Vps13-like proteins provide phosphatidylethanolamine for GPI anchor synthesis in the ER

Glycosylphosphatidylinositol (GPI) is a glycolipid membrane anchor found on surface proteins in all eukaryotes. It is synthesized in the ER membrane. Each GPI anchor requires three molecules of ethanolamine phosphate (P-Etn), which are derived from phosphatidylethanolamine (PE). We found that efficient GPI anchor synthesis in Saccharomyces cerevisiae requires Csf1; cells lacking Csf1 accumulate GPI precursors lacking P-Etn. Structure predictions suggest Csf1 is a tube-forming lipid transport protein like Vps13. Csf1 is found at contact sites between the ER and other organelles. It interacts with the ER protein Mcd4, an enzyme that adds P-Etn to nascent GPI anchors, suggesting Csf1 channels PE to Mcd4 in the ER at contact sites to support GPI anchor biosynthesis. CSF1 has orthologues in Caenorhabditis elegans (lpd-3) and humans (KIAA1109/TWEEK); mutations in KIAA1109 cause the autosomal recessive neurodevelopmental disorder Alkuraya-Kučinskas syndrome. Knockout of lpd-3 and knockdown of KIAA1109 reduced GPI-anchored proteins on the surface of cells, suggesting Csf1 orthologues in human cells support GPI anchor biosynthesis.

Stability Analysis of Steel Welded Tubes Forming Process Using Numerical Simulations

In this paper, the research results of the stability of steel welded tubes forming process are presented. The aim of this research is to determine influence of geometrical and tribological parameters on stability of the process and to determine optimal values of influential process parameters. A research plan with variation of influential parameters was made, on the basis of which experimental and numerical experiments were performed. Tube forming was performed in one operation in a two-part tool made of hard metal by a combination of widening and narrowing. The geometrical factors observed during experiments are length, outer diameter and thicknesses of steel welded tube as a billet. Friction conditions in contact between tool and tubular workpiece are considered in two cases, the first one when standard machine oil is used as a lubricant and the second one when tube billet surface is phosphated. Based on results of experiments, influencing factors on stability of tube forming process were analysed and optimal production technology was recommended, including optimal values of influencing factors. Results obtained by experimental research were confirmed through numerical experiments based on finite element method.

Sequence-Defined Nanotubes Assembled from IR780-Conjugated Peptoids for Chemophototherapy of Malignant Glioma

Near-infrared (NIR) laser-induced phototherapy through NIR agents has demonstrated the great potential for cancer therapy. However, insufficient tumor killing due to the nonuniform heat or cytotoxic singlet oxygen (1O2) distribution over tumors from phototherapy results in tumor recurrence and inferior outcomes. To achieve high tumor killing efficacy, one of the solutions is to employ the combinational treatment of phototherapy with other modalities, especially with chemotherapeutic agents. In this paper, a simple and effective multimodal therapeutic system was designed via combining chemotherapy, photothermal therapy (PTT), and photodynamic therapy (PDT) to achieve the polytherapy of malignant glioma which is one of the most aggressive tumors in the brain. IR-780 (IR780) dye-labeled tube-forming peptoids (PepIR) were synthesized and self-assembled into crystalline nanotubes (PepIR nanotubes). These PepIR nanotubes showed an excellent efficacy for PDT/PTT because the IR780 photosensitizers were effectively packed and separated from each other within crystalline nanotubes by tuning IR780 density; thus, a self-quenching of these IR780 molecules was significantly reduced. Moreover, the efficient DOX loading achieved due to the nanotube large surface area contributed to an efficient and synergistic chemotherapy against glioma cells. Given the unique properties of peptoids and peptoid nanotubes, we believe that the developed multimodal DOX-loaded PepIR nanotubes in this work offer great promises for future glioma therapy in clinic.

Cold Forging Effect on the Microstructure of Motorbike Shock Absorbers Fabricated by Tube Forming in a Closed Die

Motorbike shock absorbers made with a closed die employ a tube-forming process that is more sensitive than that of a solid billet, because the tube is usually too thin-walled to conserve material. During tube forming, defects such as folding and cracking occur due to unstable tube forming and abnormal material flow. It is therefore essential to understand the relationship between the appearance of defects and the number of forming steps to optimize technological parameters. Based on both finite element method (FEM) simulations and microstructural observations, we demonstrate the important role of the number and methodology of the forming steps on the material flow, defects, and metal fiber anisotropy of motorbike shock absorbers formed from a thin-walled tube. We find limits of the thickness and height ratios of the tube that must be held in order to avoid defects. Our study provides an important guide to workpiece and processing design that can improve the forming quality of products using tube forming.

Reciprocal Antagonism between MicroRNA-138 and SIRT1 and Its Implications for the Angiogenesis of Endothelial Cells

MicroRNAs and sirtuins are important epigenetic regulators of gene expression and both contribute significantly to postnatal vascular development. However, the crosstalk between miRNAs and sirtuins in the modulation of angiogenesis has rarely been discussed. Here, we investigated the interactions between miR-138 and sirtuins in the process of angiogenesis. We found that overexpression of miR-138 markedly suppressed the proliferation, migration, and tube-forming capacities of the endothelial cells. And, miR-138 inhibitor-treated endothelial cells showed a reversed phenotype. Furthermore, miR-138 plays a negative role in vascular development in vivo. Western blot and qPCR assays demonstrated that SIRT1 was silenced by miR-138, and a luciferase reporter assay showed that miR-138 bound to the 3′-UTR of SIRT1. The re-expression of SIRT1 alleviated miR-138-mediated suppression of angiogenesis. Furthermore, silencing SIRT1 could boost the level of miR-138. And, upon miR-138 inhibitor treatment, SIRT1 silencing no longer reduced the angiogenic ability of endothelial cells significantly. These results demonstrated that the circuitry involving miR-138 and SIRT1 may participate in vascular homeostasis and also offered the possibility of identifying a new approach in the treatment of angiogenic diseases.