Host genetics and gut microbiota synergistically regulate feed utilization in egg-type chickens.

BACKGROUND: Feed efficiency is a crucial economic trait in poultry industry. Both host genetics and gut microbiota influence feed efficiency. However, the associations between gut microbiota and host genetics, as well as their combined contributions to feed efficiency in laying hens during the late laying period, remain largely unclear. METHODS: In total, 686 laying hens were used for whole-genome resequencing and liver transcriptome sequencing. 16S rRNA gene sequencing was conducted on gut chyme (duodenum, jejunum, ileum, and cecum) and fecal samples from 705 individuals. Bioinformatic analysis was performed by integrating the genome, transcriptome, and microbiome to screen for key genetic variations, genes, and gut microbiota associated with feed efficiency. RESULTS: The heritability of feed conversion ratio (FCR) and residual feed intake (RFI) was determined to be 0.28 and 0.48, respectively. The ileal and fecal microbiota accounted for 15% and 10% of the FCR variance, while the jejunal, cecal, and fecal microbiota accounted for 20%, 11%, and 10% of the RFI variance. Through SMR analysis based on summary data from liver eQTL mapping and GWAS, we further identified four protein-coding genes, SUCLA2, TNFSF13B, SERTM1, and MARVELD3, that influence feed efficiency in laying hens. The SUCLA2 and TNFSF13B genes were significantly associated with SNP 1:25664581 and SNP rs312433097, respectively. SERTM1 showed significant associations with rs730958360 and 1:33542680 and is a potential causal gene associated with the abundance of Corynebacteriaceae in feces. MARVELD3 was significantly associated with the 1:135348198 and was significantly correlated with the abundance of Enterococcus in ileum. Specifically, a lower abundance of Enterococcus in ileum and a higher abundance of Corynebacteriaceae in feces were associated with better feed efficiency. CONCLUSIONS: This study confirms that both host genetics and gut microbiota can drive variations in feed efficiency. A small portion of the gut microbiota often interacts with host genes, collectively enhancing feed efficiency. Therefore, targeting both the gut microbiota and host genetic variation by supporting more efficient taxa and selective breeding could improve feed efficiency in laying hens during the late laying period.

Revolutionizing patient education with GPT-4o: A new approach to preventing surgical site infections in total hip arthroplasty.

Total hip arthroplasty (THA) is a common surgical procedure known for its generally positive outcomes, but it also comes with the risk of surgical site infections (SSIs), which can result in significant complications and higher healthcare costs. Effective patient education plays a vital role in reducing these risks, as well-informed patients are more likely to take preventive measures and identify early signs of complications. The advent of advanced language models like GPT-4o has opened new avenues for patient education, potentially revolutionizing the way information is delivered and understood. This research letter explores the utility of GPT-4o in enhancing patient education specifically related to SSIs following THA. The capabilities of GPT-4o include offering tailored educational materials, providing 24/7 availability, facilitating humanized interactive learning, and supporting multilingual education. These features significantly improve patient understanding, engagement, and adherence to preventive measures, enhancing the overall quality of healthcare services. However, challenges such as equitable access, language and cultural barriers, and data privacy must be addressed. Utilizing GPT-4o's advanced AI capabilities can revolutionize patient education, thereby decreasing the incidence of SSIs and enhancing postoperative recovery for THA patients.

Müller cells harboring exosomal lncRNA OGRU modulates microglia polarization in diabetic retinopathy via serving as miRNA sponges.

