Expanding molecular modeling and design tools to non-natural sidechains.

Protein-protein interactions encode the wiring diagram of cellular signaling pathways and their deregulations underlie a variety of diseases, such as cancer. Inhibiting protein-protein interactions with peptide derivatives is a promising way to develop new biological and therapeutic tools. Here, we develop a general framework to computationally handle hundreds of non-natural amino acid sidechains and predict the effect of inserting them into peptides or proteins. We first generate all structural files (pdb and mol2), as well as parameters and topologies for standard molecular mechanics software (CHARMM and Gromacs). Accurate predictions of rotamer probabilities are provided using a novel combined knowledge and physics based strategy. Non-natural sidechains are useful to increase peptide ligand binding affinity. Our results obtained on non-natural mutants of a BCL9 peptide targeting beta-catenin show very good correlation between predicted and experimental binding free-energies, indicating that such predictions can be used to design new inhibitors. Data generated in this work, as well as PyMOL and UCSF Chimera plug-ins for user-friendly visualization of non-natural sidechains, are all available at http://www.swisssidechain.ch. Our results enable researchers to rapidly and efficiently work with hundreds of non-natural sidechains.

Synapses on motoneuron dendrites in the brachial section of the frog spinal cord: a computer-aided electron microscopic study of cobalt-filled cells.

Cobalt-labelled motoneuron dendrites of the frog spinal cord at the level of the second spinal nerve were photographed in the electron microscope from long series of ultrathin sections. Three-dimensional computer reconstructions of 120 dendrite segments were analysed. The samples were taken from two locations: proximal to cell body and distal, as defined in a transverse plane of the spinal cord. The dendrites showed highly irregular outlines with many 1-2 microns-long 'thorns' (on average 8.5 thorns per 100 microns 2 of dendritic area). Taken together, the reconstructed dendrite segments from the proximal sites had a total length of about 250 microns; those from the distal locations, 180 microns. On all segments together there were 699 synapses. Nine percent of the synapses were on thorns, and many more close to their base on the dendritic shaft. The synapses were classified in four groups. One third of the synapses were asymmetric with spherical vesicles; one half were symmetric with spherical vesicles; and one tenth were symmetric with flattened vesicles. A fourth, small class of asymmetric synapses had dense-core vesicles. The area of the active zones was large for the asymmetric synapses (median value 0.20 microns 2), and small for the symmetric ones (median value 0.10 microns 2), and the difference was significant. On average, the areas of the active zones of the synapses on thin dendrites were larger than those of synapses on large calibre dendrites. About every 4 microns 2 of dendritic area received one contact. There was a significant difference between the areas of the active zones of the synapses at the two locations. Moreover, the number per unit dendritic length was correlated with dendrite calibre. On average, the active zones covered more than 4% of the dendritic area; this value for thin dendrites was about twice as large as that of large calibre dendrites. We suggest that the larger active zones and the larger synaptic coverage of the thin dendrites compensate for the longer electrotonic distance of these synapses from the soma.

Maintenance Asset Management Project -- Phase II, July 31, 2013

Expanded abstract: Iowa Department of Transportation (IA DOT) is finalizing research to streamline field inventory/inspection of culverts by Maintenance and Construction staff while maximizing the use of tablet technologies. The project began in 2011 to develop some new best practices for field staff to assist in the inventory, inspection and maintenance of assets along the roadway. The team has spent the past year working through the complexities of identifying the most appropriate tablet hardware for field data collection. A small scale deployment of tablets occurred in spring of 2013 to collect several safety related assets (culverts, signs, guardrail, and incidents). Data can be collected in disconnected or connected modes and there is an associated desktop environment where data can be viewed and queried after being synced into the master database. The development of a deployment plan and related workflow processes are underway; which will eventually feed information into IA DOTs larger asset management system and make the information available for decision making. The team is also working with the IA DOT Design Office on Computer Aided Drafting (CAD) data processing and the IA DOT Construction office with a new digital As-Built plan process to leverage the complete data life-cycle so information can be developed once and leveraged by the Maintenance staff farther along in the process.

