Search

The development of novel, safe, and efficient pest and disease control technologies for agricultural crops remains a pivotal area of research. In this study, by combining ZIF-8 and ZIF-90, a water-stable, pH-responsive bilayer MOF nanoparticle (NP) named Z8@Z90 was created, and tebuconazole (TEB) was added to form T@Z8@Z90, used for controlling peanut southern blight. The loading efficiency of TEB within the T@Z8@Z90 reached 26.15%, enabling rapid release in acidic environments triggered by oxalic acid (OA) secreted by Sclerotium rolfsii . In vitro experiments showed that T@Z8@Z90 can regulate the oxalic acid secretion of S. rolfsii and destroy its cell membrane structure. Additional experiments revealed that T@Z8@Z90 reduced sclerotial formation, decreased the total protein content of sclerotia, and influenced their sensitivity to pesticides, thereby mitigating the risk of reinfection by S. rolfsii . Notably, T@Z8@Z90 exhibited efficient translocation within peanut seedlings, being absorbed through the roots and transported to the leaves. At a concentration of 200 mg/L, T@Z8@Z90 exhibited high safety profiles for peanut seedling growth compared to the TEB suspension. Moreover, T@Z8@Z90 is safer for earthworms than TEB SC. Overall, this study offers valuable insights for the management of soil-borne diseases in agriculture and contributes to the advancement of sustainable agricultural practices.

Lung squamous cell carcinoma (LUSC) is associated with high mortality and has few therapeutic options. Chemotherapy remains the main treatment for LUSC patients, but multi-drug resistance has become the dominant challenge in the failure of chemotherapy in various cancers. Therefore, the effective therapeutic strategy for LUSC patients is an urgent unmet need. Here, we found vasohibin-2 (VASH2) was a prognostic biomarker for LUSC patients, and VASH2 promoted the malignant biological behaviors of LUSC cells and chemoresistance by increasing the detyrosination of α-tubulin. The high level of detyrosinated-tubulin was negatively associated with patient prognosis. Blocking the tubulin carboxypeptidase (TCP) activity of VASH2 inhibited the xenograft tumor growth and improved the treatment efficacy of paclitaxel in vivo. Results revealed that VASH2-induced increase in tubulin detyrosination boosted the binding of kinesin family member 3C (KIF3C) to microtubules and enhanced KIF3C-dependent endosomal recycling of EGFR, leading to the prolonged activation of PI3K/Akt/mTOR signaling. This study demonstrated that VASH2 was not only a prognostic biomarker but also a promising therapeutic target in LUSC, which offers a novel insight that combination of chemotherapy and EpoY, a TCP inhibitor, may be a promising treatment strategy for LUSC patients., (© 2024. The Author(s).)

In this phase II study, 47 patients with locally advanced, resectable esophageal squamous cell carcinoma (ESCC) received three cycles of pembrolizumab plus chemotherapy, followed by Da Vinci robot-assisted surgery. The primary endpoints were safety and major pathological response (MPR). Key secondary endpoints included complete pathological response (pCR) and survival. No grade ≥3 adverse events or surgical delays occurred during neoadjuvant therapy. Among 46 patients studied for efficacy, the MPR and pCR rates were 72% and 41%, respectively. After a median follow-up of 27.2 months, the 2-year overall survival (OS) and disease-free survival (DFS) rates were 91% and 89%, respectively. Expansion of TRGC2 + NKT cells in peripheral blood correlated with neoadjuvant treatment effectiveness, which was validated by in vitro organoid experiments and external cancer datasets, and its functional classification and mechanism of action were further explored. These findings show preoperative pembrolizumab plus chemotherapy is a promising therapeutic strategy for resectable ESCC., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Current knowledge about the prognostic role of interleukin-33 (IL-33) in lung squamous cell carcinoma (LUSC) remains limited, particularly in stage II-III patients. This study aimed to verify the correlation between IL-33 expression and poor prognosis in stage II-III LUSC patients at both gene and protein levels and to investigate the potential role of IL-33 blockade in combination with immune checkpoint inhibitors (ICIs) in perioperative immunotherapy., Methods: A retrospective analysis was conducted of 103 patients with stage II-III LUSC who underwent surgical resection at Tianjin Medical University Cancer Institute & Hospital from November 1, 2004, to November 30, 2006. Of these, 83 patients were included based on complete follow-up data, and were divided into a gene expression group (38 patients) and a protein expression group (45 patients). IL-33 expression was analyzed using real-time quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry (IHC). The correlation between IL-33 expression and overall survival (OS) was assessed using Kaplan-Meier survival analysis. Additionally, IHC results from 20 patients were used to explore the correlation between IL-33, programmed death ligand 1 (PD-L1), and Ki-67 expression levels. The total follow-up time exceeded 60 months, and the study endpoint was OS., Results: Patients with high IL-33 expression had significantly shorter OS compared to those with low IL-33 expression, both at the gene (P=0.006) and protein expression (P=0.01). Logistic regression analysis confirmed IL-33 as an independent prognostic factor for poor survival in stage II-III LUSC (P gene =0.04, P protein =0.009). Additionally, a significant positive correlation was observed between the protein expression of IL-33 (P=0.03), PD-L1 (P<0.001), and Ki-67 (P=0.01), indicating that high expression of these markers is associated with worse prognosis., Conclusions: High IL-33 expression in cancer tissues is associated with poor prognosis in stage II-III LUSC. IL-33 blockade combined with ICIs may provide new treatment regimens and ideas for perioperative immunotherapy in stage II-III LUSC patients., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1122/coif). N.S. obtained research grants from Eli Lilly, Chugai Pharmaceutical, Taiho Pharmaceutical, Pfizer, Ono Pharmaceutical, Nippon Kayaku, Takeda Pharmaceutical, Eisai, Shionogi, Daiichi Sankyo, and Boehringer Ingelheim and received speaking honoraria from Eli Lilly, AstraZeneca, MSD, Chugai Pharmaceutical, Taiho Pharmaceutical, Pfizer, Ono Pharmaceutical, Nippon Kayaku, Takeda Pharmaceutical, Daiichi Sankyo, Boehringer Ingelheim, Novartis, Kyowa Kirin, and Bristol Myers Squibb. W.M.B. received honoraria for lectures or educational events from AstraZeneca, Boehringer, Novartis, MSD, BMS, Lilly, Pfizer and Roche, received support for attending meetings and/or travel from Boehringer, Roche Pharma, and AstraZeneca, served on advisory board of Astra Zeneca, Boehringer, Novartis, MSD, Lilly Pharma, BMS, and Roche, and received equipment, material, drugs, medical writing, gifts or other services from Boehringer for medical writing. W.M.B.’s patent application EP21183549.1 (method for predicting a clinical response towards an immune checkpoint inhibitor based on pretreatment therewith) was filed with regard to the results of this study. The other authors have no conflicts of interest to declare., (2024 AME Publishing Company. All rights reserved.)

Starch is the main component of wheat (Triticum aestivum L.) flour, and its quality directly affects the processing quality of the final product. To investigate the genetic basis of starch, this study assessed the starch quality traits of 341 winter wheat varieties/lines grown in Emin and Qitai during the years 2019-2020 and 2020-2021. A genome-wide association study was conducted with the genotype data obtained from wheat 40K breeding chips using the mixed linear model. Wheat starch quality traits exhibited coefficients of variation ranging from 1.43% to 23.66% and broad-sense heritabilities between 0.37 and 0.87. All traits followed an approximately normal distribution, except for T. There were highly significant correlations among starch quality traits, with the strongest correlation observed between final viscosity (FV) and trough viscosity (TV) (r = 0.748), followed by peak viscosity and breakdown (BD) (r = 0.679). Thirty-four single-nucleotide polymorphism markers significantly and stably associated with starch quality traits were identified, clustering in 31 genetic loci. These included one locus for TV, six loci for BD, three loci for FV, two loci for peak time (PT), 12 loci for T, five loci for falling number, and two loci for damaged starch. One PT-related block of 410 kb was identified in the region of 596 Mb on chromosome 5A, where significant phenotypic differences were observed between different haplotypes. One Kompetitive allele-specific PCR (KASP) marker for T was developed on chromosome 7B, and two KASP markers for BD were developed on chromosome 7A. Four candidate genes possibly affecting BD during grain development were identified on chromosome 7A, including TraesCS7A02G225100.1, TraesCS7A02G225900.1, TraesCS7A02G226400.1, and TraesCS7A02G257100.1. The results have significant implications for utilizing marker-assisted selection in breeding to improve wheat starch quality., (© 2024 The Author(s). The Plant Genome published by Wiley Periodicals LLC on behalf of Crop Science Society of America.)