Diabetic retinopathy (DR) is one of the most common complications of diabetes mellitus which is associated with visual loss and blindness worldwide. However, the effective treatments for both early- and late-stage DR remains lacking. A streptozotocin (STZ)-induced diabetic mice model and high glucose (HG)-treated Müller cell model were established. M1/M2 microglia polarization was assessed by immunofluorescence (IF) staining and flow cytometry. Expression of lncRNA OGRU, cytokines and other key molecules were detected by qRT-PCR or western blot. ELISA assay was employed to monitor cytokine secretion. Müller cell-derived exosomes were isolated and characterized by nanopartical tracking analysis (NTA), western blot and transmission electron microscopy (TEM), and exosome uptake assay was used to monitor the intercellular transport of exosomes. Associations among lncRNA-miRNA-mRNA networks were validated by RNA pull-down and RNA immunoprecipitation (RIP) and dual luciferase assays. Increased M1 polarization but decreased M2 polarization of retinal microglia were observed in DR mice. HG-treated Müller cell-derived exosomes transported OGRU into microglia and promoted microglia polarization toward M1 phenotype. Mechanistically, OGRU served as a competing endogenous RNA (ceRNA) for miR-320-3p, miR-221-3p and miR-574-5p to regulate AR, PFKFB3 and GLUT1 expression in microglia, respectively. Loss of miR-320-3p/miR-221-3p/miR-574-5p or reinforced AR/PFKFB3/GLUT1 abrogated OGRU silencing-mediated microglia polarization in vitro. In vivo studies further showed that OGRU/miR-320-3p/AR, OGRU/miR-221-3p/PFKFB3 and OGRU/miR-574-5p/GLUT1 axes regulated microglia polarization in DR mice. Collectively, Müller cells-derived exosomal OGRU regulated microglia polarization in DR via modulating OGRU/miR-320-3p/AR, OGRU/miR-221-3p/PFKFB3 and OGRU/miR-574-5p/GLUT1 axes.

The advance of ultrasound-enabled diagnostics and therapeutics.

Point-of-care ultrasound demonstrates significant potential in biomedical research due to its noninvasive, real-time visualization, cost-effectiveness, and other biological benefits. Ultrasound irradiation can precisely control the mechanical and physicochemical effects on pathogenic lesions, enabling real-time visualization, tunable tissue penetration depth, and therapeutic applications. This review summarizes recent advancements in ultrasound-enabled diagnostics and therapeutics, focusing on mechanochemical effects that can be directly integrated into biomedical applications. Additionally, the structure-functionality relationships of sonotheranostic nanoplatforms are systematically discussed, providing insights into the underlying biological effects. Finally, the limitations of current ultrasonic medicine are discussed, along with potential expansions to facilitate patient-centered translations.

Dissecting the genetic basis of UV-B responsive metabolites in rice.

BACKGROUND: UV-B, an important environmental factor, has been shown to affect the yield and quality of rice (Oryza sativa) worldwide. However, the molecular mechanisms underlying the response to UV-B stress remain elusive in rice. RESULTS: We perform comprehensive metabolic profiling of leaves from 160 diverse rice accessions under UV-B and normal light conditions using a widely targeted metabolomics approach. Our results reveal substantial differences in metabolite accumulation between the two major rice subspecies indica and japonica, especially after UV-B treatment, implying the possible role and mechanism of metabolome changes in subspecies differentiation and the stress response. We next conduct a transcriptome analysis from four representative rice varieties under UV-B stress, revealing genes from amino acid and flavonoid pathways involved in the UV-B response. We further perform a metabolite-based genome-wide association study (mGWAS), which reveals 3307 distinct loci under UV-B stress. Identification and functional validation of candidate genes show that OsMYB44 regulates tryptamine accumulation to mediate UV-B tolerance, while OsUVR8 interacts with OsMYB110 to promote flavonoid accumulation and UV-B tolerance in a coordinated manner. Additionally, haplotype analysis suggests that natural variation of OsUVR8groupA contributes to UV-B resistance in rice. CONCLUSIONS: Our study reveals the complex biochemical and genetic foundations that govern the metabolite dynamics underlying the response, tolerance, and adaptive strategies of rice to UV-B stress. These findings provide new insights into the biochemical and genetic basis of the metabolome underlying the crop response, tolerance, and adaptation to UV-B stress.

