A Target Class Ligandability Evaluation of WD40 Repeat-Containing Proteins.

Target class-focused drug discovery has a strong track record in pharmaceutical research, yet public domain data indicate that many members of protein families remain unliganded. Here we present a systematic approach to scale up the discovery and characterization of small molecule ligands for the WD40 repeat (WDR) protein family. We developed a comprehensive suite of protocols for protein production, crystallography, and biophysical, biochemical, and cellular assays.

Potent synergy and sustained bactericidal activity of polymyxins combined with Gram-positive only class of antibiotics versus four Gram-negative bacteria.

Background: Gram-negative bacteria (GNB) are becoming increasingly resistant to a wide variety of antibiotics. There are currently limited treatments for GNB, and the combination of antibiotics with complementary mechanisms has been reported to be a feasible strategy for treating GNB infection. The inability to cross the GNB outer membrane (OM) is an important reason that a broad spectrum of Gram-positive only class of antibiotics (GPOAs) is lacking.

Mechanism and deterioration pattern of sandstone surrounding rock voiding at bottom of heavy-haul railway tunnel.

This study combines laboratory experiments and discrete element simulation methods to analyze the mechanism and deterioration patterns of sandstone surrounding rock voiding the bottom of a heavy-haul railway tunnel. It is based on previously acquired measurement data from optical fiber grating sensors installed in the Taihangshan Mountain Tunnel of the Wari Railway. By incorporating rock particle wastage rate results, a method for calculating the peak strength and elastic modulus attenuation of surrounding rock is proposed.

Discovery of DNL343: A Potent, Selective, and Brain-Penetrant eIF2B Activator Designed for the Treatment of Neurodegenerative Diseases.

Eukaryotic translation initiation factor 2B (eIF2B) is a key component of the integrated stress response (ISR), which regulates protein synthesis and stress granule formation in response to cellular insult. Modulation of the ISR has been proposed as a therapeutic strategy for treatment of neurodegenerative diseases such as vanishing white matter (VWM) disease and amyotrophic lateral sclerosis (ALS) based on its ability to improve cellular homeostasis and prevent neuronal degeneration. Herein, we report the small-molecule discovery campaign that identified potent, selective, and CNS-penetrant eIF2B activators using both structure- and ligand-based drug design.

Discovery of a First-in-Class Small-Molecule Ligand for WDR91 Using DNA-Encoded Chemical Library Selection Followed by Machine Learning.

WD40 repeat-containing protein 91 (WDR91) regulates early-to-late endosome conversion and plays vital roles in endosome fusion, recycling, and transport. WDR91 was recently identified as a potential host factor for viral infection. We employed DNA-encoded chemical library (DEL) selection against the WDR domain of WDR91, followed by machine learning to predict ligands from the synthetically accessible Enamine REAL database.

Matrix measure-based distributed impulsive consensus on nonlinear multi-agent systems with mixed time-varying delays.

This paper concentrates on researching the global and exponential leader-following consensus issue for an array of nonlinear multi-agent systems with the system time-varying delay and the distributed time-varying delay. An innovative distributed impulsive controller is proposed to force the states of all agents to track the trajectories of leader agent. By jointly introducing the matrix measure protocol, the comparison principle for impulsive systems, and the average impulsive interval, sufficient criteria for the realization of leader-following consensus are derived.

A sensitive LC-MS/MS assay to quantitate free payload Aur0101 from ADC PYX-201 in rat and monkey plasma.

Aur0101 is a cytotoxic and small-molecule microtubule depolymerizing agent, and is the payload conjugated to antibody-drug conjugate PYX-201. Developing and validating a sensitive bioanalytical method to quantitate Aur0101 was novel and crucial in preclinical PYX-201 studies. Reference standard Aur0101 and its stable isotope labelled internal standard Aur0101-d were used in this LC-MS/MS method.

Deep Learning Approach for the Discovery of Tumor-Targeting Small Organic Ligands from DNA-Encoded Chemical Libraries.

DNA-Encoded Chemical Libraries (DELs) have emerged as efficient and cost-effective ligand discovery tools, which enable the generation of protein-ligand interaction data of unprecedented size. In this article, we present an approach that combines DEL screening and instance-level deep learning modeling to identify tumor-targeting ligands against carbonic anhydrase IX (CAIX), a clinically validated marker of hypoxia and clear cell renal cell carcinoma. We present a new ligand identification and hit-to-lead strategy driven by machine learning models trained on DELs, which expand the scope of DEL-derived chemical motifs.

