Sarcolemma-localized nNOS is required to maintain activity after mild exercise

Many neuromuscular conditions are characterized by an exaggerated exercise-induced fatigue response that is disproportionate to activity level. This fatigue is not necessarily correlated with greater central or peripheral fatigue in patients, and some patients experience severe fatigue without any demonstrable somatic disease. Except in myopathies that are due to specific metabolic defects, the mechanism underlying this type of fatigue remains unknown. With no treatment available, this form of inactivity is a major determinant of disability. Here we show, using mouse models, that this exaggerated fatigue response is distinct from a loss in specific force production by muscle, and that sarcolemma-localized signalling by neuronal nitric oxide synthase (nNOS) in skeletal muscle is required to maintain activity after mild exercise. We show that nNOS-null mice do not have muscle pathology and have no loss of muscle-specific force after exercise but do display this exaggerated fatigue response to mild exercise. In mouse models of nNOS mislocalization from the sarcolemma, prolonged inactivity was only relieved by pharmacologically enhancing the cGMP signal that results from muscle nNOS activation during the nitric oxide signalling response to mild exercise. Our findings suggest that the mechanism underlying the exaggerated fatigue response to mild exercise is a lack of contraction-induced signalling from sarcolemma-localized nNOS, which decreases cGMP-mediated vasomodulation in the vessels that supply active muscle after mild exercise. Sarcolemmal nNOS staining was decreased in patient biopsies from a large number of distinct myopathies, suggesting a common mechanism of fatigue. Our results suggest that patients with an exaggerated fatigue response to mild exercise would show clinical improvement in response to treatment strategies aimed at improving exercise-induced signalling.     

Trench-parallel flow and seismic anisotropy in the Mariana and Andean subduction systems

Shear-wave splitting measurements above the mantle wedge of the Mariana and southern Andean subduction zones show trench-parallel seismically fast directions close to the trench and abrupt rotations to trench-perpendicular anisotropy in the back arc. These patterns of seismic anisotropy may be caused by three-dimensional flow associated with along-strike variations in slab geometry. The Mariana and Andean subduction systems are associated with the largest along-strike variations of slab geometry observed on Earth and are ideal for testing the link between slab geometry and solid-state creep processes in the mantle. Here we show, with fully three-dimensional non-newtonian subduction zone models, that the strong curvature of the Mariana slab and the transition to shallow slab dip in the Southern Andes give rise to strong trench-parallel stretching in the warm-arc and warm-back-arc mantle and to abrupt rotations in stretching directions that are accompanied by strong trench-parallel stretching. These models show that the patterns of shear-wave splitting observed in the Mariana and southern Andean systems may be caused by significant three-dimensional flow induced by along-strike variations in slab geometry.     

Rationality and irrationality in the history of continental drift: Was the hypothesis of continental drift worthy of pursuit?

The revolution in geology, initiated with Alfred Wegener’s theory of continental drift, has been the subject of many philosophical discussions aiming at resolving the problem of rationality underlying this historical episode. Even though the debate included analyses in terms of scientific methodology, applications of concrete accounts of epistemic justification to this case study have been rare. In particular, the question as to whether Wegener’s theory was epistemically worthy of pursuit in the first half of the twentieth century, that is, in its early development, remained open or inadequately addressed. The aim of this paper is to offer an answer to this question. The evaluation of Drift will be done by means of an account of theory evaluation suitable for the context of pursuit, developed in ?e?elja and Straßer (accepted for publication). We will argue that pursuing the theory of continental drift was rational, i.e., that it was irrational to reject its pursuit as unworthy.     

Cholesteryl ester transfer protein and its inhibition

Cholesteryl ester transfer protein (CETP) is a plasma glycoprotein that facilitates the transfer of cholesteryl esters from the atheroprotective high density lipoprotein (HDL) to the proatherogenic low density lipoprotein cholesterol (LDL) and very low density lipoprotein cholesterol (VLDL) leading to lower levels of HDL but raising the levels of proatherogenic LDL and VLDL. Inhibition of CETP is considered a potential approach to treat dyslipidemia. However, discussions regarding the role of CETP-mediated lipid transfer in the development of atherosclerosis and CETP inhibition as a potential strategy for prevention of atherosclerosis have been controversial. Although many animal studies support the hypothesis that inhibition of CETP activity may be beneficial, negative phase III studies on clinical endpoints with the CETP inhibitor torcetrapib challenged the future perspectives of CETP inhibitors as potential therapeutic agents. The review provides an update on current understanding of the molecular mechanisms involved in CETP activity and its inhibition.     

