204 research outputs found
Recommended from our members
Abstract P07: Inhibition of androgen-regulated TMPRSS2 and lipogenic enzymes in prostate and lung carcinoma cell lines by a cisplatin prodrug
No full textAbstract The main causative agent for the global pandemic of COVID-19 is caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Developing therapeutic strategies to stop the virus is the hour of need. According to the recent clinical reports, it is seen that an androgen-regulated host cell serine protease TMPRSS2 acts on the spike protein of the SARS-CoV-2 virus which interacts with the host angiotensin-converting enzyme 2 (ACE2) and enters the host cell to cause the infection. Reports also suggest that TMPRSS2 is regulated by androgen present in prostate cells and it is highly expressed in PCa patients. Our lab has recently synthesized a new cisplatin prodrug which is a conjugate of lauric acid and cisplatin that potentially works very effectively in various androgen dependent and independent prostate cancer (PCa) cells. The cisplatin prodrug unlike other conventional platinum drugs is involved in inhibition of one of the major metabolic pathways of the PCa cells. Preliminary results show that, the prodrug in combination with the anti-androgen bicalutamide has an increased inhibition on the expression of TMPRSS2 in androgen dependent PCa and lung carcinoma cells along with down-regulation of some the lipogenic enzymes in-vitro. Here, we propose that the prodrug inhibits one of the mitochondrial metabolic pathways making the PCa cells sensitive towards cisplatin-based chemotherapy along with reducing the expression of TMPRSS2. Once completed, our work will provide an inside story of cisplatin prodrug mediated alteration of lipogenesis of cells in PCa tumor microenvironment resulting in a platform that has the potential to reduce the burden of cancer aggressiveness in both androgen dependent and independent PCa and also can be used as a potent chemotherapeutic agent against COVID-19. Citation Format: Subham Guin, Bapurao Surnar, Uttara Basu, Shanta Dhar. Inhibition of androgen-regulated TMPRSS2 and lipogenic enzymes in prostate and lung carcinoma cell lines by a cisplatin prodrug [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2021 Feb 3-5. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(6_Suppl):Abstract nr P07
Do rules control power? GATT articles and arrangements in the Uruguay Round
No full textMany complain and offer evidence that in recent years the GATT system has become more power-oriented, less stable, and less equitable. A concern to reverse this drift was one of the motives that brought the international community to agree to undertake the Uruguay Round. Rules control power, assumed the signers of the Punte del Este declaration, therefore elaborating and extending GATT rules would move the international community toward a fairer, more stable international trading system. Finger and Dhar contend that the opposite is true. Particularly in the 1980s, the elaboration and application of GATT rules has been an exercise in the application of economic and political power, not in its control. GATT rules, in theory, are there to limit national trade restrictions. Finger and Dhar contend that in fact things work the other way around: national practice comes first, and determines what the GATT rules mean. GATT's rules do not put limits on national practices, but provide international santion for these practices. Such rules are not part of the thereforelution but are part of the problem. Theirs is a situation-specific argument, say Finger and Dhar, not a generic one. Their target is not"rules", nor is it"GATT". Rather, it is the GATT rules.Rules of Origin,TF054105-DONOR FUNDED OPERATION ADMINISTRATION FEE INCOME AND EXPENSE ACCOUNT,Common Carriers Industry,Transport and Trade Logistics,Trade Policy
Recommended from our members
Cisplatin Prodrug Mediated Sensitization of Fatty Acid Oxidation Driven Castrate Resistant Prostate Cancer
No full textProstate cancer (PCa) is a common cancer among American men and ranks second in terms of mortality in the United States. The current treatment modalities, castration, prostatectomy, radiation therapy, and androgen deprivation therapy (ADT) can only partially extend the life expectancy of the patients but eventually fail to completely cure the disease. Despite undergoing castration, patients still experience disease recurrence. This recurrence is led by the binding of the basal androgens present in blood plasma to the androgen receptor (AR). At this stage, the disease becomes castrate resistant prostate cancer (CRPC) showing resistance towards ADT, and there is no effective treatment available. In recent times, targeting energy metabolism pathways has gained immense interest as a potential therapeutic target. We envision that targeting the altered metabolism of PCa cells with a cisplatin prodrug, Platin-L, would disrupt the cancer cell's metabolism and sensitize them to cisplatin chemotherapy. The metabolically challenged cells would show a shift towards glucose oxidation, becoming vulnerable leading towards apoptosis. To delve deeper into understanding how Platin-L can be used to target the ADT resistant population we hypothesize whether inhibition of FAO by Platin-L may modulate AR activity and re-sensitize the ADT resistant cells. Androgens play a crucial role in fostering the growth, nourishment, and maintenance of PCa. Downregulation of FAO in castrate resistant PCa leads to changes in AR signaling pathway. Our study aims to investigate the downstream effects of the proteins involved in lipid metabolism which is controlled by AR signaling using both qualitative and quantitative analytic methods. To achieve our goals, we first verified whether Platin-L can target the cisplatin resistance in PCa and re-sensitize PCa towards cisplatin-based chemotherapy. Based on our preliminary studies in androgen-dependent and androgen-responsive PCa cell variants, we observe an effective therapeutic potential of Platin-L for re-sensitizing PCa towards ADT
