Enantioselective Divergent Syntheses of Diterpenoid Pyrones.

Capitalizing a synergy between late-stage C(sp3)-H alkynylation and a series of transition metal-catalyzed alkyne functionalization reactions, we reported herein enantioselective divergent synthesis of 10 diterpenoid pyrones within 14-16 steps starting from chiral pool enoxolone, including the first enantioselective synthesis of higginsianins A, B, D, E, and metarhizin C. Our synthesis also highlights an unprecedented biomimetic oxidative rearrangement of α-pyrone into 3(2H)-furanone, as well as applications of Echavarren C(sp3)-H alkynylation reaction and Toste chiral counterion-mediated Au-catalyzed intramolecular allene hydroalkoxylation in natural product synthesis.

Knockdown of LOX-1 ameliorates bone quality and generation of type H blood vessels in diabetic mice.

Our previous studies have shown that lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1) is expressed in liver sinusoidal endothelial cells, and oxidized low-density lipoprotein induces liver sinusoidal dysfunction and defenestration through the LOX-1/ROS/NF-kB pathway, revealing that LOX-1 can mediate liver sinusoidal barrier function, involved in the regulation of non-alcoholic fatty liver disease. Here, we investigated whether, in the context of bone metabolic diseases, LOX-1 could affect bone quality and type H blood vessels in diabetic mice. We used db/db mice as model and found that LOX-1 knockdown can ameliorate bone quality and type H blood vessel generation in db/db mice. This further verifies our hypothesis that LOX-1 is involved in the regulation of bone quality and type H blood vessel homeostasis, thus inhibiting osteoporosis progression in db/db mice.

Effects of Guizhi and Erxian Decoction on menopausal hot flashes: insights from the gut microbiome and metabolic profiles.

AIMS: To examine the influence of GED on the gut microbiota and metabolites using a bilateral ovariectomized (OVX) rat model. We tried to elucidate the underlying mechanisms of GED in the treatment of menopausal hot flashes. METHODS AND RESULTS: 16S rRNA sequencing, metabonomics, molecular biological analysis, and fecal microbiota transplantation (FMT) were conducted to elucidate the mechanisms by which GED regulates the gut microbiota. GED significantly reduced OVX-induced hot flashes and improved disturbances in the gut microbiota metabolites. Moreover, FMT validated that the gut microbiota can trigger hot flashes, while GED can alleviate hot flash symptoms by modulating the composition of the gut microbiota. Specifically, GED upregulated the abundance of Blautia, thereby increasing l(+)-ornithine levels for the treatment of menopausal hot flashes. Additionally, GED affected endothelial nitric oxide synthase and heat shock protein 70 (HSP70) levels in the hypothalamic preoptic area by changing the gut microbiota composition. CONCLUSIONS: Our study illuminated the underlying mechanisms by which GED attenuated the hot flashes through modulation of the gut microbiota and explored the regulatory role of the gut microbiota on HSP70 expression in the preoptic anterior hypothalamus, thereby establishing a foundation for further exploration of the role of the gut-brain axis in hot flashes.

RIOK3 potentially regulates osteogenesis-related pathways in ankylosing spondylitis and the differentiation of bone marrow mesenchymal stem cells.

RNA-binding proteins (RBPs), which are key effectors of gene expression, play critical roles in inflammation and immune regulation. However, the potential biological function of RBPs in ankylosing spondylitis (AS) remains unclear. We identified differentially expressed genes (DEGs) in peripheral blood mononuclear cells (PBMCs) of five patients with AS and three healthy persons by RNA-seq, obtained differentially expressed RBPs by overlapping DEGs and RBPs summary table. RIOK3 was selected as a target RBP and knocked down in mouse bone marrow mesenchymal stem cells (mBMSCs), and transcriptomic studies of siRIOK3 mBMSCs were performed again using RNA-seq. Results showed that RIOK3 knockdown inhibited the expression of genes related to osteogenic differentiation, ribosome function, and ß-interferon pathways in mBMSCs. In vitro experiments have shown that RIOK3 knockdown reduced the osteogenic differentiation ability of mBMSCs. Collectively, RIOK3 may affect the differentiation of mBMSCs and participate in the pathogenesis of AS, especially pathological bone formation.

Electronic Noses: From Gas-Sensitive Components and Practical Applications to Data Processing.

