Discovery and preclinical profile of YK-2168, a differentiated selective CDK9 inhibitor in clinical development.

Emerging clinical evidence indicates that selective CDK9 inhibition may provide clinical benefits in the management of certain cancers. Many CDK9 selective inhibitors have entered clinical developments, and are being investigated. No clear winner has emerged because of unforeseen toxicity often observed in clinic with these agents. Therefore, a novel agent with differentiated profiles is still desirable. Herein, we report our design, syntheses of a novel azaindole series of selective CDK9 inhibitors. SAR studies led to a preclinical candidate YK-2168. YK2168 exhibited improved CDK9 selectivity over AZD4573 and BAY1251152; also showed differentiated intravenous PK profile and remarkable solid tumor efficacy in a mouse gastric cancer SNU16 CDX model in preclinical studies. YK-2168 is currently in clinical development in China (CTR20212900).

RNA-Seq analysis reveals the different mechanisms triggered by bovine and equine after infection with FMDV.

BACKGROUND: Foot-and-mouth disease virus (FMDV) is an important pathogen of the MicroRNA virus family. Infection of livestock can cause physical weakness, weight loss, reduced milk production, and a significant reduction in productivity for an extended period. It also causes a high mortality rate in young animals, seriously affecting livestock production. The host range of FMDV is mainly limited to cloven-hoofed animals such as cattle and sheep, while odd-toed ungulates such as horses and donkeys have natural resistance to FMDV. The mechanism underlying this resistance in odd-toed ungulates remains unclear. OBJECTIVE: This study aimed to analyze the differences between FMDV-infected cattle and horses to provide valuable insights into the host-FMDV interaction mechanisms, thereby contributing to the control of foot-and-mouth disease and promoting the development of the livestock industry. METHODS: We observed the distribution of integrins, which help FMDV enter host cells, in the nasopharyngeal tissues of cattle and horses using immunohistochemistry. Then, we employed high-throughput RNA sequencing (RNA-Seq) to study the changes in host gene expression in the nasopharyngeal epithelial tissues of cattle and horses after FMDV infection. We performed enrichment analysis of GO and KEGG pathways after FMDV infection and validated related genes through qPCR. RESULTS: The immunohistochemical results showed that both cattle and horses had four integrin receptors that could assist FMDV entry into host cells. The transcriptome analysis revealed that after FMDV infection, pro-apoptotic genes such as caspase-3 (CASP3) and cytochrome C (CYCS) were upregulated in cattle, while apoptosis-inhibiting genes such as NAIP and BCL2A1 were downregulated. In contrast, the expression trend of related genes in horses was opposite to that in cattle. Additionally, autophagy-related genes such as beclin 1, ATG101, ATG4B, ATG4A, ATG13, and BCL2A1 were downregulated in cattle after FMDV infection, indicating that cattle did not clear the virus through autophagy. However, key autophagy genes including ATG1, ATG3, ATG9, ATG12, and ATG16L1 were significantly upregulated in horses after viral infection. CONCLUSION: Both water buffaloes and Mongolian horses express integrin receptors that allow FMDV entry into cells. Therefore, the resistance of Mongolian horses to FMDV may result from more changes in intracellular mechanisms, including processes such as autophagy and apoptosis. Significant differences were observed between water buffaloes and Mongolian horses in these processes, suggesting that these processes influence FMDV replication and synthesis.

Psychological resilience and associated factors in caring for mass burn patients among rescue nurses: A cross-sectional study.

This current study explored the relationship between challenge-hindrance stressors, coping style, and psychological resilience among rescue nurses caring for mass burn patients. METHODS: This study is multicenter and cross-sectional. Registered nurses who saved and cared for extensively burned patients at two tertiary hospitals in mainland China between January and August of 2023 were selected through purposeful sampling. Online surveys were used to gather data. Multiple linear regression and Pearson correlation were used to examine the link between challenge-hindrance stressors, coping style, and psychological resilience. RESULTS: 121 nurses completed the online questionnaires. The mean score for psychological resilience was 63.80 ± 11.63, for the challenge-stressor 16.23 ± 4.38, and for hindrance-stressor 9.85 ± 3.89. The total score for positive coping style was 23.69 ± 7.73, and that for the negative coping style 11.45 ± 5.21. Pearson analysis showed total resilience score was positively correlated with challenge stressors (r = 0.697, p＜0.05) and positive coping style (r = 0.616, p＜0.05), and negatively correlated with the hindrance stressors (r = -0.512, p＜0.05) and negative coping style (r = -0.589, p＜0.05) among rescuer nurses. Multiple linear regression analyses identified that having attended rescues before, challenge-hindrance, and coping style are the potential influencing factors of resilience. CONCLUSION: In mass burns accidents, rescuer nurses have a medium level of psychological resilience, which positively and significantly correlated with challenge stressors and positive coping style. It is suggested that more attention should be devoted to the target population to formulate effective intervention plans, reduce psychological impact, and improve their capacity for coping with disasters.