Reynoutria multiflora (Thunb.) Moldenke and its ingredient suppress lethal prostate cancer growth by inducing CDC25B-CDK1 mediated cell cycle arrest.

BACKGROUND: Reynoutria multiflora (Thunb.) Moldenke (Polygonum multiflorum Thunb, PM) is a medicinal plant that was an element of traditional Chinese medicine (TCM) for centuries as a treatment for a wide range of conditions. Recent studies reported that PM suppressed prostate cancer growth in an AR-dependent manner. However, its role and mechanism in the treatment of advanced prostate cancer remain to be explored. This study aims to explore the anti-tumor role and potential mechanism of PM on prostate cancer. METHODS: Cell viability, colony formation, fluorescence-activated cell sorting (FACS), and wound-healing assays were conducted to evaluate the tumor suppression effect of PM on lethal prostate cancer models in vitro. A xenograft mice model was established to detect the impact of PM on tumor growth and evaluate its biosafety in vivo. Integrative network pharmacology, RNA-seq, and bioinformatics were applied to determine the mechanisms of PM in prostate cancer. Molecular docking, cellular thermal shift assay (CETSA), CRISPR-Cas13, RT-qPCR, and WB were collaboratively employed to identify the potential anti-tumor ingredient derived from PM and its corresponding targets. RESULTS: PM significantly suppressed the growth of prostate cancer and sensitized prostate cancer to AR antagonists. Mechanistically, PM induced G2/M-phase cell-cycle arrest by modulating the phosphorylation of CDK1. Additionally, polygalacic acid derived from PM and its structural analog suppress prostate cancer growth by targeting CDC25B, a master regulator of the cell cycle that governs CDK1 phosphorylation. CONCLUSION: PM and its ingredient polygalacic acid suppress lethal prostate cancer growth by regulating the CDC25B-CDK1 axis to induce cell cycle arrest.

Calcium deposition in chicken eggshells: role of host genetics and gut microbiota.

Eggshell is predominantly composed of calcium carbonate, making up about 95% of its composition. Eggshell quality is closely related to the amount of calcium deposition in the shell, which requires chickens to maintain a robust state of calcium metabolism. In this study, we introduced a novel parameter, Total Eggshell Weight (TESW), which measures the total weight of eggshells produced by chickens over a period of 10 consecutive d, providing valuable information on the intensity of calcium metabolism in chickens. Genome-wide association study (GWAS) was conducted to explore the genetic determinants of eggshell calcification in a population of 570 Rhode Island Red laying hens at 90 wk of age. This study revealed a significant association between a specific SNP (rs14249431) and TESW. Additionally, using random forest modeling and 2-tailed testing, we identified 3 genera, Lactobacillus in the jejunum, Lactobacillus, and Fournierella in the cecum, that exhibited a significant association with TESW. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis of claudin-1 and occludin genes in individuals with low TESW and high abundance of jejunal Lactobacillus confirmed that the inhibitory effect of jejunal Lactobacillus on calcium uptake was achieved through the up-regulation of tight junctions in intestinal epithelial cells. Notably, both host and microbial factors influence TESW, displaying a mutually influential relationship between them. The microbiome-wide Genome-Wide Association Study (mb-GWAS) identified significant associations between these 3 genera and specific genomic variants, such as rs316115020 and rs316420452 on chromosome 5, rs313198529 on chromosome 11, linked to Lactobacillus in the cecum. Moreover, rs312552529 on chromosome 1 exhibited potential association with Fournierella in the cecum. This study highlights the influence of host genetics and gut microbiota on calcium deposition in eggshells during the late laying phase, providing a foundational reference for studying calcium metabolism in hens.

Molecular responses reveal that two glutathione S-transferase CsGSTU8s contribute to detoxification of glyphosate in tea plants (Camellia sinensis).