Embedding TiOmicrospheres into the active layer as light scatterers in a perovskite photodetector to boost light harvesting.

Here, TiOmicrospheres with particle sizes of 200-400 nm are embedded in p-i-n perovskite photodetectors, which are used as light scatterers. This approach was implemented to change the light transfer path in the perovskite layer, which gives the device higher photon-capture ability in a specific incident wavelength range. Compared with a pristine device, the photocurrent and responsivity of the device based on such a structure are obviously enhanced in the ranges of 560-610 nm and 730-790 nm.

Quantitation of total antibody (tAb) from antibody drug conjugate (ADC) PYX-201 in rat and monkey plasma using an enzyme-linked immunosorbent assay (ELISA) and its application in preclinical studies.

PYX-201 is an investigative ADC oncology drug composed of a monoclonal human immunoglobulin G (IgG) antibody targeting the extra domain B splice variant of fibronectin (EDB + FN) conjugated to an auristatin payload through a cleavable linker. Effective measurement of PYX-201 tAb is the key to ADC drug PYX-201 preclinical pharmacokinetics (PK) assessment. PYX-201 monoclonal antibody (mAb) was used as the reference standard, goat anti-human IgG polyclonal antibody (pAb) or rabbit anti-human Kappa light chain mAb was employed as the capture antibody, and mouse mAb or goat pAb anti-human IgG the crystallizable fragment (Fc) (horseradish peroxidase (HRP)) was utilized as the detection antibody in this ELISA.

Filling a nick in NIK: Extending the half-life of a NIK inhibitor through structure-based drug design.

Inhibition of NF-κB inducing kinase (NIK) has been pursued as a promising therapeutic target for autoimmune disorders due to its highly regulated role in key steps of the NF-κB signaling pathway. Previously reported NIK inhibitors from our group were shown to be potent, selective, and efficacious, but had higher human dose projections than desirable for immunology indications. Herein we report the clearance-driven optimization of a NIK inhibitor guided by metabolite identification studies and structure-based drug design.

Aperiodically intermittent event-triggered pinning control on cluster synchronization of directed complex networks.

This paper is dedicated to investigating the exponential cluster synchronization in a class of nonlinearly coupled complex networks with non-identical nodes and an asymmetrical coupling matrix. A novel aperiodically intermittent pinning control (APIPC) protocol is presented, which takes full account of the cluster-tree topology structure of the networks and pins only the nodes in the current cluster that have directional links to neighboring clusters. Since it is difficult to precisely determine the intermittent control instants and rest instants of APIPC in advance, the event-triggered mechanism (ETM) is thus proposed.

Application of New Sensor Technology and Few-Shot Learning in Education Based on IoT Era.

In recent years, with the rapid development of emerging Internet of Things technology and short-range wireless communication technology, smart healthcare monitoring network technology has become a research hotspot. It provides convenience for people and enhances the development of people's own healthcare awareness. This paper aims to study how to make its application in the field of smart healthcare education more applicable through the use of related technologies in the Internet of Things era and few-shot learning.

Matrix Measure-Based Event-Triggered Impulsive Quasi-Synchronization on Coupled Neural Networks.

In this article, the quasi-synchronization for a kind of coupled neural networks with time-varying delays is investigated via a novel event-triggered impulsive control approach. In view of the randomly occurring uncertainties (ROUs) in the communication channels, the global quasi-synchronization for the coupled neural networks within a given error bound is considered instead of discussing the complete synchronization. A kind of distributed event-triggered impulsive controllers is presented with considering the Bernoulli stochastic variables based on ROUs, which works at each event-triggered impulsive instant.

Aperiodically intermittent saturation consensus on multi-agent systems with discontinuous dynamics.

This paper mainly investigates the exponential consensus problem for the multi-agent systems (MASs) with nonlinear discontinuous dynamics and time-varying delay. A novel aperiodically intermittent distributed control strategy is proposed to force the state of each agent to the common trajectory, where the configuration of control width and rest width can be aperiodic. Meanwhile, in order to limit the control effects into certain reasonable ranges, an improved saturation algorithm is proposed, which effectively reduces the non-smoothness of the control signal.

Influence of aging on chronic unpredictable mild stress-induced depression-like behavior in male C57BL/6J mice.

Depression is a common psychiatric disorder that can occur throughout an individual's lifespan. Chronic unpredictable mild stress (CUMS) protocol is currently the most commonly used to develop an animal model of depression. Due to the variable duration and procedure of CUMS, it is difficult to reproduce and explore the mechanism of CUMS-induced depression effectively.

Depression-/Anxiety-Like Behavior Alterations in Adult Slit2 Transgenic Mice.

