Small-molecule pyrimidine inhibitors of the cdc2-like (Clk) and dual specificity tyrosine phosphorylation-regulated (Dyrk) kinases: Development of chemical probe ML315

Substituted pyrimidine inhibitors of the Clk and Dyrk kinases have been developed, exploring structure-activity relationships around four different chemotypes. The most potent compounds have low-nanomolar inhibitory activity against Clk1, Clk2, Clk4, Dyrk1A and Dyrk1B. Kinome scans with 442 kinases using agents representing three of the chemotypes show these inhibitors to be highly selective for the Clk and Dyrk families. Further off-target pharmacological evaluation with ML315, the most selective agent, supports this conclusion

TRPA1- FGFR2 binding event is a regulatory oncogenic driver modulated by miRNA-142-3p

YesRecent evidence suggests that the ion channel TRPA1 is implicated in lung adenocarcinoma (LUAD) where its role and mechanism of action remain unknown. We have previously established that the membrane receptor FGFR2 drives LUAD progression through aberrant protein-protein interactions mediated via its C-terminal proline rich motif. Here, we report that the N-terminal ankyrin repeats of TRPA1 directly bind to the C-terminal proline rich motif of FGFR2 inducing the constitutive activation of the receptor, thereby prompting LUAD progression and metastasis. Furthermore, we show that upon metastasis to the brain, TRPA1 gets depleted, an effect triggered by the transfer of TRPA1-targeting exosomal microRNA (miRNA-142-3p) from brain astrocytes to cancer cells. This downregulation, in turn, inhibits TRPA1-mediated activation of FGFR2 hindering the metastatic process. Our study reveals a direct binding event and characterizes the role of TRPA1 ankyrin repeats in regulating FGFR2-driven oncogenic process; a mechanism that is hindered by miRNA-142-3p.Faculty of Biological Sciences at the University of Leeds, Wellcome Trust Seed Award, Royal Society Research Grant RG150100, MR/K021303/1, Swedish Research Council (2014-3801) and the Medical Faculty at Lund University

Basel III: dehybridisation of capital

One of the core problems in the credit crisis of 2007-08, which continued in an attenuated form through 2011, is the risk of national banking failure stemming from inadequate banking capital. Basel II, whose main purpose was to set out standards for the regulation of capital of internationally active banks, had encouraged a hybridization of capital which was dramatically reversed by the announcement of Basel III in December 2009. This paper explores the rationale for the new capital standard under Basel III. We focus on the link between excessive hybridization of tier 1 capital as a result of implementing Basel II, and the subsequent need for government sponsored bailouts during periods of high liquidity risk. This linkage indicates that Basel II had failed to mitigate liquidity risk, and perversely, amplified it by allowing hybrid financial instruments to be treated with equity-like certainty. Basel III in effect represents a failure of the financial economic models of Basel II. To allay these failures, we propose that substantive legal distinctions replace financial risk metrics in drawing distinctions between equity, hybrid capital and debt with regards to core capital. These distinctions will provide a sense of certainty and financial stability to banking capital

A systems study on the non-penicillin tablet and capsule production of Sydenham, Laboratories Inc.

