Sustained translational repression by eIF2α-P mediates prion neurodegeneration

The mechanisms leading to neuronal death in neurodegenerative disease are poorly understood. Many of these disorders, including Alzheimer's, Parkinson's and prion diseases, are associated with the accumulation of misfolded disease-specific proteins. The unfolded protein response is a protective cellular mechanism triggered by rising levels of misfolded proteins. One arm of this pathway results in the transient shutdown of protein translation, through phosphorylation of the α-subunit of eukaryotic translation initiation factor, eIF2. Activation of the unfolded protein response and/or increased eIF2α-P levels are seen in patients with Alzheimer's, Parkinson's and prion diseases, but how this links to neurodegeneration is unknown. Here we show that accumulation of prion protein during prion replication causes persistent translational repression of global protein synthesis by eIF2α-P, associated with synaptic failure and neuronal loss in prion-diseased mice. Further, we show that promoting translational recovery in hippocampi of prion-infected mice is neuroprotective. Overexpression of GADD34, a specific eIF2α-P phosphatase, as well as reduction of levels of prion protein by lentivirally mediated RNA interference, reduced eIF2α-P levels. As a result, both approaches restored vital translation rates during prion disease, rescuing synaptic deficits and neuronal loss, thereby significantly increasing survival. In contrast, salubrinal, an inhibitor of eIF2α-P dephosphorylation, increased eIF2α-P levels, exacerbating neurotoxicity and significantly reducing survival in prion-diseased mice. Given the prevalence of protein misfolding and activation of the unfolded protein response in several neurodegenerative diseases, our results suggest that manipulation of common pathways such as translational control, rather than disease-specific approaches, may lead to new therapies preventing synaptic failure and neuronal loss across the spectrum of these disorders.     

Forensic Science: Current State and Perspective by a Group of Early Career Researchers

Forensic science and its influence on policing and the criminal justice system have increased since the beginning of the twentieth century. While the philosophies of the forensic science pioneers remain the pillar of modern practice, rapid advances in technology and the underpinning sciences have seen an explosion in the number of disciplines and tools. Consequently, the way in which we exploit and interpret the remnant of criminal activity are adapting to this changing environment. In order to best exploit the trace, an interdisciplinary approach to both research and investigation is required. In this paper, nine postdoctoral research fellows from a multidisciplinary team discuss their vision for the future of forensic science at the crime scene, in the laboratory and beyond. This paper does not pretend to be exhaustive of all fields of forensic science, but describes a portion of the postdoctoral fellows’ interests and skills.     

Association of dwarfism and floral induction with a grape 'green revolution' mutation

The transition from vegetative to reproductive growth is an essential process in the life cycle of plants. Plant floral induction pathways respond to both environmental and endogenous cues and much has been learnt about these genetic pathways by studying mutants of Arabidopsis. Gibberellins (GAs) are plant growth regulators important in many aspects of plant growth and in Arabidopsis they promote flowering. Here we provide genetic evidence that GAs inhibit flowering in grapevine. A grapevine dwarf mutant derived from the L1 cell layer of the champagne cultivar Pinot Meunier produces inflorescences along the length of the shoot where tendrils are normally formed. The mutated gene associated with the phenotype is a homologue of the wheat 'green revolution' gene Reduced height-1 (ref. 6) and the Arabidopsis gene GA insensitive (GAI). The conversion of tendrils to inflorescences in the mutant demonstrates that the grapevine tendril is a modified inflorescence inhibited from completing floral development by GAs.     

Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase

Poly(ADP-ribose) polymerase (PARP1) facilitates DNA repair by binding to DNA breaks and attracting DNA repair proteins to the site of damage. Nevertheless, PARP1-/- mice are viable, fertile and do not develop early onset tumours. Here, we show that PARP inhibitors trigger gamma-H2AX and RAD51 foci formation. We propose that, in the absence of PARP1, spontaneous single-strand breaks collapse replication forks and trigger homologous recombination for repair. Furthermore, we show that BRCA2-deficient cells, as a result of their deficiency in homologous recombination, are acutely sensitive to PARP inhibitors, presumably because resultant collapsed replication forks are no longer repaired. Thus, PARP1 activity is essential in homologous recombination-deficient BRCA2 mutant cells. We exploit this requirement in order to kill BRCA2-deficient tumours by PARP inhibition alone. Treatment with PARP inhibitors is likely to be highly tumour specific, because only the tumours (which are BRCA2-/-) in BRCA2+/- patients are defective in homologous recombination. The use of an inhibitor of a DNA repair enzyme alone to selectively kill a tumour, in the absence of an exogenous DNA-damaging agent, represents a new concept in cancer treatment.     

