Design and Synthesis of DDR1 Inhibitors with a Desired Pharmacophore Using Deep Generative Models

Discoidin domain receptor 1 (DDR1) inhibitors with a desired pharmacophore were designed using deep generative models (DGMs). DDR1 is a receptor tyrosine kinase activated by matrix collagens and implicated in diseases such as cancer, fibrosis and hypoxia. Herein we describe the synthesis and inhibitory activity of compounds generated from DGMs. Three compounds were found to have sub-micromolar inhibitory activity. The most potent of which, compound 3 (N-(4-chloro-3-((pyridin-3-yloxy)methyl)phenyl)-3-(trifluoromethyl)benzamide), had an IC₅₀ value of 92.5 nM. Furthermore, these compounds were predicted to interact with DDR1, which have a desired pharmacophore derived from a known DDR1 inhibitor. The results of synthesis and experiments indicated that our de novo design strategy is practical for hit identification and scaffold hopping.     

Gangliosides as Signaling Regulators in Cancer

At the plasma membrane, gangliosides, a group of glycosphingolipids, are expressed along with glycosphingolipids, phospholipids, and cholesterol in so-called lipid rafts that interact with signaling receptors and related molecules. Most cancers present abnormalities in the intracellular signal transduction system involved in tumor growth, invasion, and metastasis. To date, the roles of gangliosides as regulators of signal transduction have been reported in several cancer types. Gangliosides can be expressed by the exogenous ganglioside addition, with their endogenous expression regulated at the enzymatic level by targeting specific glycosyltransferases. Accordingly, the relationship between changes in the composition of cell surface gangliosides and signal transduction has been investigated by controlling ganglioside expression. In cancer cells, several types of signaling molecules are positively or negatively regulated by ganglioside expression levels, promoting malignant properties. Moreover, antibodies against gangliosides have been shown to possess cytotoxic effects on ganglioside-expressing cancer cells. In the present review, we highlight the involvement of gangliosides in the regulation of cancer cell signaling, and we explore possible therapies targeting ganglioside-expressing cancer.     

Learning about Enzyme Stability against Organic Cosolvents from Structural Insights by Ion Mobility Mass Spectrometry

Ion mobility spectrometry (IMS) coupled with mass spectrometry (MS) enables the investigation of protein folding in solution. Herein, a proof-of-concept for obtaining structural information about the folding of a protein in dependency of the amount of an organic cosolvent in the aqueous medium by means of this IMS-MS method is presented. By analyzing the protein with native nano-electrospray ionization IMS-MS, the impact of acetonitrile as a representative organic cosolvent and/or pH values on the folding of an enzyme was successfully evaluated in a fast and straightforward fashion, as exemplified for an ene reductase from Gluconobacter oxydans. The IMS-MS results are in agreement with findings from the nicotinamide adenine dinucleotide phosphate (NADPH)-based spectrophotometric enzyme activity tests under analogous conditions, and thus, also rationalizing these “wet” analytical data. For this ene reductase, a higher tolerance against CH₃CN in the presence of a buffer was observed by both analytical methods. The results suggest that this IMS-MS methodology could be a useful complementary tool to existing methods in process optimization and fine-tuning of solvent conditions for biotransformations.     

Clinical evaluation of a reagent for detection of DNA of Mycobacterium tuberculosis complex using the ligase chain reaction (LCR) method

We evaluated the clinical efficacy of LCR MTB, a reagent developed by Abbott in the USA, in the full automatic ligase chain reaction (LCR) for detection of DNA of M. tuberculosis complex using a thermostable ligase. Using 458 samples isolated from patients with tuberculosis, LCR was compared with a smear method and with a culture method, and was also compared with two other methods of gene amplification, MTD and Amplicor, using 340 and 200 of the 458 samples, respectively. The LCR method detected M. tuberculosis in 49.8% (228/458) of the samples, and was superior to the smear method (31.9%, 146/458) and the culture method (39.1%, 179/458) in sensitivity. The LCR method was also superior to the MTD and Amplicor methods; sensitivity were 37.9% (129/340) for MTD vs. 47.6% (162/340) for LCR, and 56.5% (113/200) for Amplicor vs. 59.5% (119/200) for LCR. These favorable results and the convenience of the LCR method, which enables rapid detection of target genes with a high degree of sensitivity, strongly suggest that LCR MTB is useful as a reagent for detection of M. tuberculosis using nucleic acid amplification.     

