Structure Based Ligand Design for Monoamine Transporters and Mitogen Activated Kinase 5

Depression is a major psychological disorder that affects a person\u27s mental and physical abilities. The National Institute of Mental Health (NIMH) classified it as a serious medical illness. It causes huge economic, as well as financial impact on the people, and it is also becoming a major public health issue. Antidepressant drugs are prescribed to mitigate the suffering caused by this disorder. Different generations of antidepressants have been developed with dissimilar mechanisms of action. According to the Center for Disease Control, the usage of antidepressants has skyrocketed by 400 percent increase over 2005- 2008 survey period. This dramatic rise in usage indicates that these are the most prescribed drugs in the US. Even with the FDA mandated black box warning of increased suicidal thoughts upon use of selected antidepressants, these drugs are still being used at a higher rate. All classes of antidepressants are plagued by side effects with mainly sexual dysfunction common among them. To avoid the adverse effects, an emphasis is to discover novel structural drug scaffolds that can be further developed as a new generation of antidepressants. The importance of this research is to discover structurally novel antidepressants by performing in silico virtual screening (VS) of chemical databases using the serotonin transporter (SERT). In the absence of a SERT crystal structure, a homology model was developed. The homology model was utilized to develop the first structure-based pharmacophore for the extracellular facing secondary ligand binding pocket. The pharmacophore captured the necessary drug-SERT interaction pattern for SERT inhibitory action. This pharmacophore was employed as one of the filters for VS of candidate ligands. The ten compounds identified were purchased and tested pharmacologically. Out of the ten hits, three structurally novel ligands were identified as lead compounds. Two of these compounds exhibited selectivity towards SERT; the remaining lead compound was selective towards the dopamine transporter and displayed cocaine inhibition. The two SERT selective compounds will provide new opportunities in the development of novel therapeutics to treat depression. For dopamine transporter (DAT), the study was based on recently developed structurally diverse photo probes. In an effort to better understand the binding profile similarities among these different scaffolds, the photo probes were docked into DAT. The finger print analysis of the interaction pattern of docked poses was performed to identify the inhibitor-binding sites. For mitogen activated protein kinase 5 (MEK5), given the lack of structural information, a homology model of MEK5 was developed to guide the rational design of inhibitors. Docking of known MEK5 inhibitors into the homology model was performed to understand the inhibitory interaction profile. Several series of analogues were designed utilizing the generated interaction profile

Zero-shot Conversational Summarization Evaluations with small Large Language Models

Large Language Models (LLMs) exhibit powerful summarization abilities. However, their capabilities on conversational summarization remains under explored. In this work we evaluate LLMs (approx. 10 billion parameters) on conversational summarization and showcase their performance on various prompts. We show that the summaries generated by models depend on the instructions and the performance of LLMs vary with different instructions sometimes resulting steep drop in ROUGE scores if prompts are not selected carefully. We also evaluate the models with human evaluations and discuss the limitations of the models on conversational summarizationComment: Accepted at RoF0Mo workshop at Neurips 202

FeDCOR: An Institutional CORDRA Registry

FeDCOR (Federation of DSpace using CORDRA) is a registry-based federation system for DSpace instances. It is based on the CORDRA model. The first article in this issue of D-Lib Magazine describes the Advanced Distributed Learning-Registry (ADL-R) [1], which is the first operational CORDRA registry, and also includes an introduction to CORDRA. That introduction, or other prior knowledge of the CORDRA effort, is recommended for the best understanding of this article, which builds on that base to describe in detail the FeDCOR approach

Application of Spatial Statistics in Transportation Engineering

“Everything is related to everything else, but near things are more related than distant things” is the first law of geography. It can be hypothesized that spatially, occurrence of a crash can exhibit similarities. To identify spatial patterns of crashes, this chapter presents spatial autocorrelation techniques such as Moran’s I and the Getis-Ord Gi*statistics; spatial interpolation such as kriging; and nonparametric probability density function and kernel density (K). The aim of this chapter is to provide application of spatial statistics in transportation engineering specifically to identify crash concentrations and patterns of clusters in a study area