Between play and design : the emergence of hybrid-identity in single-player videogames

Pour respecter les droits auteur, la version electronique de cette thèse a été dépouillée de ses documents visuels et audio-visuels. La version intégrale de la thèse a été déposée au Service de la gestion des documents et des archives de l'Université de Montréal.

FEM based Virtual Prototyping and Design of Third Harmonic Excitation System for Low Voltage Brushless Alternators

Salient pole brushless alternators coupled to IC engines are extensively used as stand-by power supply units for meeting in- dustrial power demands. Design of such generators demands high power to weight ratio, high e ciency and low cost per KVA out- put. Moreover, the performance characteristics of such machines like voltage regulation and short circuit ratio (SCR) are critical when these machines are put into parallel operation and alterna- tors for critical applications like defence and aerospace demand very low harmonic content in the output voltage. While designing such alternators, accurate prediction of machine characteristics, including total harmonic distortion (THD) is essential to mini- mize development cost and time. Total harmonic distortion in the output voltage of alternators should be as low as possible especially when powering very sophis- ticated and critical applications. The output voltage waveform of a practical AC generator is replica of the space distribution of the ux density in the air gap and several factors such as shape of the rotor pole face, core saturation, slotting and style of coil disposition make the realization of a sinusoidal air gap ux wave impossible. These ux harmonics introduce undesirable e ects on the alternator performance like high neutral current due to triplen harmonics, voltage distortion, noise, vibration, excessive heating and also extra losses resulting in poor e ciency, which in turn necessitate de-rating of the machine especially when connected to non-linear loads. As an important control unit of brushless alternator, the excitation system and its dynamic performance has a direct impact on alternator's stability and reliability. The thesis explores design and implementation of an excitation i system utilizing third harmonic ux in the air gap of brushless al- ternators, using an additional auxiliary winding, wound for 1=3rd pole pitch, embedded into the stator slots and electrically iso- lated from the main winding. In the third harmonic excitation system, the combined e ect of two auxiliary windings, one with 2=3rd pitch and another third harmonic winding with 1=3rd pitch, are used to ensure good voltage regulation without an electronic automatic voltage regulator (AVR) and also reduces the total harmonic content in the output voltage, cost e ectively. The design of the third harmonic winding by analytic methods demands accurate calculation of third harmonic ux density in the air gap of the machine. However, precise estimation of the amplitude of third harmonic ux in the air gap of a machine by conventional design procedures is di cult due to complex geome- try of the machine and non-linear characteristics of the magnetic materials. As such, prediction of the eld parameters by conven- tional design methods is unreliable and hence virtual prototyping of the machine is done to enable accurate design of the third har- monic excitation system. In the design and development cycle of electrical machines, it is recognized that the use of analytical and experimental methods followed by expensive and in exible prototyping is time consum- ing and no longer cost e ective. Due to advancements in com- putational capabilities over recent years, nite element method (FEM) based virtual prototyping has become an attractive al- ternative to well established semi-analytical and empirical design methods as well as to the still popular trial and error approach followed by the costly and time consuming prototyping. Hence, by virtually prototyping the alternator using FEM, the important performance characteristics of the machine are predicted. Design of third harmonic excitation system is done with the help of results obtained from virtual prototype of the machine. Third harmonic excitation (THE) system is implemented in a 45 KVA ii experimental machine and experiments are conducted to validate the simulation results. Simulation and experimental results show that by utilizing third harmonic ux in the air gap of the ma- chine for excitation purposes during loaded conditions, triplen harmonic content in the output phase voltage is signi cantly re- duced. The prototype machine with third harmonic excitation system designed and developed based on FEM analysis proved to be economical due to its simplicity and has the added advan- tage of reduced harmonics in the output phase voltage.

