Exploring MERTK inhibitor binding mechanisms: insights from adaptive steered molecular dynamics and free energy calculation.

MERTK, a promising drug target for the treatment of human leukemia and solid tumors, and the development of its small molecule inhibitors holds significant clinical potential. However, the underlying reasons for the varying activities among these inhibitors and the specifics of their binding mechanism have not been systematically investigated. By combining conventional molecular dynamics simulations, adaptive steered molecular dynamics simulations and binding free energy calculations based on molecular mechanics Poisson-Boltzmann surface area, the interaction modes of four MERTK inhibitors and dissociation behavior are discussed in detail.

Maternal prepregnancy overweight/obesity increase the risk of low Apgar scores in twins: a population-based cohort study in China.

Objective: While prepregnancy overweight or obesity is known to negatively impact maternal health, its effect on twin infants is not well understood. Therefore, we conducted a nationwide, multicenter retrospective study to investigate the association between maternal prepregnancy weight and health outcomes in twins.

Study Design: This study collected data from 22 healthcare units across 12 regions in China between January 2018 and December 2020.

Discovery of novel spirocyclic derivates as potent androgen receptor antagonists.

We report herein the development of a series of novel AR antagonists characterized by a spirocyclic scaffold, employing scaffold hopping and structure-based drug design strategies. Most of the spirocyclic derivatives exhibited enhanced AR antagonistic activity and superior antiproliferative activity against LNCaP cells compared to enzalutamide. Among them, compound 21 demonstrated moderate antiproliferative activity against enzalutamide resistant prostate cancer cell lines and exhibited favorable in vitro metabolic stability.

Phosphorylation of the prokaryotic histone-like protein H-NS modulates bacterial virulence in Salmonella Typhimurium.

H-NS is a prokaryotic histone-like protein that binds to bacterial chromosomal DNA with important regulatory roles in gene expression. Unlike histone proteins, hitherto post-translational modifications of H-NS are still largely uncharacterized, especially in bacterial pathogens. Salmonella Typhimurium is a primary enteric pathogen and its virulence is mainly dependent on specialized type III secretion systems (T3SSs), which were evolutionarily acquired via horizontal gene transfer.

A 4D tensor-enhanced multi-dimensional convolutional neural network for accurate prediction of protein-ligand binding affinity.

Protein-ligand interactions are the molecular basis of many important cellular activities, such as gene regulation, cell metabolism, and signal transduction. Protein-ligand binding affinity is a crucial metric of the strength of the interaction between the two, and accurate prediction of its binding affinity is essential for discovering drugs' new uses. So far, although many predictive models based on machine learning and deep learning have been reported, most of the models mainly focus on one-dimensional sequence and two-dimensional structural characteristics of proteins and ligands, but fail to deeply explore the detailed interaction information between proteins and ligand atoms in the binding pocket region of three-dimensional space.

An Emerging Way for Bacteria to Engage with Host Cells via Protein ADP-riboxanation.

Post-translational modifications (PTMs) are increasingly recognized as important strategies used by bacterial pathogens to modulate host cellular functions. Protein ADP-riboxanation, a derivative of ADP-ribosylation, has recently emerged as a new biochemical way by which bacterial pathogens interact with host cells. Recent studies have revealed that this modification has broad regulatory roles in host processes including cell death, protein translation, and stress granule formation.

Graph Curvature Flow-Based Masked Attention.

Graph neural networks (GNNs) have revolutionized drug discovery in chemistry and biology, enhancing efficiency and reducing resource demands. However, classical GNNs often struggle to capture long-range dependencies due to challenges like oversmoothing and oversquashing. Graph Transformers address these issues by employing global self-attention mechanisms that allow direct information exchange between any pair of nodes, enabling the modeling of long-range interactions.

Transition-Metal-Free Late-Stage Decarboxylative -Difluoroallylation of Primary Alkyl Acids.

A transition-metal-free late-stage decarboxylative -difluoroallylation of carboxylic acids with α-trifluoromethyl alkenes has been described by the use of organo-photoredox catalysis. Both primary alkyl and heteroaryl acids were readily incorporated. This approach merits feedstock materials, mild reaction conditions, and wide functionality tolerance.

Integrating Convolution and Sparse Coding for Learning Low-Dimensional Discriminative Image Representations.

This work investigates the problem of efficiently learning discriminative low-dimensional (LD) representations of multiclass image objects. We propose a generic end-to-end approach that jointly optimizes sparse dictionary and convolutions for learning LOW-dimensional discriminative image representations, named SparConvLow, taking advantage of convolutional neural networks (CNNs), dictionary learning, and orthogonal projections. The whole learning process can be summarized as follows.

A simple and label-free fluorescent DNA sensor for visual detection of aptamer-based berberine.

The intrinsic fluorescence of berberine is very weak, which can be enhanced by its interaction with specific aptamers. A simple and sensitive DNA sensor for visual detection of berberine has here been established. When using this sensor, there was a good linear relationship between the change in fluorescence intensity of berberine and the concentration of berberine in the range of 16-2000 nM, with a detection limit of 5.

Preparation of kakkatin derivatives and their anti-tumor activity.