Tea plant (Camellia sinensis) is an important economical crop that frequently suffers from various herbicides, especially glyphosate. However, the molecular responses and regulatory mechanisms of glyphosate stress in tea plants remain poorly understood. Here, we reported a transcriptome dataset and identified large number of differentially expressed genes (DEGs) under glyphosate exposure. Next, two glutathione S-transferase genes (CsGSTU8-1 and CsGSTU8-2) that upregulated significantly were screened as candidate genes. Tissue-specific expression patterns showed that both CsGSTU8-1 and CsGSTU8-2 had extremely high expression levels in the roots and were predominantly localized in the nucleus and plasma membrane based on subcellular localization. Both were significantly upregulated at different time points under various stressors, including drought, cold, salt, pathogen infections, and SA treatments. An enzymatic activity assay showed that CsGSTU8-1 catalyzes the conjugation of glutathione with 2,4-dinitrochlorobenzene (CDNB). Functional analysis in yeast verified that the two genes significantly contributed to the detoxification of glyphosate, and CsGSTU8-1 had a stronger role in detoxification than CsGSTU8-2. Taken together, these findings provide insights into the molecular responses of tea plants to glyphosate and the functions of CsGSTU8s in glyphosate detoxification, which can be used as a promising genetic resource for improving herbicide resistance in tea cultivars.

Enhancing zinc biofortification and mitigating cadmium toxicity in soil-earthworm-spinach systems using different zinc sources.

Cadmium (Cd) pollution poses significant threats to soil organisms and human health by contaminating the food chain. This study aimed to assess the impact of various concentrations (50, 250, and 500 mg·kg-1) of zinc oxide nanoparticles (ZnO NPs), bulk ZnO, and ZnSO4 on morphological changes and toxic effects of Cd in the presence of earthworms and spinach. The results showed that Zn application markedly improved spinach growth parameters (such as fresh weight, plant height, root length, and root-specific surface area) and root morphology while significantly reducing Cd concentration and Cd bioconcentration factors (BCF-Cd) in spinach and earthworms, with ZnO NPs exhibiting the most pronounced effects. Earthworm, spinach root, and shoot Cd concentration decreased by 82.3 %, 77.0 %, and 75.6 %, respectively, compared to CK. Sequential-step extraction (BCR) analysis revealed a shift in soil Cd from stable to available forms, consistent with the available Cd (DTPA-Cd) results. All Zn treatments significantly reduced Cd accumulation, alleviated Cd-induced stress, and promoted spinach growth, with ZnO NPs demonstrating the highest Cd reduction and Zn bioaugmentation efficiencies compared to bulk ZnO and ZnSO4 at equivalent concentrations. Therefore, ZnO NPs offer a safer and more effective option for agricultural production and soil heavy metal pollution management than other Zn fertilizers.

Hemin regulates platelet clearance in hemolytic disease by binding to GPIbα.

Hemolysis is associated with thrombosis and vascular dysfunction, which are the pathological components of many diseases. Hemolytic products, including hemoglobin and hemin, activate platelets (PLT). Despite its activation, the effect of hemolysis on platelet clearance remains unclear, It is critical to maintain a normal platelet count and ensure that circulating platelets are functionally viable. In this study, we used hemin, a degradation product of hemoglobin, as a potent agonist to treat platelets and simulate changes in vivo in mice. Hemin treatment induced activation and morphological changes in platelets, including an increase in intracellular Ca2+ levels, phosphatidylserine (PS) exposure, and cytoskeletal rearrangement. Fewer hemin-treated platelets were cleared by macrophages in the liver after transfusion than untreated platelets. Hemin bound to glycoprotein Ibα (GPIbα), the surface receptor in hemin-induced platelet activation and aggregation. Furthermore, hemin decreased GPIbα desialylation, as evidenced by reduced Ricinus communis agglutinin I (RCA- I) binding, which likely extended the lifetime of such platelets in vivo. These data provided new insight into the mechanisms of GPIbα-mediated platelet activation and clearance in hemolytic disease.

