RAGE Mediates Accelerated Diabetic Vein Graft Atherosclerosis Induced by Combined Mechanical Stress and AGEs via Synergistic ERK Activation

Aims/Hypothesis: Diabetes with hypertension rapidly accelerates vascular disease, but the underlying mechanism remains unclear. We evaluated the hypothesis that the receptor of advanced glycation end products (RAGE) might mediate combined signals initiated by diabetes-related AGEs and hypertension-induced mechanical stress as a common molecular sensor. Methods: In vivo surgical vein grafts created by grafting vena cava segments from C57BL/6J mice into the common carotid arteries of streptozotocin (STZ)-treated and untreated isogenic mice for 4 and 8 weeks were analyzed using morphometric and immunohistochemical techniques. In vitro quiescent mouse vascular smooth muscle cells (VSMCs) with either knockdown or overexpression of RAGE were subjected to cyclic stretching with or without AGEs. Extracellular signalregulated kinase (ERK) phosphorylation and Ki-67 expression were investigated. Results: Significant increases in neointimal formation, AGE deposition, Ki-67 expression, and RAGE were observed in the vein grafts of STZ-induced diabetic mice. The highest levels of ERK phosphorylation and Ki-67 expression in VSMCs were induced by simultaneous stretch stress and AGE exposure. The synergistic activation of ERKs and Ki-67 in VSMCs was significantly inhibited by siRNA-RAGE treatment and enhanced by over-expression of RAGE. Conclusion: RAGE may mediate synergistically increased ERK activation and VSMC proliferation induced by mechanica

The Caenorhabditis elegans Gene mfap-1 Encodes a Nuclear Protein That Affects Alternative Splicing

RNA splicing is a major regulatory mechanism for controlling eukaryotic gene expression. By generating various splice isoforms from a single pre–mRNA, alternative splicing plays a key role in promoting the evolving complexity of metazoans. Numerous splicing factors have been identified. However, the in vivo functions of many splicing factors remain to be understood. In vivo studies are essential for understanding the molecular mechanisms of RNA splicing and the biology of numerous RNA splicing-related diseases. We previously isolated a Caenorhabditis elegans mutant defective in an essential gene from a genetic screen for suppressors of the rubberband Unc phenotype of unc-93(e1500) animals. This mutant contains missense mutations in two adjacent codons of the C. elegans microfibrillar-associated protein 1 gene mfap-1. mfap-1(n4564 n5214) suppresses the Unc phenotypes of different rubberband Unc mutants in a pattern similar to that of mutations in the splicing factor genes uaf-1 (the C. elegans U2AF large subunit gene) and sfa-1 (the C. elegans SF1/BBP gene). We used the endogenous gene tos-1 as a reporter for splicing and detected increased intron 1 retention and exon 3 skipping of tos-1 transcripts in mfap-1(n4564 n5214) animals. Using a yeast two-hybrid screen, we isolated splicing factors as potential MFAP-1 interactors. Our studies indicate that C. elegans mfap-1 encodes a splicing factor that can affect alternative splicing.National Natural Science Foundation (China) (Grant 30971639)United States. National Institutes of Health (Grant GM24663

Morphological diversity of single neurons in molecularly defined cell types.

Dendritic and axonal morphology reflects the input and output of neurons and is a defining feature of neuronal types1,2, yet our knowledge of its diversity remains limited. Here, to systematically examine complete single-neuron morphologies on a brain-wide scale, we established a pipeline encompassing sparse labelling, whole-brain imaging, reconstruction, registration and analysis. We fully reconstructed 1,741 neurons from cortex, claustrum, thalamus, striatum and other brain regions in mice. We identified 11 major projection neuron types with distinct morphological features and corresponding transcriptomic identities. Extensive projectional diversity was found within each of these major types, on the basis of which some types were clustered into more refined subtypes. This diversity follows a set of generalizable principles that govern long-range axonal projections at different levels, including molecular correspondence, divergent or convergent projection, axon termination pattern, regional specificity, topography, and individual cell variability. Although clear concordance with transcriptomic profiles is evident at the level of major projection type, fine-grained morphological diversity often does not readily correlate with transcriptomic subtypes derived from unsupervised clustering, highlighting the need for single-cell cross-modality studies. Overall, our study demonstrates the crucial need for quantitative description of complete single-cell anatomy in cell-type classification, as single-cell morphological diversity reveals a plethora of ways in which different cell types and their individual members may contribute to the configuration and function of their respective circuits

Improvement of microstructure and properties in twin-roll casting 7075 sheet by lower casting speed and compound field

Well-developed dendrites and severe macro and micro segregations in 7075 sheet produced by horizontal twin-roll casting (TRC) deteriorates the hot-workability and properties of the sheet, which makes an obstacle for the successful use of this technology. In this paper, lower casting speed and a pulsed electric-magnetostatic compound field are used to refine microstructure and abate segregation in TRC 7075 sheet. The dendrite arm space decreases from 20 ¿m to 8¿13 ¿m and the micro-segregation degree of Mg, Zn and Cu decreases when casting speed decreases from 1.5 m/min to 0.75 m/min. The center macro-segregation belt disappears in the 0.75 m/min sheet. The as-cast structure and the dendritic segregation in the 0.75 m/min sheet are further refined and abated respectively by the compound field. The secondary dendrite arm size decreases to 5¿8 ¿m in the field sheet. The 0.75 m/min sheet casted with the field shows better mechanical properties after homogenization and hot rolling. The optimization mechanism of lower casting speed and the field was discussed with the aid of classical solidification theory and electromagnetism

Stability Region Exploring of Shunt Active Power Filters Based on Output Admittance Modeling

A shunt active power filter (SAPF) is coupled with load admittance in weak grid conditions, which poses a challenge to stability analysis. In this article, the admittance model of the SAPF is developed, which reveals the coupling mechanism between SAPF and load concisely and accurately. On top of that, the stability region of the system is investigated. The passivity region of the load admittance to guarantee the system stability is first explored. However, the passivity region has a very narrowband at a specific frequency, which makes it difficult to achieve. The stability region is then studied and it turns out to be an extension of the passivity region, and especially the narrowband is expanded. Therefore, the stability region is much easier to meet. The stability-oriented design is then summarized in a flowchart. In the end, the effectiveness of the newly defined stability region is verified by experimental results.DC systems, Energy conversion & Storag