Background and Aim: Whether chemotherapy can improve the prognosis of invasive intraductal papillary-mucinous carcinoma (IPMC) still remains unclear. The aim of this study is to observe the difference in survival time of patients with invasive IPMC receiving or not receiving chemotherapy., Methods: 117 patients with invasive IPMC were included in The Surveillance, Epidemiology, and End Results (SEER) database. These patients were subsequently divided into two subgroups according to whether they received chemotherapy or not: the non-chemotherapy group (patients who did not receivechemotherapy, N = 58), the chemotherapy group (patients who received chemotherapy, N = 59). The overall survival (OS) and cancer specific survival (CSS) of two treatment groups were evaluated., Results: Before adjusting for pathology grade, the Kaplan-Meier analysis showed that the difference of survival time is not significant between non-chemotherapy group and chemotherapy group (P > 0.05), but the land-mark analysis showed that short-term death risk of the chemotherapy group is significantly lower than non-chemotherapy group (P < 0.05). After adjust the pathology grade, survival time of the chemotherapy group is significantly longer than non-chemotherapy group (P < 0.05). Univariate and multivariate Cox regression showed that chemotherapy was an independent prognostic protective factor for invasive IPMC (P < 0.05). Land-mark analysis showed that short-term death risk of the chemotherapy group is significantly lower than non-chemotherapy group in N1-N2 subgroup (P < 0.05)., Conclusion: Chemotherapy is an independent protective factor IPMC, especially reducing the risk of short-term death for IPMC patients with lymph node metastasis., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

In primary cell types, intracellular deoxynucleotide triphosphate (dNTP) levels are tightly regulated in a cell cycle-dependent manner. We report that prime editing efficiency is increased by mutations that improve the enzymatic properties of Moloney murine leukemia virus reverse transcriptase and treatments that increase intracellular dNTP levels. In combination, these modifications produce substantial increases in precise editing rates., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: The actual situation and influencing factors of prophylactic use of proton pump inhibitors (PPIs) in internal medicine inpatients receiving glucocorticoid therapy are rarely reported. This study aimed to investigate the current status and influencing factors of prophylactic use of PPIs in internal medicine inpatients receiving glucocorticoid therapy to provide a basis for rational prophylactic use of PPIs., Methods: Internal medicine inpatients receiving glucocorticoid therapy from February 2023 to September 2023 were included. Information on the prophylactic use of PPIs was collected and analyzed by clinical pharmacists. Associated factors with prophylactic use of PPIs were analyzed by univariable and multivariable logistic regression., Results: 980 inpatients were finally included in our study, of which 271 (27.7%) inpatients received prophylactic use of PPIs. Among the inpatients prescribed PPIs, 90 inpatients received a standard dose of PPIs twice a day. Multiple logistic regression analysis showed that age ≥80 years [OR = 7.009, 95% CI (1.424, 34.495), p = 0.017], history of gastroesophageal reflux disease (GERD) [OR = 2.047, 95% CI (1.338, 3.133), p = 0.001], low platelet count [OR = 0.997, 95% CI (0.994, 0.999), p = 0.004], number of concomitant diseases [OR = 1.104, 95% CI (1.056, 1.153), p < 0.001], junior doctors [OR = 1.755, 95% CI (1.248, 2.468), p = 0.001], glucocorticoid dose (higher than 50 mg, measured by methylprednisolone) [OR = 2.455, 95% CI (1.371, 4.395), p = 0.003], antiplatelet agents [OR = 2.567, 95% CI (1.456, 4.524), p = 0.001], immunosuppressants [OR = 1.477, 95% CI (1.014, 2.153), p = 0.042], and betahistine [OR = 5.503, 95% CI (1.124, 26.950), p = 0.035] were associated with more prophylactic use of PPIs., Conclusion: The prophylactic use of PPIs in internal medicine inpatients receiving glucocorticoid therapy is common in China. Clinical pharmacists will take targeted measures to promote the rational use of PPIs according to the results of this study., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Liu, Li, Wu and Han.)

Nasopharyngeal carcinoma (NPC), a squamous cell carcinoma originating in the nasopharynx, is a leading malignancy in south China and other south and east Asia areas. It is frequently associated with Epstein-Barr virus (EBV) infection, while there are also some NPC patients without EBV infection. Here, it is shown that the EBV+ (EBV positive) and EBV- (EBV negative) NPCs contain both shared and distinct genetic abnormalities, among the latter are increased mutations in TP53. To investigate the functional roles of NPC-associated genetic alterations, primary, orthotopic, and genetically defined NPC models were developed in mice, a key tool missed in the field. These models, initiated with gene-edited organoids of normal nasopharyngeal epithelium, faithfully recapitulated the pathological features of human disease. With these models, it is found that Trp53 and Cdkn2a deficiency are crucial for NPC initiation and progression. And latent membrane protein1 (LMP1), an EBV-coding oncoprotein, significantly promoted the distal metastasis. Further, loss of TGFBR2, which is frequently disrupted both in EBV- and EBV+ NPCs, dramatically accelerated the progression and lung metastasis of NPC probably by altering tumor microenvironment. Taken together, this work establishes a platform to dissect the genetic mechanisms underlying NPC pathogenesis and might be of value for future translational studies., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Gastrointestinal tumors, the second leading cause of human mortality, are characterized by their association with inflammation. Currently, progress in the early diagnosis and effective treatment of gastrointestinal tumors is limited. Recent whole-genome analyses have underscored their profound heterogeneity and extensive genetic and epigenetic reprogramming. Epigenetic reprogramming pertains to dynamic and hereditable alterations in epigenetic patterns, devoid of concurrent modifications in the underlying DNA sequence. Common epigenetic modifications encompass DNA methylation, histone modifications, noncoding RNA, RNA modifications, and chromatin remodeling. These modifications possess the potential to invoke or suppress a multitude of genes associated with cancer, thereby governing the establishment of chromatin configurations characterized by diverse levels of accessibility. This intricate interplay assumes a pivotal and indispensable role in governing the commencement and advancement of gastrointestinal cancer. This article focuses on the impact of epigenetic reprogramming in the initiation and progression of gastric cancer, esophageal cancer, and colorectal cancer, as well as other uncommon gastrointestinal tumors. We elucidate the epigenetic landscape of gastrointestinal tumors, encompassing DNA methylation, histone modifications, chromatin remodeling, and their interrelationships. Besides, this review summarizes the potential diagnostic, therapeutic, and prognostic targets in epigenetic reprogramming, with the aim of assisting clinical treatment strategies., Competing Interests: The authors declare no conflict of interests., (© 2024 The Author(s). MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.)