Diagnostic value of artificial intelligence-assisted CTA for the assessment of atherosclerosis plaque: a systematic review and meta-analysis.

Background: Artificial intelligence (AI) has increasingly been applied to computed tomography angiography (CTA) images to aid in the assessment of atherosclerotic plaque. Our aim was to explore the diagnostic accuracy of AI-assisted CTA for plaque diagnosis and classification through a systematic review and meta-analysis. Methods: A systematic literature review was performed by searching PubMed, EMBASE, and the Cochrane Library according to PRISMA guidelines. Original studies evaluating the diagnostic accuracy of radiomics, machine-learning, or deep-learning techniques applied to CTA images for detecting stenosis, calcification, or plaque vulnerability were included. The quality and risk of bias of the included studies were evaluated using the QUADAS-2 tool. The meta-analysis was conducted using STATA software (version 17.0) to pool sensitivity, specificity, and area under the receiver operating characteristic curve (AUROC) to determine the overall diagnostic performance. Results: A total of 11 studies comprising 1,484 patients were included. There was low risk of bias and substantial heterogeneity. The overall pooled AUROC for atherosclerotic plaque assessment was 0.96 [95% confidence interval (CI) 0.94-0.97] across 21 trials. Of these, for ≥50% stenosis detection, the AUROC was 0.95 (95% CI 0.93-0.96) in five studies. For identifying ≥70% stenosis, the AUROC was 0.96 (95% CI 0.94-0.97) in six studies. For calcium detection, the AUROC was 0.92 (95% CI 0.90-0.94) in six studies. Conclusion: Our meta-analysis demonstrates that AI-assisted CTA has high diagnostic accuracy for detecting stenosis and characterizing plaque composition, with optimal performance in detecting ≥70% stenosis. Systematic Review Registration: https://www.crd.york.ac.uk/, PROSPERO, identifier (CRD42023431410).

Effects of low-frequency ultrasound combined with microbubbles on breast cancer xenografts in nude mice.

The aim of this study was to explore the effects of low-frequency ultrasound (US) combined with microbubbles (MBs) on breast cancer xenografts and explain its underlying mechanisms. A total of 20 xenografted nude mice were randomly divided into four groups: a group treated with US plus MBs (the US + MBs group), a group treated with US alone (the US group), a group treated with MBs alone (the MBs group), and a control group. In different groups, mice were treated with different US and injection regimens on an alternate day, three times in total. Histological changes, apoptosis of cells, microvascular changes, and the apoptosis index (AI) and microvascular density (MVD) of the breast cancer xenograft were analyzed after the mice were sacrificed. Results indicated that the tumor volume in the US + MBs group was smaller than that in the other three groups (p < 0.001 for all). The rate of tumor growth inhibition in the US + MBs group was significantly higher than that in the US and MBs groups (p < 0.001 for both). There were no significant differences in histological changes among the four groups. However, the AI was higher in the US + MBs group than that in the other three groups while the MVD was lower (p < 0.001 for all). All in all, low-frequency US combined with MBs can effectively slow down the growth of breast cancer in nude mice. In summary, low-frequency US combined with MBs has a significant effect on breast cancer treatment. Cavitation, thermal effects, and mechanical effects all play a vital role in the inhibition of tumor growth.

Magnetite Nanoparticle Assemblies and Their Biological Applications: A Review.