Artificial olfaction, also known as an electronic nose, is a gas identification device that replicates the human olfactory organ. This system integrates sensor arrays to detect gases, data acquisition for signal processing, and data analysis for precise identification, enabling it to assess gases both qualitatively and quantitatively in complex settings. This article provides a brief overview of the research progress in electronic nose technology, which is divided into three main elements, focusing on gas-sensitive materials, electronic nose applications, and data analysis methods. Furthermore, the review explores both traditional MOS materials and the newer porous materials like MOFs for gas sensors, summarizing the applications of electronic noses across diverse fields including disease diagnosis, environmental monitoring, food safety, and agricultural production. Additionally, it covers electronic nose pattern recognition and signal drift suppression algorithms. Ultimately, the summary identifies challenges faced by current systems and offers innovative solutions for future advancements. Overall, this endeavor forges a solid foundation and establishes a conceptual framework for ongoing research in the field.

Phlorizin, an Important Glucoside: Research Progress on Its Biological Activity and Mechanism.

Phlorizin, as a flavonoid from a wide range of sources, is gradually becoming known for its biological activity. Phlorizin can exert antioxidant effects by regulating the IL-1ß/IKB-α/NF-KB signaling pathway. At the same time, it exerts its antibacterial activity by reducing intracellular DNA agglutination, reducing intracellular protein and energy synthesis, and destroying intracellular metabolism. In addition, phlorizin also has various pharmacological effects such as antiviral, antidiabetic, antitumor, and hepatoprotective effects. Based on domestic and foreign research reports, this article reviews the plant sources, extraction, and biological activities of phlorizin, providing a reference for improving the clinical application of phlorizin.

Sense of coherence in stroke: A concept analysis with Rodger's evolutionary approach.

Sense of coherence (SoC) refers to how individuals cope with stress and maintain health, yet its concept remains no consensus about how it is defined and applied in the context of stroke care. This study aims to clarify the concept of SoC by reviewing its applications in various stroke populations and its changes across different stages of stroke. The adapted steps of Rodger's evolutionary approach of concept analysis were used to explore the attributes, surrogate or related terms, antecedents, and consequences of SoC in stroke. Twenty-five articles were included after evaluating 1065 records and 80 full-text articles. The SoC's attributes, characterized with dynamicity of comprehensibility, manageability, and meaningfulness in stroke, lie within the different stroke phases (acute, sub-acute and chronic). There is no surrogate term to SoC. Related terms included coping, resistance resources, resilience, hardiness, and readiness. Antecedents related to stroke survivors and informal caregivers included sociodemographic factors, body functioning factors, social factors, stroke-related factors, and caring factors. Consequences for stroke survivors, informal caregivers, and dyads included psychological status, health behavior, marital satisfaction, care provision, and perception of rehabilitation needs. The findings of the concept analysis of SoC in stroke reveal that this concept extends beyond survivors experienced stroke, and its comprehensive understanding needs considering various aspects including the SoC of informal caregivers, dyads, and family. This paper serves as a novel perspective for future stroke care, focusing on the needs for dynamic monitoring and adaptations to changes of SoC at different stages of stroke care. A proper understanding of SoC can also contribute to developing assessment tools and theoretical models in stroke care with some emphasis on the phases of strokes (attributes), demographic and functional characteristics (antecedents), and both stroke survivor-caregiver-related outcomes sensitive to SoC.

Enantioselective Synthesis of the 1,3-Dienyl-5-Alkyl-6-Oxy Motif: Method Development and Total Synthesis.

The 1,3-dienyl-5-alkyl-6-oxy motif is widely found in various types of bioactive natural products. However, present synthesis is mainly non-asymmetric which relied upon different olefination or transition metal-catalyzed cross-coupling reactions using enantioenriched precursors. Herein, based upon a newly developed enantioselective α-alkylation of conjugated polyenoic acids, a variety of 1,3-dienyl-5-alkyl-6-oxy motif (with E-configured internal olefin) was generated as the corresponding α-adducts in a highly enantioselective and diastereoselective manner. Utilizing 1,3-dienyl-5-alkyl-6-oxy motif as key intermediates, we further demonstrated their synthetic potential by expedient total syntheses of three types of natural products (glutarimide antibiotics, α-pyrone polyketides and Lupin alkaloids) within 4-7 steps.

