Milk Run Design: Definitions, Concepts and Solution Approaches

Efficient inbound networks in the European automotive industry rely on a set of different transport concepts including milk runs - understood as regularly scheduled pickup tours. The complexity of designing such a mixed network makes decision support necessary: In this book we provide definitions, mathematical models and a solution method for the Milk Run Design problem and introduce indicators assessing the performance of established milk runs in relation to alternative transport concepts

Milk Run Design: Definitions, Concepts and Solution Approaches

Efficient inbound networks in the European automotive industry rely on a set of different transport concepts including milk runs - understood as regularly scheduled pickup tours. The complexity of designing such a mixed network makes decision support necessary: In this thesis we provide definitions, mathematical models and a solution method for the Milk Run Design problem and introduce indicators assessing the performance of established milk runs in relation to alternative transport concepts

Stellar Clusters in NGC 1313: Evidence for Infant Mortality

We present evidence that infant mortality of stellar clusters is likely to be a major and very efficient process for the dissolution of young clusters in the spiral galaxy NGC 1313. Performing stellar PSF photometry on archival HST/ACS images of the galaxy, we find that a large fraction of early B-type stars are seen outside of star clusters and well spread within the galactic disk, consistent with the scenario of infant mortality. We also calculate the UV flux produced by the stars in and out the clusters and find that 75 to 90% of the UV flux in NGC 1313 is produced by stars outside the clusters. These results suggest that the infant mortality of star clusters is probably the underlying cause of the diffuse UV emission in starburst galaxies. Infant mortality would also explain the numerous B-type stars observed in the background field of our Galaxy as well. We exclude the possibility that unresolved low-mass star clusters and scaled OB associations might be the main source for the diffuse UV emission.Comment: 5 pages, 3 figures, accepted for publication in the Astrophysical Journal Letter

Partnerships for skills training in the care home sector

Aim: This paper describes an initiative in North East London that aimed to facilitate access to training for care-home staff by using a mobile skills-centre in the form of an adapted bus. Background: It has proved difficult to take a strategic approach to quality assurance in care homes and the first comprehensive national training strategy for the sector was not published until 2000. Staff value and benefit from training, but organizing the provision of education and training may be problematic, given resource constraints and staffing levels that make it difficult to release staff to go off-site. Method: Collaboration between the School of Community and Health Sciences, City University London; My Home Life, an initiative led by Help the Aged in collaboration with the National Care Forum and City University London; local care homes; local primary care trusts (PCTs); and the Centre for Excellence in Teaching and Learning at City University London and Queen Mary University of London. The project involved facilitation, training in the mobile skills-centre and evaluation through questionnaires. Findings: The project was successful at a number of different levels: providing training to care-home staff; fostering collaborative relationships between care homes and PCTs; providing a forum to enable a wider educational discussion of care-home needs; and stimulating the planning of future education programmes for care-home staff and of the provision in care homes of student nurse placements

Intracellular signaling cascades in the dopaminergic specification of fetal mesencephalic neural progenitor cells.