Magnetite nanoparticles (Fe3O4 NPs) have garnered significant attention over the past twenty years, primarily due to their superparamagnetic properties. These properties allow the NPs to respond to external magnetic fields, making them particularly useful in various technological applications. One of the most fascinating aspects of Fe3O4 NPs is their ability to self-assemble into complex structures. Research over this period has focused heavily on how these nanoparticles can be organized into a variety of superstructures, classified by their dimensionality-namely one-dimensional (1D), two-dimensional (2D), and three-dimensional (3D) configurations. Despite a wealth of studies, the literature lacks a systematic review that synthesizes these findings. This review aims to fill that gap by providing a thorough overview of the recent progress made in the fabrication and organization of Fe3O4 NP assemblies via a bottom-up self-assembly approach. This methodology enables the controlled construction of assemblies at the nanoscale, which can lead to distinctive functionalities compared to their individual counterparts. Furthermore, the review explores the diverse applications stemming from these nanoparticle assemblies, particularly emphasizing their contributions to important areas such as imaging, drug delivery, and the diagnosis and treatment of cancer.

Dual-Prodrug-Based Hyaluronic Acid Nanoplatform Provides Cascade-Boosted Drug Delivery for Oxidative Stress-Enhanced Chemotherapy.

Insufficient drug accumulation in tumors severely limits the antitumor efficiency of hyaluronic acid (HA) nanomedicine in solid tumors due to superficial penetration depth, low cell uptake, and nonspecific drug release. Hence, we constructed a dual NO prodrug (alkynyl-JSK) and doxorubicin prodrug (cis-DOX)-conjugated HA nanoparticle (HA-DOX-JSK NPs), which achieved cascade-boosted drug delivery efficiency based on a relay strategy of NO-mediated deep tumor penetration─HA target CD44 tumor cell uptake─tumor microenvironment (TME)-responsive drug release. The nanoparticle demonstrated sustained and locoregionally GSH/GST-triggered NO release and GSH/pH-responsive DOX release in the tumor. The released NO first mediated collagen degradation, causing deep tumor penetration of nanoparticles in the dense extracellular matrix. Immediately, HA was relayed to enhance CD44-targeted tumor cell uptake, and then, the nanoparticles were finally triggered by specific TME to release DOX and NO in the deep tumor. Relying on the relayed delivery strategy, a significant improvement of DOX accumulation in tumors was realized. Moreover, NO depleted GSH-induced intracellular reactive oxygen species, enhancing DOX chemotherapy. Based on this strategy, the tumor inhibition rate in breast cancer was up to 87.8% in vivo. The relay drug-delivery HA system would greatly cascade-boost drug accumulation in deep tumors for efficient solid tumor therapy.

Breaking graphite through a ball-milling process: the thermal conductivity and mechanical properties of polyethylene composites.

Exfoliated graphite platelets (EGPs) have attracted extensive attention owing to their exceptional combinations of thermal conductivity and mechanical properties. Mechanical exfoliation is a facile and high-throughput approach to produce single-layer or few-layer graphite platelets. Herein, octadecylamine (ODA)-grafted EGP (ODA@EGP) and subsequent polyethylene/ODA@EGP (PE/ODA@EGP) composites with different contents of ODA@EGPs were successfully prepared via ball-milling and melt-mixing methods, respectively. The thermal conductivity, crystallinity, and mechanical properties of the composites were investigated using tensile tests, the hot-wire method, differential scanning calorimetry (DSC), scanning electron microscopy (SEM), X-ray diffraction (XRD) analysis, and thermogravimetric analysis (TGA). The results demonstrated that the thermal conductivity, mechanical properties, and thermal stability of the composites can be improved by regulating the additive contents of ODA@EGPs. When the content of ODA@EGPs was 10 wt%, the thermal conductivity of the composite reached up to 1.276 W (m-1 K-1), which is 216% higher than that of bare PE, while the tensile strength of the composite was 38.4% higher than that of PE. Additionally, thermal decomposition temperature increased by 16.2 °C. Therefore, the PE/ODA@EGP nanocomposites have great application potential in thermal management.

The abnormalities of brain function in females with primary insomnia: a resting-state functional magnetic resonance imaging study.

