Actin filaments form a size-dependent diffusion barrier around centrosomes.

The centrosome, a non-membranous organelle, constrains various soluble molecules locally to execute its functions. As the centrosome is surrounded by various dense components, we hypothesized that it may be bordered by a putative diffusion barrier. After quantitatively measuring the trapping kinetics of soluble proteins of varying size at centrosomes by a chemically inducible diffusion trapping assay, we find that centrosomes are highly accessible to soluble molecules with a Stokes radius of less than 5.8 nm, whereas larger molecules rarely reach centrosomes, indicating the existence of a size-dependent diffusion barrier at centrosomes. The permeability of this barrier is tightly regulated by branched actin filaments outside of centrosomes and it decreases during anaphase when branched actin temporally increases. The actin-based diffusion barrier gates microtubule nucleation by interfering with γ-tubulin ring complex recruitment. We propose that actin filaments spatiotemporally constrain protein complexes at centrosomes in a size-dependent manner.

Hit Identification Driven by Combining Artificial Intelligence and Computational Chemistry Methods: A PI5P4K-ß Case Study.

Computer-aided drug design (CADD), especially artificial intelligence-driven drug design (AIDD), is increasingly used in drug discovery. In this paper, a novel and efficient workflow for hit identification was developed within the ID4Inno drug discovery platform, featuring innovative artificial intelligence, high-accuracy computational chemistry, and high-performance cloud computing. The workflow was validated by discovering a few potent hit compounds (best IC50 is ∼0.80 µM) against PI5P4K-ß, a novel anti-cancer target. Furthermore, by applying the tools implemented in ID4Inno, we managed to optimize these hit compounds and finally obtained five hit series with different scaffolds, all of which showed high activity against PI5P4K-ß. These results demonstrate the effectiveness of ID4inno in driving hit identification based on artificial intelligence, computational chemistry, and cloud computing.

Sensing, Imaging, and Therapeutic Strategies Endowing by Conjugate Polymers for Precision Medicine.

Conjugated polymers (CPs) have promising applications in biomedical fields, such as disease monitoring, real-time imaging diagnosis, and disease treatment. As a promising luminescent material with tunable emission, high brightness and excellent stability, CPs are widely used as fluorescent probes in biological detection and imaging. Rational molecular design and structural optimization have broadened absorption/emission range of CPs, which are more conductive for disease diagnosis and precision therapy. This review provides a comprehensive overview of recent advances in the application of CPs, aiming to elucidate their structural and functional relationships. The fluorescence properties of CPs and the mechanism of detection signal amplification are first discussed, followed by an elucidation of their emerging applications in biological detection. Subsequently, CPs-based imaging systems and therapeutic strategies are illustrated systematically. Finally, recent advancements in utilizing CPs as electroactive materials for bioelectronic devices are also investigated. Moreover, the challenges and outlooks of CPs for precision medicine are discussed. Through this systematic review, it is hoped to highlight the frontier progress of CPs and promote new breakthroughs in fundamental research and clinical transformation.

Organic Semiconducting Polymers for Augmenting Biosynthesis and Bioconversion.

Solar-driven biosynthesis and bioconversion are essential for achieving sustainable resources and renewable energy. These processes harness solar energy to produce biomass, chemicals, and fuels. While they offer promising avenues, some challenges and limitations should be investigated and addressed for their improvement and widespread adoption. These include the low utilization of light energy, the inadequate selectivity of products, and the limited utilization of inorganic carbon/nitrogen sources. Organic semiconducting polymers offer a promising solution to these challenges by collaborating with natural microorganisms and developing artificial photosynthetic biohybrid systems. In this Perspective, we highlight the latest advancements in the use of appropriate organic semiconducting polymers to construct artificial photosynthetic biohybrid systems. We focus on how these systems can enhance the natural photosynthetic efficiency of photosynthetic organisms, create artificial photosynthesis capability of nonphotosynthetic organisms, and customize the value-added chemicals of photosynthetic synthesis. By examining the structure-activity relationships and emphasizing the mechanism of electron transfer based on organic semiconducting polymers in artificial photosynthetic biohybrid systems, we aim to shed light on the potential of this novel strategy for artificial photosynthetic biohybrid systems. Notably, these coupling strategies between organic semiconducting polymers and organisms during artificial photosynthetic biohybrid systems will pave the way for a more sustainable future with solar fuels and chemicals.