Simulation and Design of a high speed Solid State Switch for Excimer Laser

Excimerlaser sind gepulste Gaslaser, die Laseremission in Form von Linienstrahlung – abhängig von der Gasmischung – im UV erzeugen. Der erste entladungsgepumpte Excimerlaser wurde 1977 von Ischenko demonstriert. Alle kommerziell verfügbaren Excimerlaser sind entladungsgepumpte Systeme. Um eine Inversion der Besetzungsdichte zu erhalten, die notwendig ist, um den Laser zum Anschwingen zu bekommen, muss aufgrund der kurzen Wellenlänge sehr stark gepumpt werden. Diese Pumpleistung muss von einem Impulsleistungsmodul erzeugt werden. Als Schaltelement gebräuchlich sind Thyratrons, Niederdruckschaltröhren, deren Lebensdauer jedoch sehr limitiert ist. Deshalb haben sich seit Mitte der 1990iger Jahre Halbleiterschalter mit Pulskompressionsstufen auch in dieser Anwendung mehr und mehr durchgesetzt. In dieser Arbeit wird versucht, die Pulskompression durch einen direkt schaltenden Halbleiterstapel zu ersetzen und dadurch die Verluste zu reduzieren sowie den Aufwand für diese Pulskompression einzusparen. Zudem kann auch die maximal mögliche Repetitionsrate erhöht werden. Um die Belastung der Bauelemente zu berechnen, wurden für alle Komponenten möglichst einfache, aber leistungsfähige Modelle entwickelt. Da die normalerweise verfügbaren Daten der Bauelemente sich aber auf andere Applikationen beziehen, mussten für alle Bauteile grundlegende Messungen im Zeitbereich der späteren Applikation gemacht werden. Für die nichtlinearen Induktivitäten wurde ein einfaches Testverfahren entwickelt um die Verluste bei sehr hohen Magnetisierungsgeschwindigkeiten zu bestimmen. Diese Messungen sind die Grundlagen für das Modell, das im Wesentlichen eine stromabhängige Induktivität beschreibt. Dieses Modell wurde für den „magnetic assist“ benützt, der die Einschaltverluste in den Halbleitern reduziert. Die Impulskondensatoren wurden ebenfalls mit einem in der Arbeit entwickelten Verfahren nahe den späteren Einsatzparametern vermessen. Dabei zeigte sich, dass die sehr gebräuchlichen Class II Keramikkondensatoren für diese Anwendung nicht geeignet sind. In der Arbeit wurden deshalb Class I Hochspannungs- Vielschicht- Kondensatoren als Speicherbank verwendet, die ein deutlich besseres Verhalten zeigen. Die eingesetzten Halbleiterelemente wurden ebenfalls in einem Testverfahren nahe den späteren Einsatzparametern vermessen. Dabei zeigte sich, dass nur moderne Leistungs-MOSFET´s für diesen Einsatz geeignet sind. Bei den Dioden ergab sich, dass nur Siliziumkarbid (SiC) Schottky Dioden für die Applikation einsetzbar sind. Für die Anwendung sind prinzipiell verschiedene Topologien möglich. Bei näherer Betrachtung zeigt sich jedoch, dass nur die C-C Transfer Anordnung die gewünschten Ergebnisse liefern kann. Diese Topologie wurde realisiert. Sie besteht im Wesentlichen aus einer Speicherbank, die vom Netzteil aufgeladen wird. Aus dieser wird dann die Energie in den Laserkopf über den Schalter transferiert. Aufgrund der hohen Spannungen und Ströme müssen 24 Schaltelemente in Serie und je 4 parallel geschaltet werden. Die Ansteuerung der Schalter wird über hochisolierende „Gate“-Transformatoren erreicht. Es zeigte sich, dass eine sorgfältig ausgelegte dynamische und statische Spannungsteilung für einen sicheren Betrieb notwendig ist. In der Arbeit konnte ein Betrieb mit realer Laserkammer als Last bis 6 kHz realisiert werden, der nur durch die maximal mögliche Repetitionsrate der Laserkammer begrenzt war.

