High-throughput decoding of antitrypanosomal drug efficacy and resistance

The concept of disease-specific chemotherapy was developed a century ago. Dyes and arsenical compounds that displayed selectivity against trypanosomes were central to this work, and the drugs that emerged remain in use for treating human African trypanosomiasis (HAT). The importance of understanding the mechanisms underlying selective drug action and resistance for the development of improved HAT therapies has been recognized, but these mechanisms have remained largely unknown. Here we use all five current HAT drugs for genome-scale RNA interference target sequencing (RIT-seq) screens in Trypanosoma brucei, revealing the transporters, organelles, enzymes and metabolic pathways that function to facilitate antitrypanosomal drug action. RIT-seq profiling identifies both known drug importers and the only known pro-drug activator, and links more than fifty additional genes to drug action. A bloodstream stage-specific invariant surface glycoprotein (ISG75) family mediates suramin uptake, and the AP1 adaptin complex, lysosomal proteases and major lysosomal transmembrane protein, as well as spermidine and N-acetylglucosamine biosynthesis, all contribute to suramin action. Further screens link ubiquinone availability to nitro-drug action, plasma membrane P-type H(+)-ATPases to pentamidine action, and trypanothione and several putative kinases to melarsoprol action. We also demonstrate a major role for aquaglyceroporins in pentamidine and melarsoprol cross-resistance. These advances in our understanding of mechanisms of antitrypanosomal drug efficacy and resistance will aid the rational design of new therapies and help to combat drug resistance, and provide unprecedented molecular insight into the mode of action of antitrypanosomal drugs.     

Proton-proton correlations observed in two-proton radioactivity of 94Ag

The stability and spontaneous decay of naturally occurring atomic nuclei have been much studied ever since Becquerel discovered natural radioactivity in 1896. In 1960, proton-rich nuclei with an odd or an even atomic number Z were predicted to decay through one- and two-proton radioactivity, respectively. The experimental observation of one-proton radioactivity was first reported in 1982, and two-proton radioactivity has now also been detected by experimentally studying the decay properties of 45Fe (refs 3, 4) and 54Zn (ref. 5). Here we report proton-proton correlations observed during the radioactive decay of a spinning long-lived state of the lightest known isotope of silver, 94Ag, which is known to undergo one-proton decay. We infer from these correlations that the long-lived state must also decay through simultaneous two-proton emission, making 94Ag the first nucleus to exhibit one- as well as two-proton radioactivity. We attribute the two-proton emission behaviour and the unexpectedly large probability for this decay mechanism to a very large deformation of the parent nucleus into a prolate (cigar-like) shape, which facilitates emission of protons either from the same or from opposite ends of the 'cigar'.     

Evolution: a catfish that can strike its prey on land

An important step towards understanding the evolution of terrestriality in vertebrates is to identify how the aquatic ancestors of tetrapods were able to access ground-based prey. We have discovered that the 'eel catfish' Channallabes apus, an inhabitant of the muddy swamps of tropical Africa, has a remarkable ability to forage and capture prey on land. The animal's capacity to bend its head down towards the ground while feeding seems to be an essential feature that may have enabled fish to make the transition from an aquatic to a terrestrial mode.     

Early oxygenation of the terrestrial environment during the Mesoproterozoic

Geochemical data from ancient sedimentary successions provide evidence for the progressive evolution of Earth's atmosphere and oceans. Key stages in increasing oxygenation are postulated for the Palaeoproterozoic era (～2.3?billion years ago, Gyr ago) and the late Proterozoic eon (about 0.8?Gyr ago), with the latter implicated in the subsequent metazoan evolutionary expansion. In support of this rise in oxygen concentrations, a large database shows a marked change in the bacterially mediated fractionation of seawater sulphate to sulphide of Δ(34)S?相似文献   

高性能基音检测新方法

本基音检测方法是利用汉语语音结构特点,以主循环为基本概念,在时域上处理确定浊音音段的基音,而对清浊不明晰的音段,从时、频域两方面进行基音估算,并设计了基音选择逻辑和清浊音判断逻辑。实验结果表明,本方法的性能明显优于大多数流行的基音检测器,且计算速度快,是自相关方法和倒谱法的４倍和８倍。     

Stability of Traveling Waves Solutions for Nonlinear Cellular Neural Networks with Distributed Delays

Journal of Systems Science and Complexity - This paper investigates the exponential stability of traveling wave solutions for nonlinear delayed cellular neural networks. As a continuity of the past...