What is the context? Hemolysis is a primary hematological disease. Hemolysis is a pathological complication of several diseases.Hemin, a degradation product of cell-free hemoglobin, has been proven to be a more potent agonist than hemoglobin for directly activating platelets.Platelet membrane glycoproteins (GP), including GPIb-IX and GPIIb/IIIa complexes, play crucial roles in platelet hemostasis.Desialylation (loss of sialic acid residues) of GPIbα, is believed to regulate physiological platelet clearance through liver macrophages and hepatocytes.What is new? In this study, we evaluated the effects of hemolysis on platelet clearance. We first analyzed the influence of hemin at 0-50 µM on platelets in vitro before exploring the mechanism underlying hemin-induced platelet activation and its role in platelet clearance in vitro and in vivo.Our analyses suggest that: Hemin bound to GPIbα on the platelet surface with high affinity.Platelet clearance occurred slowly in the liver and spleen after hemin treatment.Platelets exhibited significant significantly reduced GPIbα surface expression and desialylation after hemin treatment.Platelets exhibited significant significantly reduced GPIbα surface expression and desialylation after hemin treatment.What is the impact? This study provides new insights into the role of hemin in the mechanisms of GPIbα-mediated platelets activation and clearance in diseases associated with hemolysis.

Mechanism of baicalein in treatment of castration-resistant prostate cancer based on network pharmacology and cell experiments.

Objective: Baicalein, one of the most abundant flavonoids found in Chinese herb Scutellaria baicalensis Georgi, exhibits pharmacological activities against various cancers. However, the precise pharmacological mechanism of baicalein in treating castration-resistant prostate cancer (CRPC) remains elusive. This study aimed to elucidate the potential mechanism of baicalein against CRPC through a combination of network pharmacology and experimental approaches, thereby providing new avenues for research in CRPC treatment. Methods: The pharmacological and molecular properties of baicalein were obtained using the TCMSP database. Baicalein-related targets were collected from multiple sources including SwissTargetPrediction, PharmMapper and CTD. Targets related to CRPC were acquired from DisGeNET, GeneCards, and CTD. The protein-protein interaction (PPI) was analyzed using STRING 11.5, and Cytoscape 3.7.2 software was utilized to explore the core targets of baicalein on CRPC. GO and KEGG pathway enrichment analysis were performed using DAVID database. Cell experiments were carried out to confirm the validity of the targets. Results: A total of 131 potential targets of baicalein for the treatment of CRPC were obtained. Among them, TP53, AKT1, ALB, CASP3, and HSP90AA1, etc., were recognized as core targets by Cytoscape 3.7.2. GO function enrichment analysis yielded 926 entries, including 703 biological process (BP) terms, 84 cellular component (CC) terms and 139 molecular function (MF) terms. The KEGG pathway enrichment analysis unveiled 159 signaling pathways, mainly involved in Pathways in cancer, prostate cancer, AGE-RAGE signaling pathway in diabetic complications, TP53 signaling pathway, and PI3K-Akt signaling pathway, etc. Cell experiments confirmed that baicalein may inhibit the proliferation of CRPC cells and induce cell cycle arrest in the G1 phase. This effect could be associated with the TP53/CDK2/cyclin E1 pathway. In addition, the results of CETSA suggest that baicalein may directly bind to TP53. Conclusion: Based on network pharmacology analysis and cell experiments, we have predicted and validated the potential targets and related pathways of baicalein for CRPC treatment. This comprehensive approach provides a scientific basis for elucidating the molecular mechanism underlying the action of baicalein in CRPC treatment. Furthermore, these findings offer valuable insights and serve as a reference for the research and development of novel anti-CRPC drugs.

Identification and Comprehensive Analysis of circRNA-miRNA-mRNA Regulatory Networks in A2780 Cells Treated with Resveratrol.