Established in 1971, SYDENHAM Laboratories Inc. (SLI) derives its name from one of the great British physicians, Dr. Thomas SYDENHAM SLI manufactures non-penicillin, penicillin and cephalexin oral drug preparations in the following dosage forms: tablet, capsule, syrup, and Powder for Suspension. Non-penicillin and cephalexin products are manufactured in separate buildings with exclusive air-handling systems to ensure zero-cross t. SLI also manufactures food supplements in the above dosage forms. The company is included in the pharmacy industry. The product line comprises of three parts - the non-penicillin, penicillin, and cephalexin oral preparations in the following dosage forms: capsule, tablet, and syrup (liquid). In conducting a situation appraisal, the company\u27s strengths, weaknesses, opportunities and threats were determined. Sydenham\u27s strengths included its high attendance rate, low rejects, low deviation between their target and actual output, and minimal product returns. On the other hand, like all other companies, Sydenham has its weaknesses. The company\u27s total cancelled orders amounted to 31.39% of the total orders for the year 2004. In addition, the machines are not fully utilized to its maximum capacity. The company also has an opportunity by using an existing machine which could well double the output of the production. The threats of the company include the Peso-Dollar exchange rates since raw materials are imported, and a threat of mislabeling product which may cause the company to be shut down. The corresponding seriousness, urgency, resource, and growth of the weaknesses, opportunity, and threats were evaluated. Based on the WOT-SURG analysis, the problem that has the most impact on the system was identified it was the 31.39% cancelled orders. This problem has resulted into opportunity costs of Php889,460.70 monthly. A fishbone diagram was created to fully determine the root of the problem. The possible causes of the cancellation of orders are the production line bottleneck, machine downtime, poor production scheduling, standards, and worker productivity. Due to the problem, the company has incurred opportunity costs totaling to Php10,673,528.44 in the year 2004. A Pareto Analysis was used to narrow down the initial causes to the true roots of the problem. The Kepner-Tregoe Decision Analysis (KTDA) was used to evaluate the alternative solutions formulated for each final cause. The proposed solutions to reduce cancelled orders are as follows: Introduce a program for production scheduling, hire additional supervisors to monitor workers, and utilize available Sigma Mixer. ; The costs and benefits of the proposed solutions were evaluated. The computed net present value (NPV) of the proposed solutions was positive, making them beneficial for the company. The total net benefits incurred due to the proposed solutions amount to Php9,891,233.19. The net present value was evaluated over a five year time period, which amounted to Php23,889,349.90. Since the NPV is positive, the proposed solutions are financially feasible and will be beneficial to the company

Structure activity relationships of human galactokinase inhibitors

Classic Galactosemia is a rare inborn error of metabolism that is caused by deficiency of galactose-1-phosphate uridyltransferase (GALT), an enzyme within the Leloir pathway that is responsible for the conversion of galactose-1-phosphate (gal-1-p) and UDP-glucose to glucose-1-phosphate and UDP-galactose. This deficiency results in elevated intracellular concentrations of its substrate, gal-1-p, and this increased concentration is believed to be the major pathogenic mechanism in Classic Galactosemia. Galactokinase (GALK) is an upstream enzyme of GALT in the Leloir pathway and is responsible for conversion of galactose and ATP to gal-1-p and ADP. Therefore, it was hypothesized that the identification of a small-molecule inhibitor of human GALK would act to prevent the accumulation of gal-1-p and offer a novel entry therapy for this disorder. Herein we describe a quantitative high-throughput screening campaign that identified a single chemotype that was optimized and validated as a GALK inhibito

Small-molecule pyrimidine inhibitors of the cdc2-like (Clk) and dual specificity tyrosine phosphorylation-regulated (Dyrk) kinases: Development of chemical probe ML315

Substituted pyrimidine inhibitors of the Clk and Dyrk kinases have been developed, exploring structure-activity relationships around four different chemotypes. The most potent compounds have low-nanomolar inhibitory activity against Clk1, Clk2, Clk4, Dyrk1A and Dyrk1B. Kinome scans with 442 kinases using agents representing three of the chemotypes show these inhibitors to be highly selective for the Clk and Dyrk families. Further off-target pharmacological evaluation with ML315, the most selective agent, supports this conclusion

BioAssay Research Database (BARD): chemical biology and probe-development enabled by structured metadata and result types

BARD, the BioAssay Research Database (https://bard.nih.gov/) is a public database and suite of tools developed to provide access to bioassay data produced by the NIH Molecular Libraries Program (MLP). Data from 631 MLP projects were migrated to a new structured vocabulary designed to capture bioassay data in a formalized manner, with particular emphasis placed on the description of assay protocols. New data can be submitted to BARD with a user-friendly set of tools that assist in the creation of appropriately formatted datasets and assay definitions. Data published through the BARD application program interface (API) can be accessed by researchers using web-based query tools or a desktop client. Third-party developers wishing to create new tools can use the API to produce stand-alone tools or new plug-ins that can be integrated into BARD. The entire BARD suite of tools therefore supports three classes of researcher: those who wish to publish data, those who wish to mine data for testable hypotheses, and those in the developer community who wish to build tools that leverage this carefully curated chemical biology resource