Lessons of trade liberalization in Latin America for economies in transition
No full textAfter four decades as prime examples of inward-looking trade policies and import-substituting industrialization, several Latin American countries undertook comprehensive trade liberalization and macroeconomic adjustment in the 1980s. The authors contend that the experiences in those countries are relevant for the economies in Eastern Europe and the former Soviet Union in transition from socialism to market economies. In all of these Latin American countries, the move toward an outward orientation occurred: when the economy was facing a large negative external shock because of falling terms of trade and rising debt payments; after several decades of protectionism; and under severe macroeconomic imbalances. The authors study the reform package of trade liberalization, stabilization, and supporting policies in Argentina, Bolivia, Chile, Mexico, and Uruguay. They conclude that for the economies in transition: Rationalizing the foreign trade regime is crucial for the success of stabilization measures. Rapid, far-reaching reform is possible in sectors that were subject to prolonged periods of heavy protection. Sustained growth requires a comprehensive reform package, with supporting policies for labor, capital, and domestic product markets. Liberalization of the financial sector requires investigating the links between commercial banks and private sector firms. If trade liberalization is to succeed in the long run, it is important to study the evolution of the real exchange rate and measures to stabilize it. In the final section of the paper, the authors study the recent impetus toward trade liberalization through regional arrangements in Latin America. The issue is relevant to countries in Eastern Europe and the former Soviet Union because they belonged to the CMEA, a regional trading arrangement, and because such arrangements are evolving anew among countries in the former Soviet Union.Economic Theory&Research,Environmental Economics&Policies,Economic Stabilization,TF054105-DONOR FUNDED OPERATION ADMINISTRATION FEE INCOME AND EXPENSE ACCOUNT,Macroeconomic Management
Reconfigurable and heterogeneous architectures for efficient computing
No full textThe saturation of single-thread performance, along with the advent of the power wall, has resulted in the need for efficient use of area and power budgets. With the end of Dennard scaling, and the slow down of Moore's law, scaling from one process node to another no longer delivers gains in performance or power for general-purpose computing. Thus, there is an increase in the adoption of specialized hardware, tuned to the requirements of the application or domain. These accelerators promise high performance and energy efficiency. However, with the increasing complexity and resource requirements of applications and algorithms, there is also a need for more flexibility in these accelerator platforms. Along with high performance and energy efficiency, they must be able to cope with changes at an application and algorithmic level. In the face of these challenges, this dissertation explores the use of reconfiguration to balance flexibility, performance, and energy efficiency.
We begin by presenting three novel approaches that explore the use of reconfiguration in the three dominant computing devices -- CPUs, GPUs, and FPGAs. First, we consider general-purpose GPU (GPGPU) computing and highlight the inefficiencies in GPGPU, and identify opportunities to leverage reconfiguration to address these inefficiencies. Our solution is novel reconfigurable GPU architecture that can adapt to the needs of GPUs by dynamically allocating computational and memory resources among GPU cores (SMs). Second, we consider the limitations of dynamic partial reconfiguration (DPR) in modern FPGAs. We observe that while DPR is a potentially powerful technique, it is difficult to leverage. Thus, we propose an end-to-end methodology to leverage dynamic partial reconfiguration in FPGAs. The approach scales from edge to cloud devices, and presents an overlay architecture and an integer linear programming (ILP) based scheduler and mapper. We also demonstrate the ability to simultaneously map multiple applications to one FPGA, and explore different scheduling and sharing strategies. Third, we attempt to bridge the gap between the efficiency of reconfigurable computing and near-memory computing for general-purpose computing. Thus, we consider a modern multi-core CPU, and propose a novel architecture that uses SRAM arrays in the last level cache to create a reconfigurable computing fabric. Our approach is cheap, fast, energy-efficient, non-invasive, and flexible.
