measurement clarifies the way of being of entities. Newton is not claiming that measurement reveals all aspects of an entity. But if we measure something then it exists as a magnitude in space and as a magnitude in time. This is why in DeGrav Newton’s conception of existence really helps to “lay truer foundations of the mechanical sciences.”     

Purity and Danger of an Information Infrastructure

We critically assess deep-seated assumptions and images of an information infrastructure, namely, that it needs to be uniform, tidy, and nonfragmented. This is necessary because our perception of order is socially constructed and, more importantly, because it has implications. Based on an historical reconstruction of the establishment of a Lotus Notes-based infrastructure in an internationally oriented oil company with 17,000 employees, we describe and analyze the productive role that appeals to an orderly infrastructure play. We trace its sources and describe how it operates. We also identify the implications in terms of choice of technological solution, delegation of organizational roles, and making organizational actors (in)visible.     

On the continuity of reference of the elements: a response to Hendry

Robin Hendry has recently argued that although the term ‘element’ has traditionally been used in two different senses (basic substance and simple substance), there has nonetheless been a continuity of reference. The present article examines this author’s historical and philosophical claims and suggests that he has misdiagnosed the situation in several respects. In particular it is claimed that Hendry’s arguments for the nature of one particular element, oxygen, do not generalize to all elements as he implies. The second main objection is to Hendry’s view that the qua problem can be illuminated by appeal to the intention of scientists.     

Resurrecting ancestral alcohol dehydrogenases from yeast

Modern yeast living in fleshy fruits rapidly convert sugars into bulk ethanol through pyruvate. Pyruvate loses carbon dioxide to produce acetaldehyde, which is reduced by alcohol dehydrogenase 1 (Adh1) to ethanol, which accumulates. Yeast later consumes the accumulated ethanol, exploiting Adh2, an Adh1 homolog differing by 24 (of 348) amino acids. As many microorganisms cannot grow in ethanol, accumulated ethanol may help yeast defend resources in the fruit. We report here the resurrection of the last common ancestor of Adh1 and Adh2, called Adh(A). The kinetic behavior of Adh(A) suggests that the ancestor was optimized to make (not consume) ethanol. This is consistent with the hypothesis that before the Adh1-Adh2 duplication, yeast did not accumulate ethanol for later consumption but rather used Adh(A) to recycle NADH generated in the glycolytic pathway. Silent nucleotide dating suggests that the Adh1-Adh2 duplication occurred near the time of duplication of several other proteins involved in the accumulation of ethanol, possibly in the Cretaceous age when fleshy fruits arose. These results help to connect the chemical behavior of these enzymes through systems analysis to a time of global ecosystem change, a small but useful step towards a planetary systems biology.     

Myosin IXB variant increases the risk of celiac disease and points toward a primary intestinal barrier defect

Celiac disease is probably the best-understood immune-related disorder. The disease presents in the small intestine and results from the interplay between multiple genes and gluten, the triggering environmental factor. Although HLA class II genes explain 40% of the heritable risk, non-HLA genes accounting for most of the familial clustering have not yet been identified. Here we report significant and replicable association (P = 2.1 x 10(-6)) to a common variant located in intron 28 of the gene myosin IXB (MYO9B), which encodes an unconventional myosin molecule that has a role in actin remodeling of epithelial enterocytes. Individuals homozygous with respect to the at-risk allele have a 2.3-times higher risk of celiac disease (P = 1.55 x 10(-5)). This result is suggestive of a primary impairment of the intestinal barrier in the etiology of celiac disease, which may explain why immunogenic gluten peptides are able to pass through the epithelial barrier.