Targeting mitochondria by α-tocopheryl succinate kills neuroblastoma cells irrespective of MycN oncogene expression

Amplification of the MycN oncogene characterizes a subset of highly aggressive neuroblastomas, the most common extracranial solid tumor of childhood. However, the significance of MycN amplification for tumor cell survival is controversial, since down-regulation of MycN was found to decrease markedly neuroblastoma sensitivity towards conventional anticancer drugs, cisplatin, and doxorubicin. Here, we show that a redox-silent analogue of vitamin E, α-tocopheryl succinate (α-TOS), which triggers apoptotic cell death via targeting mitochondria, can kill tumor cells irrespective of their MycN expression level. In cells overexpressing MycN, as well as cells in which MycN was switched off, α-TOS stimulated rapid entry of Ca(2+) into the cytosol, compromised Ca(2+) buffering capacity of the mitochondria and sensitized them towards mitochondrial permeability transition and subsequent apoptotic cell death. Prevention of mitochondrial Ca(2+) accumulation or chelation of cytosolic Ca(2+) rescued the cells. Thus, targeting mitochondria might be advantageous for the elimination of tumor cells with otherwise dormant apoptotic pathways.     

Comprehensive review of methods for prediction of intrinsic disorder and its molecular functions

Computational prediction of intrinsic disorder in protein sequences dates back to late 1970 and has flourished in the last two decades. We provide a brief historical overview, and we review over 30 recent predictors of disorder. We are the first to also cover predictors of molecular functions of disorder, including 13 methods that focus on disordered linkers and disordered protein–protein, protein–RNA, and protein–DNA binding regions. We overview their predictive models, usability, and predictive performance. We highlight newest methods and predictors that offer strong predictive performance measured based on recent comparative assessments. We conclude that the modern predictors are relatively accurate, enjoy widespread use, and many of them are fast. Their predictions are conveniently accessible to the end users, via web servers and databases that store pre-computed predictions for millions of proteins. However, research into methods that predict many not yet addressed functions of intrinsic disorder remains an outstanding challenge.     

Is Leibnizian Calculus Embeddable in First Order Logic?

To explore the extent of embeddability of Leibnizian infinitesimal calculus in first-order logic (FOL) and modern frameworks, we propose to set aside ontological issues and focus on procedural questions. This would enable an account of Leibnizian procedures in a framework limited to FOL with a small number of additional ingredients such as the relation of infinite proximity. If, as we argue here, first order logic is indeed suitable for developing modern proxies for the inferential moves found in Leibnizian infinitesimal calculus, then modern infinitesimal frameworks are more appropriate to interpreting Leibnizian infinitesimal calculus than modern Weierstrassian ones.     

Hemoglobin as a source of iron overload in multiple sclerosis: does multiple sclerosis share risk factors with vascular disorders?

Although iron is known to be essential for the normal development and health of the central nervous system, abnormal iron deposits are found in and around multiple sclerosis (MS) lesions that themselves are closely associated with the cerebral vasculature. However, the origin of this excess iron is unknown, and it is not clear whether this is one of the primary causative events in the pathogenesis of MS, or simply another consequence of the long-lasting inflammatory conditions. Here, applying a systems biology approach, we propose an additional way for understanding the neurodegenerative component of the disease caused by chronic subclinical extravasation of hemoglobin, in combination with multiple other factors including, but not limited to, dysfunction of different cellular protective mechanisms against extracellular hemoglobin reactivity and oxidative stress. Moreover, such considerations could also shed light on and explain the higher susceptibility of MS patients to a wide range of cardiovascular disorders.     

The Prospects for Machine Discovery in Linguistics

The article reports the results from the developmentof four data-driven discovery systems, operating inlinguistics. The first mimics the induction methods ofJohn Stuart Mill, the second performs componentialanalysis of kinship vocabularies, the third is ageneral multi-class discrimination program, and thefourth finds logical patterns in data. These systemsare briefly described and some arguments are offeredin favour of machine linguistic discovery. Thearguments refer to the strength of machines incomputationally complex tasks, the guaranteedconsistency of machine results, the portability ofmachine methods to new tasks and domains, and thepotential machines provide for our gaining newinsights.     

A recyclable catalyst that precipitates at the end of the reaction

Homogeneous catalysts--which exist in the same (usually liquid) phase as reactants and products--are usually more selective than heterogeneous catalysts and far less affected by limitations due to slow transport of reactants and products, but their separation from reaction products can be costly and inefficient. This has stimulated the development of strategies that facilitate the recycling of homogeneous catalysts. Some of these methods exploit the preference of a catalyst for one of two solvents with thermoregulated miscibility; others exploit a dramatic decrease in catalyst solubility as one reagent is consumed or temperature changed after completion of the reaction. Here we describe a tungsten catalyst for the solvent-free hydrosilylation of ketones that retains its activity until essentially all of the liquid substrate is converted to liquid products, which we can then simply decant to separate the catalyst that precipitates from the products of the reaction. We attribute the ability of the catalyst to retain its solubility and hence activity until completion of the reaction to the transient formation of liquid clathrate that contains a few molecules of the substrate per molecule of the otherwise solid catalyst. Insights into the fundamental processes controlling the formation of this liquid clathrate might help to tailor other catalysts and substrates, so as to develop efficient and solvent-free schemes for reactions of practical interest.     

