Residual Cx45 and its relationship to Cx43 in murine ventricular myocardium

Gap junction channels in ventricular myocardium are required for electrical and metabolic coupling between cardiac myocytes and for normal cardiac pump function. Although much is known about expression patterns and remodeling of cardiac connexin (Cx)43, little is known about the less abundant Cx45, which is required for embryonic development and viability, is downregulated in adult hearts, and is pathophysiologically upregulated in human end-stage heart failure. We applied quantitative immunoblotting and immunoprecipitation to native myocardial extracts, immunogold electron microscopy to cardiac tissue and membrane sections, electrophysiological recordings to whole hearts, and high-resolution tandem mass spectrometry to Cx45 fusion protein, and developed two new tools, anti-Cx45 antisera and Cre(+);Cx45 floxed mice, to facilitate characterization of Cx45 in adult mammalian hearts. We found that Cx45 represents 0.3% of total Cx protein (predominantly 200 fmol Cx43 protein/µg ventricular protein) and colocalizes with Cx43 in native ventricular gap junctions, particularly in the apex and septum. Cre(+);Cx45 floxed mice express 85% less Cx45, but do not exhibit overt electrophysiologic abnormalities. Although the basal phosphorylation status of native Cx45 remains unknown, CaMKII phosphorylates eight Ser/Thr residues in Cx45 in vitro. Thus, although downregulation of Cx45 does not produce notable deficits in electrical conduction in adult, disease-free hearts, Cx45 is a target of the multifunctional kinase CaMKII, and the phosphorylation status of Cx45 and the role of Cx43/Cx45 heteromeric gap junction channels in both normal and diseased hearts merits further investigation

Conserved molecular interactions in centriole-to-centrosome conversion.

Centrioles are required to assemble centrosomes for cell division and cilia for motility and signalling. New centrioles assemble perpendicularly to pre-existing ones in G1-S and elongate throughout S and G2. Fully elongated daughter centrioles are converted into centrosomes during mitosis to be able to duplicate and organize pericentriolar material in the next cell cycle. Here we show that centriole-to-centrosome conversion requires sequential loading of Cep135, Ana1 (Cep295) and Asterless (Cep152) onto daughter centrioles during mitotic progression in both Drosophila melanogaster and human. This generates a molecular network spanning from the inner- to outermost parts of the centriole. Ana1 forms a molecular strut within the network, and its essential role can be substituted by an engineered fragment providing an alternative linkage between Asterless and Cep135. This conserved architectural framework is essential for loading Asterless or Cep152, the partner of the master regulator of centriole duplication, Plk4. Our study thus uncovers the molecular basis for centriole-to-centrosome conversion that renders daughter centrioles competent for motherhood.J.F., Z.L., S.S. and N.S.D. are supported from Programme Grant to D.M.G. from Cancer Research UK. H.R. is supported from MRC Programme Grant to D.M.G. J.F. thank the British Academy and the Royal Society for Newton International Fellowship and Z.L. thanks the Federation of European Biochemical Societies for the Long-Term postdoctoral Fellowship. The authors thank Nicola Lawrence and Alex Sossick for assistance with 3D-SIM.This is the author accepted manuscript. The final version is available from NPG via http://dx.doi.org/10.1038/ncb327

Stochastic Expression of the Interferon-β Gene

The analysis of stochastic interferon-beta gene expression in virus-infected mammalian cells reveals that the levels of components required for virtually every step in the virus induction pathway are limiting

Role of Scrib and Dlg in anterior-posterior patterning of the follicular epithelium during Drosophila oogenesis