Ovarian cancer (OC) is one of the most commonplace gynecological malignancies. This study explored the effects of resveratrol (RES) on OC cell proliferation and apoptosis. Proliferation activity was measured for A2780 cells treated with RES for 24 h and 48 h at concentrations of 0, 10, 25, 50, 75, 100, 150, 200, and 300 µM. RNA sequencing (RNA-seq) was performed to analyze the circular RNA (circRNA), microRNA (miRNA), and messenger RNA (mRNA) expression spectrum. The differentially expressed genes included 460 circRNAs, 1988 miRNAs, and 1671 mRNAs, and they were subjected to analyses including Gene Ontology, the Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome enrichment. We selected signaling pathways enriched in the cell processes by mRNA KEGG, comprehensively analyzed the circRNA-miRNA-mRNA regulatory network, and verified several miRNAs expressed in the regulatory network diagram using the quantitative real-time polymerase chain reaction. The data showed that the cell proliferation of A2780 cells treated with RES for 24 h or 48 h decreased with increasing concentrations of RES. The circRNA-miRNA-mRNA regulatory network that we constructed provides new insights into the ability of RES to inhibit cell proliferation and promote apoptosis in A2780 cells.

Mechanisms of hepatic steatosis in chickens: integrated analysis of the host genome, molecular phenomics and gut microbiome.

Hepatic steatosis is the initial manifestation of abnormal liver functions and often leads to liver diseases such as nonalcoholic fatty liver disease in humans and fatty liver syndrome in animals. In this study, we conducted a comprehensive analysis of a large chicken population consisting of 705 adult hens by combining host genome resequencing; liver transcriptome, proteome, and metabolome analysis; and microbial 16S ribosomal RNA gene sequencing of each gut segment. The results showed the heritability (h2 = 0.25) and duodenal microbiability (m2 = 0.26) of hepatic steatosis were relatively high, indicating a large effect of host genetics and duodenal microbiota on chicken hepatic steatosis. Individuals with hepatic steatosis had low microbiota diversity and a decreased genetic potential to process triglyceride output from hepatocytes, fatty acid ß-oxidation activity, and resistance to fatty acid peroxidation. Furthermore, we revealed a molecular network linking host genomic variants (GGA6: 5.59-5.69 Mb), hepatic gene/protein expression (PEMT, phosphatidyl-ethanolamine N-methyltransferase), metabolite abundances (folate, S-adenosylmethionine, homocysteine, phosphatidyl-ethanolamine, and phosphatidylcholine), and duodenal microbes (genus Lactobacillus) to hepatic steatosis, which could provide new insights into the regulatory mechanism of fatty liver development.

Reciprocal regulation between RACGAP1 and AR contributes to endocrine therapy resistance in prostate cancer.

BACKGROUND: Endocrine resistance driven by sustained activation of androgen receptor (AR) signaling pathway in advanced prostate cancer (PCa) is fatal. Characterization of mechanisms underlying aberrant AR pathway activation to search for potential therapeutic strategy is particularly important. Rac GTPase-activating protein 1 (RACGAP1) is one of the specific GTPase-activating proteins. As a novel tumor proto-oncogene, overexpression of RACGAP1 was related to the occurrence of various tumors. METHODS: Bioinformatics methods were used to analyze the relationship of expression level between RACGAP1 and AR as well as AR pathway activation. qRT-PCR and western blotting assays were performed to assess the expression of AR/AR-V7 and RACGAP1 in PCa cells. Immunoprecipitation and immunofluorescence experiments were conducted to detect the interaction and co-localization between RACGAP1 and AR/AR-V7. Gain- and loss-of-function analyses were conducted to investigate the biological roles of RACGAP1 in PCa cells, using MTS and colony formation assays. In vivo experiments were conducted to evaluate the effect of RACGAP1 inhibition on the tumor growth. RESULTS: RACGAP1 was a gene activated by AR, which was markedly upregulated in PCa patients with CRPC and enzalutamide resistance. AR transcriptionally activated RACGAP1 expression by binding to its promoter region. Reciprocally, nuclear RACGAP1 bound to the N-terminal domain (NTD) of both AR and AR-V7, blocking their interaction with the E3 ubiquitin ligase MDM2. Consequently, this prevented the degradation of AR/AR-V7 in a ubiquitin-proteasome-dependent pathway. Notably, the positive feedback loop between RACGAP1 and AR/AR-V7 contributed to endocrine therapy resistance of CRPC. Combination of enzalutamide and in vivo cholesterol-conjugated RIG-I siRNA drugs targeting RACGAP1 induced potent inhibition of xenograft tumor growth of PCa. CONCLUSION: In summary, our results reveal that reciprocal regulation between RACGAP1 and AR/AR-V7 contributes to the endocrine resistance in PCa. These findings highlight the therapeutic potential of combined RACGAP1 inhibition and enzalutamide in treatment of advanced PCa.