Zero-resistance states induced by electromagnetic-wave excitation in GaAs/AlGaAs heterostructures

The observation of vanishing electrical resistance in condensed matter has led to the discovery of new phenomena such as, for example, superconductivity, where a zero-resistance state can be detected in a metal below a transition temperature T(c) (ref. 1). More recently, quantum Hall effects were discovered from investigations of zero-resistance states at low temperatures and high magnetic fields in two-dimensional electron systems (2DESs). In quantum Hall systems and superconductors, zero-resistance states often coincide with the appearance of a gap in the energy spectrum. Here we report the observation of zero-resistance states and energy gaps in a surprising setting: ultrahigh-mobility GaAs/AlGaAs heterostructures that contain a 2DES exhibit vanishing diagonal resistance without Hall resistance quantization at low temperatures and low magnetic fields when the specimen is subjected to electromagnetic wave excitation. Zero-resistance-states occur about magnetic fields B = 4/5 Bf and B = 4/9 Bf, where Bf = 2pifm*/e,m* is the electron mass, e is the electron charge, and f is the electromagnetic-wave frequency. Activated transport measurements on the resistance minima also indicate an energy gap at the Fermi level. The results suggest an unexpected radiation-induced, electronic-state-transition in the GaAs/AlGaAs 2DES.     

Palaeoclimatology: the record for marine isotopic stage 11

The marine isotopic stage 11 (MIS 11) is an extraordinarily long interglacial period in the Earth's history that occurred some 400,000 years ago and lasted for about 30,000 years. During this period there were weak, astronomically induced changes in the distribution of solar energy reaching the Earth. The conditions of this orbital climate forcing are similar to those of today's interglacial period, and they rendered the climate susceptible to other forcing--for example, to changes in the level of atmospheric carbon dioxide. Here we use ice-core data from the Antarctic Vostok core to reconstruct a complete atmospheric carbon dioxide record for MIS 11. The record indicates that values for carbon dioxide throughout the interglacial period were close to the Earth's pre-industrial levels and that both solar energy and carbon dioxide may have helped to make MIS 11 exceptionally long. Anomalies in the oceanic carbonate system recorded in marine sediments at the time, for example while coral reefs were forming, apparently left no signature on atmospheric carbon dioxide concentrations.     

In situ multi-satellite detection of coherent vortices as a manifestation of Alfvénic turbulence

Turbulence in fluids and plasmas is a ubiquitous phenomenon driven by a variety of sources-currents, sheared flows, gradients in density and temperature, and so on. Turbulence involves fluctuations of physical properties on many different scales, which interact nonlinearly to produce self-organized structures in the form of vortices. Vortex motion in fluids and magnetized plasmas is typically governed by nonlinear equations, examples of which include the Navier-Stokes equation, the Charney-Hasegawa-Mima equations and their numerous generalizations. These nonlinear equations admit solutions in the form of different types of vortices that are frequently observed in a variety of contexts: in atmospheres, in oceans and planetary systems, in the heliosphere, in the Earth's ionosphere and magnetosphere, and in laboratory plasma experiments. Here we report the discovery by the Cluster satellites of a distinct class of vortex motion-short-scale drift-kinetic Alfvén (DKA) vortices-in the Earth's magnetospheric cusp region. As is the case for the larger Kelvin-Helmholtz vortices observed previously, these dynamic structures should provide a channel for transporting plasma particles and energy through the magnetospheric boundary layers.     

Seismological evidence for mosaic structure of the surface of the Earth's inner core

The transition from the Earth's solid inner core to liquid outer core is the location where the inner core grows and from which compositional convection in the outer core originates. Most seismological models of the Earth describe the inner-core boundary as sharp and simple, although experimental data requiring the presence of a thin transition layer at the bottom of the outer core have been reported. The density jump at the inner-core boundary--an important parameter determining gravitational energy release and constraining the compositional difference between the inner and outer core-is also not well known. Estimates of this density jump obtained using free-oscillation eigenfrequencies give low values of 0.25-1.0 g cm(-3), whereas a method using the amplitude ratio of core-reflected phases yielded values of 0.6-1.8 g cm(-3) (refs 14, 15, 16-17). Here we analyse properties of waves precritically reflected from the Earth's inner core (PKiKP phases) that show significant variability in amplitude, consistent high-frequency content and stable travel times with respect to a standard Earth model. We infer that the data are best explained by a mosaic structure of the inner core's surface. Such a mosaic may be composed of patches in which the transition from solid inner to liquid outer core includes a thin partially liquid layer interspersed with patches containing a sharp transition.