Network modeling links breast cancer susceptibility and centrosome dysfunction

Many cancer-associated genes remain to be identified to clarify the underlying molecular mechanisms of cancer susceptibility and progression. Better understanding is also required of how mutations in cancer genes affect their products in the context of complex cellular networks. Here we have used a network modeling strategy to identify genes potentially associated with higher risk of breast cancer. Starting with four known genes encoding tumor suppressors of breast cancer, we combined gene expression profiling with functional genomic and proteomic (or 'omic') data from various species to generate a network containing 118 genes linked by 866 potential functional associations. This network shows higher connectivity than expected by chance, suggesting that its components function in biologically related pathways. One of the components of the network is HMMR, encoding a centrosome subunit, for which we demonstrate previously unknown functional associations with the breast cancer-associated gene BRCA1. Two case-control studies of incident breast cancer indicate that the HMMR locus is associated with higher risk of breast cancer in humans. Our network modeling strategy should be useful for the discovery of additional cancer-associated genes.     

复杂网络: 结构和动力学

(续本刊2006年第4期) 6 应用 本章将讨论前述理论在实际网络中的应用,包括网络的结构和动力学两方面的问题.首先回顾社会网络的某些结构并考虑两类社会网络(意见形成和博弈模型)的动态演化,然后探讨因特网和万维网的统计属性,最后集中讨论生物和医学复杂网络,如分子成分之间的相互作用网和神经网络.     

复杂网络:结构和动力学

耦合的生物化学系统、神经网络、相互作用的群居物种、互联网和万维网只是由大量高度相互连接的动态个体组成的系统的少数几个例子。获取这类系统的全局特征的首选方法是建立图模型——图中的点代表动态个体，边代表个体间的相互作用。一方面，科学家们需要处理结构问题如刻画一个复杂连线体系的拓扑结构、揭示建立在现实网络基础上的统一原理，以及完善模型从而模拟网络的增长和复制网络结构特性；另一方面，在研究复杂网络动力学时会产生许多相关问题，例如研究一个大的动态系统如何通过复杂连接的相互作用来表现集体行为的。我们回顾了近来在研究复杂网络的结构和动力学方面的主要概念以及取得的结果，总结了这些思想在许多不同学科包括从非线性科学到生物学、从统计力学到医药学以及工程学等领域的有关应用。     

Ocean-like water in the Jupiter-family comet 103P/Hartley 2

For decades, the source of Earth's volatiles, especially water with a deuterium-to-hydrogen ratio (D/H) of (1.558?±?0.001)?×?10(-4), has been a subject of debate. The similarity of Earth's bulk composition to that of meteorites known as enstatite chondrites suggests a dry proto-Earth with subsequent delivery of volatiles by local accretion or impacts of asteroids or comets. Previous measurements in six comets from the Oort cloud yielded a mean D/H ratio of (2.96?±?0.25)?×?10(-4). The D/H value in carbonaceous chondrites, (1.4?±?0.1)?×?10(-4), together with dynamical simulations, led to models in which asteroids were the main source of Earth's water, with ≤10 per cent being delivered by comets. Here we report that the D/H ratio in the Jupiter-family comet 103P/Hartley 2, which originated in the Kuiper belt, is (1.61?±?0.24)?×?10(-4). This result substantially expands the reservoir of Earth ocean-like water to include some comets, and is consistent with the emerging picture of a complex dynamical evolution of the early Solar System.     

复杂网络:结构与动力学

(续本刊2006年第3期) 　　3 静态与动态鲁棒性 　　网络的鲁棒性是指当网络中的部分节点或边被破坏时,网络仍然能够继续维持其功能的能力.这是一个具有明显实际意义的论题,因为它直接影响着任何发生在网络上的过程的效率,而且它也是复杂网络文献中最早被探索的论题之一.……     

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.     

A synthetic vaccine protects humans against challenge with asexual blood stages of Plasmodium falciparum malaria

We have previously shown that a mixture of three synthetic peptides (83.1, 55.1, 35.1), corresponding to fragments of the relative molecular mass 83,000 (83K), 55K and 35K Plasmodium falciparum merozoite-specific proteins, induces protection in Aotus triviroatus monkeys experimentally infected with P. falciparum. Here we describe two polymeric synthetic hybrid proteins based on these peptides that delay or suppress the development of parasitaemia in immunized human volunteers.     

Ultrastructural study of somatotroph cells from mice bearing a fast growing transplanted hepatoma, in different periods of the tumor development.

The presence of a transplanted, fast-growing hepatoma (SS1-K) produces conspicuous ultrastructural changes in pituitary STH cells of C3H-S male mice. These changes are suggestive of an increased secretion of growth hormone only during the first stages of the tumor development. The hepatoma influence does not seem to be clearly related to the illumination regimen or time of killing.     

Group II metabotropic glutamate receptors and schizophrenia

Schizophrenia is one of the most common mental illnesses, with hereditary and environmental factors important for its etiology. All antipsychotics have in common a high affinity for monoaminergic receptors. Whereas hallucinations and delusions usually respond to typical (haloperidol-like) and atypical (clozapine-like) monoaminergic antipsychotics, their efficacy in improving negative symptoms and cognitive deficits remains inadequate. In addition, devastating side effects are a common characteristic of monoaminergic antipsychotics. Recent biochemical, preclinical and clinical findings support group II metabotropic glutamate receptors (mGluR2 and mGluR3) as a new approach to treat schizophrenia. This paper reviews the status of general knowledge of mGluR2 and mGluR3 in the psychopharmacology, genetics and neuropathology of schizophrenia