Background: The neuropathologic mechanism of primary insomnia (PI) of females remains unclear. This study aims to investigate the features of amplitude of low-frequency fluctuations (ALFF) and regional homogeneity (ReHo) in females with PI using functional magnetic resonance imaging (fMRI), and then explore the abnormalities of functional connectivity (FC). Materials and methods: A total of 39 female PI patients and 31 female healthy controls (HC) were enrolled in the study. The sleep condition was assessed using the Pittsburgh Sleep Quality Index (PSQI), and Insomnia Severity Index (ISI), and their depressive symptom was evaluated using the Hamilton Depression Scale (HAMD-24). The rs-fMRI was once conducted for every subject. ReHo, ALFF, and ROI-based FC were used to analyze the changes of brain function. Results: ALFF values were increased in the Cerebelum_4_5_L, as well as decreased ALFF in the bilateral Frontal_Sup_Medial (SFGmed), Angular_L (ANG.L), Parietal_Inf_R (IPL.R), SupraMarginal_R (SMG.R), and Postcentral_R (PoCG.R). ReHo values were increased in the Temporal_Pole_Mid_R (TPOsup.R), as well as decreased ReHo in the Insula_R (INS.R), Frontal_Inf_Oper_R (ORBinf.R), Putamen_R (PUT.R), Rolandic_Oper_R (ROL.R), bilateral Cingulum_Post (PCG), bilateral Frontal_Sup_Medial (SFGmed), bilateral anterior cingulate and paracingulate gyri (ACG), and the bilateral precuneus (PCUN). Across the entire brain, there was a decline in the FC between Angular_R and Frontal_Sup_Medial_L. Conclusion: Alterations in brain regions of female patients with PI involved multiple functional networks, including the default mode network, the salience network, the central executive network, and the limbic network. Reduced coordination between functional networks may be an important mechanism for insomnia and may lead to reduced cognitive function and decision-making ability.

Regulation of Molecular Microheterogeneity in Electrolytes Enables Ampere-Hour-Level Aqueous LiMn2O4||Li4Ti5O12 Pouch Cells.

Aqueous batteries are attractive due to their high safety and fast reaction kinetics, but the narrow electrochemical stability window of H2O limits their applications. It is a big challenge to broaden the electrochemical operation window of aqueous electrolytes while retaining fast reaction kinetics. Here, a new organic aqueous mixture electrolyte of manipulatable (3D) molecular microheterogeneity with H2O-rich and H2O-poor domains is demonstrated. H2O-poor domains molecularly surround the reformed microclusters of H2O molecules through interfacial H-bonds, which thus not only inhibit the long-range transfer of H2O but also allow fast and consecutive Li+ transport. This new design enables low-voltage anodes reversibly cycling with aqueous-based electrolytes and high ionic conductivity of 4.5 mS cm-1. LiMn2O4||Li4Ti5O12 full cells demonstrate excellent cycling stability over 1000 cycles under various C rates and a low temperature of -20 °C. 1 Ah pouch cell delivers a high energy density of 79.3 Wh kg-1 and high Coulombic efficiency of 99.4% at 1 C over 200 cycles. This work provides new insights into the design of electrolytes based on the molecular microheterogeneity for rechargeable batteries.

Genetic Variants in p53 Pathway Genes Affect Survival of Patients with HBV-Related Hepatocellular Carcinoma.

Purpose: P53 is a suppressor gene closely related to carcinogenesis. However, the associations between genetic variants in the p53 signaling pathway and prognosis in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) remain unknown. The current study aims to analyze associations between the single nucleotide polymorphisms (SNPs) in p53 pathway-related genes and survival of patients with HBV-HCC. Methods: We evaluated the associations between 4698 SNPs in 70 genes of the p53 pathway and overall survival (OS) of 866 patients in additive genetic models by using Cox proportional hazards regression analysis. Stepwise multivariable Cox regression analysis was conducted to determine the independent effects of identified SNPs in single-locus analyses. The expression of quantitative trait loci (eQTL) was also analyzed using data from GTEx and 1000 Genomes Project, and functional prediction of SNPs was performed by using RegulomeDB v2.2, 3DSNP v2.0, HaploReg v4.2 and VannoPortal. Results: We found that two novel SNPs of CD82 rs7925603 A > G and PMAIP1 rs4396625 A > T, were significantly and independently associated with OS [adjusted hazards ratios (HRs) and 95% confidence intervals (CI) were 1.27 (1.10-1.48) and 0.77 (0.66-0.91), respectively; P = 0.001 and = 0.002, respectively] and that the combined risk genotypes of these SNPs showed a significant association with OS in patients with HBV-HCC (P trend < 0.001). Further eQTL analysis in the GTEx dataset showed that the rs7925603 G allele was associated with lower CD82 mRNA expression levels, while the rs4396625 T allele was associated with higher PMAIP1 mRNA expression levels in whole blood cells. Conclusion: We identified two observed survival-associated SNPs in CD82 and PMAIP1 in the p53 pathway, which influenced HBV-HCC survival possibly through a mechanism of altering mRNA expression. Large studies are warranted to validate our findings.

