Defective membrane repair in dysferlin-deficient muscular dystrophy

Muscular dystrophy includes a diverse group of inherited muscle diseases characterized by wasting and weakness of skeletal muscle. Mutations in dysferlin are linked to two clinically distinct muscle diseases, limb-girdle muscular dystrophy type 2B and Miyoshi myopathy, but the mechanism that leads to muscle degeneration is unknown. Dysferlin is a homologue of the Caenorhabditis elegans fer-1 gene, which mediates vesicle fusion to the plasma membrane in spermatids. Here we show that dysferlin-null mice maintain a functional dystrophin-glycoprotein complex but nevertheless develop a progressive muscular dystrophy. In normal muscle, membrane patches enriched in dysferlin can be detected in response to sarcolemma injuries. In contrast, there are sub-sarcolemmal accumulations of vesicles in dysferlin-null muscle. Membrane repair assays with a two-photon laser-scanning microscope demonstrated that wild-type muscle fibres efficiently reseal their sarcolemma in the presence of Ca2+. Interestingly, dysferlin-deficient muscle fibres are defective in Ca2+-dependent sarcolemma resealing. Membrane repair is therefore an active process in skeletal muscle fibres, and dysferlin has an essential role in this process. Our findings show that disruption of the muscle membrane repair machinery is responsible for dysferlin-deficient muscle degeneration, and highlight the importance of this basic cellular mechanism of membrane resealing in human disease.     

Quantum distribution of protons in solid molecular hydrogen at megabar pressures

Solid hydrogen, a simple system consisting only of protons and electrons, exhibits a variety of structural phase transitions at high pressures. Experimental studies based on static compression up to about 230 GPa revealed three relevant phases of solid molecular hydrogen: phase I (high-temperature, low-pressure phase), phase II (low-temperature phase) and phase III (high-pressure phase). Spectroscopic data suggest that symmetry breaking, possibly related to orientational ordering, accompanies the transition into phases II and III. The boundaries dividing the three phases exhibit a strong isotope effect, indicating that the quantum-mechanical properties of hydrogen nuclei are important. Here we report the quantum distributions of protons in the three phases of solid hydrogen, obtained by a first-principles path-integral molecular dynamics method. We show that quantum fluctuations of protons effectively hinder molecular rotation--that is, a quantum localization occurs. The obtained crystal structures have entirely different symmetries from those predicted by the conventional simulations which treat protons classically.     

A signature of cosmic-ray increase in AD 774-775 from tree rings in Japan

Increases in (14)C concentrations in tree rings could be attributed to cosmic-ray events, as have increases in (10)Be and nitrate in ice cores. The record of the past 3,000 years in the IntCal09 data set, which is a time series at 5-year intervals describing the (14)C content of trees over a period of approximately 10,000 years, shows three periods during which (14)C increased at a rate greater than 3‰ over 10 years. Two of these periods have been measured at high time resolution, but neither showed increases on a timescale of about 1 year (refs 11 and 12). Here we report (14)C measurements in annual rings of Japanese cedar trees from ad 750 to ad 820 (the remaining period), with 1- and 2-year resolution. We find a rapid increase of about 12‰ in the (14)C content from ad 774 to 775, which is about 20 times larger than the change attributed to ordinary solar modulation. When averaged over 10 years, the data are consistent with the decadal IntCal (14)C data from North American and European trees. We argue that neither a solar flare nor a local supernova is likely to have been responsible.     

Variants in KCNQ1 are associated with susceptibility to type 2 diabetes mellitus

We carried out a multistage genome-wide association study of type 2 diabetes mellitus in Japanese individuals, with a total of 1,612 cases and 1,424 controls and 100,000 SNPs. The most significant association was obtained with SNPs in KCNQ1, and dense mapping within the gene revealed that rs2237892 in intron 15 showed the lowest Pvalue (6.7 x 10(-13), odds ratio (OR) = 1.49). The association of KCNQ1 with type 2 diabetes was replicated in populations of Korean, Chinese and European ancestry as well as in two independent Japanese populations, and meta-analysis with a total of 19,930 individuals (9,569 cases and 10,361 controls) yielded a P value of 1.7 x 10(-42) (OR = 1.40; 95% CI = 1.34-1.47) for rs2237892. Among control subjects, the risk allele of this polymorphism was associated with impairment of insulin secretion according to the homeostasis model assessment of beta-cell function or the corrected insulin response. Our data thus implicate KCNQ1 as a diabetes susceptibility gene in groups of different ancestries.     

Underdetermination and decomposition in Kepler's Astronomia Nova

This paper examines the underdetermination between the Ptolemaic, Copernican, and the Tychonic theories of planetary motions and its attempted resolution by Kepler. I argue that past philosophical analyses of the problem of the planetary motions have not adequately grasped a method through which the underdetermination might have been resolved. This method involves a procedure of what I characterize as decomposition and identification. I show that this procedure is used by Kepler in the first half of the Astronomia Nova, where he ultimately claims to have refuted the Ptolemaic theory, thus partially overcoming the underdetermination. Finally, I compare this method with other views of scientific inference such as bootstrapping.     

Strong coupling between local moments and superconducting 'heavy' electrons in UPd2Al3

The electronic structure of heavy-fermion compounds arises from the interaction of nearly localized 4f- or 5f-shell electrons (with atomic magnetic moments) with the free-electron-like itinerant conduction-band electrons. In actinide or rare-earth heavy-fermion materials, this interaction yields itinerant electrons having an effective mass about 100 times (or more) the bare electron mass. Moreover, the itinerant electrons in UPd2Al3 are found to be superconducting well below the magnetic ordering temperature of this compound, whereas magnetism generally suppresses superconductivity in conventional metals. Here we report the detection of a dispersive excitation of the ordered f-electron moments, which shows a strong interaction with the heavy superconducting electrons. This 'magnetic exciton' is a localized excitation which moves through the lattice as a result of exchange forces between the magnetic moments. By combining this observation with previous tunnelling measurements on this material, we argue that these magnetic excitons may produce effective interactions between the itinerant electrons, and so be responsible for superconductivity in a manner analogous to the role played by phonons in conventional superconductors.