Emergence of supra-national organisations: mechanisms behind their evolution

Ein wichtiges Charakteristikum des modernen politischen Systems ist der Aufstieg regionaler Gruppierungen und regionaler Zusammenschlüsse von Nationalstaaten. Wenngleich das Hauptziel solcher Zusammenschlüsse meist die Kooperation auf dem Gebiet des Handels ist, hat sich daraus die verstärkte Kooperation der Mitgliedsstaaten auch auf verschiedenen anderen Gebieten ergeben, da zunehmend erkannt wurde, dass Kooperation dem Konflikt vorzuziehen sei. Die Europäische Union, die aus den Ruinen des Zweiten Weltkriegs entstand, ist eine der wenigen regionalen Zusammenschlüsse, in denen ein hohes Maß an Zusammenarbeit und Integration erreicht werden konnte. Auch in den anderen Teilen der Welt gab es zwar zahlreiche, ähnliche Zusammenschlüsse, aber aus verschiedenen Gründen überlebten viele nicht lange. Dies trifft auch auf Südasien zu, wo eine regionale Organisation, die South Asian Association for Regional Cooperation (SAARC) versucht wurde. Zwei Jahrzehnte später ist Südasien dennoch die am wenigsten integrierte Region, was auf eine ganze Reihe von Gründen zurückzuführen ist: historische, politische, ebenso wie ökonomische, trotz eines sehr hohen Entwicklungspotentials. Im Gegensatz zur Europäischen Union, die sich Institutionen mit prononciert supranationalen Elementen geschaffen hat, ist SAARC im Wesentlichen eine Organisation der Regierungen. In dieser Arbeit wird argumentiert, dass der Mangel an 'commitment institutes', die die Implementierung des Vertrages überwachen, der Hauptgrund für den nur langsamen Fortschritt in Südasien ist, während solche Einrichtungen die europäische Integration gefördert haben. Lehren aus der europäischen Erfahrung mit Faktoren, die die Integration vorantrieben, mit den Mechanismen der gemeinsamen Nutzung von Ressourcen, ethnischen Problemen, dem Handel innerhalb der Region und dem Fehlen einer gemeinsamen Identität werden untersucht und analysiert. Betont werden sowohl die formelle als auch informelle Kooperation, die Maßnahmen zur Integration sowie die Lehren, die Südasien aus der europäischen Erfahrung in den fünf genannten Feldern ziehen kann. Die Rolle, die Austauschprogrammen im Erziehungswesen und den persönlichen Kontakten im Lichte der europäischen Erfahrung zukommt, wird ebenso untersucht. Schließlich sind die möglichen Vorteile einer engeren Kooperation in Südasien Gegenstand der Arbeit, die eine rasche Beseitigung der Armut verspricht und die Erreichung höherer Entwicklungsniveaus in vergleichsweise kurzer Zeit.One of the important features of the modern political system is the rise of regional groupings and regional arrangements comprising of nation states. Even though the main aim for such arrangements is usually cooperation in trade, it also resulted in greater cooperation among the member states in various other areas as it is increasingly realised that cooperation is the preferred way over conflict. The European Union that evolved from the ruins of the second world war is among the only regional arrangements that had achieved a high degree of cooperation and integration. Despite the mushrooming up of similar arrangements elsewhere, many of them could not survive long due to various reasons. South Asian region also experimented with a regional cooperation by setting up an arrangement called the South Asian Association for Regional Cooperation (SAARC). However, even after two decades, it still remains the least integrated region, owing to many reasons--historical, political as well as economic, despite huge potential for development. This is because the SAARC largely is an Inter-Governmental Organisation while the European Union had set up institutions with clear supra-national elements. This paper argues that the lack of "commitment institutes" to oversee the implementation of the treaty is the main reason for slow progress in South Asia while such institutions helped in European integration. Lessons from European experience over factors driving towards cooperation, mechanisms for resource sharing, ethnic complexities and intra-regional trade and the lack of a common identity are examined and analysed. Emphasis is laid on both formal and informal cooperation and integration measures and the lessons south Asia can learn from the European experience in the above five areas are examined. The role of education exchange and people to people contacts are examined from the European experience. The potential benefits of deeper cooperation in South Asia are examined as it is one of the quick means to eradicate poverty and achieve higher levels of developments in a comparatively short time-span

