Systematic documentation and analysis of human genetic variation in hemoglobinopathies using the microattribution approach

We developed a series of interrelated locus-specific databases to store all published and unpublished genetic variation related to hemoglobinopathies and thalassemia and implemented microattribution to encourage submission of unpublished observations of genetic variation to these public repositories. A total of 1,941 unique genetic variants in 37 genes, encoding globins and other erythroid proteins, are currently documented in these databases, with reciprocal attribution of microcitations to data contributors. Our project provides the first example of implementing microattribution to incentivise submission of all known genetic variation in a defined system. It has demonstrably increased the reporting of human variants, leading to a comprehensive online resource for systematically describing human genetic variation in the globin genes and other genes contributing to hemoglobinopathies and thalassemias. The principles established here will serve as a model for other systems and for the analysis of other common and/or complex human genetic diseases.     

Fras1 deficiency results in cryptophthalmos,renal agenesis and blebbed phenotype in mice

Loss of tight association between epidermis and dermis underlies several blistering disorders and is frequently caused by impaired function of extracellular matrix (ECM) proteins. Here we describe a new protein in mouse, Fras1, that is specifically detected in a linear fashion underlying the epidermis and the basal surface of other epithelia in embryos. Loss of Fras1 function results in the formation of subepidermal hemorrhagic blisters as well as unilateral or bilateral renal agenesis during mouse embryogenesis. Postnatally, homozygous Fras1 mutants have fusion of the eyelids and digits and unilateral renal agenesis or dysplasia. The defects observed in Fras1-/- mice phenocopy those of the existing bl (blebbed) mouse mutants, which have been considered a model for the human genetic disorder Fraser syndrome. We show that bl/bl homozygous embryos are devoid of Fras1 protein, consistent with the finding that Fras1 is mutated in these mice. In sum, our data suggest that perturbations in the composition of the extracellular space underlying epithelia could account for the onset of the blebbed phenotype in mouse and Fraser syndrome manifestation in human.     

Are common fragile sites merely structural domains or highly organized “functional” units susceptible to oncogenic stress?

Common fragile sites (CFSs) are regions of the genome with a predisposition to DNA double-strand breaks in response to intrinsic (oncogenic) or extrinsic replication stress. CFS breakage is a common feature in carcinogenesis from its earliest stages. Given that a number of oncogenes and tumor suppressors are located within CFSs, a question that emerges is whether fragility in these regions is only a structural “passive” incident or an event with a profound biological effect. Furthermore, there is sparse evidence that other elements, like non-coding RNAs, are positioned with them. By analyzing data from various libraries, like miRbase and ENCODE, we show a prevalence of various cancer-related genes, miRNAs, and regulatory binding sites, such as CTCF within CFSs. We propose that CFSs are not only susceptible structural domains, but highly organized “functional” entities that when targeted, severe repercussion for cell homeostasis occurs.     

An inhibitor of Bcl-2 family proteins induces regression of solid tumours

Proteins in the Bcl-2 family are central regulators of programmed cell death, and members that inhibit apoptosis, such as Bcl-X(L) and Bcl-2, are overexpressed in many cancers and contribute to tumour initiation, progression and resistance to therapy. Bcl-X(L) expression correlates with chemo-resistance of tumour cell lines, and reductions in Bcl-2 increase sensitivity to anticancer drugs and enhance in vivo survival. The development of inhibitors of these proteins as potential anti-cancer therapeutics has been previously explored, but obtaining potent small-molecule inhibitors has proved difficult owing to the necessity of targeting a protein-protein interaction. Here, using nuclear magnetic resonance (NMR)-based screening, parallel synthesis and structure-based design, we have discovered ABT-737, a small-molecule inhibitor of the anti-apoptotic proteins Bcl-2, Bcl-X(L) and Bcl-w, with an affinity two to three orders of magnitude more potent than previously reported compounds. Mechanistic studies reveal that ABT-737 does not directly initiate the apoptotic process, but enhances the effects of death signals, displaying synergistic cytotoxicity with chemotherapeutics and radiation. ABT-737 exhibits single-agent-mechanism-based killing of cells from lymphoma and small-cell lung carcinoma lines, as well as primary patient-derived cells, and in animal models, ABT-737 improves survival, causes regression of established tumours, and produces cures in a high percentage of the mice.     

New records of rare deep-water fish species in the Eastern Ionian Sea (Mediterranean Sea)

We report new species records and information related to meristic, morphometric, bathymetric and biological characteristics that increase our knowledge of the deep ichthyofauna of the Ionian Sea (E. Mediterranean). The material was collected with long lines from 300 to 800 m deep in the Eastern Ionian Sea in June and October 2010. The fish species Schedophilus ovalis (Cuvier, 1833) (Osteichthyes: Centrolophidae), Sudis hyalina Rafinesque, 1810 (Osteicthyes: Paralepididae), Brama brama (Bonnaterre, 1788) (Osteichthyes: Bramidae) and Trachipterus trachypterus (Gmelin, 1789) (Osteichthyes: Trachipteridae) were recorded for the first time in the Eastern Ionian Sea. The absence of these new or rare species from the ichthyofauna of the study area to date is probably related to the absence of adequate sampling and catching techniques, although environmental factors could also be involved.     

Model Reference Adaptive Control for Networked Distributed Systems with Strong Interconnections and Communication Delays

In recent years, networked distributed control systems (NDCS) have received research attention. Two of the main challenges that such systems face are possible delays in the communication network and the effect of strong interconnections between agents. This paper considers an NDCS that has delays in the communication network, as well as strong interconnections between its agents. The control objective is to make each agent track efficiently a reference model by attenuating the effect of strong interconnections via feedback based on the delayed information. First, the authors assume that each agent knows its own dynamics, as well as the interconnection parameters, but receives information about the states of its neighbors with some communication delay. The authors propose a distributed control scheme and prove that if the interconnections can be weakened and if the communication delays are small enough, then the proposed scheme guarantees that the tracking error of each agent is bounded with a bound that depends on the size of the weakened interconnections and delays, and reduces to zero as these uncertainties reduce to zero. The authors then consider a more realistic situation where the interconnections between agents are unknown despite the cooperation and sharing of state information. For this case the authors propose a distributed adaptive control scheme and prove that the proposed scheme guarantees that the tracking errors are bounded and small in the mean square sense with respect to the size of the weakened interconnections and delays, provided the weakened interconnections and time delays are small enough. The authors then consider the case that each agent knows neither its dynamics nor the interconnection matrices. For this case the authors propose a distributed adaptive control scheme and prove that the proposed scheme guarantees that the tracking errors are bounded and small in the mean square sense provided the weakened interconnections and time delays are small enough. Finally, the authors present an illustrative example to present the applicability and effectiveness of the proposed schemes.     

Positional identification of TNFSF4, encoding OX40 ligand, as a gene that influences atherosclerosis susceptibility

Ath1 is a quantitative trait locus on mouse chromosome 1 that renders C57BL/6 mice susceptible and C3H/He mice resistant to diet-induced atherosclerosis. The quantitative trait locus region encompasses 11 known genes, including Tnfsf4 (also called Ox40l or Cd134l), which encodes OX40 ligand. Here we report that mice with targeted mutations of Tnfsf4 had significantly (P 相似文献