Discovery of two ent-atisane diterpenoid lactones with AChE inhibitory activity from the roots of Euphorbia fischeriana.

Euphorlactone A (1), a rare rearranged ent-atisane norditerpenoid with an undescribed 3-nor-2,4-olide-ent-atisane scaffold, and euphorlactone B (2), a new ent-atisane diterpenoid with an unprecedented seven-membered lactone ring C, were isolated from the roots of Euphorbia fischeriana. Their planar structures with absolute configurations were extensively elucidated by analysis of 1D and 2D NMR data, electronic circular dichroism (ECD) calculations, Rh2(OCOCF3)4-induced ECD curves, and single-crystal X-ray diffraction. Euphorlactone A (ELA) showed a remarkable AChE (acetylcholinesterase) inhibitory activity (IC50 = 2.13 ± 0.06 µM and Ki = 0.058 µM), which was five times stronger than that of the positive control (rivastigmine, IC50 = 12.46 ± 0.82 µM), and further in vitro enzyme inhibition kinetic analysis and molecular docking studies were performed to investigate the AChE inhibitory mechanism.

Triple combination of SPR741, clarithromycin, and erythromycin against Acinetobacter baumannii and its tolerant phenotype.

AIMS: Extensively drug-resistant (XDR) Acinetobacter baumannii poses a severe threat to public health due to its ability to form biofilms and persister cells, which contributes to critical drug resistance and refractory device-associated infections. A novel strategy to alleviate such an emergency is to identify promising compounds that restore the antimicrobial susceptibility of existing antibiotics against refractory infections. METHODS AND RESULTS: Here, we found a significant synergy among three combinations of SPR741, clarithromycin and erythromycin with a potent antimicrobial activity against XDR A. baumannii (SPR741/CLA/E at 8/10/10 µg ml-1 for XDR AB1069 and at 10/16/10 µg ml-1 for XDR AB1208, respectively). Moreover, the triple combination therapy exhibits a significant antipersister and antibiofilm effect against XDR strains. Mechanistic studies demonstrate that SPR741 may promote intracellular accumulation of macrolides by permeabilizing the outer membrane as well as disrupting membrane potential and further enhance the quorum sensing inhibition activity of the macrolides against XDR A. baumannii and its biofilms. In addition, the triple combination of SPR741 with clarithromycin and erythromycin was not easy to induce resistance in A. baumannii and had effective antimicrobial activity with low toxicity in vivo. SIGNIFICANCE AND IMPACT OF THE STUDY: Collectively, these results reveal the potential of SPR741 in combination with clarithromycin and erythromycin as a clinical therapy for refractory infections caused by XDR A. baumannii.

Incidence of acute kidney injury after hematopoietic stem cell transplantation in children: a systematic review and meta-analysis.

While acute kidney injury (AKI) has been reported after hematopoietic stem cell transplantation (HCT) in children, the incidence of this condition in the pediatric population has not been fully addressed. To assess the incidence of pediatric AKI after HCT treatment,we conducted a systematic literature review. Databases PubMed, Embase, Cochrane Library, and WOS were searched as of June 2022 to identify studies on the incidence and the risk of death in AKI children undergoing HCT. Random effects and generic inverse variance methods were used, and effect estimates were subsequently derived from individual studies. Twelve cohort studies with 2 159 HCT cases were included in this analysis. The combined estimated incidence of AKI and severe AKI (stage AKI III) was 51% (95% confidence interval (CI) 39-64%) and 12% (95%CI 4-24%), respectively. The estimated incidence of AKI based on RIFLE (pRIFLE), AKIN, and KDIGO criteria was 61% (95%CI 40-82% score I 95.1%), 64% (95%CI 49-79% score I 90.4%), and 51% (95%CI 2-100% score 99.0%), respectively. However, we found no significant correlation between the years of publication of the included studies and the incidence of AKI.  Conclusions: AKI affects approximately half of the children after HCT. With the advancements in medical techniques, it is expected that AKI in this population will decrease gradually. What is Known: • Hematopoietic stem cell transplantation is recognized as a treatment for malignant and non-malignant diseases in children. • Hematopoietic stem cell transplantation causes acute kidney injury in children. What is New: • This metanalysis showed that the overall frequency of post-HCT AKI in children is 51%. • The frequency of severe AKI after HCT was found to be 12%.