SAPAPs. A family of PSD-95/SAP90-associated proteins localized at postsynaptic density

PSD-95/SAP90 is a member of membrane-associated guanylate kinases localized at postsynaptic density (PSD) in neuronal cells. Membrane-associated guanylate kinases are a family of signaling molecules expressed at various submembrane domains which have the PDZ (DHR) domains, the SH3 domain, and the guanylate kinase domain. PSD-95/SAP90 interacts with N-methyl-D-aspartate receptors 2A/B, Shaker-type potassium channels, and brain nitric oxide synthase through the PDZ (DHR) domains and clusters these molecules at synaptic junctions. However, neither the function of the SH3 domain or the guanylate kinase domain of PSD-95/SAP90, nor the protein interacting with these domains has been identified. We have isolated here a novel protein family consisting of at least four members which specifically interact with PSD-95/SAP90 and its related proteins through the guanylate kinase domain, and named these proteins SAPAPs (SAP90/PSD-95-Associated Proteins). SAPAPs are specifically expressed in neuronal cells and enriched in the PSD fraction. SAPAPs induce the enrichment of PSD-95/SAP90 to the plasma membrane in transfected cells. Thus, SAPAPs may have a potential activity to maintain the structure of PSD by concentrating its components to the membrane area.     

Correlation Analysis for Simultaneously Controlling Reliability and Validity

The purpose of the present study is to propose a procedure for correlation analysis of several (especially two) sets of variables, which includes canonical correlation analysis, principal component analysis, and multiple regression analysis as a special case. The proposed method derives components from each set of variables which maximize the weighted geometric mean of two types of indicators: one is the contribution rate of the components for their original variables, the other is the squared correlation between the components. In terms of the test theory, the former are indicators of reliability and the latter are indicators of concurrent validity. Through the numerical examples applying this method to the data of two Japanese language personality inventory, the method is shown to be particularly useful when determining the weights for test items.

     

Ramp‐setup design technique in three‐electrode surface‐discharge ACPDPs

Abstract— A simple model to calculate changes in wall voltage during weak discharge in three‐electrode ACPDPs was developed. A change in the wall voltage vector has an intrinsic direction for each discharge, which not only reveals the basis of problems in the ramp setup but also simplifies the analysis of cell operation during setup. New ramp‐setup waveforms designed for this model widened the operating margin.     

A new electric power network for effective transportation of small power of dispersed generation plants

This paper proposes a new electric power network that makes it possible for many types of dispersed generation plants owned by nonutility organizations to participate in an electric power market without the disadvantages of existing power utility and customers. This power network is called an open electric energy network (OEEN) because the network is open to the many types of plants for the participation. For achieving such openness, electric power storage devices, load controller at each customer and data communication network are installed in OEEN; the flow of excess electric power generated by each plant is controlled autonomously and in a distributed way. That is, the control is done by transmitting the data on excess electric power such as generation and demand point, power quality, price, etc., from each dispersed generation plant to the power storage devices and the load controllers through the communication network. Since this data-driven power flow control is similar to the mail system for a packet with the addresses of sender and receiver, it is called packet electric power transportation. In OEEN the storage device plays a different role from load leveling. Therefore, the way to determine the storage capacity differs from the conventional approach. In this paper, the applicability of queuing theory for determining the capacity is also discussed.     

Extended integral equation formulation for scattering problems froma cylindrical scatterer

An extended integral equation is developed for electromagnetic scattering from a perfectly conducting cylinder and a dielectric cylinder. The conventional surface integral equations cannot yield unique solutions when the wavenumber of the electromagnetic wave is equal to an eigenwavenumber of the system. Several methods to overcome this difficulty have been presented, but each method includes some drawbacks. A numerical method is proposed in which the boundary element method is applied to the extended integral equations with the observation points lying on a closed surface inside the scatterer. It is shown that the extended integral equations have unique solutions for any given wavenumber. As examples, plane wave scattering from a perfectly conducting elliptic cylinder, a dielectric elliptic cylinder, and a dielectric rectangular cylinder is numerically analyzed