Oncogenically active MYD88 mutations in human lymphoma

The activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) remains the least curable form of this malignancy despite recent advances in therapy. Constitutive nuclear factor (NF)-κB and JAK kinase signalling promotes malignant cell survival in these lymphomas, but the genetic basis for this signalling is incompletely understood. Here we describe the dependence of ABC DLBCLs on MYD88, an adaptor protein that mediates toll and interleukin (IL)-1 receptor signalling, and the discovery of highly recurrent oncogenic mutations affecting MYD88 in ABC DLBCL tumours. RNA interference screening revealed that MYD88 and the associated kinases IRAK1 and IRAK4 are essential for ABC DLBCL survival. High-throughput RNA resequencing uncovered MYD88 mutations in ABC DLBCL lines. Notably, 29% of ABC DLBCL tumours harboured the same amino acid substitution, L265P, in the MYD88 Toll/IL-1 receptor (TIR) domain at an evolutionarily invariant residue in its hydrophobic core. This mutation was rare or absent in other DLBCL subtypes and Burkitt's lymphoma, but was observed in 9% of mucosa-associated lymphoid tissue lymphomas. At a lower frequency, additional mutations were observed in the MYD88 TIR domain, occurring in both the ABC and germinal centre B-cell-like (GCB) DLBCL subtypes. Survival of ABC DLBCL cells bearing the L265P mutation was sustained by the mutant but not the wild-type MYD88 isoform, demonstrating that L265P is a gain-of-function driver mutation. The L265P mutant promoted cell survival by spontaneously assembling a protein complex containing IRAK1 and IRAK4, leading to IRAK4 kinase activity, IRAK1 phosphorylation, NF-κB signalling, JAK kinase activation of STAT3, and secretion of IL-6, IL-10 and interferon-β. Hence, the MYD88 signalling pathway is integral to the pathogenesis of ABC DLBCL, supporting the development of inhibitors of IRAK4 kinase and other components of this pathway for the treatment of tumours bearing oncogenic MYD88 mutations.     

Structure-based design of non-natural amino-acid inhibitors of amyloid fibril formation

Many globular and natively disordered proteins can convert into amyloid fibrils. These fibrils are associated with numerous pathologies as well as with normal cellular functions, and frequently form during protein denaturation. Inhibitors of pathological amyloid fibril formation could be useful in the development of therapeutics, provided that the inhibitors were specific enough to avoid interfering with normal processes. Here we show that computer-aided, structure-based design can yield highly specific peptide inhibitors of amyloid formation. Using known atomic structures of segments of amyloid fibrils as templates, we have designed and characterized an all-D-amino-acid inhibitor of the fibril formation of the tau protein associated with Alzheimer's disease, and a non-natural L-amino-acid inhibitor of an amyloid fibril that enhances sexual transmission of human immunodeficiency virus. Our results indicate that peptides from structure-based designs can disrupt the fibril formation of full-length proteins, including those, such as tau protein, that lack fully ordered native structures. Because the inhibiting peptides have been designed on structures of dual-β-sheet 'steric zippers', the successful inhibition of amyloid fibril formation strengthens the hypothesis that amyloid spines contain steric zippers.     

Ten cities cross-sectional questionnaire survey of children asthma and other allergies in China

Asthma,rhinitis and eczema(allergic or non-allergic)have increased throughout the world during the last decades,especially among children.Changes in the indoor environment are suspected to be important causes.China has experienced a dramatic change in indoor environmental exposures during the past two decades.However,such changes and their associations with children’s asthma and other health aspects have not been thoroughly studied.China,Children,Homes,Health(CCHH),Phase I,was a cross-sectional questionnaire survey of 48219 children 1–8 years old in 10 Chinese cities during 2010–2012.The questionnaire includes the International Study of Asthma and Allergies in Childhood(ISAAC)core health questions and additional questions regarding housing,life habits and outdoor environment.In health analyses,children aged 3–6 years old were included.The prevalences of doctor diagnosed asthma varied from 1.7%to 9.8%(mean 6.8%),a large increase from 0.91%in 1999 and 1.50%in2000.The prevalence of wheeze,rhinitis and atopic eczema(last 12 months)varied from 13.9%to 23.7%,24.0%to 50.8%and4.8%to 15.8%,respectively.Taiyuan had the lowest prevalences of all illnesses and Shanghai the highest,except for wheezewhere the highest value was for Urumqi.We found(1)no obvious association between disease prevalences and ambient PM10concentrations and(2)higher prevalences of disease in humid climates with hot summers and cold winters,but with no centrally heated buildings.Associations between the diseases and economic status as indexed by Gross Domestic Product(GDP)requires further study.     

Orthorhombic crystal structure of an insulin mutant B9Asp at 0.20 nm resolution

Human B9(Ser~i'Asp) insulin, a fast-absorption insulin analogue, was obtained by site-directed mutagenesis at B9 position. The orthorhombic crystal structure of B9Asp insulin was analyzed by crystallography at 0.20 nm resolution. Although no significant change of its overall conformation was observed, the local conformation flanking B9 site differed greatly from native T6 human insulin. The substitution of serine at B9 position by aspartic acid resulted in obvious alteration of local hydrophobic and hydrophilic interactions. As a result, the insulin dimer became unstable and the capability of the hexamer formation was diminished extensively. All these properties contribute to the fast-absorption of B9Asp, In addition, the open state of N-terminus of B-chain, which differs from T- or R- state, might suggest a new conformational state in the monomer or dimer insulin.     

The Generalised Liar Paradox: A Quantum Model and Interpretation

The formalism of abstracted quantum mechanics is applied in a model of the generalized Liar Paradox. Here, the Liar Paradox, a consistently testable configuration of logical truth properties, is considered a dynamic conceptual entity in the cognitive sphere (Aerts, Broekaert, &; Smets, [Foundations of Science 1999, 4, 115–132; International Journal of Theoretical Physics, 2000, 38, 3231–3239]; Aerts and colleagues[Dialogue in Psychology, 1999, 10; Proceedings of Fundamental Approachs to Consciousness, Tokyo ’99; Mind in Interaction]. Basically, the intrinsic contextuality of the truth-value of the Liar Paradox is appropriately covered by the abstracted quantum mechanical approach. The formal details of the model are explicited here for the generalized case. We prove the possibility of constructing a quantum model of the m-sentence generalizations of the Liar Paradox. This includes (i) the truth–falsehood state of the m-Liar Paradox can be represented by an embedded 2m-dimensional quantum vector in a (2m) ^m -dimensional complex Hilbert space, with cognitive interactions corresponding to projections, (ii) the construction of a continuous ‘time’ dynamics is possible: typical truth and falsehood value oscillations are described by Schrödinger evolution, (iii) Kirchoff and von Neumann axioms are satisfied by introduction of ‘truth-value by inference’ projectors, (iv) time invariance of unmeasured state.     

Forecasting the Antwerp maritime steel traffic flow: A case study

This paper uses multivariate time series models to specify the maritime steel traffic flow in the port of Antwerp. The time series considered are the total outgoing and total incoming maritime steel traffic and the total steel production in the EEC. The obtained time series models provide useful insight into the general behaviour of the maritime steel traffic flow during the period 1971–82. In particular, they provide a quantitative interpretation of important changes which took place in the European steel industry during that period. The multivariate time series models produce forecasts which are a substantial improvement over those obtained by univariate time series models. This is especially the case for the series of total incoming maritime steel traffic in the port of Antwerp, when differencing and transformation of the original data are applied.     

概论高校财务管理

新形势下 ,高校应建立健全内部财管理体制 ,合理配置资源 ,提高办学效益