Genetic variants of m6A modification genes are associated with survival of HBV-related hepatocellular carcinoma.

N6-methyladenosine (m6A) is a dynamic and reversible modification process involving in a series of important biological and pathophysiological processes, including the progression of cancers. Herein, we aimed to assess the relationships of genetic variants in m6A modification genes with the survival of hepatitis B virus -related hepatocellular carcinoma (HBV-HCC). We performed a two-stage survival analysis to investigate the associations of 4425 single nucleotide polymorphisms (SNPs) in 36 m6A modification genes with the overall survival (OS) of HBV-HCC patients. Then, the identified SNPs were further used to functionally annotate. We identified that METTL3 rs1263790 (A > G) and ADARB1 rs57884102 (C > T) were significantly associated with the HBV-HCC OS (hazard ratios [HR] = 0.68, 95% confidence interval [CI] = 0.52-0.89, p = 0.004; and HR = 1.70, 95% CI = 1.33-2.18, p < 0.001, respectively). Combined analysis revealed that patients carrying more risk genotypes of two variants had a progressively poorer OS. Moreover, the expression quantitative trait loci (eQTL) analysis indicated that rs1263790 G allele decreased mRNA expression levels of METTL3 in 483 cell-cultured fibroblasts samples. And we found the mRNA expression levels of METTL3 and ADARB1 in HCC tissues were higher than in normal tissues, and the higher METTL3 and the lower ADARB1 were associated with poorer HCC OS. Our results demonstrated that two novel genetic variants (METTL3 rs1263790 and ADARB1 rs57884102) may be potential prognostic markers for HBV-HCC, but these results need larger different ethnic cohorts and functional experiments to validate in the future.

Novel genetic variants in the NLRP3 inflammasome-related PANX1 and APP genes predict survival of patients with hepatitis B virus-related hepatocellular carcinoma.

BACKGROUND: The nod-like receptor protein 3 (NLRP3) is one of the most characterized inflammasomes involved in the pathogenesis of several cancers, including hepatocellular carcinoma (HCC). However, the effects of genetic variants in the NLRP3 inflammasome-related genes on survival of hepatitis B virus (HBV)-related HCC patients are unclear. METHODS: We performed multivariable Cox proportional hazards regression analysis to evaluate associations between 299 single-nucleotide polymorphisms (SNPs) in 16 NLRP3 inflammasome-related genes and overall survival (OS) of 866 patients with HBV-related HCC. We further performed expression quantitative trait loci (eQTL) analysis using the data from the GTEx project and 1000 Genomes projects, and performed differential expression analysis using the TCGA dataset to explore possible molecular mechanisms underlying the observed associations. RESULTS: We found that two functional SNPs (PANX1 rs3020013 A > G and APP rs9976425 C > T) were significantly associated with HBV-related HCC OS with the adjusted hazard ratio (HR) of 0.83 [95% confidence interval (CI) = 0.73-0.95, P = 0.008], and 1.26 (95% CI = 1.02-1.55, P = 0.033), respectively. Moreover, the eQTL analysis revealed that the rs3020013 G allele was correlated with decreased mRNA expression levels of PANX1 in both normal liver tissues (P = 0.044) and whole blood (P < 0.001) in the GTEx dataset, and PANX1 mRNA expression levels were significantly higher in HCC samples and associated with a poorer survival of HCC patients. However, we did not observe such correlations for APP rs9976425. CONCLUSIONS: These results indicated that SNPs in the NLRP3 inflammasome-related genes may serve as potential biomarkers for HBV-related HCC survival, once replicated by additional larger studies.

Crystallization-Driven Controlled 2D Self-Assemblies via Aqueous RAFT Emulsion Polymerization.