Lignin, renowned for its renewable, biocompatible, and environmentally benign characteristics, holds immense potential as a sustainable feedstock for agrochemical formulations. In this study, raw dealkaline lignin (DAL) underwent a purification process involving two sequential solvent extractions. Subsequently, an enzyme-responsive nanodelivery system (Pyr@DAL-NPs), was fabricated through the solvent self-assembly method, with pyraclostrobin (Pyr) loaded into lignin nanoparticles. The Pyr@DAL-NPs shown an average particle size of 250.4 nm, demonstrating a remarkable loading capacity of up to 54.70 % and an encapsulation efficiency of 86.15 %. Notably, in the presence of cellulase and pectinase at a concentration of 2 mg/mL, the release of Pyr from the Pyr@DAL-NPs reached 92.66 % within 120 h. Furthermore, the photostability of Pyr@DAL-NPs was significantly improved, revealing a 2.92-fold enhancement compared to the commercially available fungicide suspension (Pyr SC). Bioassay results exhibited that the Pyr@DAL-NPs revealed superior fungicidal activity against Botrytis cinerea over Pyr SC, with an EC 50 value of 0.951 mg/L. Additionally, biosafety assessments indicated that the Pyr@DAL-NPs effectively declined the acute toxicity of Pyr towards zebrafish and posed no negative effects on the healthy growth of strawberry plants. In conclusion, this study presents a viable and promising strategy for developing environmentally friendly controlled-release systems for pesticides, offering the unique properties of lignin., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Although gut microbiota and serum metabolite composition have been observed to be altered in patients with non-alcoholic fatty liver disease (NAFLD), previous observational studies have demonstrated inconsistent results. As this may be influenced by factors such as confounders and reverse causality, we used Mendelian randomization to clarify the causal effect of gut microbiota and blood metabolites on NAFLD., Methods: In this research, we performed a two-step Mendelian randomization analysis by utilizing genome-wide association study (GWAS) data obtained from MiBioGen and UK Biobank. To mitigate potential errors, we employed False Discovery Rate (FDR) correction and linkage unbalanced regression (LDSC) analysis. Sensitivity analyses including cML-MA and bidirectional Mendelian randomization were performed to ensure the robustness of the results., Results: In this study, a total of nine gut microbiota and seven metabolites were found to be significantly associated with NAFLD. MR analysis of the above findings revealed a causal relationship between Ruminococcus2 and cysteine-glutathione disulfide (OR = 1.17, 95%CI = 1.006-1.369, P = 0.041), as well as 3-indoleglyoxylic acid (OR = 1.18, 95%CI = 1.011-1.370, P = 0.036). For each incremental standard deviation in Ruminococcus2 abundance, there was a corresponding 26% reduction in NAFLD risk (OR = 0.74, 95%CI = 0.61-0.89, P = 0.0012), accompanied by a 17% increase in cysteine-glutathione disulfide levels (OR = 1.17, 95%CI = 1.01-1.37, P = 0.041) and an 18% increase in 3-indoleglyoxylic acid levels (OR = 1.18, 95%CI = 0.81-1.00, P = 0.036). The proportion mediated by cysteine-glutathione disulfide is 11.2%, while the proportion mediated by 3-indoleglyoxylic acid is 7.5%., Conclusion: Our study suggests that increased abundance of specific gut microbiota may reduce the risk of developing NAFLD, and this relationship could potentially be mediated through blood metabolites., (© 2024. The Author(s).)

Stripe or yellow rust (YR) caused by Puccinia striiformis tritici (Pst) is an important foliar disease affecting wheat production globally. Resistant varieties are the most economically and environmentally effective way to manage this disease. The common winter wheat (Triticum aestivum L.) cultivar Luomai 163 exhibited resistance to Pst races CYR32 and CYR33 at the seedling stage and showed a high level adult plant resistance in the field. To understand the genetic basis of YR resistance in this cultivar, 142 F5 recombinant inbred lines (RILs) derived from cross Apav#1 × LM163 and both parents were genotyped with the 16K SNP array and bulked segregant analysis sequencing (BSA-Seq). The analysis detected a major gene, YrLM163, at the seedling stage associated with the 1BL.1RS translocation. Additionally, three genes for resistance at the adult plant stage were detected on chromosome arms 1BL (Lr46/Yr29/Pm39/Sr58), 6BS and 6BL in Luomai 163, whereas Apav#1 contributed resistance at a QTL on 2BL. These QTL explained YR disease severity variations ranging from 6.9 to 54.8%. KASP markers KASP-2BL, KASP-6BS and KASP-6BL for three novel loci QYr.hzau-2BL, QYr.hzau-6BS and QYr.hzau-6BL were developed and validated. QYr.hzau-1BL, QYr.hzau-2BL and QYr.hzau-6BS showed varying degrees of resistance to YR when present individually or in combination based on genotype and phenotype analysis of a panel of 570 wheat accessions. Six RILs combining resistance alleles of all QTL, showing higher resistance to YR in the field than Luomai 163 with disease severities of 10.7-16.0%, are important germplasm resources for breeding programs to develop YR resistant wheat varieties with good agronomic traits.

Accumulating evidence suggests that lymphangiogenesis plays a crucial role in lymphatic metastasis, leading to tumor immune tolerance. However, the specific mechanism remains unclear. In this study, miR-431-5p was markedly downregulated in both gastric cancer (GC) tissues and plasma exosomes, and its expression were correlated negatively with LN metastasis and poor prognosis. Mechanistically, miR-431-5p weakens the TGF-β1/SMAD2/3 signaling pathway by targeting ZEB1, thereby suppressing the secretion of VEGF-A and ANG2, which in turn hinders angiogenesis, lymphangiogenesis, and lymph node (LN) metastasis in GC. Experiments using a popliteal LN metastasis model in BALB/c nude mice demonstrated that miR-431-5p significantly reduced popliteal LN metastasis. Additionally, miR-431-5p enhances the efficacy of anti-PD1 treatment, particularly when combined with galunisertib, anti-PD1 treatment showing a synergistic effect in inhibiting GC progression in C57BL/6 mice. Collectively, these findings suggest that miR-431-5p may modulate the TGF-β1/SMAD2/3 pathways by targeting ZEB1 to impede GC progression, angiogenesis, and lymphangiogenesis, making it a promising therapeutic target for GC management., (© 2024 Wiley Periodicals LLC.)

Purpose: Although microsatellite stability/Epithelial-mesenchymal transition (MSS/EMT) subtypes have been reported in multiple cancer prognosis studies, strong confounding factors between MSS/EMT (usually with Lauren's diffuse phenotype) and diffuse gastric cancer (GC) may obscure the independent prognostic value of diffuse GC. Additionally, recent studies suggest a strong correlation between mural stratification based on CT and diffuse GC. This study aims to investigate potential prognostic factors of MSS diffuse GC using mural stratification and to develop a risk assessment model., Methods: This retrospective study included 131 patients with MSS diffuse GC who underwent radical surgery. Univariate and multivariate Cox proportional hazards regression analysis was used to identify model predictors and construct a nomogram for overall survival (OS) and recurrence-free survival (RFS) risks. The model's performance was evaluated using ROC, accuracy, and C-index. Internal validation of the model was conducted using the bootstrap resampling method., Results: Among 131 cases, 60 cases (45.8%) exhibited grade 2 mural stratification, which correlated with a poorer tumor prognosis and a more invasive phenotype. Furthermore, a nomogram for predicting OS and RFS prognosis was established based on multivariate results (age, extranodal invasion, mural stratification, and/or P53). The nomogram demonstrated excellent performance, with an AUC of 0.859 (95% CI 0.794-0.924) for OS and 0.859 (95% CI 0.789-0.929) for RFS. Internal validation using 1000 bootstrap samples yielded AUC values of 0.845 and 0.846 for OS and RFS, respectively., Conclusion: Grade 2 mural stratification based on CT imaging revealed a more aggressive invasive phenotype, characterized by increased LN metastasis, higher rates of peritoneal metastasis, and a poorer short-term prognosis. Furthermore, the CT phenotype-based nomogram demonstrates favorable discrimination and calibration, enabling convenient individual short-term prognostic evaluation following resection of MSS diffuse GC., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: The aim of our study is to find a better way to identify a group of papillary thyroid carcinoma (PTC) with more aggressive behaviors and to provide a prediction model for lymph node metastasis to assist in clinic practice., Methods: Targeted sequencing of DNA/RNA was used to detect genetic alterations. Gene expression level was measured by quantitative real-time PCR, western blotting or immunohistochemistry. CCK8, transwell assay and flow cytometry were used to investigate the effects of concomitant gene alterations in PTC. LASSO-logistics regression algorithm was used to construct a nomogram model integrating radiomic features, mutated genes and clinical characteristics., Results: 172 high-risk variants and 7 fusion types were detected. The mutation frequencies in BRAF, TERT, RET, ATM and GGT1 were significantly higher in cancer tissues than benign nodules. Gene fusions were detected in 16 samples (2 at the DNA level and 14 at the RNA level). ATM mutation (ATM MUT ) was frequently accompanied by BRAF MUT , TERT MUT or gene fusions. ATM MUT alone or ATM co-mutations were significantly positively correlated with lymph node metastasis. Accordingly, ATM knock-down PTC cells bearing BRAF V600E , KRAS G12R or CCDC6-RET had higher proliferative ability and more aggressive potency than cells without ATM knock-down in vitro. Furthermore, combining gene alterations and clinical features significantly improved the predictive efficacy for lymph node metastasis of radiomic features, from 71.5 to 87.0%., Conclusions: Targeted sequencing of comprehensive genetic alterations in PTC has high prognostic value. These alterations, in combination with clinical and radiomic features, may aid in predicting invasive PTC with higher accuracy., (© 2024. The Author(s).)