Neural stem (progenitor) cells (NPCs) from fetal tissue are an ideal transplantable cell source. They divide rapidly, are able to generate cells of all three neural lineages and do not divide uncontrolled once transplanted into a host organism. To obtain large quantities of cells for transplantation strategies and to eliminate primary cell contaminations, long periods of in vitro cultivation are necessary. Mouse NPCs are a crucial tool for further investigations of neural stem cells because they make the employment of transgenic animals in vivo and cells in vitro possible. So far only short-term expanded fetal mouse NPCs have been shown to generate dopaminergic neurons and it is not clear whether this was due to differentiation or a result of increased survival of primary dopaminergic neurons. The aims of the thesis were to characterize mouse fetal NPCs, to establish the long-term expansion of fetal mouse NPCs and the generation of dopaminergic neurons in long-term expanded fetal mouse NPCs, to investigate the signaling mechanisms involved in the differentiation of mouse fetal NPCs towards the dopaminergic phenotype and to compare short and long-term expanded NPCs. Long-term expanded fetal mesencephalic NPCs could be grown under suspension and adherent culture conditions and showed self- renewing capacity as well as markers typical for NPCs. They could be differentiated into the three major cell types of the nervous system, but suspension NPCs had a larger potential to generate neurons than adherently grown NPCs. Signaling cascades involved in this process were p38 and Erk1/2 mediated. Long-term expanded NPCs did not have the potential to generate neuronal sub-types. Importantly, they did not generate dopaminergic neurons. Mouse fetal NPCs from three different developmental stages (E10, E12, and E14) were employed but were not able to differentiate into dopaminergic neurons using factors known to stimulate in vitro dopaminergic specification. When cultivated in vitro for short periods, fetal mesencephalic NPCs were able to generate dopaminergic neurons. By eliminating all primary Th- positive neurons, FACS-sorting of NPCs proved a de novo generation of dopaminergic neurons, because after cultivation and differentiation of Th- depleted cell solutions dopaminergic neurons were present in the culture. However, these newly generated neurons failed to incorporate BrdU, making a generation without cell division from precursors probable. The precursor population of short cultures differed from long-term expanded cultures suggesting an ‘aging’ effect of in vitro conditions. IL-1 was a potent inducer of the dopaminergic neuronal phenotype in short-term expanded in vitro cultures and was expressed in vitro as well as in vivo at E14. Several important conclusions concerning fetal mouse stem cell behavior could be drawn from the results of this work: Firstly, the results showed for the first time that in fetal mouse mesencephalic NPCs dopaminergic neurons differentiate from precursors without cell division, therefore consuming those progenitors. Therein fetal mouse NPCs differ significantly from rat and human NPCs or respond differently to the same in vitro conditions that need to be optimized for fetal mouse NPCs. Secondly, less committed precursors find appropriate conditions to proliferate but not to generate the more committed DA precursors that are able to generate dopaminergic neurons. The hallmarks of stem cells, self-renewal and multipotentiality, seem to be part of a delicate balance, that, when unsettled, goes in favor of one side without the possibility of returning to the previous status. Further research should focus on two coherent issues: the isolation of more pure populations of progenitors and the more precise characterization of progenitor populations to find out which in vitro conditions need to be provided to keep the balance between proliferation and differentiation potential. The knowledge gained about stem cells this way would help establish cell sources for transplantation strategies.Stammzellen sind ein wichtiges Werkzeug für regenerative Therapien im Bereich der neurodegenerativen Erkrankungen wie der Parkinson’schen Erkrankung. Ein besonderer Vorteil von Stammzellen gegenüber dem bereits zur Transplantation verwendeten Primärgewebe, ist ihre Fähigkeit zur fortlaufenden Zellteilung, so dass ausreichende Mengen zur Transplantation zur Verfügung stehen. Der Vorteil von fetalen neuralen Stammzellen (fNSZ) ist ihre genomische Stabilität, die dazu führt, dass bei Transplantationen keine Tumore entstehen. Dennoch ist der Großteil ihrer Eigenschaften und Potentiale noch unbekannt und die optimalen Wachstumsbedingungen für eine lange in vitro Kultur und optimale Differenzierung in dopaminerge Neuronen müssen erforscht werden, um bessere Transplantate herzustellen. Insbesondere Stammzellen der Maus sind für die Forschung von immenser Wichtigkeit, da sie die Arbeit mit transgenen Tieren ermöglichen. Die Zielsetzungen dieser Arbeit waren die Charakterisierung der fNSZ der Maus, die Langzeitexpansion und die anschließende Differenzierung in dopaminerge Neurone. Die Signalkaskaden der frühen Differenzierung und die Unterschiede von kurz- und langzeitkultivierten Stammzellen wurden untersucht. Es konnte gezeigt werden, dass fNSZ der Maus nach Langzeitkultivierung in alle Zelltypen des zentralen Nervensystems, also Neuronen und Glia differenzieren und die dabei aktivierten Signalkaskaden p38 und Erk1/2 vermittelt sind. Das Differenzierungspotential zu neuronalen Subtypen (also auch zu dopaminergen Nervenzellen) verloren diese fetalen Stammzellen unter Kulturbedingungen schnell. Das steht im Gegensatz zu fetalen Stammzellen aus Ratte oder dem Menschen, die auch nach langer Kultivierung ihr dopaminerge Potential erhalten. Nur nach Kurzzeitkultivierung waren dopaminerge Neurone nachzuweisen, die jedoch nicht durch Zellteilung aus Vorläuferzellen hervorgegangen waren. Die Eliminierung aller primären Neurone aus der Mittelhirnisolation durch FACS-sorting von Th-Gfp transgenen Mäusen bewies die de novo Generation der dopaminergen Neurone aus Vorläuferzellen ohne Zellteilung während der Kultivierung der Stammzellen. Diese Ergebnisse zeigten, dass in fetalen mesenzephalen NSZ der Maus dopaminerge Neurone von spezialisierten Vorläuferzellen differenzieren, wodurch diese der Kultur verloren gehen. Weniger spezialisierte Vorläuferzellen finden Bedingungen, die ihre Kultivierung ermöglichen, sind aber nicht in der Lage, spezifischere Vorläuferzellen zu bilden. Die Markenzeichen von Stammzellen, Selbsterneuerung (durch Zellteilung) und das Potential, die Zelltypen des Nervensystems zu generieren, scheinen fein balancierte Zustände zu sein, die bei einer Störung nicht wiederherzustellen sind. Die Ergebnisse dieses Projektes sind von großer Bedeutung für die Forschung zur Zellersatztherapie der Parkinson’schen Erkrankung, deren ultimatives Ziel es ist, eine sichere und verlässlich expandierbare Zellquelle zu etablieren, die fähig ist, in dopaminerge Neurone zu differenzieren. Solche Stammzellen würden Bemühungen um Transplantationsstrategien für neurodegenerative Erkrankungen unterstützen und vorantreiben