Finally, this dissertation concludes by considering the lessons learned from exploiting reconfiguration on CPUs, GPUs, and FPGAs, and asks how a modern reconfigurable computing device should be designed. With the explosion of data, large computational workloads, and increasing demands of efficiency, we propose a new memory-centric reconfigurable architecture, capable of fast dynamic reconfiguration and altering its compute to memory ratio and organization. We demonstrate significantly higher performance, density, and memory capacity than modern FPGAs.Submission published under a 24 month embargo labeled 'U of I Access', the embargo will last until 2023-05-01The student, Ashutosh Dhar, accepted the attached license on 2021-04-22 at 19:11.The student, Ashutosh Dhar, submitted this Dissertation for approval on 2021-04-22 at 19:22.This Dissertation was approved for publication on 2021-04-23 at 08:48.DSpace SAF Submission Ingestion Package generated from Vireo submission #16518 on 2021-09-16 at 17:05:00Made available in DSpace on 2021-09-17T02:34:45Z (GMT). No. of bitstreams: 2
DHAR-DISSERTATION-2021.pdf: 3961974 bytes, checksum: 3ede57178748228b2b08944c761b3fcf (MD5)
LICENSE.txt: 4210 bytes, checksum: 16c27b2fae4dabc5e151a01dea7680c0 (MD5)
Previous issue date: 2021-04-23Embargo set by: Seth Robbins for item 118575
Lift date: 2023-09-17T02:34:57Z
Reason: Author requested U of Illinois access only (OA after 2yrs) in Vireo ETD systemAuthor requested U of Illinois access only (OA after 2yrs) in Vireo ETD systemU of I Onl
Fourth-order stability analysis for capillary-gravity waves on finite-depth currents with constant vorticity
No full textThis article may be downloaded for personal use only. Any other use requires prior permission of the author and AIP Publishing. This article appeared in A. K. Dhar and James T. Kirby , "Fourth-order stability analysis for capillary-gravity waves on finite-depth currents with constant vorticity", Physics of Fluids 35, 026601 (2023) https://doi.org/10.1063/5.0136002 and may be found at https://doi.org/10.1063/5.0136002. This article will be embargoed until 02/01/2024.We derive a fourth-order nonlinear evolution equation (NLEE) for narrow-banded Stokes wave in finite depth in the presence of surface tension and a mean flow with constant vorticity. The two-dimensional capillary-gravity wave motion on the surface of finite depth is considered here. The analysis is limited to one horizontal dimension, parallel to the direction of wave propagation, in order to take advantage of a formulation using potential flow theory. This evolution equation is then employed to examine the effect of vorticity on the Benjamin–Feir instability (BFI) of the Stokes capillary-gravity wave trains. It is found that the vorticity modifies significantly the modulational instability and in the case of finite depth, the combined effect of vorticity and capillarity is to enhance the instability growth rate influenced by capillarity when the vorticity is negative. The key point is that the present fourth-order analysis exhibits considerable deviations in the stability properties from the third-order analysis and gives better results consistent with the exact numerical results. Furthermore, the influence of linear shear current on Peregrine breather (PB) is studied.This work was started during a visit by Professor A. K. Dhar to the University of Delaware. Professor J.T. Kirby was supported by the National Science Foundation, Physical Oceanography Program under Grant No. OCE-1756355. Professor A. K. Dhar wishes to acknowledge and sincerely thank the Indian Institute of Engineering Science and Technology, Shibpur for providing him the financial support through CPDA under Grant No. RDO/453/18. We thank the referees for their suggestions for improving the manuscript
Frame Game as Teaching Methodology in Higher Education: The Case of RElastiCity
No full textThe objective of the study is to illustrate the use of the frame game, RElastiCity as a framework to learn about the resilience of urban areas and the shocks and stresses in those areas. The question is if use of the frame game as a basis for game co-design is a useful approach to explore complex systems and its dynamics. This study covers the exploratory application of the approach in two university courses in the Netherlands. The results show divergent student experiences between the two courses. The main difference between the courses was the scope of the co-design assignment and the amount of time students had to complete the design process. It was found that using frame games as a framework for understanding complex systems is useful if students have sufficient time to investigate the topic, develop the game and playtest the game.Green Open Access added to TU Delft Institutional Repository 'You share, we take care!' - Taverne project https://www.openaccess.nl/en/you-share-we-take-care Otherwise as indicated in the copyright section: the publisher is the copyright holder of this work and the author uses the Dutch legislation to make this work public.Organisation & GovernanceDesign Conceptualization and Communicatio
