The power of images: mathematics and metaphysics in Hobbes's optics

This paper deals with Hobbes's theory of optical images, developed in his optical magnum opus, ‘A Minute or First Draught of the Optiques’ (1646), and published in abridged version in De homine (1658). The paper suggests that Hobbes's theory of vision and images serves him to ground his philosophy of man on his philosophy of body. Furthermore, since this part of Hobbes's work on optics is the most thoroughly geometrical, it reveals a good deal about the role of mathematics in Hobbes's philosophy. The paper points to some difficulties in the thesis of Shapin and Schaffer, who presented geometry as a ‘paradigm’ for Hobbes's natural philosophy. It will be argued here that Hobbes's application of geometry to optics was dictated by his metaphysical and epistemological principles, not by a blind belief in the power of geometry. Geometry supported causal explanation, and assisted reason in making sense of appearances by helping the philosopher understand the relationships between the world outside us and the images it produces in us. Finally the paper broadly suggests how Hobbes's theory of images may have triggered, by negative example, the flourishing of geometrical optics in Restoration England.     

Melanogenesis from tryptophan. Biogenetic experiments with harding-passey mouse melanoma

Riassunto Il triptofano¹⁴C-uniformemente marcato nell'anello benzenico e il triptofano marcato¹⁴C nel metilene sono incorporati in modo significativo nella melanina del melanoma di Harding-Passey del topo.5-ossitriptofano e 5-ossitriptamina non mostrano invece una significativa incorporazione nella stessa melanina. L'incorporazione ottenuta con il triptofano marcato sia nel nucleo che nel metilene è all'incirca uguale a quella ottenuta per somministrazione di tirosina-2-C¹⁴, per cui anche il triptofano deve essere considerato un precursore delle melanine.     

Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation

Activating B-RAF(V600E) (also known as BRAF) kinase mutations occur in ～7% of human malignancies and ～60% of melanomas. Early clinical experience with a novel class I RAF-selective inhibitor, PLX4032, demonstrated an unprecedented 80% anti-tumour response rate among patients with B-RAF(V600E)-positive melanomas, but acquired drug resistance frequently develops after initial responses. Hypotheses for mechanisms of acquired resistance to B-RAF inhibition include secondary mutations in B-RAF(V600E), MAPK reactivation, and activation of alternative survival pathways. Here we show that acquired resistance to PLX4032 develops by mutually exclusive PDGFRβ (also known as PDGFRB) upregulation or N-RAS (also known as NRAS) mutations but not through secondary mutations in B-RAF(V600E). We used PLX4032-resistant sub-lines artificially derived from B-RAF(V600E)-positive melanoma cell lines and validated key findings in PLX4032-resistant tumours and tumour-matched, short-term cultures from clinical trial patients. Induction of PDGFRβ RNA, protein and tyrosine phosphorylation emerged as a dominant feature of acquired PLX4032 resistance in a subset of melanoma sub-lines, patient-derived biopsies and short-term cultures. PDGFRβ-upregulated tumour cells have low activated RAS levels and, when treated with PLX4032, do not reactivate the MAPK pathway significantly. In another subset, high levels of activated N-RAS resulting from mutations lead to significant MAPK pathway reactivation upon PLX4032 treatment. Knockdown of PDGFRβ or N-RAS reduced growth of the respective PLX4032-resistant subsets. Overexpression of PDGFRβ or N-RAS(Q61K) conferred PLX4032 resistance to PLX4032-sensitive parental cell lines. Importantly, MAPK reactivation predicts MEK inhibitor sensitivity. Thus, melanomas escape B-RAF(V600E) targeting not through secondary B-RAF(V600E) mutations but via receptor tyrosine kinase (RTK)-mediated activation of alternative survival pathway(s) or activated RAS-mediated reactivation of the MAPK pathway, suggesting additional therapeutic strategies.     

North Pacific seasonality and the glaciation of North America 2.7 million years ago

In the context of gradual Cenozoic cooling, the timing of the onset of significant Northern Hemisphere glaciation 2.7 million years ago is consistent with Milankovitch's orbital theory, which posited that ice sheets grow when polar summertime insolation and temperature are low. However, the role of moisture supply in the initiation of large Northern Hemisphere ice sheets has remained unclear. The subarctic Pacific Ocean represents a significant source of water vapour to boreal North America, but it has been largely overlooked in efforts to explain Northern Hemisphere glaciation. Here we present alkenone unsaturation ratios and diatom oxygen isotope ratios from a sediment core in the western subarctic Pacific Ocean, indicating that 2.7 million years ago late-summer sea surface temperatures in this ocean region rose in response to an increase in stratification. At the same time, winter sea surface temperatures cooled, winter floating ice became more abundant and global climate descended into glacial conditions. We suggest that the observed summer warming extended into the autumn, providing water vapour to northern North America, where it precipitated and accumulated as snow, and thus allowed the initiation of Northern Hemisphere glaciation.     

Purification of diphtheria toxin by chromatography on Cibacron Blue-Sepharose

Diphtheria toxin binds to Cibacron Blue-Agarose and may be eluted by increasing the ionic strength of the elution buffer. Experiments using difference spectroscopy showed that the interaction between toxin and dye is ionic rather than hydrophobic, and therefore it is of a different nature with respect to that usually found in nucleotide-requiring enzymes.     

Large scale preparation of oxidized streptolysin O using molecular filtration

Summary Oxidized streptolysin O, suitable for the determination of antistreptolysin O in whole blood, has been prepared from crude broth culture ofS. pyogenes by molecular filtration using membranes with nominal mol. wt limit 10,000.     

The decomposition of forecast in seasonal arima models

This paper presents a procedure to break down the forecast function of a seasonal ARIMA model in terms of its permanent and transitory components. Both depend on the initial values at the forecast origin, but their structures are fixed and independent of this origin. The permanent component is an estimate of the long-run projection of the corresponding economic variable and the transitory element describes the approach towards the permanent one. Within the permanent component a distinction is made between the factors that depend on the initial conditions of the system and those that are deterministic. The procedure is compared to other methods presented in the literature and illustrated in an example.