Effect of prosocial behavior on school bullying victimization among children and adolescents: Peer and student-teacher relationships as mediators.

INTRODUCTION: In this study, we examined the relationship between prosocial behavior and school bullying victimization in children and adolescents. We also tested the mediating effects of peer alienation and student-teacher closeness, as well as the moderating effect of the educational stage. METHODS: In total, 538 children and adolescents were recruited from three suburban schools in Beijing, China (252 boys, 286 girls; mean age = 12.47; 237 elementary school students, 101 middle school students, and 200 high school students). The participants were asked to complete the measures of prosocial behavior, peer alienation, and student-teacher closeness at the initial time point and reported school bullying victimization 3 months later. RESULTS: We found that prosocial behavior was directly and negatively associated with traditional bullying victimization (i.e., physical, nonphysical, and relational); however, it had no direct association with cyberbullying victimization. Prosocial behavior was indirectly associated with school bullying victimization (except in the relational dimension) via peer alienation, but no indirect effect of student-teacher closeness was found. Besides, the associations between prosocial behavior, peer alienation, student-teacher closeness, and bullying victimization were found equally among elementary, middle, and high school students. CONCLUSIONS: The findings suggest that prosocial behavior is an important factor associated with decreased school bullying victimization, and peer relationships play a mediating role in this association. Our study extends the current understanding of prosocial behavior primarily as a consequence of child and adolescent development to an antecedent (of school bullying victimization), which contributes to a more comprehensive view of prosocial behavior.

Artificial Tactile Sensing System with Photoelectric Output for High Accuracy Haptic Texture Recognition and Parallel Information Processing.

Developing multifunctional artificial sensory systems is an important task for constructing future artificial neural networks. A system with multisignal output capability is highly required by the rising demand for high-throughput data processing in the Internet of Things (IoT) society. Here, a novel dual-output artificial tactile sensing (DOATS) system with parallel output of photoelectric signals was proposed. Because of the ionic-electronic coupling mechanism in light-emitting synaptic (LES) devices in the DOATS system, modulating electric current and light emission can coexist through ion accumulation and electron-hole recombination. As a result, the DOATS system can realize the simulation of human tactile information, and the recognition of 16 kinds of fabrics was demonstrated with an accuracy rate of 94.1%. A photoelectric hybrid artificial neural network was proposed, which achieved efficient and accurate multitask operation. The DOATS system proposed in this work is promising for implementing photoelectric hybrid neural network and promoting the development of interactive artificial intelligence.

Inhibitors against Two PDZ Domains of MDA-9 Suppressed Migration of Breast Cancer Cells.

Melanoma differentiation-associated gene 9 (MDA-9) is a small adaptor protein with tandem PDZ domains that promotes tumor progression and metastasis in various human cancers. However, it is difficult to develop drug-like small molecules with high affinity due to the narrow groove of the PDZ domains of MDA-9. Herein, we identified four novel hits targeting the PDZ1 and PDZ2 domains of MDA-9, namely PI1A, PI1B, PI2A, and PI2B, using a protein-observed nuclear magnetic resonance (NMR) fragment screening method. We also solved the crystal structure of the MDA-9 PDZ1 domain in complex with PI1B and characterized the binding poses of PDZ1-PI1A and PDZ2-PI2A, guided by transferred paramagnetic relaxation enhancement. The protein-ligand interaction modes were then cross-validated by the mutagenesis of the MDA-9 PDZ domains. Competitive fluorescence polarization experiments demonstrated that PI1A and PI2A blocked the binding of natural substrates to the PDZ1 and PDZ2 domains, respectively. Furthermore, these inhibitors exhibited low cellular toxicity, but suppressed the migration of MDA-MB-231 breast carcinoma cells, which recapitulated the phenotype of MDA-9 knockdown. Our work has paved the way for the development of potent inhibitors using structure-guided fragment ligation in the future.

Prevalence of Helicobacter pylori infection in China: A systematic review and meta-analysis.