<p>Abstract</p> <p>Background</p> <p>Proper patterning of the follicle cell epithelium over the egg chamber is essential for the <it>Drosophila </it>egg development. Differentiation of the epithelium into several distinct cell types along the anterior-posterior axis requires coordinated activities of multiple signaling pathways. Previously, we reported that <it>lethal(2)giant larvae </it>(<it>lgl</it>), a <it>Drosophila </it>tumor suppressor gene, is required in the follicle cells for the posterior follicle cell (PFC) fate induction at mid-oogenesis. Here we explore the role of another two tumor suppressor genes, <it>scribble </it>(<it>scrib</it>) and <it>discs large </it>(<it>dlg</it>), in the epithelial patterning.</p> <p>Results</p> <p>We found that removal of <it>scrib </it>or <it>dlg </it>function from the follicle cells at posterior terminal of the egg chamber causes a complete loss of the PFC fate. Aberrant specification and differentiation of the PFCs in the mosaic clones can be ascribed to defects in coordinated activation of the EGFR, JAK and Notch signaling pathways in the multilayered cells. Meanwhile, the clonal analysis revealed that loss-of-function mutations in <it>scrib/dlg </it>at the anterior domains result in a partially penetrant phenotype of defective induction of the stretched and centripetal cell fate, whereas specification of the border cell fate can still occur in the most anterior region of the mutant clones. Further, we showed that <it>scrib </it>genetically interacts with <it>dlg </it>in regulating posterior patterning of the epithelium.</p> <p>Conclusion</p> <p>In this study we provide evidence that <it>scrib </it>and <it>dlg </it>function differentially in anterior and posterior patterning of the follicular epithelium at oogenesis. Further genetic analysis indicates that <it>scrib </it>and <it>dlg </it>act in a common pathway to regulate PFC fate induction. This study may open another window for elucidating role of <it>scrib/dlg </it>in controlling epithelial polarity and cell proliferation during development.</p

Multicriteria Scalable Graph Drawing via Stochastic Gradient Descent, (SGD)^2

Readability criteria, such as distance or neighborhood preservation, are often used to optimize node-link representations of graphs to enable the comprehension of the underlying data. With few exceptions, graph drawing algorithms typically optimize one such criterion, usually at the expense of others. We propose a layout approach, Multicriteria Scalable Graph Drawing via Stochastic Gradient Descent, (SGD)^2, that can handle multiple readability criteria. (SGD)^2 can optimize any criterion that can be described by a differentiable function. Our approach is flexible and can be used to optimize several criteria that have already been considered earlier (e.g., obtaining ideal edge lengths, stress, neighborhood preservation) as well as other criteria which have not yet been explicitly optimized in such fashion (e.g., node resolution, angular resolution, aspect ratio). The approach is scalable and can handle large graphs. A variation of the underlying approach can also be used to optimize many desirable properties in planar graphs, while maintaining planarity. Finally, we provide quantitative and qualitative evidence of the effectiveness of (SGD)^2: we analyze the interactions between criteria, measure the quality of layouts generated from (SGD)^2 as well as the runtime behavior, and analyze the impact of sample sizes. The source code is available on github and we also provide an interactive demo for small graphs.National Science FoundationImmediate accessThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

High-Dimensional Feature Selection Based on Improved Binary Ant Colony Optimization Combined with Hybrid Rice Optimization Algorithm

In the realm of high-dimensional data analysis, numerous fields stand to benefit from its applications, including the biological and medical sectors that are crucial for computer-aided disease diagnosis and prediction systems. However, the presence of a significant number of redundant or irrelevant features can adversely affect system accuracy and real-time diagnosis efficiency. To mitigate this issue, this paper proposes two innovative wrapper feature selection (FS) methods that integrate the ant colony optimization (ACO) algorithm and hybrid rice optimization (HRO). HRO is a recently developed metaheuristic that mimics the breeding process of the three-line hybrid rice, which is yet to be thoroughly explored in the context of solving high-dimensional FS problems. In the first hybridization, ACO is embedded as an evolutionary operator within HRO and updated alternately with it. In the second form of hybridization, two subpopulations evolve independently, sharing the local search results to assist individual updating. In the initial stage preceding hybridization, a problem-oriented heuristic factor assignment strategy based on the importance of the knee point feature is introduced to enhance the global search capability of ACO in identifying the smallest and most representative features. The performance of the proposed algorithms is evaluated on fourteen high-dimensional biomedical datasets and compared with other recently advanced FS methods. Experimental results suggest that the proposed methods are efficient and computationally robust, exhibiting superior performance compared to the other algorithms involved in this study