Hierarchical Superstructure of Plant Polyphenol and Arginine Surfactant for Long-Lasting and Target-Selective Antimicrobial Application.

Antimicrobial agents are massively used to disinfect the pathogen contaminated surfaces since the Corona Virus Disease 2019 (COVID-19) outbreak. However, their defects of poor durability, strong irritation, and high environmental accumulation are exposed. Herein, a convenient strategy is developed to fabricate long-lasting and target-selective antimicrobial agent with the special hierarchical structure through bottom-up assembly of natural gallic acid with arginine surfactant. The assembly starts from rodlike micelles, further stacking into hexagonal columns and finally interpenetrating into spherical assemblies, which avoid explosive release of antimicrobial units. The assemblies show anti-water washing and high adhesion on various surfaces; and thus, possess highly efficient and broad-spectrum antimicrobial activities even after using up to eleven cycles. Both in vitro and in vivo experiments prove that the assemblies are highly selective in killing pathogens without generating toxicity. The excellent antimicrobial virtues well satisfy the increasing anti-infection demands and the hierarchical assembly exhibits great potential as a clinical candidate.

A Highly Stereoselective Redox Isomerization-Reductive Deuteration Sequence of Propargyl Amines to α-Deuterated Amino Acids.

Herein, we report a Cu-catalyzed redox isomerization-reductive deuteration sequence, providing facile access to a range of α-deuterated amino acid esters featuring an Z-configured alkene moiety with high yields. The advantages of this sequence include mild conditions, broad substrate scope, and excellent stereoselectivity. This research also represents a rare example of the Z-selective redox isomerization of propargyl amines.

Water-soluble conjugated polymers for bioelectronic systems.

Bioelectronics is an interdisciplinary field of research that aims to establish a synergy between electronics and biology. Contributing to a deeper understanding of bioelectronic processes and the built bioelectronic systems, a variety of new phenomena, mechanisms and concepts have been derived in the field of biology, medicine, energy, artificial intelligence science, etc. Organic semiconductors can promote the applications of bioelectronics in improving original performance and creating new features for organisms due to their excellent photoelectric and electrical properties. Recently, water-soluble conjugated polymers (WSCPs) have been employed as a class of ideal interface materials to regulate bioelectronic processes between biological systems and electronic systems, relying on their satisfying ionic conductivity, water-solubility, good biocompatibility and the additional mechanical and electrical properties. In this review, we summarize the prominent contributions of WSCPs in the aspect of the regulation of bioelectronic processes and highlight the latest advances in WSCPs for bioelectronic applications, involving biosynthetic systems, photosynthetic systems, biophotovoltaic systems, and bioelectronic devices. The challenges and outlooks of WSCPs in designing high-performance bioelectronic systems are also discussed.

Circular RNA has Circ 001372-Reduced Inflammation in Ovalbumin-Induced Asthma Through Sirt1/NFAT5 Signaling Pathway by miRNA-128-3p.

In this study, we sought to investigate the prospective role of circ 001372 in modifying inflammation in ovalbumin-induced asthma. In the vivo model of asthma, the serum of circ 001372 was reduced. Down-regulation of circ 001372 increased inflammation reaction (TNF-α, IL-1ß, IL-6, and IL-18) and induced COX-2 and iNOS protein expression in vitro model through activation of NFAT5 and suppression of Sirt1. Up-regulation of circ 001372 decreased inflammation reaction (TNF-α, IL-1ß, IL-6, and IL-18) in vitro model through inactivation of NFAT5 and induction of Sirt1 by miRNA-128-3p. The miRNA-128-3p lowered the effects of circ 001372 on inflammation in vitro model. The Sirt1 inhibitor reduced the effects of circ 001372 on inflammation in vitro model. Our results revealed the serum of circ 001372 against inflammation in ovalbumin-induced asthma through Sirt1/NFAT5 by miRNA-128-3p.

Conjugated polymers for biomedical applications.

