70 research outputs found
Optimal Freight Train Classification using Column Generation
Get PDFWe consider planning of freight train classification at hump yards using integer programming. The problem involves the formation of departing freight trains from arriving trains subject to scheduling and capacity constraints. To increase yard capacity, we allow the temporary storage of early freight cars on specific mixed-usage tracks. The problem has previously been modeled using a direct integer programming model, but this approach did not yield lower
bounds of sufficient quality to prove optimality. In this paper, we
formulate a new extended integer programming model and design a column generation approach based on branch-and-price to solve
problem instances of industrial size. We evaluate the method on
historical data from the Hallsberg hump yard in Sweden, and compare
the results with previous approaches. The new method managed to find
optimal solutions in all of the 192 problem instances tried. Furthermore, no instance took more than 13 minutes to solve
to optimality using fairly standard computer hardware
Fibroblast growth factor-regulated palmitoylation of the neural cell adhesion molecule determines neuronal morphogenesis
No full textDuring development of the nervous system, short- and long-range signals cooperate to promote axonal growth, guidance, and target innervation. Particularly, a short- range signal transducer, the neural cell adhesion molecule ( NCAM), stimulates neurite outgrowth via mechanisms that require posttranslational modification of NCAM and signaling via receptors to a long-range messenger, the fibroblast growth factor ( FGF). In the present study we further characterized a mechanism which regulates the functional interplay between NCAM and FGF receptor(s). We show that activation of FGF receptor( s) by FGF2 leads to palmitoylation of the two major transmembrane NCAM isoforms, NCAM140 and NCAM180, translocation of NCAM to GM1 ganglioside-containing lipid rafts, and stimulation of neurite outgrowth of hippocampal neurons. Ablation of NCAM, mutation of NCAM140 or NCAM180 palmitoylation sites, or pharmacological suppression of NCAM signaling inhibited FGF2-stimulated neurite outgrowth. Of the 23 members of the aspartate-histidine-histidine-cysteine (DHHC) domain containing proteins, DHHC-7 most strongly stimulated palmitoylation of NCAM, and enzyme activity was enhanced by FGF2. Thus, our study uncovers a molecular mechanism by which a growth factor regulates neuronal morphogenesis via activation of palmitoylation, which in turn modifies subcellular location and thus signaling via an adhesion molecule.Deutsche Forschungsgemeinschaft [PO 732/1-2
Regulation of G protein-activated inwardly rectifying potassium channels by the neural cell adhesion molecule NCAM
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Lumped impulses, discrete displacements and a moving load analysis
No full textFinite element models are usually presented as relations between lumped forces and discrete displacements. Mostly finite element models are found by the elaboration of the method of the virtual work - which is a special case of the Galerkin's variational principle -. By application of Galerkin's variational principle to time dependent problems, considering elements bordered by ge()metry and time b()undaries, we obtain relations between lumped impulses and discrete displacements. The analogy with respect to static models which formulates relati()ns between lumped forces and discrete displacements is striking. Models are formulated using linear and quadratic displacement fields with respect to time. Free model parameters are used to manipulate numerical stability, accuracy and numerical damping. These numerical tools are used for the numerical simulation ()f a m()ving vehicle at a rail track structure. The analysis sh()ws the natural way ()f m()delling a moving structure (the train) with respect to a fixed supporting structure (the rail track).Civil Engineering and Geoscience
The type IV mucolipidosis-associated protein TRPML1 is an endolysosomal iron release channel
Get PDFTRPML1 ( mucolipin 1, also known as MCOLN1) is predicted to be an intracellular late endosomal and lysosomal ion channel protein that belongs to the mucolipin subfamily of transient receptor potential ( TRP) proteins(1-3). Mutations in the human TRPML1 gene cause mucolipidosis type IV disease ( ML4)4,5.ML4 patients have motor impairment, mental retardation, retinal degeneration and iron- deficiency anaemia. Because aberrant iron metabolism may cause neural and retinal degeneration(6,7), it may be a primary cause of ML4 phenotypes. In most mammalian cells, release of iron from endosomes and lysosomes after iron uptake by endocytosis of Fe3+- bound transferrin receptors(6), or after lysosomal degradation of ferritin - iron complexes and autophagic ingestion of iron-containing macromolecules(6,8), is the chief source of cellular iron. The divalent metal transporter protein DMT1 ( also known as SLC11A2) is the only endosomal Fe2+ transporter known at present and it is highly expressed in erythroid precursors(6,9). Genetic studies, however, suggest the existence of a DMT1-independent endosomal and lysosomal Fe2+ transport protein(9). By measuring radiolabelled iron uptake, by monitoring the levels of cytosolic and intralysosomal iron and by directly patch- clamping the late endosomal and lysosomal membrane, here we show that TRPML1 functions as a Fe2+ permeable channel in late endosomes and lysosomes. ML4 mutations are shown to impair the ability of TRPML1 to permeate Fe2+ at varying degrees, which correlate well with the disease severity. A comparison of TRPML1(-/-) ML4 and control human skin fibroblasts showed a reduction in cytosolic Fe2+ levels, an increase in intralysosomal Fe2+ levels and an accumulation of lipofuscin- like molecules in TRPML1(-/-) cells. We propose that TRPML1 mediates a mechanism by which Fe2+ is released from late endosomes and lysosomes. Our results indicate that impaired iron transportmay contribute to both haematological and degenerative symptoms of ML4 patients.Department of Molecular, Cellular ; Developmental Biology and Biological Science Scholar Program ; University of MichiganThis work is supported by start-up funds to H. X. from the Department of Molecular, Cellular, and Developmental Biology and Biological Science Scholar Program, University of Michigan. We thank U. Brunk, M. Saito, R. Hume, C. Duan, M. Akaaboune, J. Kuwada, S. Low, S. Punthambaker and S. Dellal for assistance, and D. Clapham, N. Andrews, L. DeFelice, L. Yue, D. Ren, C. Jiang and S. Xu for comments on an earlier version of the manuscript. We also thank K. Kiselyov for sharing his unpublished results on lysosomal iron staining of ML4 cells. We appreciate the encouragement and helpful comments from other members of the Xu laboratory.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62672/1/nature07311.pd
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Ion channels and calcium signaling in motile cilia
No full textThe beating of motile cilia generates fluid flow over epithelia in brain ventricles, airways, and Fallopian tubes. Here, we patch clamp single motile cilia of mammalian ependymal cells and examine their potential function as a calcium signaling compartment. Resting motile cilia calcium concentration ([Ca2+] ~170 nM) is only slightly elevated over cytoplasmic [Ca2+] (~100 nM) at steady state. Ca2+ changes that arise in the cytoplasm rapidly equilibrate in motile cilia. We measured CaV1 voltage-gated calcium channels in ependymal cells, but these channels are not specifically enriched in motile cilia. Membrane depolarization increases ciliary [Ca2+], but only marginally alters cilia beating and cilia-driven fluid velocity within short (~1 min) time frames. We conclude that beating of ependymal motile cilia is not tightly regulated by voltage-gated calcium channels, unlike that of well-studied motile cilia and flagella in protists, such as Paramecia and Chlamydomonas. DOI: http://dx.doi.org/10.7554/eLife.11066.001Version of Recor
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