BACKGROUND AND AIM: Helicobacter pylori (H. pylori) infection rates have been changing with different populations and geographic areas. We systematically evaluated the longitudinal trends in H. pylori prevalence in China over the past decades. METHODS: We performed a systematic review of literature reporting the prevalence of H. pylori infection in mainland China from 1990 to 2019 in the PubMed and China National Knowledge Infrastructure databases. We conducted a meta-analysis of qualified studies using a random effects model to estimate the pooled prevalence with a 95% confidence interval (95%CI). RESULTS: A total of 412 eligible studies with 1 377 349 subjects were included. The pooled H. pylori prevalence was 44.2% (95%CI: 43.0-45.5%) in mainland China, with an estimated 589 million individuals infected with H. pylori. The prevalence was relatively high in the Northwest (51.8%, 95%CI: 47.5-56.1%), East (47.7%, 95%CI: 45.4-50.0%), and Southwest China (46.6%, 95%CI: 42.1-51.1%). The prevalence significantly decreased from 58.3% (95%CI: 50.7-65.5%) in the period 1983-1994 to 40.0% (95%CI: 38.2-41.8%) in the period 2015-2019. The prevalence increased with age, ranging from 28.0% (95%CI: 23.9-32.5%) in children and adolescents to 46.1% (95%CI: 44.5-47.6%) in adults. CONCLUSION: Although the burden of H. pylori infections is still huge in China, the infection rate has been decreasing over the past decades. Targeted H. pylori eradication strategies may be considered in areas or populations with a high incidence of gastric cancer.

Study on the monolayer dispersion behavior of SnO2 on ZSM-5 for NOx-SCR by C3H6: the remarkable promotional effects of air plasma treatment.

Aiming to fabricate more practical catalysts for NOx-SCR with C3H6, SnO2/ZSM-5 having different SnO2 loadings was prepared and treated with DBD air plasma. The dispersion of SnO2 on the H-ZSM-5 support and their interactions were investigated with both experimental methods and DFT calculations. SnO2 displays evident monolayer dispersion behavior, getting a threshold of 0.271 mmol 100 m-2 support. Plasma treatment improves significantly the SnO2 dispersion, hence amplifying the monolayer dispersion threshold to 0.380 mmol 100 m-2. XPS and DFT calculations have testified that plasma treatment strengthens strongly the SnO2-ZSM-5 support interaction, mainly through donating electrons from Sn4+ to Al3+ in the support, thus improving the dispersion of SnO2 at the same loadings. Consequently, the catalytic performance is remarkably improved because of the generation of more abundant surface acid sites and superoxide species devoted to the reaction. The sample having a SnO2 loading near the monolayer dispersion threshold shows the optimal activity in the corresponding catalyst series, demonstrating an evident threshold effect. Over SnO2/ZSM-5, the reaction goes through a Langmuir-Hinshelwood pathway, involving the adsorption and activation of both NO and C3H6 molecules. Surface mono-dentate/bridged-nitrate and carbonate species are the main reaction intermediates.

Anti-hepatitis C virus drug simeprevir: a promising antimicrobial agent against MRSA.

Staphylococcus aureus is a major human pathogen, and the appearance of methicillin-resistant S. aureus (MRSA) renders S. aureus infections more challenging to treat. Therefore, new antimicrobial drugs are urgently needed to combat MRSA infections. Drug repurposing is an effective and feasible strategy. Here, we reported that the clinically approved anti-hepatitis C virus drug simeprevir had strong antibacterial activity against MRSA, with a minimum inhibitory concentration of 2-8 µg/mL. Simeprevir did not easily induce in vitro resistance. In addition, simeprevir significantly prevented S. aureus biofilm formation. Furthermore, simeprevir displayed limited toxicity in in vitro and in vivo assays. Moreover, simeprevir showed synergistic antimicrobial effects against both type and clinical strains of S. aureus. Simeprevir combined with gentamicin effectively reduced the bacterial burden in an MRSA-infected subcutaneous abscess mouse model. Results from a series of experiments, including membrane permeability assay, membrane potential assay, intracellular ATP level assay, and electron microscope observation, demonstrated that the action of simeprevir may be by disrupting bacterial cell membranes. Collectively, these results demonstrated the potential of simeprevir as an antimicrobial agent for the treatment of MRSA infections. KEY POINTS: • Simeprevir showed strong antibacterial activity against MRSA. • The antibacterial mechanism of simeprevir was mediated by membrane disruption and intracellular ATP depletion. • In vitro and in vivo synergistic antimicrobial efficacy between simeprevir and gentamicin was found.

The relationship between menopausal syndrome and gut microbes.