Discovery of a Covalent Inhibitor That Overcame Resistance to Venetoclax in AML Cells Overexpressing BFL-1.

Clinical and biological studies have shown that overexpression of BFL-1 is one contributing factor to venetoclax resistance. The resistance might be overcome by a potent BFL-1 inhibitor, but such an inhibitor is rare. In this study, we show that 56, featuring an acrylamide moiety, inhibited the BFL-1/BID interaction with a Ki value of 105 nM. More interestingly, 56 formed an irreversible conjugation adduct at the C55 residue of BFL-1. 56 was a selective BFL-1 inhibitor, and its MCL-1 binding affinity was 10-fold weaker, while it did not bind BCL-2 and BCL-xL. Mechanistic studies showed that 56 overcame venetoclax resistance in isogenic AML cell lines MOLM-13-OE and MV4-11-OE, which both overexpressed BFL-1. More importantly, 56 and venetoclax combination promoted stronger apoptosis induction than either single agent. Collectively, our data show that 56 overcame resistance to venetoclax in AML cells overexpressing BFL-1. These attributes make 56 a promising candidate for future optimization.

Targeting STAT3 potentiates CDK4/6 inhibitors therapy in head and neck squamous cell carcinoma.

Anti-CDK4/6 therapy has been employed for the treatment for head and neck squamous cell carcinoma (HNSCC) with CDK4/6 hyperactivation, but the response rate is relatively low. In this study, we first showed that CDK4 and CDK6 was over-expressed and conferred poor prognosis in HNSCC. Moreover, in RB-positive HNSCC, STAT3 signaling was activated induced by CDK4/6 inhibition and STAT3 promotes RB deficiency by upregulation of MYC. Thirdly, the combination of Stattic and CDK4/6 inhibitor results in striking anti-tumor effect in vitro and in Cal27 derived animal models. Additionally, phospho-STAT3 level negatively correlates with RB expression and predicts poor prognosis in patients with HNSCC. Taken together, our findings suggest an unrecognized function of STAT3 confers to CDK4/6 inhibitors resistance and presenting a promising combination strategy for patients with HNSCC.

The Laccase Family Gene CsLAC37 Participates in Resistance to Colletotrichum gloeosporioides Infection in Tea Plants.

