Flavonoids and Related Compounds as Nucleoside Transporter Inhibitors

Mammalian nucleoside transporters can be classified into two main categories, namely, equilibrative nucleoside transporters (ENTs) and concentrative nucleoside transporters (CNTs). ENTs are ubiquitous, and mediate sodium-independent bi-directional facilitated diffusion nucleoside transport processes. CNTs on the other hand, are secondary active unidirectional transporters that are sodium-dependent. Both the equilibrative and the concentrative nucleoside transporters have several family members which are ENT1 to ENT4 and CNT1 to CNT6. Over the past two decades, important advances in the understanding of nucleoside transporter functions have been made. Identification and molecular cloning of the ENT and CNT families from mammals and protozoan parasites have provided much information about the structure, function, regulation, and tissue and cellular localization. Structure–function analyses of various nucleoside transporter chimeras and mutants have revealed important elements involved in substrate and inhibitor recognition and binding. However, the mechanisms that regulate nucleoside transporters in various tissues and cell types are just beginning to be understood. Because of the ability of these transporters to handle nucleoside analogues used in the treatment of patients with cancer and viral diseases, ongoing research should allow the design of more specifically targeted new compounds or improvements to existing drugs. New drugs are welcome not only in the treatment of cancer and viral diseases, but also in cardiovascular disorders and parasitic infections. Due to the absence of crystal structures and limited information regarding the active sites of nucleoside transporters, the designing of novel inhibitors is confined to ligand-based methods. In an effort to search for novel classes of inhibitors other than the existing ones, a series of 95 different flavone and flavone-like compounds was screened against concentrative nucleoside transporters (CNT 1, 2 and 3) and equilibrative nucleoside transporters (ENT 1 and 2). The results obtained in the form of IC50 values were further utilized to perform quantitative structure–activity relationship studies which indeed helped to understand the effects of different functionalities in the inhibition of nucleoside transporters. The validated 3D-QSAR models were used for design and activity prediction of new compounds. Pharmacophore hypotheses were also generated for hCNT3 using the PHASE pharmacophore mapping program to establish structural criteria for inhibitor design, and for database searching to find new hit molecules. Additionally, fifteen compounds were selected based on SAR and screened for equilibrative nucleoside transporter inhibition for validation of QSAR models. One novel compound, XI was designed with reduced complexity in further attempts to identify the ENT pharmacophore. But the synthetic route followed to prepare compound XI, resulted in the synthesis of compounds XII and XIII, which were evaluated as a mixture and exhibited substantial inhibitory activity against hENT1, but had no significant effect on hENT2 or hCNT3.This work has identified a novel class of CNT and ENT nucleoside transporter inhibitors and delineated structural determinants of potency and transporter subtype selectivity

Routine activity theory and research ethics: a criminological approach

Presented at the Retractions conference: keeping the pool clean: prevention and management of misconduct related retractions held on July 20-21, 2016 at Hilton Fort Collins in Fort Collins, Colorado.Kenneth D. Pimple, Ph.D., is Associate Scholar at Indiana University Bloomington (IUB) and Affiliate Faculty of the Indiana University Center for Bioethics. He has twenty years-five years of experience in research, teaching, and service on practical and professional ethics with a concentration on research ethics. He is especially known for organizing faculty workshops on ethics and research ethics. His publications include two books and more than twenty invited or peer-reviewed papers in journals including Communications of the ACM, Journal of Medical Ethics, Accountability in Research, Science and Engineering Ethics, and others. His service activities have included membership on advisory boards for three projects funded by the National Science Foundation and one funded by the National Institutes of Health; the Data and Safety Monitoring Board for the Comprehensive Sickle Cell Centers of the National Heart, Lung, and Blood Institute, National Institutes of Health; Bloomington Hospital's Institutional Review Board (IRB); and a number of committees at Indiana University, including the Institutional Animal Care and Use Committee (IACUC); the Committee on Research Fraud and Misconduct; the Human Subjects Protection Education Committee; and the Human Subjects Committee (IRB).PowerPoint presentation given on Day 1: Wednesday, July 20th, 2016.Includes bibliographical references.Research misconduct is often attributed to pressure or bad apples. There is little use of these folk theories because all professional scientists in the United States are always under pressure and, apparently, bad apples are only discovered after misconduct has been committed. These theories do not offer any explanatory or predictive promise because they focus on the multifaceted individual within a multifaceted population. Until the late 20th century, efforts by criminologists trying to understand who become criminals focused on interior, individual qualities, such as temperament or faulty cognition. More recently, two closely related ways of understanding and preventing crime: the more abstract Routine Activity Theory (RAT) informing the more concrete Situational Crime Prevention (SCP). While research misconduct is not technically a crime, they are analogs, and the insights of criminology can fruitfully be applied to the practice of science. In short, we should pay attention to the ways day-to-day routines of doing science make it difficult or easy to commit research misconduct. If only one person – say a graduate student – ever saw raw data, the PI has little chance of recognizing falsification, and a PI who always or randomly scrutinizes raw data will naturally deter most would-be bad actors. In this talk, I will briefly explain RAT and SCP, provide additional examples from criminology and possibly useful examples for science.This conference was funded by the Office of Research Integrity, U.S. Department of Health and Human Services, grant #ORIIR15001

Variation with Time of the Current in an Ozonizer Contraction (Discharge) Under D. C. Excitation

The count rate in Siemen ozonizer type tubes filled with dry air at Various low pressures, as measured by direct current impulse potential passing through it, has been found to decrease with the time during which the discharge is maintained reaching eventually a minimum value. It is concluded that this decrease is due to species formed during the discharge and adsorbed on the glass surface. It is also concluded that the ionization in the gaseous phase is small, and that the count rate Occurs by a sudden release of a cascade of electrons from the cathode, these electrons being responsible for decay formation through an air-atom mechanism

Review of 'A Dictionary of Narratology' by Gerald Prince

Book Review

An Inversion of the 'You're Going to Die!' Joke

Topics and Comment

The Inmates of Eigenmann: A Look at Door Decoration in a Graduate Dormitory

Paper

Evaluation of volar locking plate fixation for management of intra-articular fractures of distal end of radius

Background: With the increase in high velocity trauma, the incidence of intra-articular fractures of distal end of radius, particularly in adults- the working class of society is increasing. Normal functioning of wrist is of paramount importance for all activities of daily living and working. The present study was undertaken to evaluate the results of using volar locking plate for fixation of intra-articular fractures of distal end radius, with emphasis on return to pre-injury employment assessment.Methods: It is a combined prospective and retrospective study from January 2013 to June 2016. Twenty patients of intra-articular fractures of distal end of radius (AO type B2 and B3) were treated with volar locking plate through volar approach. The patients were regularly followed up for one year. The assessment of pain, range of motion, activity and grip strength were scored by Green and O’Brien’s system.Results: According to scoring system of Green and O’Brien the patients were assessed at 1 year follow up. 17 patients (85%) showed excellent results (scores 90-100). 2 patients (10%) showed good result (scores 80-89) while 1 patient (5%) had fair outcome (score 65-79). No patient had poor result (score less than 65). 19 patients (95%) returned to their pre-injury employment at 1 year.Conclusions: Open reduction and internal fixation with volar locking plate is reliable and excellent methods of management of intra-articular fracture of distal end of radius especially shear type of injury (AO type B2 and B3) in adults.