Computational analysis of alternative splicing in human and mice

Im ersten Teil wurden Transkript-Spleißstellen untersucht, mit dem Ziel, alternative und Referenzspleißstellen zu unterscheiden. Die Ergebnisse belegen, dass sich beide Klassen von Spleißstellen durch einen Spleißstellen-Score und vermehrtes Auftreten von Spleißfaktor-Bindemotiven in Umgebung der Spleißstellen abgrenzen lassen. Zusätzlich konnte eine positive Korrelation zwischen der Häufigkeit der Nutzung bestimmter Spleißstellen und dem Spleißstellen-Score in beiden Vergleichsklassen nachgewiesen werden. Diese Abhängigkeit impliziert, dass die Genauigkeit der Annotation alternativer Spleißvarianten mit der Anzahl beobachteter Transkripte steigt. Im zweiten Teil wurde das Spleißsignalmotiv GYNNGY untersucht, welches mehr als 40% aller überlappenden Donor-Spleißsignale ausmacht. Mittels in silico Analysen und experimenteller Validierung wurde die Plausibilität dieses subtilen Spleißmusters bestätigt. Der Vergleich mit anderen humanen Spleißvarianten sowie mit Tandem Donoren in Maus-Transkripten zeigte zudem ausgeprägte Unterschiede bezüglich des Spleißstellen-Scores, der Konservierung, sowie dem Vorkommen von Spleißfaktoren-Bindemotiven. Die Verschiebung des Leserasters durch alternatives Spleißen an GYNNGY-Donoren lässt auf eine komplexe Rolle im RNA-Reifungsprozess schließen. Im dritten Teil wurden Reaktionen des spleißosomalen Makrokomples aus publizierten, experimentellen Daten zusammengestellt und mit Hilfe der Petri-Netz-Theorie in einem qualitativen Modell dargestellt. Unter Annahme eines Steady-State Systems wurden minimale, semipositive T-Invarianten berechnet und zur Validierung des Modells herangezogen. Auf Grundlage der vollständigen Abdeckung des Reaktionsnetzwerks mit T-Invarianten konnten weitere Strukturmerkmale, wie Maximal-Gemeinsame Transitions.Mengen und T-Cluster berechnet werden, welche wichtige Stadien des Spleißosomaufbaus widerspiegeln

A Hybrid Algorithm for the Vehicle Routing Problem with Pickup and Delivery and 3D Loading Constraints

In this paper, we extend the classical Pickup and Delivery Problem (PDP) to an integrated routing and three-dimensional loading problem, called PDP with 3D loading constraints (3L-PDP). A set of routes of minimum total length has to be determined such that each request is transported from a loading site to the corresponding unloading site. In the 3L-PDP, each request is given as a set of 3D rectangular items (boxes) and the vehicle capacity is replaced by a 3D loading space. We investigate which constraints will ensure that no reloading effort will occur, i.e. that no box is moved after loading and before unloading. A spectrum of 3L-PDP variants is introduced with different characteristics in terms of reloading effort. We propose a hybrid algorithm for solving the 3L-PDP consisting of a routing and a packing procedure. The routing procedure modifies a well-known large neighborhood search for the 1D-PDP. A tree search heuristic is responsible for packing boxes. Computational experiments were carried out using 54 newly proposed 3L-PDP benchmark instances

A two-stage packing procedure for a Portuguese trading company

This case study deals with a two-stage packing problem that has to be solved in the daily distribution process of a Portuguese trading company. At the first stage boxes including goods are to be packed on pallets while at the second stage these pallets are loaded into one or more trucks. The boxes have to be transported to different customers and the actual goal is to guarantee a sufficient utilization of the truck loading spaces. A two-stage packing procedure is proposed to cover both problem stages. First boxes are loaded onto pallets using a well-known container loading algorithm. Then trucks are filled with loaded pallets by means of a new tree search algorithm. The applicability and performance of the two-stage approach was evaluated with a set of instances that are based on actual company data

The split delivery vehicle routing problem with three-dimensional loading constraints

 The Split Delivery Vehicle Routing Problem with three-dimensional loading constraints (3L-SDVRP) combines vehicle routing and three-dimensional loading with additional packing constraints. In the 3L-SDVRP splitting deliveries of customers is basically possible, i.e. a customer can be visited in two or more tours. We examine essential problem features and introduce two problem variants. In the first variant, called 3L-SDVRP with forced splitting, a delivery is only split if the demand of a customer cannot be transported by a single vehicle. In the second variant, termed 3L-SDVRP with optional splitting, splitting customer deliveries can be done any number of times. We propose a hybrid algorithm consisting of a local search algorithm for routing and a genetic algorithm and several construction heuristics for packing. Numerical experiments are conducted using three sets of instances with both industrial and academic origins. One of them was provided by an automotive logistics company in Shanghai; in this case some customers per instance have a total freight volume larger than the loading space of a vehicle. The results prove that splitting deliveries can be beneficial not only in the one-dimensional case but also when goods are modeled as three-dimensional items

Container Loading Problems: A State-of-the-Art Review

Container loading is a pivotal function for operating supply chains efficiently. Underperformance results in unnecessary costs (e.g. cost of additional containers to be shipped) and in an unsatisfactory customer service (e.g. violation of deadlines agreed to or set by clients). Thus, it is not surprising that container loading problems have been dealt with frequently in the operations research literature. It has been claimed though that the proposed approaches are of limited practical value since they do not pay enough attention to constraints encountered in practice.In this paper, a review of the state-of-the-art in the field of container loading will be given. We will identify factors which - from a practical point of view - need to be considered when dealing with container loading problems and we will analyze whether and how these factors are represented in methods for the solution of such problems. Modeling approaches, as well as exact and heuristic algorithms will be reviewed. This will allow for assessing the practical relevance of the research which has been carried out in the field. We will also mention several issues which have not been dealt with satisfactorily so far and give an outlook on future research opportunities