Double expressor lymphoma (DEL), characterized by high expressions of both MYC and BCL-2, displays poor prognosis after current therapies. The HDAC inhibitor chidamide has been approved for treatment of T cell lymphoma, but its efficacy on B cell lymphoma is unclear. Here, by combining inhibition screening and transcriptomic analyses, we found that the sensitivity of B lymphoma cells to chidamide was positively correlated with the expression levels of MYC. Chidamide treatment reduced MYC protein levels and repressed MYC pathway in B lymphoma cells with high MYC expressions. Ectopic expression of MYC in chidamide-insensitive B lymphoma cells increased their response to chidamide. Thus, we proposed that adding chidamide into R-CHOP (CR-CHOP) might be effective for DEL, and retrospectively analyzed 185 DEL patients treated in West China Hospital. 80% of patients showed response to CR-CHOP treatment. In the median follow-up of 42 months, CR-CHOP significantly improve the survival for DEL patients with R-IPI ≤2. Totally 35 patients underwent autologous stem cell transplantation (ASCT) in remission and demonstrated a trend for better survival. Combining CR-CHOP with ASCT resulted in the most superior PFS and OS above all. For response patients, CR-CHOP reduced relapse with better PFS than R-CHOP-like regimens with or without ASCT. Taken together, our data indicated that chidamide repressed the MYC pathway in B lymphoma and is potentially efficacious to treat DEL., Competing Interests: None., (AJCR Copyright © 2024.)

Immune checkpoint inhibitors (ICIs) represent a promising treatment for hepatocellular carcinoma (HCC) due to their capacity for abundant lymphocyte infiltration. However, some patients with HCC respond poorly to ICI therapy due to the presence of various immunosuppressive factors in the tumor microenvironment. Our research reveals that a macrophage-coated tumor cluster (MCTC) signifies a unique spatial structural organization in HCC correlating with diminished recurrence-free survival and overall survival in a total of 572 HCC cases from 3 internal cohorts and 2 independent external validation cohorts. Mechanistically, tumor-derived macrophage-associated lectin Mac-2 binding protein (M2BP) induces MCTC formation and traps immunocompetent cells at the edge of MCTCs to induce intratumoral cytotoxic T cell exclusion and local immune deprivation. Blocking M2BP with a Mac-2 antagonist might provide an effective approach to prevent MCTC formation, enhance T cell infiltration, and thereby improve the efficacy of ICI therapy in HCC., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Acute kidney injury (AKI) is a sudden loss of renal function with a high mortality rate and inflammation is thought to be the underlying cause. The phenylpropanoid components acteoside (ACT) and isoacteoside (ISO), which were isolated from Cistanche deserticola Y.C.Ma, have been reported to have preventive effects against kidney disorders. This study aimed to investigate the anti-inflammatory properties and protective mechanisms of ACT and ISO. In this investigation, kidney function was assessed using a semi-automatic biochemical analyzer, histopathology was examined using Hematoxylin-Eosin staining and immunohistochemistry, and the concentration of inflammatory cytokines was assessed using an enzyme-linked immunosorbent assay (ELISA) test. In addition, using Western blot and q-PCR, the expression of proteins and genes connected to the NF-κB signaling pathway in mice with lipopolysaccharide (LPS)-induced AKI was found. The findings showed that under AKI intervention in LPS group, ACT group and ISO group, the expression of Rela (Rela gene is responsible for the expression of NFκB p65 protein) and Tlr4 mRNA was considerably elevated (P<0.01), which led to a significant improvement in the expression of MyD88, TLR4, Iκ-Bɑ and NF-κB p65 protein (P<0.001). The levels of Alb, Crea and BUN (P<0.001) increased along with the release of downstream inflammatory factors such as IL-1β, IL-6, Cys-C, SOD1 and TNF-α (P<0.001). More importantly, the study showed that ISO had a more favorable impact on LPS-induced AKI mice than ACT. In conclusion, by inhibiting NF-κB signaling pathway, ACT and ISO could relieve renal failure and inflammation in AKI, offering a fresh possibility for the therapeutic management of the condition., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Lian et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: The aim of this study was to identify the risk factors for postoperative adverse events in children with duplex kidney undergoing upper pole heminephrectomy., Methods: We collected clinical data from pediatric patients with duplex kidney who underwent upper pole heminephrectomy. Based on the presence or absence of postoperative adverse events, the patients were divided into two groups: an adverse events group ( n  = 16) and a non- adverse events group ( n  = 37), using multivariate logistic regression analysis to screen for independent risk factors for postoperative adverse events., Results: Through univariate and multivariate analysis, we found that the presence of upper renal ureterocele ( P  = 0.042, OR = 7.116, 95% CI 1.073-47.172), as well as the presence of accessory renal artery type ( P  = 0.016, OR = 10.639, 95% CI 1.551-72.978) and other types ( P  = 0.039, OR = 3.644, 95% CI 0.351-37.836) as the upper kidney's blood supply artery increase the risk of postoperative adverse events, with these differences being statistically significant., Conclusions: In pediatric patients with duplex kidney undergoing upper pole heminephrectomy, the presence of upper renal ureterocele and the presence of accessory renal artery type and other types as the upper kidney's blood supply artery are independent risk factors for postoperative adverse events., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Wang, Cui, Chu, Han, Liu, Zhao and Fan.)

To date, transforming environmental energy into electricity through a non-mechanical way is challenging. Herein, a series of photomechaelectric (PME) polyurethanes containing azobenzene-based photoisomer units and ionic liquid-based dipole units are synthesized, and corresponding PME nanogenerators (PME-NGs) to harvest electricity are fabricated. The dependence of the output performance of PME-NGs on the structure of the polyurethane is evaluated. The results show that the UV light energy can directly transduce into alternating-current (AC) electricity by PME-NGs via a non-mechanical way. The optimal open-circuit voltage and short-circuit current of PME-NGs under UV illumination reach 17.4 V and 696 µA, respectively. After rectification, the AC electricity can be further transformed into direct-current (DC) electricity and stored in a capacitor to serve as a power system to actuate typical microelectronics. The output performance of PME-NGs is closely related to the hard segment content of the PME polyurethane and the radius of counter anions in the dipole units. Kelvin probe force microscopy is used to confirm the existence of the PME effect and the detailed mechanism about the generation of AC electricity in PME-NGs is proposed, referring to the back and forth drift of induced electrons on the two electrodes in contact with the PME polyurethanes., (© 2023 Wiley‐VCH GmbH.)