American Pikas ( Ochotona princeps ) in northwestern Nevada: a newly discovered population at a low-elevation site

The central tenet of island biogeography theory—that species assemblages on islands are functions of island area, isolation from mainlands, and vicariance—has been altered by the demonstrable effects that rapid climate change is imposing on insular faunas, at least in isolated mountaintops. Although populations of American pikas ( Ochotona princeps ) continue to suffer extirpations, and although the lower bounds of the pika's elevational distribution are shifting upslope across the Great Basin, we report here on the new discovery of a low-elevation population of pikas in a mountain range from which they had not been reported previously. This discovery, particularly in the context of relatively rapid ecological change, highlights the importance of seeking out original sources of information and performing spatially extensive fieldwork. Results presented here further illustrate that although thermal influences appear to be the single strongest determinant of pika distribution currently, such influences interact with a number of other factors to determine persistence.     

Rationality in the Discovery of Empirical Laws

In this paper I argue against the traditional viewthat in discovery processes there is no place forrational decisions. First I argue that some historicalprocesses in which an empirical law was developed,were rational. Second, I identify some of themethodological rules that we can follow in order to berational when constructing an empirical law. Finally,I argue that people who deny that scientific discoverycan be rational do not understand the nature ofmethodological rules.     

Augmentation of tumor angiogenesis by a Myc-activated microRNA cluster

Human adenocarcinomas commonly harbor mutations in the KRAS and MYC proto-oncogenes and the TP53 tumor suppressor gene. All three genetic lesions are potentially pro-angiogenic, as they sustain production of vascular endothelial growth factor (VEGF). Yet Kras-transformed mouse colonocytes lacking p53 formed indolent, poorly vascularized tumors, whereas additional transduction with a Myc-encoding retrovirus promoted vigorous vascularization and growth. In addition, VEGF levels were unaffected by Myc, but enhanced neovascularization correlated with downregulation of anti-angiogenic thrombospondin-1 (Tsp1) and related proteins, such as connective tissue growth factor (CTGF). Both Tsp1 and CTGF are predicted targets for repression by the miR-17-92 microRNA cluster, which was upregulated in colonocytes coexpressing K-Ras and c-Myc. Indeed, miR-17-92 knockdown with antisense 2'-O-methyl oligoribonucleotides partly restored Tsp1 and CTGF expression; in addition, transduction of Ras-only cells with a miR-17-92-encoding retrovirus reduced Tsp1 and CTGF levels. Notably, miR-17-92-transduced cells formed larger, better-perfused tumors. These findings establish a role for microRNAs in non-cell-autonomous Myc-induced tumor phenotypes.     

Influence of phosphorus supply and light intensity on mycorrhizal response inPisum-Rhizobium-Glomus symbiosis

The influence of mycorrhizal colonization withGlomus mosseae on parameters of N₂ fixation and plant growth was studied in pot experiments with pea plants (Pisum sativum L.) infected withRhizobium leguminosarum and supplied with varied levels of phosphorus (P) and nitrogen (N). Reduced light intensities were used to evaluate the dependence of the microsymbionts on assimilate supply. In plants grown with low P supply, mycorrhization increased the concentration of P in shoots, and thus N₂ fixation. Reduced light intensity significantly depressed mycorrhizal colonization and nodule growth in low-P plants. When P supply did not limit plant growth and N₂ fixation, however, the percentage of mycorrhizal colonization was reduced due to the higher P status, and the microsymbionts were not impaired by low light intensities. To maximize carbohydrate supply, another experiment was carried out at high light intensity of 900 mol m^–2s^–1 and with non-limiting P supply. Nitrogen fertilization, given as starter N, enhanced plant growth, but delayed nodule formation. Towards flowering, nodulation rapidly increased, but less so inGlomus inoculated plants. After 28 days mycorrhizal plants were lower in shoot dry weight, nodule dry weight and nitrogenase activity. The results suggest that under many, but not all, environmental conditions the host plant is able to restrict mycorrhizal colonization and, thus, to prevent impairment ofRhizobium symbiosis.deceased in May 1994     

Coexisting brittle-ductile fracturing mechanisms in fault zones of the upper crust level

Microstructural and sub-microstructural studies are conducted on calcite marble taken from the Autseib fault zone, Damara region, Namibia, SW Africa. The characteristic microstructural styles of rocks deformed in the upper crust are analyzed, including mainly the two microstructural contrasts in the tectonites: (i) coarse grains (centimeter scale) in primary rocks and in deformed clasts and extremely fine grains (micron scale) in the matrix; and (ii) macroscopic cataclastic (brittle) and microscopic mylonitic (ductile) textures. The coexistence of the macroscopic brittle and microscopic ductile textures is better explained by deformation through a comprehensive association of intragranular twinning and kinking, intraand intergranular ductile fracturing, and pressure solution along grain boundaries. Ductile fracturing, i.e. fracturing triggered and accommodated by twinning and fluid-enhanced dislocation creep and dynamic recrystallization, is among the most important mechanisms of rock deformation in the shallow crust, while grain size reduction and dynamic recrystallization are primarily nucleated and distributed due to the incoherencies along some boundaries, e.g. kink band boundaries, fractures and grain boundaries in the deformed grains.