Background: Modern pharmacological studies have confirmed that plant-derived compounds from Puerariae flos (PF) has significant biological activities against liver damage, tumors and inflammation. Kakkatin is an isoflavone polyphenolic compound isolated from PF flower. However, the effect of kakkatin and its derivatives on anti-tumor has not been well explored.

Antagonist anti-LIF antibody derived from naive human scFv phage library inhibited tumor growth in mice.

Background: Leukemia inhibitory factor (LIF) is a multifunctional member of the IL-6 cytokine family that activates downstream signaling pathways by binding to the heterodimer consisting of LIFR and gp130 on the cell surface. Previous research has shown that LIF is highly expressed in various tumor tissues (e.g.

Nasopharyngeal cancer risk assessment by country or region worldwide from 1990 to 2019.

Background: Nasopharyngeal carcinoma (NPC) is 22nd most common cancer that occurs all over the world, but the prevalence rate can exhibit significant geographical differences. The Global Burden of Disease (GBD) database provides data related to the incidence, mortality, and disease burden of NPC worldwide from 1990 to 2019. We have designed this study in order to evaluate the potential effectiveness of health care policies and strategies for NPC prevention, diagnosis and treatment in different countries or regions around the world.

Legionella maintains host cell ubiquitin homeostasis by effectors with unique catalytic mechanisms.

The intracellular bacterial pathogen Legionella pneumophila modulates host cell functions by secreting multiple effectors with diverse biochemical activities. In particular, effectors of the SidE family interfere with host protein ubiquitination in a process that involves production of phosphoribosyl ubiquitin (PR-Ub). Here, we show that effector LnaB converts PR-Ub into ADP-ribosylated ubiquitin, which is further processed to ADP-ribose and functional ubiquitin by the (ADP-ribosyl)hydrolase MavL, thus maintaining ubiquitin homeostasis in infected cells.

Binding sites and design strategies for small molecule GLP-1R agonists.

Glucagon-like peptide-1 receptor (GLP-1R) is a pivotal receptor involved in blood glucose regulation and influencing feeding behavior. It has received significant attention in the treatment of obesity and diabetes due to its potent incretin effect. Peptide GLP-1 receptor agonists (GLP-1RAs) have achieved tremendous success in the market, driving the vigorous development of small molecule GLP-1RAs.

[Risk factors for bronchopulmonary dysplasia in twin preterm infants: a multicenter study].

Objectives: To investigate the risk factors for bronchopulmonary dysplasia (BPD) in twin preterm infants with a gestational age of <34 weeks, and to provide a basis for early identification of BPD in twin preterm infants in clinical practice.

Methods: A retrospective analysis was performed for the twin preterm infants with a gestational age of <34 weeks who were admitted to 22 hospitals nationwide from January 2018 to December 2020. According to their conditions, they were divided into group A (both twins had BPD), group B (only one twin had BPD), and group C (neither twin had BPD).

Isobavachalcone: A redox antifungal agent impairs the mitochondria protein of Cryptococcus neoformans.

Isobavachalcone (IBC) is a natural small molecule with various biological activities; however, its inhibitory effects on Cryptococcus neoformans remain unclear. In our study, IBC showed a good antifungal effect. Through in vitro experiments, its minimum inhibitory concentration was 0.

Organo-photoredox catalyzed -difluoroallylation of ketone-derived dihydroquinazolinones C(sp)-C bond and C(sp)-F bond cleavage.

An organo-photoredox catalyzed -difluoroallylation of both acyclic and cyclic ketone derivatives with α-trifluoromethyl alkenes has been demonstrated, thus giving access to a diverse set of -difluoroalkenes in moderate to high yields. Pro-aromatic dihydroquinazolinones can be either pre-formed or generated for ketone activation. This reaction is characterized by readily available starting materials, mild reaction conditions, and broad substrate scope.

Legionella maintains host cell ubiquitin homeostasis by effectors with unique catalytic mechanisms.

The reversal of ubiquitination induced by members of the SidE effector family of produces phosphoribosyl ubiquitin (PR-Ub) that is potentially detrimental to host cells. Here we show that the effector LnaB functions to transfer the AMP moiety from ATP to the phosphoryl moiety of PR-Ub to convert it into ADP-ribosylated ubiquitin (ADPR-Ub), which is further processed to ADP-ribose and functional ubiquitin by the (ADP-ribosyl)hydrolase MavL, thus maintaining ubiquitin homeostasis in infected cells. Upon being activated by Actin, LnaB also undergoes self-AMPylation on tyrosine residues.

Bacterial ubiquitin ligases hijack the host deubiquitinase OTUB1 to inhibit MTORC1 signaling and promote autophagy.

Many bacterial pathogens have evolved effective strategies to interfere with the ubiquitination network to evade clearance by the innate immune system. Here, we report that OTUB1, one of the most abundant deubiquitinases (DUBs) in mammalian cells, is subjected to both canonical and noncanonical ubiquitination during infection. The effectors SidC and SdcA catalyze OTUB1 ubiquitination at multiple lysine residues, resulting in its association with a -containing vacuole.