Conjugated polymers (CPs) are a series of organic semiconductor materials with large π-conjugated backbones and delocalized electronic structures. Due to their specific photophysical properties and photoelectric effects, plenty of CPs with varied chemical structures and functions are quickly evolving in the diverse biomedical field, such as fluorescence imaging, photodynamic therapy, photothermal therapy, etc. In addition, the functionalized side chains of CPs could contribute to the expected water-solubility, biocompatibility, biological response, etc. CPs can also be prepared into nanoparticles for acquiring controllable particle size and dispersion through the common synthesis procedure. In this review, we focus on the latest developments of CPs in biotherapy, biological regulation, biological response and bioprinting applications. The major challenges and outlooks of CPs for applications in the biomedical field are also discussed.

ZHX2 promotes HIF1α oncogenic signaling in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is an aggressive and highly lethal disease, which warrants the critical need to identify new therapeutic targets. We show that Zinc Fingers and Homeoboxes 2 (ZHX2) is amplified or overexpressed in TNBC cell lines and patients. Functionally, depletion of ZHX2 inhibited TNBC cell growth and invasion in vitro, orthotopic tumor growth, and spontaneous lung metastasis in vivo. Mechanistically, ZHX2 bound with hypoxia-inducible factor (HIF) family members and positively regulated HIF1α activity in TNBC. Integrated ChIP-seq and gene expression profiling demonstrated that ZHX2 co-occupied with HIF1α on transcriptionally active promoters marked by H3K4me3 and H3K27ac, thereby promoting gene expression. Among the identified ZHX2 and HIF1α coregulated genes, overexpression of AP2B1, COX20, KDM3A, or PTGES3L could partially rescue TNBC cell growth defect by ZHX2 depletion, suggested that these downstream targets contribute to the oncogenic role of ZHX2 in an accumulative fashion. Furthermore, multiple residues (R491, R581, and R674) on ZHX2 are important in regulating its phenotype, which correspond with their roles on controlling ZHX2 transcriptional activity in TNBC cells. These studies establish that ZHX2 activates oncogenic HIF1α signaling, therefore serving as a potential therapeutic target for TNBC.

An Efficient Timer and Sizer of Biomacromolecular Motions.

Life ticks as fast as how proteins move. Computationally expensive molecular dynamics simulation has been the only theoretical tool to gauge the time and sizes of these motions, though barely to their slowest ends. Here, we convert a computationally cheap elastic network model (ENM) into a molecular timer and sizer to gauge the slowest functional motions of structured biomolecules. Quasi-harmonic analysis, fluctuation profile matching, and the Wiener-Khintchine theorem are used to define the "time periods," t, for anharmonic principal components (PCs), which are validated by nuclear magnetic resonance (NMR) order parameters. The PCs with their respective "time periods" are mapped to the eigenvalues (λENM) of the corresponding ENM modes. Thus, the power laws t(ns) = 56.1λENM-1.6 and σ2(Å2) = 32.7λENM-3.0 can be established allowing the characterization of the timescales of NMR-resolved conformers, crystallographic anisotropic displacement parameters, and important ribosomal motions, as well as motional sizes of the latter.

Macrolide-resistant Streptococcus pyogenes from Chinese pediatric patients in association with Tn916 transposons family over a 16-year period.

To investigate changes in the antimicrobial susceptibility of Streptococcus pyogenes isolates over a 16-year period, 456 group A streptococci isolates were collected from Chinese pediatric patients among 1993 to 1994 and 2005 to 2008. Susceptibilities to antibiotics were performed using agar dilution methods. The macrolide resistance genes ermB, ermTR, mefA, and tetracycline-resistant gene tetM and the int and xis genes of Tn916 family were detected by polymerase chain reaction. All 456 strains were analyzed by emm typing. Selected strains representing each emm type were further characterized by pulsed-field gel electrophoresis. The resistance rates of erythromycin and clindamycin both significantly increased during the 2 sample periods (79.7% versus 94% for erythromycin and 75.4% versus 96.9% for clindamycin). Telithromycin resistance rate increased from 20.37% to 87.93%. Among the macrolide resistance strains, the rate of strains with the genes int, xis, tetM, and ermB increased with time (16.05% versus 86.91%, P < 0.05). The emm1 and emm12 isolates had high rates of ermB gene, which increased after 16 years (65.2% versus 86.23% for emm1 and 7.7% versus 91.8% for emm12). This study demonstrates the increase in macrolide resistance in S. pyogenes in Chinese children over a 16-year period. The phenomenon may be related not only with the shift in the emm types but also with the change of macrolide-resistant mechanisms. The change of Tn916 family among the isolates may be related with the increased resistance.