Aqueous emulsion polymerization is a robust technique for preparing nanoparticles of block copolymers; however, it typically yields spherical nanoassemblies. The scale preparation of nanoassemblies with nonspherical high-order morphologies is a challenge, particularly 2D core-shell nanosheets. In this study, the polymerization-induced self-assembly (PISA) and crystallization-driven self-assembly (CDSA) are combined to demonstrate the preparation of 2D nanosheets and their aggregates via aqueous reversible addition-fragmentation chain transfer (RAFT) emulsion polymerization. First, the crucial crystallizable component for CDSA, hydroxyethyl methacrylate polycaprolactone (HPCL) macromonomer is synthesized by ring opening polymerization (ROP). Subsequently, the RAFT emulsion polymerization of HPCL is conducted to generate crystallizable nanomicelles by a grafting-through approach. This PISA process simultaneously prepared spherical latices and bottlebrush block copolymers comprising poly(N',N'-dimethylacrylamide)-block-poly(hydroxyethyl methacrylate polycaprolactone) (PDMA-b-PHPCL). The latexes are now served as seeds for inducing the formation of 2D hexagonal nanosheets, bundle-shaped and flower-like aggregation via the CDSA of PHPCL segments and unreacted HPCL during cooling. Electron microscope analysis trace the morphology evolution of these 2D nanoparticles and reveal that an appropriate crystallized component of PHPCL blocks play a pivotal role in forming a hierarchical structure. This work demonstrates significant potential for large-scale production of 2D nanoassemblies through RAFT emulsion polymerization.

One-Pot Preparation of Ratiometric Fluorescent Molecularly Imprinted Polymer Nanosensor for Sensitive and Selective Detection of 2,4-Dichlorophenoxyacetic Acid.

The development of fluorescent molecular imprinting sensors for direct, rapid, and sensitive detection of small organic molecules in aqueous systems has always presented a significant challenge in the field of detection. In this study, we successfully prepared a hydrophilic colloidal molecular imprinted polymer (MIP) with 2,4-dichlorophenoxyacetic acid (2,4-D) using a one-pot approach that incorporated polyglycerol methacrylate (PGMMA-TTC), a hydrophilic macromolecular chain transfer agent, to mediate reversible addition-fragmentation chain transfer precipitation polymerization (RAFTPP). To simplify the polymerization process while achieving ratiometric fluorescence detection, red fluorescent CdTe quantum dots (QDs) and green fluorescent nitrobenzodiazole (NBD) were introduced as fluorophores (with NBD serving as an enhancer to the template and QDs being inert). This strategy effectively eliminated background noise and significantly improved detection accuracy. Uniform-sized MIP microspheres with high surface hydrophilicity and incorporated ratiometric fluorescent labels were successfully synthesized. In aqueous systems, the hydrophilic ratio fluorescent MIP exhibited a linear response range from 0 to 25 µM for the template molecule 2,4-D with a detection limit of 0.13 µM. These results demonstrate that the ratiometric fluorescent MIP possesses excellent recognition characteristics and selectivity towards 2,4-D, thus, making it suitable for selective detection of trace amounts of pesticide 2,4-D in aqueous systems.

A Pillararene-Based Cavitand: Synthesis and Solid-State Capsular Assemblies Induced by Linear Alkanes with Specific Lengths.

Herein, a novel pillararene-based cavitand with fixed planar chirality was synthesized by the SuFEx reaction. As demonstrated by single crystal X-ray analysis, host-guest capsules involving this cavitand and linear alkanes with specific lengths are observed in the solid state. The formation of each capsule is driven by hydrogen bonding interactions between a linear alkane molecule and two cavitand molecules, as well as noncovalent interactions between the two cavitand molecules in this capsule.

Associations between modifiable risk factors and hepatocellular carcinoma: a trans-ancestry Mendelian randomization study.

