Prion-like behaviour and tau-dependent cytotoxicity of pyroglutamylated amyloid-β

Extracellular plaques of amyloid-β and intraneuronal neurofibrillary tangles made from tau are the histopathological signatures of Alzheimer's disease. Plaques comprise amyloid-β fibrils that assemble from monomeric and oligomeric intermediates, and are prognostic indicators of Alzheimer's disease. Despite the importance of plaques to Alzheimer's disease, oligomers are considered to be the principal toxic forms of amyloid-β. Interestingly, many adverse responses to amyloid-β, such as cytotoxicity, microtubule loss, impaired memory and learning, and neuritic degeneration, are greatly amplified by tau expression. Amino-terminally truncated, pyroglutamylated (pE) forms of amyloid-β are strongly associated with Alzheimer's disease, are more toxic than amyloid-β, residues 1-42 (Aβ(1-42)) and Aβ(1-40), and have been proposed as initiators of Alzheimer's disease pathogenesis. Here we report a mechanism by which pE-Aβ may trigger Alzheimer's disease. Aβ(3(pE)-42) co-oligomerizes with excess Aβ(1-42) to form metastable low-n oligomers (LNOs) that are structurally distinct and far more cytotoxic to cultured neurons than comparable LNOs made from Aβ(1-42) alone. Tau is required for cytotoxicity, and LNOs comprising 5% Aβ(3(pE)-42) plus 95% Aβ(1-42) (5% pE-Aβ) seed new cytotoxic LNOs through multiple serial dilutions into Aβ(1-42) monomers in the absence of additional Aβ(3(pE)-42). LNOs isolated from human Alzheimer's disease brain contained Aβ(3(pE)-42), and enhanced Aβ(3(pE)-42) formation in mice triggered neuron loss and gliosis at 3 months, but not in a tau-null background. We conclude that Aβ(3(pE)-42) confers tau-dependent neuronal death and causes template-induced misfolding of Aβ(1-42) into structurally distinct LNOs that propagate by a prion-like mechanism. Our results raise the possibility that Aβ(3(pE)-42) acts similarly at a primary step in Alzheimer's disease pathogenesis.     

“三极对垒”还是“四分天下”——中国在全球科技中的新角色

美国与欧盟争夺世界科技领先者的竞赛是当前研究的热点。欧洲委员会最近的研究表明,欧洲在世界科技产出中所占的比重日益增加,并宣布欧洲上世纪末处于科学产出的领先地位。为了对全球发展态势进行监测,该研究对1991-2005年共15年的数据进行了分析。对科技产出活动和影响模式的分析采用的是一套文献计量指标和技术计量指标,这套指标包括:(1)出版物产出指标,如占世界总量的份额和基于主题的出版物分布概况;(2)引文指标,如基于期刊和基于主题的归一化平均引用率;(3)国际合作论文及其影响;(4)专利指标以及专利与论文之间的相互引用关系。同时文章还讨论了国家层面的文献计量学特征的演变、"科学权重"以及科学技术关联的模式。研究结果表明,采用科学技术指标这面镜子所反映的"三极对垒"模式在21世纪将不会长久,中国正在挑战一流科学经济强国的地位,并且其成为世界第二大科技强国的时代正在到来。     

Defining disposition concepts: A brief history of the problem

The aim of this paper is twofold. Firstly, I give a brief account of the history of the debate on the problem of defining disposition concepts from its beginning in the late 1920s until today. This account is divided into four parts, corresponding with 2, 3, 4 and 5 of the paper, each of which deals with a major period of the debate. Section 2 reports up to the mid-1950s. Section 3 deals with important contributions to the discussion between 1955 and 1958. However, the progress made around that time was far ahead of the logical theory and techniques which were needed for foundational reasons and for a better understanding of the basic notions. Some logical techniques appropriate for that aim were developed in the late 1960s and early 1970s. Though not uncontroversial, those logical techniques resulted in improvements of the insights gained in the mid-1950s; I shall report on those logical techniques and their application to the problem of defining disposition concepts in Section 4. In the early 1990s, however, the whole tradition of defining disposition concepts in terms of conditionals has been challenged by some strong counter-examples which are treated in Section 5. Finally, the second of the aims of this paper is explored in Section 6, in which I sketch very briefly the current stage of the debate by discussing and evaluating the most recent approaches to the subject.     