Background: The prevalence and characteristics of inappropriate use of proton pump inhibitors (PPIs) to prevent stress-related mucosal disease (SRMD) during the perioperative period and its associated factors are rarely reported. This study aimed to investigate the prevalence and characteristics of inappropriate prophylactic use of proton pump inhibitors (PPIs) during the perioperative period and identify its associated factors in a tertiary care and academic teaching hospital in China and to provide evidence for regulation authorities and pharmacists to take targeted measures to promote rational drug use., Methods: Inpatients who underwent surgical operations and received prophylactic use of PPIs from June 2022 to November 2022 were included in this retrospective study. The appropriateness of perioperative prophylactic use of PPIs was evaluated by clinical pharmacists. Associated factors with inappropriate perioperative prophylactic use of PPIs were analyzed by univariable and multivariable logistic regression., Results: Four-hundred seventy-two patients were finally included in this study, of which 131 (27.75%) patients had at least one problem with inappropriate perioperative prophylactic use of PPIs. The three most common problems were drug use without indication (52.0%), inappropriate usage and dosage (34.6%), and inappropriate duration of medication (6.7%). Multiple logistic regression analysis showed that oral dosage form of PPIs [OR = 18.301, 95% CI (7.497, 44.671), p < 0.001], discharge medication of PPIs [OR = 11.739, 95% CI (1.289, 106.886), p = 0.029], and junior doctors [OR = 9.167, 95% CI (3.459, 24.299), p < 0.001] were associated with more inappropriate prophylactic use of PPIs. Antithrombotics [OR = 0.313, 95% CI (0.136, 0.721), p = 0.006] and prolonged postoperative hospital stay (longer than 15 days) [OR = 0.262, 95% CI (0.072, 0.951), p = 0.042] were associated with less inappropriate prophylactic use of PPIs., Conclusions: The inappropriate prophylactic use of PPIs during the perioperative period is common. Regulation authorities and pharmacists should take more targeted measures to promote the rational prophylactic use of PPIs during the perioperative period., (© 2024. The Author(s).)

Interactions between polysaccharides and ionic liquids (ILs) at the molecular level are essential to elucidate the dissolution and/or plasticization mechanism of polysaccharides. Herein, saccharide-based ILs (SILs) were synthesized, and cellulose membrane was soaked in different SILs to evaluate the interactions between SILs and cellulose macromolecules. The relevant results showed that the addition of SILs into cellulose can effectively reduce the intra- and/or inter-molecular hydrogen bonds of polysaccharides. Glucose-based IL showed the intensest supramolecular interactions with cellulose macromolecules compared to sucrose- and raffinose-based ILs. Two-dimensional correlation and perturbation-correlation moving window Fourier transform infrared techniques were for the first time used to reveal the dynamic variation of the supramolecular interactions between SILs and cellulose macromolecules. Except for the typical HO⋯H interactions of cellulose itself, stronger -Cl⋯HO hydrogen bonding interactions were detected in the specimen of SILs-modified cellulose membranes. Supramolecular interactions of -Cl⋯H, HO⋯H, C-Cl⋯H, and -C=O⋯H between SILs and cellulose macromolecules sequentially responded to the stimuli of temperature. This work provides a new perspective to understanding the interaction mechanism between polysaccharides and ILs, and an avenue to develop the next-generation ILs for dissolving or thermoplasticizing polysaccharide materials., Competing Interests: Declaration of competing interest The authors declare no competing interest., (Copyright © 2024. Published by Elsevier B.V.)

Objective: Accurate prediction of preoperative occult peritoneal metastasis (OPM) is critical to selecting appropriate therapeutic regimen for gastric cancer (GC). Considering the clinical practicability, we develop and validate a visible nomogram that integrates the CT images and clinicopathological parameters for the individual preoperative prediction of OPM in GC., Methods: This retrospective study included 520 patients who underwent staged laparoscopic exploration or peritoneal lavage cytology (PLC) examination. Univariate and multivariate logistic regression results were used to screen model predictors and construct nomograms of OPM risk. The performance of the model was detected by using ROC, accuracy, and C-index. The bootstrap resampling method was considered internal validation of the model. The Delong test was used to evaluate the difference in AUC between the two models., Results: Grade 2 mural stratification, tumor thickness, and the Lauren classification diffuse were significant predictors of OPM (p < 0.05). The nomogram of these three factors (compared with the original model) showed a higher predictive effect (p < 0.001). The area under the curve (AUC) of the model was 0.830 (95% CI 0.788-0.873), and the internally validated AUC of 1000 bootstrap samples was 0.826 (95% CI 0.756-0.870). The sensitivity, specificity, and accuracy were 76.0%, 78.8%, and 78.3%, respectively., Conclusions: CT phenotype-based nomogram demonstrates favorable discrimination and calibration, and it can be conveniently used for preoperative individual risk rating of OPM in GC., Clinical Relevance Statement: In this study, the preoperative OPM prediction model based on CT images (mural stratification, tumor thickness) combined with pathological parameters (the Lauren classification) showed excellent predictive ability in GC, and it is also suitable for clinicians to use rather than limited to professional radiologists., Key Points: • Nomogram based on CT image analysis can effectively predict occult peritoneal metastasis in gastric cancer (training area under the curve (AUC) = 0.830 and bootstrap AUC = 0.826). • Nomogram model combined with CT features performed better than the original model (established using only clinicopathological parameters) in differentiating occult peritoneal metastasis of gastric cancer., (© 2023. The Author(s), under exclusive licence to European Society of Radiology.)

Immune-checkpoint inhibitors (ICIs), different from traditional cancer treatment models, have shown unprecedented anti-tumor effects in the past decade, greatly improving the prognosis of many malignant tumors in clinical practice. At present, the most widely used ICIs in clinical immunotherapy for a variety of solid tumors are monoclonal antibodies against cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed cell death protein 1 (PD-1) and their ligand PD-L1. However, tumor patients may induce immune-related adverse events (irAEs) while performing immunotherapy, and irAE is an obstacle to the prospect of ICI treatment. IrAE is a non-specific disease caused by immune system imbalance, which can occur in many tissues and organs. For example, skin, gastrointestinal tract, endocrine system and lung. Although the exact mechanism is not completely clear, related studies have shown that irAE may develop through many ways. Such as excessive activation of autoreactive T cells, excessive release of inflammatory cytokines, elevated levels of autoantibodies, and common antigens between tumors and normal tissues. Considering that the occurrence of severe IrAE not only causes irreversible damage to the patient's body, but also terminates immunotherapy due to immune intolerance. Therefore, accurate identification and screening of sensitive markers of irAE are the main beneficiaries of ICI treatment. Additionally, irAEs usually require specific management, the most common of which are steroids and immunomodulatory therapies. This review aims to summarize the current biomarkers for predicting irAE in gastric cancer and their possible mechanisms., (© 2023. The Author(s).)