Estado situacional de los modelos basados en agentes y su impacto en la investigación organizacional

En un mundo hiperconectado, dinámico y cargado de incertidumbre como el actual, los métodos y modelos analíticos convencionales están mostrando sus limitaciones. Las organizaciones requieren, por tanto, herramientas útiles que empleen tecnología de información y modelos de simulación computacional como mecanismos para la toma de decisiones y la resolución de problemas. Una de las más recientes, potentes y prometedoras es el modelamiento y la simulación basados en agentes (MSBA). Muchas organizaciones, incluidas empresas consultoras, emplean esta técnica para comprender fenómenos, hacer evaluación de estrategias y resolver problemas de diversa índole. Pese a ello, no existe (hasta donde conocemos) un estado situacional acerca del MSBA y su aplicación a la investigación organizacional. Cabe anotar, además, que por su novedad no es un tema suficientemente difundido y trabajado en Latinoamérica. En consecuencia, este proyecto pretende elaborar un estado situacional sobre el MSBA y su impacto sobre la investigación organizacional.

Design for design: support for creative practice in computer-supported collaborative work (CSCW) in design

This paper describes a novel methodology for observing and analysing collaborative design by using the concepts of cognitive dimensions related to concept-based misfit analysis. The study aims at gaining an insight into support for creative practice of graphical communication in collaborative design processes of designers while sketching within a shared white board and audio conferencing environment. Empirical data on design processes have been obtained from observation of groups of student designers solving an interior space-planning problem of a lounge-diner in a shared virtual environment. The results of the study provide recommendations for the design and development of interactive systems to support such collaborative design activities.

The implementation of a low-cost production-line inspection system

This article describes an application of computers to a consumer-based production engineering environment. Particular consideration is given to the utilisation of low-cost computer systems for the visual inspection of components on a production line in real time. The process of installation is discussed, from identifying the need for artificial vision and justifying the cost, through to choosing a particular system and designing the physical and program structure.

Standardized evaluation of algorithms for computer-aided diagnosis of dementia based on structural MRI: The CADDementia challenge

Algorithms for computer-aided diagnosis of dementia based on structural MRI have demonstrated high performance in the literature, but are difficult to compare as different data sets and methodology were used for evaluation. In addition, it is unclear how the algorithms would perform on previously unseen data, and thus, how they would perform in clinical practice when there is no real opportunity to adapt the algorithm to the data at hand. To address these comparability, generalizability and clinical applicability issues, we organized a grand challenge that aimed to objectively compare algorithms based on a clinically representative multi-center data set. Using clinical practice as the starting point, the goal was to reproduce the clinical diagnosis. Therefore, we evaluated algorithms for multi-class classification of three diagnostic groups: patients with probable Alzheimer's disease, patients with mild cognitive impairment and healthy controls. The diagnosis based on clinical criteria was used as reference standard, as it was the best available reference despite its known limitations. For evaluation, a previously unseen test set was used consisting of 354 T1-weighted MRI scans with the diagnoses blinded. Fifteen research teams participated with a total of 29 algorithms. The algorithms were trained on a small training set (n = 30) and optionally on data from other sources (e.g., the Alzheimer's Disease Neuroimaging Initiative, the Australian Imaging Biomarkers and Lifestyle flagship study of aging). The best performing algorithm yielded an accuracy of 63.0% and an area under the receiver-operating-characteristic curve (AUC) of 78.8%. In general, the best performances were achieved using feature extraction based on voxel-based morphometry or a combination of features that included volume, cortical thickness, shape and intensity. The challenge is open for new submissions via the web-based framework: http://caddementia.grand-challenge.org.

Computer-aided Structure Elucidation of Neolignans

This paper describes a new module of the expert system SISTEMAT used for the prediction of the skeletons of neolignans by (13)C NMR, (1)H NMR and botanical data obtained from the literature. SISTEMAT is composed of MACRONO, SISCONST, C13MACH, H1MACH and SISOCBOT programs, each analyzing data of the neolignan in question to predict the carbon skeleton of the compound. From these results, the global probability is computed and the most probable skeleton predicted. SISTEMAT predicted the skeletons of 75% of the 20 neolignans tested, in a rapid and simple procedure demonstrating its advantage for the structural elucidation of new compounds.