595 research outputs found
Axon guidance receptors: Endocytosis, trafficking and downstream signaling from endosomes
No full textDuring the development of the nervous system, axons extend through complex environments. Growth cones at the axon tip allow axons to find and innervate their appropriate targets and form functional synapses. Axon pathfinding requires axons to respond to guidance signals and these cues need to be detected by specialized receptors followed by intracellular signal integration and translation. Several downstream signaling pathways have been identified for axon guidance receptors and it has become evident that these pathways are often initiated from intracellular vesicles called endosomes. Endosomes allow receptors to traffic intracellularly, re-locating receptors from one cellular region to another. The localization of axon guidance receptors to endosomal compartments is crucial for their function, signaling output and expression levels. For example, active receptors within endosomes can recruit downstream proteins to the endosomal membrane and facilitate signaling. Also, endosomal trafficking can re-locate receptors back to the plasma membrane to allow re-activation or mediate downregulation of receptor signaling via degradation. Accumulating evidence suggests that axon guidance receptors do not follow a pre-set default trafficking route but may change their localization within endosomes. This re-routing appears to be spatially and temporally regulated, either by expression of adaptor proteins or co-receptors. These findings shed light on how signaling in axon guidance is regulated and diversified - a mechanism which explains how a limited set of guidance cues can help to establish billions of neuronal connections. In this review, we summarize and discuss our current knowledge of axon guidance receptor trafficking and provide directions for future research
Neuronal Subset-Specific Migration and Axonal Wiring Mechanisms in the Developing Midbrain Dopamine System
No full textThe midbrain dopamine (mDA) system is involved in the control of cognitive and motor behaviors, and is associated with several psychiatric and neurodegenerative diseases. mDA neurons receive diverse afferent inputs and establish efferent connections with many brain areas. Recent studies have unveiled a high level of molecular and cellular heterogeneity within the mDA system with specific subsets of mDA neurons displaying select molecular profiles and connectivity patterns. During mDA neuron development, molecular differences between mDA neuron subsets allow the establishment of subset-specific afferent and efferent connections and functional roles. In this review, we summarize and discuss recent work defining novel mDA neuron subsets based on specific molecular signatures. Then, molecular cues are highlighted that control mDA neuron migration during embryonic development and that facilitate the formation of selective patterns of efferent connections. The review focuses largely on studies that show differences in these mechanisms between different subsets of mDA neurons and for which in vivo data is available, and is concluded by a section that discusses open questions and provides directions for further research
Kinetic and spectroscopic characterization of the putative monooxygenase domain of human MICAL-1
No full textComposite Floors: A Theoretical Research into the Design of Steel-Concrete Composite Floors with a Bigger Unpropped Span of 7.2 m
No full textIn the Netherlands buildings are designed using a grid with multiples of 3.6 meter. Within these designs floor spans of 7.2 meter are popular (double grid size). The deep decks of composite floors at this moment in time are designed to reach an unpropped span of 5.5 meter. This master research is focused on finding a possible deck design for a steel-concrete composite floor slab that can span 7.2 m and that is constructed without the need of temporary supports. This resulted in the JorFlor, a light-weight, big span steel-concrete composite floor that can compete with current floor systems.Design & ConstructionStructural EngineeringCivil Engineering and Geoscience
Tensile-compression ring: A study for football stadia roof structures
No full textIntroduction A tensile-compression ring structure is derived from the spoke wheel principle. The general shape of the ground plan of a regular football stadium, which is more oval or rectangular shaped, is in contradiction with the spoke wheel principle. The goal of the thesis is to investigate the use and attractiveness of the spoke wheel principle for football stadia Research The thesis consists of an analysis and design component. The spoke wheel principle for the use for bicycles and for roof structures have been analysed. By designing a roof structure more insight is gained and conclusions can be made regarding the use of the spoke wheel roof structures for football stadia. Analysis The strength and stiffness of the wheel depends on the amount of ring action in the structure. When a tensile load acts on the ring, the ring becomes compressed and ring action arises. This principle can be applied for roof structures. The more ring action