A planetary system as the origin of structure in Fomalhaut's dust belt

The Sun and >15 per cent of nearby stars are surrounded by dusty disks that must be collisionally replenished by asteroids and comets, as the dust would otherwise be depleted on timescales <10(7) years (ref. 1). Theoretical studies show that the structure of a dusty disk can be modified by the gravitational influence of planets, but the observational evidence is incomplete, at least in part because maps of the thermal infrared emission from the disks have low linear resolution (35 au in the best case). Optical images provide higher resolution, but the closest examples (AU Mic and beta Pic) are edge-on, preventing the direct measurement of the azimuthal and radial disk structure that is required for fitting theoretical models of planetary perturbations. Here we report the detection of optical light reflected from the dust grains orbiting Fomalhaut (HD 216956). The system is inclined 24 degrees away from edge-on, enabling the measurement of disk structure around its entire circumference, at a linear resolution of 0.5 au. The dust is distributed in a belt 25 au wide, with a very sharp inner edge at a radial distance of 133 au, and we measure an offset of 15 au between the belt's geometric centre and Fomalhaut. Taken together, the sharp inner edge and offset demonstrate the presence of planetary-mass objects orbiting Fomalhaut.     

The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth

Many tumour cells have elevated rates of glucose uptake but reduced rates of oxidative phosphorylation. This persistence of high lactate production by tumours in the presence of oxygen, known as aerobic glycolysis, was first noted by Otto Warburg more than 75 yr ago. How tumour cells establish this altered metabolic phenotype and whether it is essential for tumorigenesis is as yet unknown. Here we show that a single switch in a splice isoform of the glycolytic enzyme pyruvate kinase is necessary for the shift in cellular metabolism to aerobic glycolysis and that this promotes tumorigenesis. Tumour cells have been shown to express exclusively the embryonic M2 isoform of pyruvate kinase. Here we use short hairpin RNA to knockdown pyruvate kinase M2 expression in human cancer cell lines and replace it with pyruvate kinase M1. Switching pyruvate kinase expression to the M1 (adult) isoform leads to reversal of the Warburg effect, as judged by reduced lactate production and increased oxygen consumption, and this correlates with a reduced ability to form tumours in nude mouse xenografts. These results demonstrate that M2 expression is necessary for aerobic glycolysis and that this metabolic phenotype provides a selective growth advantage for tumour cells in vivo.     

用于万维网内容挖掘的图论技术

本书是由新加坡世界科技出版公司出版的《机器感知与人工智能》丛书的第62卷。图形是用来表示某些具有结构（即关系）信息的物体或系统的数据结构。图形应用于许多领域，从软件工程到人工智能。但是与最为流行的矢量模型相比，在机器学习中图形的利用则是有限的．但矢量模型未能捕获结构信息。     

A transforming mutation in the pleckstrin homology domain of AKT1 in cancer

Although AKT1 (v-akt murine thymoma viral oncogene homologue 1) kinase is a central member of possibly the most frequently activated proliferation and survival pathway in cancer, mutation of AKT1 has not been widely reported. Here we report the identification of a somatic mutation in human breast, colorectal and ovarian cancers that results in a glutamic acid to lysine substitution at amino acid 17 (E17K) in the lipid-binding pocket of AKT1. Lys 17 alters the electrostatic interactions of the pocket and forms new hydrogen bonds with a phosphoinositide ligand. This mutation activates AKT1 by means of pathological localization to the plasma membrane, stimulates downstream signalling, transforms cells and induces leukaemia in mice. This mechanism indicates a direct role of AKT1 in human cancer, and adds to the known genetic alterations that promote oncogenesis through the phosphatidylinositol-3-OH kinase/AKT pathway. Furthermore, the E17K substitution decreases the sensitivity to an allosteric kinase inhibitor, so this mutation may have important clinical utility for AKT drug development.     

Anatomy,reach and classification of the parasitoid complex of a common British moth,Anthophila fabriciana (L.) (Choreutidae)

The small plurivoltine moth Anthophila fabriciana is widespread and often abundant in Britain wherever its main larval foodplant, stinging nettle, occurs. It overwinters as a larva (first generation) then has one or more partly overlapping summer broods (notionally second generation). A total of 5017 larvae were collected and reared from widely distributed populations in Britain, and the resulting 2167 host mortalities due to parasitoids were assessed. Small collections of pupae were also made. Altogether 25 parasitoid species, including secondary parasitoids, were found. Larval parasitism was heaviest in the second generation. In each generation there was a dominant parasitoid that was absent from the other. Summary information on the developmental biology and host range (expressed quantitatively and resulting from very broad rearing programmes) for each parasitoid is given. They are classed as ‘absolute specialists’, ‘taxon oligospecialists’, ‘niche oligospecialists’, ‘niche generalists’, ‘casuals’ and ‘strays’. Both kinds of oligospecialists can be ‘paraspecialists’ if only one potential host occurs locally. Although constructing a quantitative food web is not appropriate, providing both source web and sink web data in quantitative form enables the parasitoid complex to be understood in the wider context of the ecosystem, necessary for both biodiversity and nature conservation interests. In Appendix 1, parasitoids reared from other European Choreutidae are listed quantitatively.