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.     

Mitochondrial dysfunction and apoptosis in myopathic mice with collagen VI deficiency

Collagen VI is an extracellular matrix protein that forms a microfilamentous network in skeletal muscles and other organs. Inherited mutations in genes encoding collagen VI in humans cause two muscle diseases, Bethlem myopathy and Ullrich congenital muscular dystrophy. We previously generated collagen VI-deficient (Col6a1-/-) mice and showed that they have a muscle phenotype that strongly resembles Bethlem myopathy. The pathophysiological defects and mechanisms leading to the myopathic disorder were not known. Here we show that Col6a1-/- muscles have a loss of contractile strength associated with ultrastructural alterations of sarcoplasmic reticulum (SR) and mitochondria and spontaneous apoptosis. We found a latent mitochondrial dysfunction in myofibers of Col6a1-/- mice on incubation with the selective F1F(O)-ATPase inhibitor oligomycin, which caused mitochondrial depolarization, Ca2+ deregulation and increased apoptosis. These defects were reversible, as they could be normalized by plating Col6a1-/- myofibers on collagen VI or by addition of cyclosporin A (CsA), the inhibitor of mitochondrial permeability transition pore (PTP). Treatment of Col6a1-/- mice with CsA rescued the muscle ultrastructural defects and markedly decreased the number of apoptotic nuclei in vivo. These findings indicate that collagen VI myopathies have an unexpected mitochondrial pathogenesis that could be exploited for therapeutic intervention.     

Observation of rare-earth segregation in silicon nitride ceramics at subnanometre dimensions

Silicon nitride (Si3N4) ceramics are used in numerous applications because of their superior mechanical properties. Their intrinsically brittle nature is a critical issue, but can be overcome by introducing whisker-like microstructural features. However, the formation of such anisotropic grains is very sensitive to the type of cations used as the sintering additives. Understanding the origin of dopant effects, central to the design of high-performance Si3N4 ceramics, has been sought for many years. Here we show direct images of dopant atoms (La) within the nanometre-scale intergranular amorphous films typically found at grain boundaries, using aberration corrected Z-contrast scanning transmission electron microscopy. It is clearly shown that the La atoms preferentially segregate to the amorphous/crystal interfaces. First-principles calculations confirm the strong preference of La for the crystalline surfaces, which is essential for forming elongated grains and a toughened microstructure. Whereas principles of micrometre-scale structural design are currently used to improve the mechanical properties of ceramics, this work represents a step towards the atomic-level structural engineering required for the next generation of ceramics.     

Enhancements of energetic particles near the heliospheric termination shock

The spacecraft Voyager 1 is at a distance greater than 85 au from the Sun, in the vicinity of the termination shock that marks the abrupt slowing of the supersonic solar wind and the beginning of the extended and unexplored distant heliosphere. This shock is expected to accelerate 'anomalous cosmic rays', as well as to re-accelerate Galactic cosmic rays and low-energy particles from the inner Solar System. Here we report a significant increase in the numbers of energetic ions and electrons that persisted for seven months beginning in mid-2002. This increase differs from any previously observed in that there was a simultaneous increase in Galactic cosmic ray ions and electrons, anomalous cosmic rays and low-energy ions. The low-intensity level and spectral energy distribution of the anomalous cosmic rays, however, indicates that Voyager 1 still has not reached the termination shock. Rather, the observed increase is an expected precursor event. We argue that the radial anisotropy of the cosmic rays is expected to be small in the foreshock region, as is observed.     

RNAi-mediated gene silencing in non-human primates

The opportunity to harness the RNA interference (RNAi) pathway to silence disease-causing genes holds great promise for the development of therapeutics directed against targets that are otherwise not addressable with current medicines. Although there are numerous examples of in vivo silencing of target genes after local delivery of small interfering RNAs (siRNAs), there remain only a few reports of RNAi-mediated silencing in response to systemic delivery of siRNA, and there are no reports of systemic efficacy in non-rodent species. Here we show that siRNAs, when delivered systemically in a liposomal formulation, can silence the disease target apolipoprotein B (ApoB) in non-human primates. APOB-specific siRNAs were encapsulated in stable nucleic acid lipid particles (SNALP) and administered by intravenous injection to cynomolgus monkeys at doses of 1 or 2.5 mg kg(-1). A single siRNA injection resulted in dose-dependent silencing of APOB messenger RNA expression in the liver 48 h after administration, with maximal silencing of >90%. This silencing effect occurred as a result of APOB mRNA cleavage at precisely the site predicted for the RNAi mechanism. Significant reductions in ApoB protein, serum cholesterol and low-density lipoprotein levels were observed as early as 24 h after treatment and lasted for 11 days at the highest siRNA dose, thus demonstrating an immediate, potent and lasting biological effect of siRNA treatment. Our findings show clinically relevant RNAi-mediated gene silencing in non-human primates, supporting RNAi therapeutics as a potential new class of drugs.     

Genome sequencing in microfabricated high-density picolitre reactors

The proliferation of large-scale DNA-sequencing projects in recent years has driven a search for alternative methods to reduce time and cost. Here we describe a scalable, highly parallel sequencing system with raw throughput significantly greater than that of state-of-the-art capillary electrophoresis instruments. The apparatus uses a novel fibre-optic slide of individual wells and is able to sequence 25 million bases, at 99% or better accuracy, in one four-hour run. To achieve an approximately 100-fold increase in throughput over current Sanger sequencing technology, we have developed an emulsion method for DNA amplification and an instrument for sequencing by synthesis using a pyrosequencing protocol optimized for solid support and picolitre-scale volumes. Here we show the utility, throughput, accuracy and robustness of this system by shotgun sequencing and de novo assembly of the Mycoplasma genitalium genome with 96% coverage at 99.96% accuracy in one run of the machine.     

Mesembrioxylon obscurum , a new combination for Araucarioxylon? obscurum Knowlton, from the Upper Jurassic Morrison Formation, Wyoming

A reinvestigation of the type specimen of Araucarioxylon? obscurum Knowlton (1900) from the Upper Jurassic Morrison Formation in the Freezeout Hills of Wyoming has determined that this fossil should be transferred to Mesembrioxylon Seward (1919) as M. obscurum comb. nov. (Knowlton) Medlyn and Tidwell. Knowlton (1900), who was uncertain of its appropriate generic disposition, tentatively referred the wood to Araucarioxylon because it had obscure growth rings and relatively low ray height. Reexamination of Knowltons slides demonstrates that the wood has uniseriate, rarely biseriate rays, podocarpoid pitting, and diffuse axial parenchyma, none of which Knowlton mentioned. Tracheary pitting is mostly separate, round, uniseriate, occasionally biseriate and, when biseriate, opposite to subopposite. The smooth-walled crossfields exhibit 1-3 thin-bordered podocarpaceous pits per field. All of these features are present in Mesembrioxylon Seward.