BACKGROUND: Gut microbes were closely related to women's health. Previous studies reported that the gut microbes of premenopausal women were different from those of postmenopausal women. However, little was known about the relationship between gut microbiota dysbiosis and menopausal syndrome (MPS). The aim of this study was to explore the relationship between MPS and gut microbes. METHODS: Patients with MPS (P group, n = 77) and healthy women (H group, n = 24) at menopause were recruited in this study. The stool specimen and clinical parameters (demographic data, follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), et al) of participants' were collected. We evaluated the differences in gut microbes by 16S ribosomal RNA gene sequencing. We used LEfSe to identify gut microbes with varying abundances in different groups. The Spearman correlation coefficients of clinical parameters and gut microbes were calculated. PICRUSt was used to predict the potential KEGG Ortholog functional profiles of microbial communities. RESULTS: The abundance of 14 species differed substantially between the MPS and menopausal healthy women (LDA significance threshold > 2.0) according to LEfSe analysis. Using Spearman's correlation analysis, it was discovered that E2 had a positive correlation with Aggregatibacter segnis, Bifidobacterium animalis, Acinetobacter guillouiae (p < 0.05, these three species were enriched in menopausal healthy women), while FSH and LH had a negative correlation with them (p < 0.05). KEGG level3 metabolic pathways relevant to cardiovascular disease and carbohydrate metabolism were enriched in the MPS (p < 0.05), according to functional prediction by PICRUST and analyzed by Dunn test. CONCLUSION: There was gut microbiota dysbiosis in MPS, which is reflected in the deficiency of the abundance of Aggregatibacter segnis, Bifidobacterium animalis and Acinetobacter guillouiae related to the level of sex hormones. In MPS individuals, species with altered abundances and unique functional pathways were found.

A novel bactericidal small molecule, STK-35, and its derivative, STK-66, as antibacterial agents against Gram-negative pathogenic bacteria in vitro and in vivo.

Due to the increasing rate of antibiotic resistance and the emergence of persister cells of Gram-negative pathogenic bacteria, the development of new antibacterial agents is urgently needed to deal with this problem. Our results indicated that both newly identified small molecule STK-35 and its derivative STK-66 exhibited effective antibacterial properties against a variety of Gram-negative pathogens including Acinetobacter baumannii, Escherichia coli, Pseudomonas aeruginosa and Klebsiella pneumoniae. The minimal inhibitory concentrations and minimal bactericidal concentrations ranges were 0·0625-8 µg ml-1 and 0·125-16 µg ml-1 , respectively, while no haemolytic activity and mammalian cell cytotoxicity were observed. The time-killing assays showed STK-35/66 had strong bactericidal activity against Gram-negative pathogens. STK-35/66 also showed different degrees of synergistic antibacterial activity with conventional antibiotics and exhibited persister cells killing activity. Moreover, STK-35/66 effectively eradicated the pre-formed biofilms of P. aeruginosa and A. baumannii. In addition, STK-35/66 significantly increased the survival rate of E. coli infected mice and induced a decrease in bacterial load of the peritonitis model. In nutshell, these results suggested that STK-35/66 possessed antimicrobial activity against Gram-negative pathogenic bacteria in vitro and in vivo, which could be considered as potential substitutes for the treatment of Gram-negative pathogenic infections after further structure optimization.

Fragment-Based Discovery of AF9 YEATS Domain Inhibitors.

YEATS (YAF9, ENL, AF9, TAF14, SAS5) family proteins recognize acylated histones and in turn regulate chromatin structure, gene transcription, and stress signaling. The chromosomal translocations of ENL and mixed lineage leukemia are considered oncogenic drivers in acute myeloid leukemia and acute lymphoid leukemia. However, known ENL YEATS domain inhibitors have failed to suppress the proliferation of 60 tested cancer cell lines. Herein, we identified four hits from the NMR fragment-based screening against the AF9 YEATS domain. Ten inhibitors of new chemotypes were then designed and synthesized guided by two complex structures and affinity assays. The complex structures revealed that these inhibitors formed an extra hydrogen bond to AF9, with respect to known ENL inhibitors. Furthermore, these inhibitors demonstrated antiproliferation activities in AF9-sensitive HGC-27 cells, which recapitulated the phenotype of the CRISPR studies against AF9. Our work will provide the basis for further structured-based optimization and reignite the campaign for potent AF9 YEATS inhibitors as a precise treatment for AF9-sensitive cancers.