TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis

Recently, TDP-43 was identified as a key component of ubiquitinated aggregates in amyotrophic lateral sclerosis (ALS), an adult-onset neurological disorder that leads to the degeneration of motor neurons. Here we report eight missense mutations in nine individuals--six from individuals with sporadic ALS (SALS) and three from those with familial ALS (FALS)--and a concurring increase of a smaller TDP-43 product. These findings further corroborate that TDP-43 is involved in ALS pathogenesis.     

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.     

Mutations in LRP2, which encodes the multiligand receptor megalin, cause Donnai-Barrow and facio-oculo-acoustico-renal syndromes

Donnai-Barrow syndrome is associated with agenesis of the corpus callosum, congenital diaphragmatic hernia, facial dysmorphology, ocular anomalies, sensorineural hearing loss and developmental delay. By studying multiplex families, we mapped this disorder to chromosome 2q23.3-31.1 and identified LRP2 mutations in six families with Donnai-Barrow syndrome and one family with facio-oculo-acoustico-renal syndrome. LRP2 encodes megalin, a multiligand uptake receptor that regulates levels of diverse circulating compounds. This work implicates a pathway with potential pharmacological therapeutic targets.     

Free Knot Splines for Supervised Classification

Data in many different fields come to practitioners through a process naturally described as functional. We propose a classification procedure of oxidation curves. Our algorithm is based on two stages: fitting the functional data by linear splines with free knots and classifying the estimated knots which estimate useful oxidation parameters. A real data set on 57 oxidation curves is used to illustrate our approach.     

实变函数基本理论

本书是法国布巴基学派编写的《数学基础》系列丛书中的一本，按1976年法文版英译。这套丛书对于法国数学和数学教育的发展起了推动作用，在国际数学界也有一定影响。本书介绍了一元函数微积分的基本理论。     

Predictive models of molecular machines involved in Caenorhabditis elegans early embryogenesis

Although numerous fundamental aspects of development have been uncovered through the study of individual genes and proteins, system-level models are still missing for most developmental processes. The first two cell divisions of Caenorhabditis elegans embryogenesis constitute an ideal test bed for a system-level approach. Early embryogenesis, including processes such as cell division and establishment of cellular polarity, is readily amenable to large-scale functional analysis. A first step toward a system-level understanding is to provide 'first-draft' models both of the molecular assemblies involved and of the functional connections between them. Here we show that such models can be derived from an integrated gene/protein network generated from three different types of functional relationship: protein interaction, expression profiling similarity and phenotypic profiling similarity, as estimated from detailed early embryonic RNA interference phenotypes systematically recorded for hundreds of early embryogenesis genes. The topology of the integrated network suggests that C. elegans early embryogenesis is achieved through coordination of a limited set of molecular machines. We assessed the overall predictive value of such molecular machine models by dynamic localization of ten previously uncharacterized proteins within the living embryo.     

Is the process of localized lysosomal exocytosis responsible for the cytolytic action of killer T-lymphocytes?]

In this paper, we formulate the hypothesis that in the process of target cell lysis a lysosomal enzyme regurgitation, performed by killer cells at the level of the target effector junction, accounts for the target lesion which precedes the lysis (lethal hit). This process of exocytosis, similar to the one described previously in polymorphonuclear neutrophils is supported by cytological studies performed directly on identified killers isolated by micromanipulation. Light and electron microscopy observations confirm a previous report which describes the effector cells rich in lysosomal bodies. In addition, when a killer cell is associated with a target cell to form a conjugate, lysosomes are concentrated near the cell junction and, after incubation at 37 degrees C, acid phosphatases may be detected at the junction. Lysosomal enzyme exocytosis explains why target lysis needs an effector target binding to occur and also the other conditions required for any exocytosis process such as Ca++ in the medium, integrity of the microtubular apparatus, a low level of cyclic AMP and energy dependancy.     

Presence of a protein disulfide isomerase (EC 5.3.4.1) in wheat germ]

The presence of a protein disulfide isomerase (rearrangease) in wheat embryo has been demonstrated by its ability in reactivating randomly cross-linked ribonuclease. This activity requires a dialysable cofactor; after dialysis, the activity is recovered by addition of reduced glutathione. The enzyme can be precipitated by 70% saturation ammonium sulfate.