Solving the Pickup and Delivery Problem with 3D Loading Constraints and Reloading Ban

In this paper, we extend the classical Pickup and Delivery Problem (PDP) to an integrated routing and three-dimensional loading problem, called PDP with 3D loading constraints (3L-PDP). A set of routes of minimum total length has to be determined such that each request is transported from a loading site to the corresponding unloading site. In the 3L-PDP, each request is given as a set of 3D rectangular items (boxes) and the vehicle capacity is replaced by a 3D loading space. This paper is the second one in a series of articles on 3L-PDP. In both articles we investigate which constraints will ensure that no reloading effort will occur, i.e. that no box is moved after loading and before unloading. In this paper, the focus is laid on the so-called reloading ban, a packing constraint that ensures identical placements of same boxes in different packing plans. We propose a hybrid algorithm for solving the 3L-PDP with reloading ban consisting of a routing and a packing procedure. The routing procedure modifies a well-known large neighborhood search for the 1D-PDP. A tree search heuristic is responsible for packing boxes. Computational experiments were carried out using 54 3L-PDP benchmark instances

A hybrid algorithm for the vehicle routing problem with three-dimensional loading constraints and mixed backhauls

In this paper, a variant of the vehicle routing problem with mixed backhauls (VRPMB) is presented, i.e. goods have to be delivered from a central depot to linehaul customers, and, at the same time, goods have to be picked up from backhaul customers and brought to the depot. Both types of customers can be visited in mixed sequences. The goods to be delivered or picked up are three-dimensional (cuboid) items. Hence, in addition to a routing plan, a feasible packing plan for each tour has to be provided considering a number of loading constraints. The resulting problem is the vehicle routing problem with three-dimensional loading constraints and mixed backhauls (3L-VRPMB)

A hybrid solution approach for the 3L-VRP with simultaneous delivery and pickups

This paper deals with a special vehicle routing problem with backhauls where each customer receives items from a depot and, at the same time, returns items back to the depot. Moreover, time windows are assumed and three-dimensional loading constraints are to be observed, i.e. the items are three-dimensional boxes and packing constraints, e.g. regarding load stability, are to be met. The resulting problem is the vehicle routing problem with simultaneous delivery and pickup (VRPSDP), time windows, and three-dimensional loading constraints (3L-VRPSDPTW). This problem occurs, for example, if retail stores are supplied by a central warehouse and wish to return packaging material.A particular challenge of the problem is to transport delivery and pickup items simultaneously on the same vehicle. In order to avoid any reloading effort during a tour, we consider two different loading approaches of vehicles: (i) loading from the back side with separation of the loading space into a delivery section and a pickup section and (ii) loading at the long side. A hybrid algorithm is proposed for the 3L-VRPSDPTW consisting of an adaptive large neighbourhood search for the routing and different packing heuristics for the loading part of the problem. Extensive numerical experiments are conducted with VRPSDP instances from the literature and newly generated instances for the 3LVRPSDPTW

High-Rate Capable Floating Strip Micromegas

We report on the optimization of discharge insensitive floating strip Micromegas (MICRO-MEsh GASeous) detectors, fit for use in high-energy muon spectrometers. The suitability of these detectors for particle tracking is shown in high-background environments and at very high particle fluxes up to 60MHz/cm$^2$. Measurement and simulation of the microscopic discharge behavior have demonstrated the excellent discharge tolerance. A floating strip Micromegas with an active area of 48cm$\times$50cm with 1920 copper anode strips exhibits in 120GeV pion beams a spatial resolution of 50$\mu$m at detection efficiencies above 95%. Pulse height, spatial resolution and detection efficiency are homogeneous over the detector. Reconstruction of particle track inclination in a single detector plane is discussed, optimum angular resolutions below $5^\circ$ are observed. Systematic deviations of this $\mu$TPC-method are fully understood. The reconstruction capabilities for minimum ionizing muons are investigated in a 6.4cm$\times$6.4cm floating strip Micromegas under intense background irradiation of the whole active area with 20MeV protons at a rate of 550kHz. The spatial resolution for muons is not distorted by space charge effects. A 6.4cm$\times$6.4cm floating strip Micromegas doublet with low material budget is investigated in highly ionizing proton and carbon ion beams at particle rates between 2MHz and 2GHz. Stable operation up to the highest rates is observed, spatial resolution, detection efficiencies, the multi-hit and high-rate capability are discussed.Comment: Presented at ICHEP 2014, accepted for publication in Nuclear Physics B Proceedings Supplement

PICOSEC: Charged particle timing at sub-25 picosecond precision with a Micromegas based detector

The prospect of pileup induced backgrounds at the High Luminosity LHC (HL-LHC) has stimulated intense interest in developing technologies for charged particle detection with accurate timing at high rates. The required accuracy follows directly from the nominal interaction distribution within a bunch crossing ( σz∼5 cm, σt∼170 ps). A time resolution of the order of 20–30 ps would lead to significant reduction of these backgrounds. With this goal, we present a new detection concept called PICOSEC, which is based on a “two-stage” Micromegas detector coupled to a Cherenkov radiator and equipped with a photocathode. First results obtained with this new detector yield a time resolution of 24 ps for 150 GeV muons, and 76 ps for single photoelectrons.Peer Reviewe