A Computational Model of Concept Generalization in Cross-Modal Reference

Cross-modal interactions between visual understanding and linguistic processing substantially contribute to the remarkable robustness of human language processing.We argue that the formation of cross-modal referential links is a prerequisite for the occurrence of cross-modal interactions between vision and language.In this paper we examine a computational model for a cross-modal reference formation with respect to its robustness against conceptual underspecification in the visual modality.This investigation is motivated by the fact that natural systems are well capable of establishing a cross-modal reference between modalities with different degrees of conceptual specification.In the investigated model,conceptually underspecified context information continues to drive the syntactic disambiguation of verb-centered syntactic ambiguities as long as the visual context contains the situation arity information of the visual scene.     

Quantum engineering: an atom-sorting machine

Laser cooling and trapping techniques allow us to control and manipulate neutral atoms. Here we rearrange, with submicrometre precision, the positions and ordering of laser-trapped atoms within strings by manipulating individual atoms with optical tweezers. Strings of equidistant atoms created in this way could serve as a scalable memory for quantum information.     

Independent evolution of bitter-taste sensitivity in humans and chimpanzees

It was reported over 65 years ago that chimpanzees, like humans, vary in taste sensitivity to the bitter compound phenylthiocarbamide (PTC). This was suggested to be the result of a shared balanced polymorphism, defining the first, and now classic, example of the effects of balancing selection in great apes. In humans, variable PTC sensitivity is largely controlled by the segregation of two common alleles at the TAS2R38 locus, which encode receptor variants with different ligand affinities. Here we show that PTC taste sensitivity in chimpanzees is also controlled by two common alleles of TAS2R38; however, neither of these alleles is shared with humans. Instead, a mutation of the initiation codon results in the use of an alternative downstream start codon and production of a truncated receptor variant that fails to respond to PTC in vitro. Association testing of PTC sensitivity in a cohort of captive chimpanzees confirmed that chimpanzee TAS2R38 genotype accurately predicts taster status in vivo. Therefore, although Fisher et al.'s observations were accurate, their explanation was wrong. Humans and chimpanzees share variable taste sensitivity to bitter compounds mediated by PTC receptor variants, but the molecular basis of this variation has arisen twice, independently, in the two species.     

Continuous generation of single photons with controlled waveform in an ion-trap cavity system

The controlled production of single photons is of fundamental and practical interest; they represent the lowest excited quantum states of the radiation field, and have applications in quantum cryptography and quantum information processing. Common approaches use the fluorescence of single ions, single molecules, colour centres and semiconductor quantum dots. However, the lack of control over such irreversible emission processes precludes the use of these sources in applications (such as quantum networks) that require coherent exchange of quantum states between atoms and photons. The necessary control may be achieved in principle in cavity quantum electrodynamics. Although this approach has been used for the production of single photons from atoms, such experiments are compromised by limited trapping times, fluctuating atom-field coupling and multi-atom effects. Here we demonstrate a single-photon source based on a strongly localized single ion in an optical cavity. The ion is optimally coupled to a well-defined field mode, resulting in the generation of single-photon pulses with precisely defined shape and timing. We have confirmed the suppression of two-photon events up to the limit imposed by fluctuations in the rate of detector dark counts. The stream of emitted photons is uninterrupted over the storage time of the ion, as demonstrated by a measurement of photon correlations over 90 min.     

Determination of the connectivity of newborn neurons in mammalian olfactory circuits

The mammalian olfactory bulb is a forebrain structure just one synapse downstream from the olfactory sensory neurons and performs the complex computations of sensory inputs. The formation of this sensory circuit is shaped through activity-dependent and cell-intrinsic mechanisms. Recent studies have revealed that cell-type specific connectivity and the organization of synapses in dendritic compartments are determined through cell-intrinsic programs already preset in progenitor cells. These progenitor programs give rise to subpopulations within a neuron type that have distinct synaptic organizations. The intrinsically determined formation of distinct synaptic organizations requires factors from contacting cells that match the cell-intrinsic programs. While certain genes control wiring within the newly generated neurons, other regulatory genes provide intercellular signals and are only expressed in neurons that will form contacts with the newly generated cells. Here, the olfactory system has provided a useful model circuit to reveal the factors regulating assembly of the highly structured connectivity in mammals.