Archive Ingest and Handling Test

The Archive Ingest and Handling Test (AIHT) was a Library of Congress (LC) sponsored research project administered by Information Systems and Support Inc. (ISS). The project featured five participants: Old Dominion University Computer Science Department; Harvard University Library; Johns Hopkins University Library; Stanford University Library; Library of Congress. All five participants received identical disk drives containing copies of the 911.gmu.edu web site, a collection of 9/11 materials maintained by George Mason University (GMU). The purpose of the AIHT experiment was to perform archival forensics to determine the nature of the archive, ingest it, simulate at least one of the file formats going out of scope, export a copy of the archive, and import another version of the archive. The AIHT is further described in Shirky (2005)

Framework of Matrix Factorization to Achieve Rating Prediction Task

We propose a social client wistful estimation approach and figure every client's notion on things/items. Besides, we consider a client's own wistful properties as well as contemplate relational nostalgic impact. At that point, we consider item notoriety, which can be induced by the sentimental distributions of a client set that mirror clients' exhaustive assessment. Finally, we intertwine three components client sentiment likeness, relational nostalgic impact, and thing's notoriety closeness into our recommender framework to make a precise rating prediction. We lead an execution assessment of the three nostalgic components on a genuine dataset gathered from Yelp

Stochastic modeling of flow behavior and cell structure formation during extrusion of biopolymer melts

Master of ScienceDepartment of Grain Science and IndustrySajid AlaviExtrusion is a widely used processing technology for various food products and is also commonly applied in non-food applications involving plastics, rubber and metal. Expanded products for human and animal consumption such as snacks, breakfast cereal, pet food and aquatic food typically consist of a biopolymer matrix of starch and proteins that have natural physical, chemical and polymeric variability. Additionally, variability in extrusion parameters such as water injection and screw speed is often observed depending on the process controls employed. This can potentially lead to inconsistency in product quality. Stochastic modeling helps in studying the impact of variability of various parameters on the end product, which in turn helps in better process and product quality control. The primary purpose of this research was to develop a mathematical model for flow behavior of biopolymer melts inside extruder barrel and bubble growth dynamics after exiting the extruder using mass, heat and momentum transfer equations. This model was integrated with a Monte-Carlo based stochastic interface for input of randomly generated process data (based on experimental data acquisition) and output of simulated distributions of end-product properties such as expansion ratio and cellular architecture parameters (cell size and wall thickness). The mathematical model was experimentally validated using pilot-scale twin screw extrusion for processing of cereal-based cellular products. Process and product data were measured at different in-barrel moisture contents (19-28% dry basis) and experimental screw speeds (250-330 rpm). Experimental process parameters such as specific mechanical energy (212.8-319.3 kJ/kg), die temperature (120.7-170.6oC), die pressure (3160-7683 kPa) and product characteristics such as expansion ratio (3.29-16.94) and cell size or bubble radius (435-655 microns) compared well with simulated results from the mathematical model viz., specific mechanical energy (217.6-323.9 kJ/kg), die temperature (116.8-176.1oC), die pressure (3478-6404 kPa), expansion ratio (4.56-19.4) and bubble radius (426-728 microns). Experimental variability in product characteristics was quantified using coefficient of variation which compared well with simulation results (example, 2.5-4.9% versus 0.24-3.1% respectively for expansion ratio). The stochastic model was also used to conduct sensitivity analysis for understanding which raw material and process characteristics contribute most to product variability. Sensitivity analysis showed that the water added in extruder affects the magnitude and variability of expansion ratio the most, as compared to screw speed and consistency index

Virtual VMASC: A 3D Game Environment

The advantages of creating interactive 3D simulations that allow viewing, exploring, and interacting with land improvements, such as buildings, in digital form are manifold and range from allowing individuals from anywhere in the world to explore those virtual land improvements online, to training military personnel in dealing with war-time environments, and to making those land improvements available in virtual worlds such as Second Life. While we haven't fully explored the true potential of such simulations, we have identified a requirement within our organization to use simulations like those to replace our front-desk personnel and allow visitors to query, naVigate, and communicate virtually with various entities within the building. We implemented the Virtual VMASC 3D simulation of the Virginia Modeling Analysis and Simulation Center (VMASC) office building to not only meet our front-desk requirement but also to evaluate the effort required in designing such a simulation and, thereby, leverage the experience we gained in future projects of this kind. This paper describes the goals we set for our implementation, the software approach taken, the modeling contribution made, and the technologies used such as XNA Game Studio, .NET framework, Autodesk software packages, and, finally, the applicability of our implementation on a variety of architectures including Xbox 360 and PC. This paper also summarizes the result of our evaluation and the lessons learned from our effort