Fungal attacks have become a major obstacle in tea plantations. Colletotrichum gloeosporioides is one of the most devastating fungal pathogens in tea plantations that can severely affect tea yield and quality. However, the molecular mechanism of resistance genes involved in anthracnose is still largely unknown in tea plants. Here, we found that the laccase gene CsLAC37 was involved in the response to fungal infection based on a transcriptome analysis. The full-length CDS of CsLAC37 was cloned, and its protein sequence had the closest relationship with the Arabidopsis AtLAC15 protein compared to other AtLACs. Tissue-specific expression analysis showed that CsLAC37 had higher expression levels in mature leaves and stems than in the other tissues. Subcellular localization showed that the CsLAC37 protein was predominantly localized in the cell membrane. The expression levels of CsLAC37 were upregulated at different time points under cold, salt, SA, and ABA treatments. qRT-PCR confirmed that CsLAC37 responded to both Pestalotiopsis-like species and C. gloeosporioides infections. Functional validation showed that the hydrogen peroxide (H2O2) content increased significantly, and POD activity decreased in leaves after antisense oligonucleotide (AsODN) treatment compared to the controls. The results demonstrated that CsLAC37 may play an important role in resistance to anthracnose, and the findings provide a theoretical foundation for molecular breeding of tea varieties with resistance to fungal diseases.

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OBJECTIVES: To investigate the risk factors for the failure of ibuprofen treatment in preterm infants with hemodynamically significant patent ductus arteriosus (hsPDA). METHODS: A retrospective collection of clinical data was conducted on preterm infants with a gestational age of <34 weeks who were diagnosed with hsPDA and treated at the Department of Neonatology, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, from January 2018 to June 2023. The subjects were divided into two groups based on the treatment approach: the ibuprofen group (95 cases) and the ibuprofen plus surgery group (44 cases). The risk factors for the failure of ibuprofen treatment in preterm infants with hsPDA were identified by binary logistic regression analysis. RESULTS: The binary logistic regression analysis revealed that an increased diameter of the ductus arteriosus, a resistance index (RI) value of the middle cerebral artery ≥0.80, and prolonged total invasive mechanical ventilation time were risk factors for the failure of ibuprofen treatment in preterm infants with hsPDA (P<0.05). Receiver operating characteristic curve analysis showed that a ductus arteriosus diameter >2.85 mm, a middle cerebral artery RI value ≥0.80, and a total invasive mechanical ventilation time >16 days had significant predictive value for the failure of ibuprofen treatment in preterm infants with hsPDA (P<0.05). The combined predictive value of these three factors was the highest, with an area under the curve of 0.843, a sensitivity of 86.5%, and a specificity of 75.0% (P<0.05). CONCLUSIONS: A ductus arteriosus diameter >2.85 mm, a middle cerebral artery RI value ≥0.80, and a total invasive mechanical ventilation time >16 days are risk factors for the failure of ibuprofen treatment in preterm infants with hsPDA, and they are of significant predictive value for the necessity of surgical treatment following the failure of ibuprofen treatment.

Targeted delivery of NO donor and ROS scavenger for synergistic treatment of rheumatoid arthritis.

Rheumatoid arthritis (RA) is characterized by high level of reactive oxygen species (ROS) and proinflammatory cytokines, which facilitate the activation of the inflammatory signaling such as NF-κB pathway and exacerbate the development of inflammation. Herein, we designed a nanodrug by encapsulating the NO donor S-nitrosoglutathione (GSNO) into an emulsion and coating the surface with a polydopamine (PDA) layer to yield GSNO@PDA, which simultaneously scavenged the extra ROS and suppressed NF-κB signaling for potent RA treatment. To enhance the cellular uptake and NO generation efficiency, dextran sulfate (DS) and Cu2+ were anchored on the surface of GSNO@PDA to obtain the final formulation GSNO@PDA@DS. Our results demonstrated that GSNO@PDA@DS were successfully prepared and the modification of DS effectively boosted the cellular uptake of GSNO@PDA@DS. Moreover, GSNO@PDA@DS lowered cellular ROS and elevated intracellular NO, resulting in a decrease of M1 phenotype, inhibition of NF-κB pathway and down-regulation of proinflammatory cytokine tumor necrosis factor-α (TNF-α). Further in vivo studies confirmed that GSNO@PDA@DS significantly relieved symptoms and bone erosion by regulating the microenvironment of RA, highlighting the potential of GSNO@PDA@DS for RA therapy through ROS scavenging and NO-mediated suppression of inflammatory signaling.