Background: Oncogenic PIK3CA mutations (PIK3CA mut ) frequently occur in a higher proportion in luminal breast cancer (LBC), especially in refractory advanced cases, and are associated with changes in tumour cellular metabolism. Nevertheless, its effect on the progression of the immune microenvironment (TIME) within tumours and vital molecular events remains veiled., Methods: Multiplex immunohistochemistry (mIHC) and single-cell mass cytometry (CyTOF) was used to describe the landscape of TIME in PIK3CA mut LBC. The PIK3CA mutant cell lines were established using CRISPER/Cas9 system. The gene expression levels, protein secretion and activity of signaling pathways were measured by real-time RT-PCR, ELISA, immunofluorescence staining or western blotting. GSEA analysis, transwell chemotaxis assay, live cell imaging, flow cytometry metabolite analysis targeting arachidonic acid, Dual-luciferase reporter assay, and Chromatin immunoprecipitation assay were used to investigate the underlying function and mechanism of the PI3K/5-LOX/LTB4 axis., Results: PIK3CA mut LBC cells can induce an immunosuppressive TIME by recruiting myeloid-derived suppressor cells (MDSCs) and excluding cytotoxic T cells via the arachidonic acid (AA) metabolism pathway. Mechanistically, PIK3CA mut activates the transcription of 5-lipoxygenase (5-LOX) in a STAT3-dependent manner, which in turn directly results in high LTB4 production, binding to BLT2 on MDSCs and promoting their infiltration. Since a suppressive TIME is a critical barrier for the success of cancer immunotherapy, the strategies that can convert "cold" tumours into "hot" tumours were compared. Targeted therapy against the PI3K/5-LOX/LTB4 axis synergizing with immune checkpoint blockade (ICB) therapy achieved dramatic shrinkage in vivo., Conclusions: The results emphasize that PIK3CA mut can induce immune evasion by recruiting MDSCs through the 5-LOX-dependent AA pathway, and combination targeted therapy with ICB may provide a promising treatment option for refractory advanced LBC patients., (© 2023 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Sphingolipids are required for diverse biological functions and are degraded by specific catabolic enzymes. However, the mechanisms that regulate sphingolipid catabolism are not known. Here we characterize a transcriptional axis that regulates sphingolipid breakdown to control resistance against bacterial infection. From an RNAi screen for transcriptional regulators of pathogen resistance in the nematode C. elegans, we identified the nuclear hormone receptor nhr-66, a ligand-gated transcription factor homologous to human hepatocyte nuclear factor 4. Tandem chromatin immunoprecipitation-sequencing and RNA sequencing experiments revealed that NHR-66 is a transcriptional repressor, which directly targets sphingolipid catabolism genes. Transcriptional de-repression of two sphingolipid catabolic enzymes in nhr-66 loss-of-function mutants drives the breakdown of sphingolipids, which enhances host susceptibility to infection with the bacterial pathogen Pseudomonas aeruginosa. These data define transcriptional control of sphingolipid catabolism in the regulation of cellular sphingolipids, a process that is necessary for pathogen resistance., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Nasrallah et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Increased lymphangiogenesis and lymph node (LN) metastasis are thought to be important steps in cancer metastasis, and are associated with patient's poor prognosis. There is increasing evidence that the lymphatic system may play a crucial role in regulating tumor immune response and limiting tumor metastasis, since tumor lymphangiogenesis is more prominent in tumor metastasis and diffusion. Lymphangiogenesis takes place in embryonic development, wound healing, and a variety of pathological conditions, including tumors. Tumor cells and tumor microenvironment cells generate growth factors (such as lymphangiogenesis factor VEGF-C/D), which can promote lymphangiogenesis, thereby inducing the metastasis and diffusion of tumor cells. Nevertheless, the current research on lymphangiogenesis in gastric cancer is relatively scattered and lacks a comprehensive understanding. Therefore, in this review, we aim to provide a detailed perspective on molecules and signal transduction pathways that regulate gastric cancer lymphogenesis, which may provide new insights for the diagnosis and treatment of cancer., (© 2023. BioMed Central Ltd., part of Springer Nature.)

In order to understand the difference of quality for Chinese and CIMMYT wheat varieties (lines), we selected 153 wheat germplasm from both China and CIMMYT to explore the contribution relationship of different allelic variation combinations to wheat quality through genotyping and phenotyping, including grain hardness, polyphenol oxidase (PPO) activity, lipoxygenase (LOX) activity, yellow pigment (YP) content and protein content. In terms of flour milling quality, Chinese wheat varieties were mainly carrying Pina-D1a/Pinb-D1b , accounting for 32.0% of the total tested varieties, while the CIMMYT wheat lines were mainly carrying Pina-D1b/Pinb-D1a with 45.8% of the total collection. The distribution frequencies of subunit 1/2* and 5 + 10 were 47.0% and 42.5%, respectively, in CIMMYT varieties, however they were only 31.4% and 13.7% respectively of the Chinese wheat tested varieties. In addition, the proportion of phytoene synthase (PSY) allele, PPO allele and LOX active allele were roughly the same between Chinese and CIMMYT varieties. Based on the present study, we found that Pina gene had a greater impact on grain hardness value than Pinb gene; The influence of PPO-A1 gene on polyphenol oxidase activity was more significant than PPO-D1 gene. The high protein content of varieties mostly containing hardness genes and 1/2*/5 + 10 subunit combinations. Based on the present study, we found that the quality gene distribution of Chinese and CIMMYT varieties was quite different, for instance, the high-quality HMW-GS subunits of Chinese varieties were lower than CIMMYT lines. It will be much useful for Chinese wheat breeders to develop good quality wheat variety by crossing with 3 good strong gluten CIMMYT wheat lines by molecular marker-assisted selection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Liu, Zhang, Yin, Yan, Ren, Sang, Xu, Han, Cui, Nie, Kong, Li, Lan and Mu.)

Spodoptera frugiperda ( S. frugiperda ) is an invasive pest that threatens global crop production and food security and poses a serious threat to maize production worldwide. Metal-organic framework (MOF) nanocarriers have great potential for agricultural pest control applications. The present study successfully prepared the chemical cross-linking of iron-based metal-organic framework nanoparticles (MIL-101(Fe)-NH 2 NPs) with sodium lignosulfonate (SL) as a pH/laccase double stimuli-responsive pesticide release system. The average particle size of the prepared chlorfenapyr (CF)-loaded nanoparticles (CF@MIL-101-SL NPs) was 161.54 nm, and the loading efficiency was 44.52%. Bioactivity assays showed that CF@MIL-101-SL NPs increased the toxicity of CF to S. frugiperda and caused the rupture of the peritrophic membrane and enlargement of the midgut. Data from 16S rRNA gene sequencing showed that CF@MIL-101-SL treatment reduced the resistance of S. frugiperda to pesticides and pathogens and affected nutrient and energy availability by remodeling the intestinal microbiota of S. frugiperda . The dysregulated microbial community interacted with the broken peritrophic membrane, which exacerbated damage to the host. Nontargeted metabolomic results showed that ABC transporters may be a potential mechanism for the enhanced toxicity of CF@MIL-101-SL to S. frugiperda . In summary, the present study provides effective strategies for toxicological studies of nanopesticides against insects.

Prime editing systems have enabled the incorporation of precise edits within a genome without introducing double strand breaks. Previous studies defined an optimal primer binding site (PBS) length for the pegRNA of ∼13 nucleotides depending on the sequence composition. However, optimal PBS length characterization has been based on prime editing outcomes using plasmid or lentiviral expression systems. In this study, we demonstrate that for prime editor (PE) ribonucleoprotein complexes, the auto-inhibitory interaction between the PBS and the spacer sequence affects pegRNA binding efficiency and target recognition. Destabilizing this auto-inhibitory interaction by reducing the complementarity between the PBS-spacer region enhances prime editing efficiency in multiple prime editing formats. In the case of end-protected pegRNAs, a shorter PBS length with a PBS-target strand melting temperature near 37°C is optimal in mammalian cells. Additionally, a transient cold shock treatment of the cells post PE-pegRNA delivery further increases prime editing outcomes for pegRNAs with optimized PBS lengths. Finally, we show that prime editor ribonucleoprotein complexes programmed with pegRNAs designed using these refined parameters efficiently correct disease-related genetic mutations in patient-derived fibroblasts and efficiently install precise edits in primary human T cells and zebrafish., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