“Risk Management Can Actually Be Fun”: Using the Serious Cards for Biosafety Game to Stimulate Proper Discussions About Biosafety
No full textAs part of a Dutch Science Foundation project called T-TRIPP, the authors developed the serious game Cards for Biosafety. The aim of Cards for Biosafety is to let young biotechnology researchers learn more about biosafety. Analyses of workshops with researchers from the biotechnology domain as well as results of interviews with several biosafety officers clearly indicated the need for such a serious game with a focus on educational learning. Cards for Biosafety is a physical (also playable online on Tabletopia) round-based card game and playable with up to eight players. The game itself consists of scenario, risk and measure cards, and the task of the players is to choose risk and measure cards that fit the scenario explained by the facilitator at the beginning of each round. To test the efficiency of Cards for Biosafety as a learning tool, the authors conducted two online-workshops with twelve participants. The results of these sessions have not only shown that Cards for Biosafety is a well-designed game, but also a successful game to achieve the intended learning goal. In addition, the authors recognized that ‘fun’ is an important element in the game which leads to ‘learning’ in a very effective way. Future research should focus on the role of such positive states in serious games and their influence on learning outcomes.Green Open Access added to TU Delft Institutional Repository ‘You share, we take care!’ – Taverne project https://www.openaccess.nl/en/you-share-we-take-care Otherwise as indicated in the copyright section: the publisher is the copyright holder of this work and the author uses the Dutch legislation to make this work public.Policy AnalysisGame La
Facilitated Tabletop Games in a Mediated Environment
No full textTabletop games that require the aid of a human facilitator are typically designed for a physical environment. However, during the COVID-19 pandemic, lockdown measures prevented people from gathering. Therefore, tabletop games were sometimes played and facilitated in a mediated environment using online communication tools instead. But this setting possibly deteriorates the players’ game experience. To understand the effect of playing facilitated tabletop games in a mediated environment we measured the player experience of the game Cue Kitchen in a mixed-method study comparing physical and mediated game sessions. Forty-four players played eleven game sessions, three in a physical environment and eight in a mediated environment. Of all seven dimensions of game experience measured, only one differed significantly between the two experimental conditions: players in a mediated environment became significantly more tired than players in a physical environment. The qualitative results explained why: players in a physical setting can wander off, while players in an online setting have to stay focused on their screen and, therefore, grow more tired. The research results suggest that facilitated tabletop games may be played in a mediated environment instead of a physical environment, without significant loss of player experience.Green Open Access added to TU Delft Institutional Repository ‘You share, we take care!’ – Taverne project https://www.openaccess.nl/en/you-share-we-take-care Otherwise as indicated in the copyright section: the publisher is the copyright holder of this work and the author uses the Dutch legislation to make this work public.Policy AnalysisOrganisation & Governanc
A Concentration-Dependent Liquid Phase Separation Can Cause Toxicity upon Increased Protein Expression
No full textSummaryMultiple human diseases are associated with a liquid-to-solid phase transition resulting in the formation of amyloid fibers or protein aggregates. Here, we present an alternative mechanism for cellular toxicity based on a concentration-dependent liquid-liquid demixing. Analyzing proteins that are toxic when their concentration is increased in yeast reveals that they share physicochemical properties with proteins that participate in physiological liquid-liquid demixing in the cell. Increasing the concentration of one of these proteins indeed results in the formation of cytoplasmic foci with liquid properties. Demixing occurs at the onset of toxicity and titrates proteins and mRNAs from the cytoplasm. Focus formation is reversible, and resumption of growth occurs as the foci dissolve as protein concentration falls. Preventing demixing abolishes the dosage sensitivity of the protein. We propose that triggering inappropriate liquid phase separation may be an important cause of dosage sensitivity and a determinant of human disease
- …