can be provided, the more efficient the roof structure will become and more material will be saved. The amount of ring action in a spoke wheel depends on four key factors: strength of the ring, loads, translation and curvature. To come to a design, the influence of different design variables on the key factors have been investigated. Design For the study of the use of the spoke wheel principle for stadia roof structure, two types of roof structures are investigated: Non-pretensioned spokes In a spatial truss system beam action will play an important role in the total stiffness of the roof structure. By directly transporting the loads to the ring elements that possess sufficient curvature, the ring action is used at full extend. The results confirm that the efficiency of the structure increases. By optimizing each single element in the roof structure, using parametric modelling, a lot of material can be saved. Pretensioned spokes A cable structure is not able to provide stiffness by beam action. The stiffness of the roof structure depends on the amount of ring action in the structure. The results showed that the reference stadium possess not enough curvature to provide an efficient spoke wheel roof by means of a cable structure. Further research is needed to use the available ring action at a greater extend for cable roof structures. Conclusion Research showed that a spoke wheel roof structure is an attractive type of structure for stadia use. The amount of curvature in the roof is crucial whether it is possible to come to an efficient structural design. When there is a lack of curvature a spatial truss structure is able to provide extra stiffness to the roof. Cable structures are very dependent from ring action, it is advised to use this type of structure only for roofs that possess curvature in the complete roof. To increase the application of the cable roof structure more research is needed.Structural EngineeringCivil Engineering and Geoscience
Bio-based Railway Canopy: Application of bio-based building materials in canopies of railway stations
No full textBackground Consumption of materials is an always ongoing process. In the linear economy, or a ‘take-make-dispose’ consumption pattern there is no attention for the rest value of products. The circular economy and bio-based economy introduce that loop-back for materials at the end of their lifetime. This research is about the application of bio-based building materials in railway canopies. Problem definition Bio-based building materials are competing with the fossil- and mineral-based building materials. With the growing consumption of materials and the fact of limited availability of some materials the demand for bio-based materials is growing. But which materials (bio-based materials domain) are available and how do regulations allow the use of this materials (design domain)? Research In this research is investigated what bio-based materials are and how they could be applicated in the railway sector. In the case study is focused is on the design of a railway canopy for railway station Ede-Wageningen. The three main steps taken in the process are: (1) In the literature study the boundary conditions of the bio-based materials, bio-based economy and design rules of ProRail (Dutch railinfrastructure management organisation) are taken to define the domains. A material selection strategy is described to use these boundary condition in material selection. (2) The case is analysed and three railway canopy concepts are designed. One concept is worked out in a parametric model to make also the material selection a parameter in the design. (3) Materials are selected with the material selection strategy and the design is optimized. The consequences of the chosen materials for this design are worked out and a compared with other structural materials. Conclusions (1) Bio-based are these materials that have a renewable origin, that are not faster consumed then produced and that are taken from properly managed agriculture or forests. (2) Design rules of ProRail are currently limiting the use of bio-based materials in railway canopies. (3) The application of bio-based materials in railway canopies is possible. (4) Timber is the only bio-based materials that can be applied without strange safety factors. (5) Conservation of almost all bio-based materials is necessary but depends on climate conditions. (6) To achieve a life time of more than 20 years thorough life prolonging maintenance can be necessary. (7) Because of the CO2 consumption of crops and wood, the relative CO2 consumption of a building can be reduced by using bio-based materials. Recommendations (1) Research materials and develop design and calculation rules to make new bio-based materials competitive to other building materials. (2) Research the environmental effects of bio-based materials to make them comparable with other building materials.Building Engineering / Structural DesignStructural EngineeringCivil Engineering and Geoscience
Analysis of drainage system in Georgetown, Guyana