KMT2C and KMT2D are the most frequently mutated epigenetic genes in human cancers. While KMT2C is identified as a tumor suppressor in acute myeloid leukemia (AML), the role of KMT2D remains unclear in this disease, though its loss promotes B cell lymphoma and various solid cancers. Here, it is reported that KMT2D is downregulated or mutated in AML and its deficiency, through shRNA knockdown or CRISPR/Cas9 editing, accelerates leukemogenesis in mice. Hematopoietic stem and progenitor cells and AML cells with Kmt2d loss have significantly enhanced ribosome biogenesis and consistently, enlarged nucleolus, increased rRNA and protein synthesis rates. Mechanistically, it is found that KMT2D deficiency leads to the activation of the mTOR pathway in both mouse and human AML cells. Kmt2d directly regulates the expression of Ddit4, a negative regulator of the mTOR pathway. Consistent with the abnormal ribosome biogenesis, it is shown that CX-5461, an inhibitor of RNA polymerase I, significantly restrains the growth of AML with Kmt2d loss in vivo and extends the survival of leukemic mice. These studies validate KMT2D as a de facto tumor suppressor in AML and reveal an unprecedented vulnerability to ribosome biogenesis inhibition., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Introduction: Manganese (Mn) is an essential trace element for livestock, but little is known about the optimal Mn source and level for yak., Methods: To improve yak's feeding standards, a 48-h in vitro study was designed to examine the effect of supplementary Mn sources including Mn sulfate (MnSO 4 ), Mn chloride (MnCl 2 ), and Mn methionine (Met-Mn) at five Mn levels, namely 35 mg/kg, 40 mg/kg, 50 mg/kg, 60 mg/kg, and 70 mg/kg dry matter (includes Mn in substrates), on yak's rumen fermentation., Results: Results showed that Met-Mn groups showed higher acetate ( p < 0.05), propionate, total volatile fatty acids ( p < 0.05) levels, ammonia nitrogen concentration ( p < 0.05), dry matter digestibility (DMD), and amylase activities ( p < 0.05) compared to MnSO4 and MnCl2 groups. DMD ( p < 0.05), amylase activities, and trypsin activities ( p < 0.05) all increased firstly and then decreased with the increase of Mn level and reached high values at 40-50 mg/kg Mn levels. Cellulase activities showed high values ( p < 0.05) at 50-70 mg/kg Mn levels. Microbial protein contents ( p < 0.05) and lipase activities of Mn-Met groups were higher than those of MnSO4 and MnCl2 groups at 40-50 mg/kg Mn levels., Discussion: Therefore, Mn-met was the best Mn source, and 40 to 50 mg/kg was the best Mn level for rumen fermentation of yaks., Competing Interests: HL, CS, and YX were employed by Qinghai Pure Yak Biotechnology Co., LTD. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lu, Liu, Liu, Zhao, Bai, Cheng, Zhang, Sun, Hao and Xue.)

Deltamethrin (DM) is a widely used pesticide and has been generally detected in aquatic systems. To systematically investigate the toxic effects, zebrafish embryos were treated with various concentrations of DM for 120 h. The LC 50 was determined to be 102 μg L -1 . Lethal concentrations of DM induced severe morphological defects in the surviving individuals. Under non-lethal concentrations, DM suppressed the development of neurons in the larvae, which was associated with the reduction in locomotor activity. DM exposure induced cardiovascular toxicity, including suppressed growth of blood vessels and enhanced heart rates. DM also disrupted the development of bones in the larvae. Moreover, liver degeneration, apoptosis and oxidative stress were observed in the larvae treated with DM. Correspondingly, the transcriptional levels of the genes related to the toxic effects were altered by DM. In conclusion, the results obtained in this study provided evidence that DM showed multiple toxic effects on aquatic organisms., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Prime editors have a broad range of potential research and clinical applications. However, methods to delineate their genome-wide editing activities have generally relied on indirect genome-wide editing assessments or the computational prediction of near-cognate sequences. Here we describe a genome-wide approach for the identification of potential prime editor off-target sites, which we call PE-tag. This method relies on the attachment or insertion of an amplification tag at sites of prime editor activity to allow their identification. PE-tag enables genome-wide profiling of off-target sites in vitro using extracted genomic DNA, in mammalian cell lines and in the adult mouse liver. PE-tag components can be delivered in a variety of formats for off-target site detection. Our studies are consistent with the high specificity previously described for prime editor systems, but we find that off-target editing rates are influenced by prime editing guide RNA design. PE-tag represents an accessible, rapid and sensitive approach for the genome-wide identification of prime editor activity and the evaluation of prime editor safety., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

DNA methylation-related genes, including TET2, IDH2, and DNMT3A are highly frequently mutated in angioimmunoblastic T-cell lymphoma (AITL), an aggressive malignancy of T follicular helper (Tfh) cells associated with aberrant immune features. It has been shown that TET2 loss cooperates with RHOA G17V to promote AITL in mice but the functional role of DNMT3A mutations in AITL remains unclear. Here, we report that DNMT3A R882H , the most common mutation of DNMT3A in AITL, accelerates the development of Tet2 -/- ; RHOA G17V AITL in mice, indicated by the expansion of malignant Tfh cells and aberrant B cells, skin rash, and significantly shortened disease-free survival. To understand the underlying cellular and molecular mechanisms, we performed single-cell transcriptome analyses of lymph nodes of mice transplanted with Tet2 -/- , Tet2 -/- ; RHOA G17V or DNMT3A R882H ; Tet2 -/- ; RHOA G17V hematopoietic stem and progenitor cells. These single-cell landscapes reveal that DNMT3A mutation further activates Tfh cells and leads to rapid and terminal differentiation of B cells, probably through enhancing the interacting PD1/PD-L1, ICOS/ICOSL, CD28/CD86, and ICAM1/ITGAL pairs. Our study establishes the functional roles of DNMT3A mutation in AITL and sheds light on the molecular mechanisms of this disease., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Early-stage myeloid-derived suppressor cells are a newly defined subset of myeloid-derived suppressor cells in breast cancer tissues and related to poor prognosis in patients with breast cancer. Compared with classical myeloid-derived suppressor cells, early-stage myeloid-derived suppressor cells display exceptional immunosuppressive ability and accumulate in the tumor microenvironment to suppress innate and adaptive immunity. Previously, we demonstrated that early-stage myeloid-derived suppressor cells were SOCS3 deficiency dependent and correlated with differentiation arrest in the myeloid lineage. Autophagy is a major regulator of myeloid differentiation, but the mechanism by which autophagy regulates the development of early-stage myeloid-derived suppressor cells has not been elucidated. Here, we constructed EO771 mammary tumor-bearing conditional myeloid SOCS3 knockout mice (SOCS3MyeKO) characterized by abundant tumor-infiltrating early-stage myeloid-derived suppressor cells and exacerbated immunosuppression in vitro and in vivo. We found that early-stage myeloid-derived suppressor cells isolated from SOCS3MyeKO mice showed differentiation arrest in the myeloid lineage, which was caused by limited autophagy activation in an Wnt/mTOR-dependent manner. RNA sequencing and microRNA microarray assays revealed that miR-155-induced C/EBPβ downregulation activated the Wnt/mTOR pathway and promoted autophagy repression and differentiation arrest in early-stage myeloid-derived suppressor cells. Furthermore, inhibition of Wnt/mTOR signaling suppressed both tumor growth and the immunosuppressive functions of early-stage myeloid-derived suppressor cells. Thus, SOCS3 deficiency-dependent autophagy repression and their regulatory mechanisms could contribute to the immunosuppressive tumor microenvironment. Our study proposes a novel mechanism for promoting early-stage myeloid-derived suppressor cell survival, which might shed new light on a potential target of oncologic therapy., (© The Author(s) 2023. Published by Oxford University Press on behalf of Society for Leukocyte Biology.)

Background: Epidemic keratoconjunctivitis (EKC) is a highly contagious infectious ocular disease that has been widespread worldwide. Ophthalmic preparations of glucocorticoids (OPGs) are the supportive therapies for EKC; however, they are still controversial., Methods: We performed a systematic review and meta-analysis to evaluate the efficacy and safety of OPGs in patients with EKC. Electronic searches were conducted in PubMed, Embase, the Cochrane Library, ClinicalTrials.gov, China National Knowledge Internet (CNKI), and Wanfang Database from inception to 25 Aug 2022. We included and analyzed randomized controlled trials (RCTs) and cohort studies that compared OPGs to other positive drugs or placebo in patients with EKC., Results: Six studies (five RCTs and one retrospective cohort) involving 286 patients were included in the analysis. Compared with artificial tears, OPGs could relieve ocular symptoms faster in the acute phase of epidemic keratoconjunctivitis (AEKC). There was no significant difference in the incidence of corneal subepithelial infiltrates (SEIs) in AEKC when OPGs were used for 7 days, but there was a substantial difference for 21 and 28 days. In the chronic phase of epidemic keratoconjunctivitis (CEKC), there was no significant difference in the rate of complete elimination of SEIs at 6 months of OPGs treatment compared with immunosuppressants [RR = 1.07,95%CI (0.71,1.61), p = 0.75], as well as in the recurrence rate of SEIs after 6 months [RR = 2.05,95%CI (0.82,5.12), P = 0.13]. OPGs significantly increased intraocular pressure (IOP) at 6 months compared with immunosuppressants [MD = - 1.13,95%CI (- 1.97, - 0.30), P = 0.007]. There was no significant difference in cessation of therapy due to drug intolerance between OPGs and immunosuppressants [RR = 0.69,95%CI (0.16,2.94), p = 0.62]., Conclusions: OPGs might relieve ocular symptoms and reduce the incidence of SEIs in AEKC, whereas not recommended the therapy in CEKC. More high-quality clinical evidence is required to confirm our findings., (© 2022. The Author(s), under exclusive licence to The Drug Information Association, Inc.)