BACKGROUND: Potentially modifiable risk factors for hepatocellular carcinoma (HCC) have been investigated in observational epidemiology studies in East Asian and European populations, whereas the causal associations of most of these risk factors remain unclear. METHODS: We collected genome-wide association summary statistics of 22 modifiable risk factors in East Asians and 33 risk factors in Europeans. Genetic summary statistics of HCC were sourced from the Biobank Japan study (1,866 cases and 195,745 controls) for East Asians, and the deCODE genetics study (406 cases and 49,302 controls) and the UK Biobank (168 cases and 372 016 controls) for Europeans. Two-sample Mendelian randomization (MR) analyses were performed independently for East Asian and European populations. RESULTS: In East Asians, genetically predicted alcohol frequency, ever drinkers, aspartate aminotransferase (AST), hypothyroidism, chronic hepatitis B, and chronic hepatitis C, metabolic dysfunction-associated steatotic liver disease (MASLD), and autoimmune hepatitis were significantly associated with an increased HCC risk (P < 0.05/22). Among European population, alanine transaminase, AST, MASLD, percent liver fat, and liver iron content were significantly associated with a higher risk of HCC (P < 0.05/33). The replication dataset and meta-analysis further confirmed these results. CONCLUSIONS: Although East Asian and European populations have different factors for HCC, their common modifiable risk factors AST and MASLD for HCC, offer valuable insights for targeted intervention strategies to mitigate society burden of HCC.

Transcriptome analysis reveals hepatic disordered lipid metabolism, lipotoxic injury, and abnormal development in IUGR sheep fetuses due to maternal undernutrition during late pregnancy.

Although lipid metabolism in fetal livers under intrauterine growth restriction (IUGR) conditions has been widely studied, the implications of maternal undernutrition on fetal hepatic lipid metabolism, lipotoxic injury, and abnormal development remain largely unknown. Therefore, this study investigated the effects of maternal undernutrition on disordered hepatic lipid metabolism, lipotoxic injury, and abnormal development in IUGR sheep fetuses using transcriptome analysis. Seventeen singleton ewes were randomly divided into three groups on day 90 of pregnancy: a control group (CG; 0.63 MJ metabolic energy/body weight (ME/BW)0.75/day, n = 5), maternal undernutrition group 1 (MU1; 0.33 MJ ME/BW0.75/day, n = 6), and maternal undernutrition group 2 (MU2; 0.20 MJ ME/BW0.75/day, n = 6). The fetuses were euthanized and recovered on day 130 of pregnancy. The levels of free fatty acids (FFA) in maternal blood (P < 0.01), fetal blood (P < 0.01), and fetal livers (P < 0.05) were increased in the MU1 and MU2 groups, but fetal hepatic triglyceride (TG) levels in the MU2 group (P < 0.01) and ß-hydroxybutyrate levels in the MU1 and MU2 groups (P < 0.01) were decreased compared to the CG. Severe inflammatory cell infiltration and increased non-alcoholic fatty liver disease activity scores were observed in MU1 and MU2 fetuses (P < 0.01). Progressive deposition of fetal hepatic reticular fibers and collagen fibers in the fetal livers of the MU1 and MU2 groups and significant hepatic fibrosis were observed in the MU2 fetuses (P < 0.05). Gene set enrichment analysis showed that genes involved in lipid accumulation and FFA beta oxidation were downregulated in both MU groups compared to those in the controls. The fetal liver mRNA expression of the ß-oxidation regulator, acetyl-CoA acetyltransferase 1, and the TCA regulator, isocitrate dehydrogenase were reduced in MU1 (P < 0.05) and MU2 (P < 0.01) fetuses, and downregulated mRNA expression of long chain fatty acid CoA ligase 1 (P < 0.05) and glycerol-3-phosphate acyltransferase (P < 0.01) was observed in MU2 fetuses. Differentially expressed genes (DEGs) in MU1 versus CG (360 DEGs) and MU2 versus CG (746 DEGs) were identified using RNA sequencing. Bioinformatics analyses of the 231 intersecting DEGs between MU1 versus CG and MU2 versus CG indicated that neutrophil extracellular traps (NETs) were induced and played a central role in fetal hepatic injury in IUGR sheep. Increased maternal blood myeloperoxidase (MPO) levels (P < 0.01), NE (Elane)-positive areas in fetal liver sections (P < 0.05), and fetal liver MPO protein expression (P < 0.01) were found in the MU1 and MU2 groups; however, MPO levels were reduced in the fetal membrane (P < 0.01) and fetal blood (P < 0.05) in the MU1 group, and in the maternal-fetal placenta and fetal blood in the MU2 group (P < 0.01). Analysis of gene expression trends in the intersecting DEGs between MU1 versus CG (129 DEGs) and MU2 versus CG (515 DEGs) further revealed that 30 hub genes were essential regulators of the G2/M cell cycle, all of which were associated with hepatocellular carcinoma. G0/G1 phase cells of the fetal liver were reduced in the MU1 (P < 0.05) and MU2 (P < 0.01) groups, whereas G2/M phase cells were elevated in the MU1 and MU2 groups (P < 0.01). The representatives of upregulated hub genes and fetal liver protein expression of maternal embryonic leucine zipper kinase and protein regulator of cytokinesis 1 were progressively enhanced in the MU1 and MU2 groups (P < 0.01), and topoisomerase II alpha protein expression in the MU2 group (P < 0.05), as expected. These results indicate that FFA overload, severe lipotoxic injury, and NETs were induced, and disease-promoting regulators of the G2/M cell cycle were upregulated in the fetal liver of IUGR sheep. These findings provide new insights into the pathogenesis of impaired hepatic lipid metabolism and abnormal development and the molecular origin of post-natal liver disease in IUGR due to maternal undernutrition. This information can support the development of new therapeutic strategies.

