The curvature argument

Dasgupta (2015) has recently put forward a novel argument, which he calls the ‘curvature argument’, that aims to show that Galilean spacetime is not an ideal setting for our classical theory of motion. This paper examines the curvature argument and argues that it is not sound. The discussion yields a remark about the conditions under which a ‘symmetry argument’ demonstrates that a particular spacetime is a non-ideal setting for our theory of motion.     

“The True” in Gottlob Frege's “Über die Grundlagen der Geometrie”

In this essay, I examine the metaphysical and metalogical ramifications of Gottlob Frege's controversy with David Hilbert and Alwin Korselt, over Hilbert's Grundlagen der Geometrie. These ramifications include(1) Korselt's original appeals to general metatheoretic Deutungen (interpretations);(2) Hilbert's puzzling belief that whatever is consistent in some sense exists; and(3) Frege's semantic monist conviction that theoretical sense and reference (mathematical and other) must be eindeutig lösbar (uniquely solvable).My principal conclusions are(4) that Frege's position in (3) represented a pervasively dogmatic presumption that his newly discovered quantification theory must have a propositional metatheory (the True; the False); and(5) that this needless assumption adversely affected not only his polemic against the moderate semantic relativism of Hilbert and Korselt, but also his reception of type-theoretic ideas, and greatly facilitated his vulnerability to the sort of self-referential inconsistency Russell discovered in Grundgesetz V.These conclusions also seem to me to provide a conceptual framework for several of Frege's other arguments and reactions which might seem more particular and disparate. These include(6) his arbitrary restrictions on the range of second-order quantification, which undercut his own tentative attempts to give accounts of independence and semantic consequence;(7) his uncharacteristic hesitation, even dismay, at the prospect that such accounts might eventuate in a genuinely quantificational metamathematics, whose Gegenstände (objects) might themselves be Gedanken (thoughts); and, perhaps most revealingly(8) his otherwise quite enigmatic, quasi-stoic doctrine that genuine formal deduction must be from premises that are true.A deep reluctance to pluralize or iterate the transition from theory to meta-theory would also be consonant, of course, with Frege's vigorous insistence that there can be only one level each of linguistic Begriffe (concepts) and Gegenstände (objects). With hindsight, such an assumption may seem more gratuitous in the philosophy of language (where it contributed, I would argue, to Wittgenstein's famous transition to the mystical in 6.45 and 6.522 of the Tractatus); but its more implausible implications in this wider context seemed to emerge more slowly.In the mathematical test-case discussed here, however, such strains were immediately and painfully apparent; the first models of hyperbolic geometry were described some thirty years before Frege drafted his polemic against Hilbert's pioneering exposition. It is my hope that a careful study of Frege's lines of argument in this relatively straightforward mathematical controversy may suggest other, parallel approaches to the richer and more ambiguous problems of his philosophy of language.Niemand kann zwei Herren dienen. Man kann nicht der Wahrheit dienen und der Unwahrheit. Wenn die euklidische Geometrie wahr ist, so ist die nichteuklidische Geometrie falsch, und wenn die nichteuklidische wahr ist, so ist die euklidische Geometrie falsch.No one can serve two masters. One cannot serve truth and untruth. If Euclidean geometry is true, non-Euclidean geometry is false, and if non-Euclidean [geometry] is true, Euclidean geometry is false. Über Euklidische Geometrie [Frege 1969], p. 183.     

Apolipoprotein CIII hyperactivates β cell CaV1 channels through SR-BI/β1 integrin-dependent coactivation of PKA and Src

Apolipoprotein CIII (ApoCIII) not only serves as an inhibitor of triglyceride hydrolysis but also participates in diabetes-related pathological events such as hyperactivation of voltage-gated Ca²⁺ (Ca_V) channels in the pancreatic β cell. However, nothing is known about the molecular mechanisms whereby ApoCIII hyperactivates β cell Ca_V channels. We now demonstrate that ApoCIII increased Ca_V1 channel open probability and density. ApoCIII enhanced whole-cell Ca²⁺ currents and the Ca_V1 channel blocker nimodipine completely abrogated this enhancement. The effect of ApoCIII was not influenced by individual inhibition of PKA, PKC, or Src. However, combined inhibition of PKA, PKC, and Src counteracted the effect of ApoCIII, similar results obtained by coinhibition of PKA and Src. Moreover, knockdown of β1 integrin or scavenger receptor class B type I (SR-BI) prevented ApoCIII from hyperactivating β cell Ca_V channels. These data reveal that ApoCIII hyperactivates β cell Ca_V1 channels through SR-BI/β1 integrin-dependent coactivation of PKA and Src.     

PTC124 targets genetic disorders caused by nonsense mutations

Nonsense mutations promote premature translational termination and cause anywhere from 5-70% of the individual cases of most inherited diseases. Studies on nonsense-mediated cystic fibrosis have indicated that boosting specific protein synthesis from <1% to as little as 5% of normal levels may greatly reduce the severity or eliminate the principal manifestations of disease. To address the need for a drug capable of suppressing premature termination, we identified PTC124-a new chemical entity that selectively induces ribosomal readthrough of premature but not normal termination codons. PTC124 activity, optimized using nonsense-containing reporters, promoted dystrophin production in primary muscle cells from humans and mdx mice expressing dystrophin nonsense alleles, and rescued striated muscle function in mdx mice within 2-8 weeks of drug exposure. PTC124 was well tolerated in animals at plasma exposures substantially in excess of those required for nonsense suppression. The selectivity of PTC124 for premature termination codons, its well characterized activity profile, oral bioavailability and pharmacological properties indicate that this drug may have broad clinical potential for the treatment of a large group of genetic disorders with limited or no therapeutic options.