Slit2 is a member of the Slit family of secreted glycoproteins that plays highly conserved roles in neuronal axon guidance and cellular migration. Our previous experimental results showed Alzheimer's disease-like alterations and increased permeability of the blood-brain barrier in Slit2-overexpressing transgenic (Slit2-Tg) mice aged 8-9 months. Nevertheless, relatively little is known about behavioral alterations in adult Slit2-Tg mice (2-6 months of age).

Fixed-Time Synchronization of Complex Dynamical Networks: A Novel and Economical Mechanism.

Fixed-time synchronization of complex networks is investigated in this article. First, a completely novel lemma is introduced to prove the fixed-time stability of the equilibrium of a general ordinary differential system, which is less conservative and has a simpler form than those in the existing literature. Then, sufficient conditions are presented to realize synchronization of a complex network (with a target system) within a settling time via three different kinds of simple controllers.

Fixed-Time Synchronization of Coupled Neural Networks With Discontinuous Activation and Mismatched Parameters.

This article is concerned with fixed-time synchronization of the nonlinearly coupled neural networks with discontinuous activation and mismatched parameters. First, a novel lemma is proposed to study fixed-time stability, which is less conservative than those in most existing results. Then, based on the new lemma, a discontinuous neural network with mismatched parameters will synchronize to the target state within a settling time via two kinds of unified and simple controllers.

Inhibition of Discharge Side Reactions by Promoting Solution-Mediated Oxygen Reduction Reaction with Stable Quinone in Li-O Batteries.

Aprotic lithium-oxygen (Li-O) batteries with an ultrahigh theoretical energy density have great potential in rechargeable power supply, while their application still faces several challenges, especially poor cycle stability. To solve the problems, one of the effective strategies is to inhibit the generation of the LiO intermediate produced via a surface-mediated oxygen reduction reaction (ORR) pathway, which is an important species inducing byproduct generation and low cell cyclic stability. Herein, a series of quinones and solid materials serve as the solution-mediated and surface-mediated ORR catalysts, and it was found that the generation of LiO and byproducts from solid catalysts was inhibited by quinones.

Structure Based Design of Potent Selective Inhibitors of Protein Kinase D1 (PKD1).

We previously disclosed a series of type I 1/2 inhibitors of NF-κB inducing kinase (NIK). Inhibition of NIK by these compounds was found to be strongly dependent on the inclusion and absolute stereochemistry of a propargyl tertiary alcohol as it forms critical hydrogen bonds (H-bonds) with NIK. We report that inhibition of protein kinase D1 (PKD1) by this class of compounds is not dependent on H-bond interactions of this tertiary alcohol.

An efficient polymer coating for highly acid-stable zeolitic imidazolate frameworks based composite sponges.

Zeolitic imidazolate frameworks (ZIFs) possess tremendous potential in various adsorption and catalysis areas for their particular structures. However, the dispersibility and acid stability of ZIFs are important issues hindering their applications. To address these challenges, a transparent polydimethysiloxane (PDMS) coating was constructed to heterogeneously anchor the Cu doped ZIF-67 (Cu/ZIF-67) nanoparticles on melamine sponge surface, achieving a PDMS-coated ZIF three-dimensional composite sponge.

LP mutation on heavy chain stabilizes IgG under acidic conditions.

IgG, a common type of therapeutic antibody, is less stable during manufacturing processes compared with IgG. Aggregation and fragmentation are the two main challenges. Here, we report instability of the heavy chain (HC) C-terminal region under acidic conditions, which leads to cleavage and aggregation.

Development of Potent and Selective Pyrazolopyrimidine IRAK4 Inhibitors.

A series of pyrazolopyrimidine inhibitors of IRAK4 were developed from a high-throughput screen (HTS). Modification of an HTS hit led to a series of bicyclic heterocycles with improved potency and kinase selectivity but lacking sufficient solubility to progress in vivo. Structure-based drug design, informed by cocrystal structures with the protein and small-molecule crystal structures, yielded a series of dihydrobenzofurans.

Feedback pinning control of collective behaviors aroused by epidemic spread on complex networks.

This paper investigates feedback pinning control of synchronization behaviors aroused by epidemic spread on complex networks. Based on the quenched mean field theory, epidemic control synchronization models with the inhibition of contact behavior are constructed, combined with the epidemic transmission system and the adaptive dynamical network carrying active controllers. By the properties of convex functions and the Gerschgorin theorem, the epidemic threshold of the model is obtained, and the global stability of disease-free equilibrium is analyzed.