Enhancement of Overall Kinetics by Se-Br Chemistry in Rechargeable Li-S Batteries.

The sluggish kinetics of lithium-sulfur (Li-S) batteries severely impedes the application in extreme conditions. Bridging the sulfur cathode and lithium anode, the electrolyte plays a crucial role in regulating kinetic behaviors of Li-S batteries. Herein, we report a multifunctional electrolyte additive of phenyl selenium bromide (PhSeBr) to simultaneously exert positive influences on both electrodes and the electrolyte. For the cathode, an ideal conversion routine with lower energy barrier can be attained by the redox mediator and homogeneous catalyst derived from PhSeBr, thus improving the reaction kinetics and utilization of sulfur. Meanwhile, the presence of Se-Br bond helps to reconstruct a loose solvation sheath of lithium ions and a robust bilayer SEI with excellent ionic conductivity, which contributes to reducing the de-solvation energy and simultaneously enhancing the interfacial kinetics. The Li-S battery with PhSeBr displays superior long cycling stability with a reversible capacity of 1164.7 mAh g-1 after 300 cycles at 0.5 C rate. And the pouch cell exhibits a maximum capacity of 845.3 mAh and a capacity retention of 94.8 % after 50 cycles. Excellent electrochemical properties are also obtained in extreme conditions of high sulfur loadings and low temperature of -20 °C. This work demonstrates the versatility and practicability of the special additive, striking out an efficient but simple method to design advanced Li-S batteries.

Inclusion Complexes of Ethanamizuril with ß- and Hydroxypropyl-ß-Cyclodextrin in Aqueous Solution and in Solid State: A Comparison Study.

Ethanamizuril (EZL) is a new anticoccidial drug developed by our Shanghai Veterinary Research Institute. Since EZL is almost insoluble in water, we conducted a study to improve the solubility of EZL by forming inclusion complexes with ß-cyclodextrin (ß-CD) and hydroxypropyl-ß-cyclodextrin (HP-ß-CD). In this study, we performed molecular docking and then systematically compared the interactions of EZL with ß-CD and HP-ß-CD in both aqueous solution and the solid state, aiming to elucidate the solubilization effect and mechanism of cyclodextrins (CDs). The interactions were also examined in the solid state using DSC, PXRD, and FT-IR. The interactions of EZL with CDs in an aqueous solution were investigated using PSA, UV-vis spectroscopy, MS, 1H NMR, and 2D ROESY. The results of phase solubility experiments revealed that both ß-CD and HP-ß-CD formed inclusion complexes with EZL in a 1:1 molar ratio. Among them, HP-ß-CD exhibited higher Kf (stability constant) and CE (complexation efficiency) values as well as a stronger solubilization effect. Furthermore, the two cyclodextrins were found to interact with EZL in a similar manner. The results of our FT-IR and 2D ROESY experiments are in agreement with the theoretical results derived from molecular simulations. These results indicated that intermolecular hydrogen bonds existing between the C=O group on the triazine ring of EZL and the O-H group of CDs, as well as the hydrophobic interactions between the hydrogen on the benzene ring of EZL and the hydrogen of CDs, played crucial roles in the formation of EZL/CD inclusion complexes. The results of this study can lay the foundation for the future development of high-concentration drinking water delivery formulations for EZL.