Deletions of chromosome 17p, where TP53 gene locates, are the most frequent chromosome alterations in human cancers and associated with poor outcomes in patients. Our previous work suggested that there were p53-independent mechanisms involved in chromosome 17p deletions-driven cancers. Here, we report that altered arachidonate metabolism, due to the deficiency of mouse Alox8 on chromosome 11B3 (homologous to human ALOX15B on chromosome 17p), contributes to the B cell malignancy. While the metabolites produced from lipoxygenase pathway reduced, chromosome 11B3 deletions or Alox8 loss, lead to upregulating its paralleling cyclooxygenase pathway, indicated by the increased levels of oncometabolite prostaglandin E2. Ectopic PGE2 prevented the apoptosis and differentiation of pre-B cells. Further studies revealed that Alox8 deficiency dramatically and specifically induced Cox-2(Ptgs2) gene expression. Repressing Cox-2 by its shRNAs impaired the tumorigenesis driven by Alox8 loss. And, in turn, tumor cells with Alox8 or 11B3 loss were sensitive to the COX-2 inhibitor celecoxib. This correlation between COX-2 upregulation and chromosome 17p deletions was consistent in human B-cell lymphomas. Hence, our studies reveal that the arachidonate metabolism abnormality with unbalanced ALOX and COX pathways underlies human cancers with 17p deletions and suggest new susceptibility for this disease., (© 2023. The Author(s).)

As nucleic acid testing is playing a vital role in increasingly many research fields, the need for rapid on-site testing methods is also increasing. The test procedure often consists of three steps: Sample preparation, amplification, and detection. This review covers recent advances in on-chip methods for each of these three steps and explains the principles underlying related methods. The sample preparation process is further divided into cell lysis and nucleic acid purification, and methods for the integration of these two steps on a single chip are discussed. Under amplification, on-chip studies based on PCR and isothermal amplification are covered. Three isothermal amplification methods reported to have good resistance to PCR inhibitors are selected for discussion due to their potential for use in direct amplification. Chip designs and novel strategies employed to achieve rapid extraction/amplification with satisfactory efficiency are discussed. Four detection methods providing rapid responses (fluorescent, optical, and electrochemical detection methods, plus lateral flow assay) are evaluated for their potential in rapid on-site detection. In the final section, we discuss strategies to improve the speed of the entire procedure and to integrate all three steps onto a single chip; we also comment on recent advances, and on obstacles to reducing the cost of chip manufacture and achieving mass production. We conclude that future trends will focus on effective nucleic acid extraction via combined methods and direct amplification via isothermal methods., Competing Interests: LP was employed by Zhejiang Hongzheng Testing Co., Ltd., XG was employed by Zhejiang Gongzheng Testing Center Co., Ltd., PL was employed by Key Laboratory of Biosafety detection for Zhejiang Market Regulation, Zhejiang Fangyuan Testing Group LO.T, and YT was employed by Hangzhou Tiannie Technology Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wang, Jiang, Pan, Gu, Xiao, Liu, Tang, Fang, Li and Lu.)

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) can cause intestinal damage and ulcers and the incidence is increasing. Limonin plays an important role in the regulation of inflammatory diseases, but it has not been reported in the treatment of intestinal injury and ulcers., Methods: Indomethacin (INDO) induced intestinal injury and ulcer model in rats. The indexes related to intestinal injury were detected. Western blot and molecular docking techniques were used to detect the docking between Limonin and Nrf2. Next, ML385, an inhibitor of Nrf2/ARE signaling pathway, was applied to treat intestinal epithelial IEC-6 cells induced by INDO. And CCK8, Western blot, TUNEL, ELISA, DCFH-DA assay, kits, and immunofluorescence were conducted to detect cell activity, apoptosis, inflammatory response, oxidative stress, and tight junction again., Results: INDO can significantly induce intestinal ulcerative lesions in rats. Limonin could improve intestinal ulcerative lesions induced by INDO in rats. Limonin could reduce INDO-induced inflammatory response and oxidative stress in the small intestine of rats, and improve the intestinal barrier dysfunction induced by INDO. Limonin could dock with Nrf2 structure and activate Nrf2/ARE signaling pathway. ML385 could reverse the protective effect of Limonin against INDO-induced cell damage., Conclusion: Limonin ameliorates INDO-induced intestinal damage and ulcers through Nrf2/ARE pathway., (© 2023 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.)

The worrying emergence of multiple resistance genes to last-resort antibiotics in food animals and human populations throughout the food chain and relevant environments has been increasingly reported worldwide. Enterobacteriaceae pathogens are considered the most common reservoirs of such antibiotic resistance genes (ARGs). Thus, a rapid, efficient and accurate detection method to simultaneously screen and monitor such ARGs in Enterobacteriaceae pathogens has become an urgent need. Our study developed a recombinase polymerase amplification (RPA) assay combined with a lateral flow dipstick (LFD) for simultaneously detecting predominant resistance genes to last-resort antibiotics of Enterobacteriaceae pathogens, including mcr-1 , bla NDM-1 and tet(X4) . It is allowed to complete the entire process, including crude DNA extraction, amplification as well as reading, within 40 min at 37°C, and the detection limit is 10 1 copies/μl for mcr-1 , bla NDM-1 and tet(X4) . Sensitivity analysis showed obvious association of color signals with the template concentrations of mcr-1 , bla NDM-1 and tet(X4) genes in Enterobacteriaceae pathogens using a test strip reader ( R 2  = 0.9881, R 2  = 0.9745, and R 2  = 0.9807, respectively), allowing for quantitative detection using multiplex RPA-LFD assays. Therefore, the RPA-LFD assay can suitably help to detect multiple resistance genes to last-resort antibiotics in foodborne pathogens and has potential applications in the field., Competing Interests: LP was employed by Zhejiang Hongzheng Testing Co., Ltd, Ningbo, Zhejiang, China. XG was employed by Zhejiang Gongzheng Testing Center Co., Ltd, Hangzhou, Zhejiang, China. YT was employed by Hangzhou Tiannie Technology Co., Ltd, Hangzhou, Zhejiang, China. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lu, Wang, Pan, Gu, Lu, Chen, Zhang, Ye, Xiao, Liu, Tang, Tang, Huang, Fang and Jiang.)

Hepatocellular carcinoma (HCC) is the third-leading cause of cancer deaths globally. Although considerable progress has been made in the treatment, clinical outcomes of HCC patients are still poor. Therefore, it is necessary to find novel prognostic factors upon which prevention and treatment strategies can be formulated. Ficolin-3 (FCN3) protein is a member of the human ficolin family. It activates complement through pathways associated with mannose-binding lectin-associated serine proteases. Herein, we identified that FCN3 was downregulated in HCC tissues and decreased FCN3 expression was closely related to poor prognosis. Overexpression of FCN3 induced apoptosis and inhibited cell proliferation via the p53 signaling pathway. Mechanistically, FCN3 modulated the nuclear translocation of eukaryotic initiation factor 6 (EIF6) by binding ribosome maturation factor (SBDS), which induced ribosomal stress and activation of the p53 pathway. In addition, Y-Box Binding Protein 1 (YBX1) involved in the transcription and translation level regulation of FCN3 to SBDS. Besides, a negative feedback loop in the downstream of FCN3 involving p53, YBX1 and SBDS was identified., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)