No full textIn 2015 Georgetown, Guyana suffered from major flooding due to heavy rainfall. The use of a centuries-old agricultural drainage system for the urban drainage of the largest urbanized area of Guyana, poses problems considering flood safety. In 2016 a report was published by a ‘Dutch Risk Reduction Team’ (DRR Team) with recommendations on how to reduce the current flood vulnerability. Based on the recommendations from this DRR report. A team of seven students from the Delft University of Technology, the Netherlands, went to Georgetown and analysed the drainage system in more detail. Several methods were developed in collaboration with local students and experts which can be used to analyse the system. This was done to increase the local capability of knowledge-based decision making on drainage issues in Guyana. This student’s induced project comprises three elements of the urban drainage system: the primary drainage channels, the local (secondary and tertiary) drainage canals, and the outlet structures. The work focussed primarily on the catchment area named South-Ruimveldt.Civil Engineering and GeosciencesHydraulic Engineering / Structural EngineeringMaster project repor
A Parametric Structural Design Tool (Grasshopper Interface) for Plate Structures
No full textThe thesis presents a parametric design tool for plate structural analysis. The goal of the thesis is to establish a real-time visualized program for structural calculation and to make it parameterized. The tool is based on a visualized drawing program Rhino with Grasshopper plug-in to generate the parametric environment for the plate structural analysis. The solution of plate analysis is computed by membrane analogy. Followed by rain-flow analysis, the relation between shear force flows and the structural geometry is presented. Two computational programs will be introduced. One is out-of-plane tool; the other is for in-plane calculation.Structural and Building EngineeringStructural EngineeringCivil Engineering and Geoscience
Mutations in MICAL-1cause autosomal-dominant lateral temporal epilepsy
No full textObjective: Autosomal-dominant lateral temporal epilepsy (ADLTE) is a genetic focal epilepsy characterized by auditory symptoms. Two genes, LGI1 and RELN, encoding secreted proteins, are implicated in the etiology of ADLTE, but half of the affected families remain genetically unsolved, and the underlying molecular mechanisms are yet to be clarified. We aimed to identify additional genes causing ADLTE to better understand the genetic basis and molecular pathway underlying this epileptic disorder. Methods: A cohort of Italian ADLTE families was examined by whole exome sequencing combined with genome-wide single-nucleotide polymorphism-array linkage analysis. Results: We identified two ADLTE-causing variants in the MICAL-1 gene: a p.Gly150Ser substitution occurring in the enzymatically active monooxygenase (MO) domain and a p.Ala1065fs frameshift indel in the C-terminal domain, which inhibits the oxidoreductase activity of the MO domain. Each variant segregated with ADLTE in a single family. Examination of candidate variants in additional genes excluded their implication in ADLTE. In cell-based assays, both variants significantly increased MICAL-1 oxidoreductase activity and induced cell contraction in COS7 cells, which likely resulted from deregulation of F-actin dynamics. Interpretation: MICAL-1 oxidoreductase activity induces disassembly of actin filaments, thereby regulating the organization of the actin cytoskeleton in developing and adult neurons and in other cell types. This suggests that dysregulation of the actin cytoskeleton dynamics is a likely mechanism by which MICAL-1 pathogenic variants lead to ADLTE. Ann Neurol 2018;83:483–493
Kinetic and spectroscopic characterization of the putative monooxygenase domain of human MICAL-1
No full textMICALs form a conserved multidomain protein family essential for cytoskeletal rearrangements. To complement structural information available, we produced the FAD-containing monooxygenase-like domain of human MICAL-1 (MICAL-MO) in forms differing for the presence and location of a His-tag, which only influences the protein yields. The K(m) for NADPH of the NADPH oxidase reaction is sensitive to ionic strength and type of ions. The apparent k(cat) (pH 7) is limited by enzyme reduction by NADPH, which occurs without detectable intermediates, as established by anaerobic rapid reaction experiments. The sensitivity to ionic strength and type of ions and the pH dependence of the steady-state kinetic parameters extend MICAL-MO similarity with enzymes of the p-hydroxybenzoate hydroxylase class at the functional level. The reaction is also sensitive to solvent viscosity, providing a tool to monitor the conformational changes predicted to occur during turnover. Finally, it was confirmed that MICAL-MO promotes actin depolymerization, and it was shown that F-actin, but not G-actin, stimulates NADPH oxidation by increasing k(cat) and k(cat)/K(NADPH) (approximate to 15 and approximate to.200-fold, respectively) with an apparent K(m) for actin of 4.7 mu M, under conditions that stabilize F-actin. The time-course of NADPH oxidation shows substrate recycling, indicating the possible reversibility of MICAL effect
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