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Background and Purpose: Liver cancer is the fourth leading cause of cancer-related death worldwide, with hepatocellular carcinoma (HCC) being the most common type of primary liver cancer. APG-1252 is a small molecule inhibitor targeting Bcl-2 and Bcl-xl. However, its anti-tumor effects in HCC, alone or in combination with Cabozantinib, have not been extensively studied., Experimental: Approach: TCGA database analysis was used to analysis the gene expression levels of Bcl-2 and Bcl-xl in HCC tissues. Western blot was employed to detect the protein expression levels. And the inhibitory effects of APG-1252 and Cabozantinib on the proliferation of HCC cell lines was detected by CCK-8. The effect on the migration and invasion of HCC cells was verified by transwell assay. Huh7 xenograft model in nude mice was used to investigate the combination antitumor effect in vivo., Key Results: Our study demonstrated that APG-1252 monotherapy inhibited the proliferation and migration ability of HCC cells, and induced HCC cells apoptosis. The combination of APG-1252 and Cabozantinib showed significant synergistic antitumor effects. Furthermore, the in vivo experiment demonstrated that the combination therapy exerted a synergistic effect in delaying tumor growth, notably downregulating MEK/ERK phosphorylation levels. In terms of mechanism, Cabozantinib treatment caused an increase in the phosphorylation levels of CREB and Bcl-xl proteins, while the combination with APG-1252 mitigated this effect, thereby enhanced the antitumor effect of Cabozantinib., Conclusion and Implications: Our findings suggest that APG-1252 in combination with Cabozantinib offers a more effective treatment strategy for HCC patients, warranting further clinical investigation., 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.)

Conditions were determined for rapid, convenient, and efficient determination of 16 common mycotoxins in tea samples. Mycotoxins in tea leaves and tea infusion samples were extracted using solid-liquid extraction/liquid-liquid extraction combined with ultrasonic-assisted extraction. The extraction solvent was 2-butanone/ethyl acetate (9/1 v/v) with 0.1 % formic acid. The established conditions enabled the analysis of these mycotoxins by ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) in 5.5 min. In addition, HPLC with a temperature-controlled fluorescence detector was able to simultaneously determine 8 mycotoxins with fluorescent properties in 10 min without derivatization. Aflatoxin M1 (2.15 and 3.01 μg/kg), fumonisin B2 (198.89 μg/kg), and zearalenone (87.54 μg/kg) could be detected in commercially available pu-erh tea, green tea, and black tea products, and their total transfer rates from the products to brewed tea infusions were 64.08-65.13 %, 90.59 %, and 25.99 %, respectively. The risks of drinking mycotoxins from these tea infusions mostly showed low levels of concern., Competing Interests: Declaration of competing interest The authors have declared that there is no conflict of interest., (Copyright © 2024. Published by Elsevier Ltd.)

Nicotine is an alkaloid found in tobacco. Human exposure to nicotine primarily occurs through the use of tobacco products. To date, limited nicotine pharmacokinetic data in animals have been reported. This study exposed male Sprague-Dawley rats to vehicle (and/or air) or four doses of nicotine via nose-only inhalation (INH), oral gavage (PO), and intravenous (IV) infusion. Plasma, six tissues (brain, heart, lung, liver, kidney, and muscle), and urine were collected at multiple timepoints from 5 minutes to 48 hours post-dose. The concentrations of nicotine, cotinine, and trans-3'-hydroxycotinine (3-OH-cotinine) were determined, and the pharmacokinetic profiles were compared among the four doses for each route. The results indicated that after single nicotine dose, nicotine bioavailability was 53% via PO. Across all the administration routes and doses, nicotine was quickly distributed to all six tissues; kidney had the highest nicotine and cotinine levels, and the lung had the highest 3-OH-cotinine levels; nicotine was metabolized extensively to cotinine and cotinine was metabolized to a lesser extent to 3-OH-cotinine; the elimination of plasma nicotine, cotinine, and 3-OH-cotinine followed first-order kinetics; plasma nicotine had a shorter half-life than cotinine or 3-OH-cotinine; the half-lives of plasma nicotine, cotinine, and 3-OH-cotinine were dose- and route-independent; and nicotine and cotinine were major urinary excretions followed by 3-OH-cotinine. Nicotine, cotinine, and 3-OH-cotinine levels in plasma, tissues, and urine exhibited dose-dependent increases. These study findings improve our understanding of the pharmacokinetics of nicotine, cotinine, and 3-OH-cotinine across different routes of exposure., (Published by Oxford University Press 2024.)

End-ischemic normothermic mechanical perfusion (NMP) could provide a curative treatment to reduce cholestatic liver injury from donation after circulatory death (DCD) in donors. However, the underlying mechanism remains elusive. Our previous study demonstrated that air-ventilated NMP could improve functional recovery of DCD in a preclinical NMP rat model. Here, metabolomics analysis revealed that air-ventilated NMP alleviated DCD- and cold preservation-induced cholestatic liver injury, as shown by the elevated release of alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, and γ-glutamyl transferase (GGT) in the perfusate (p < .05) and the reduction in the levels of bile acid metabolites, including ω-muricholic acid, glycohyodeoxycholic acid, glycocholic acid, and glycochenodeoxycholate (GCDC) in the perfused livers (p < .05). In addition, the expression of the key bile acid metabolism enzyme UDP-glucuronosyltransferase 1A1 (UGT1A1), which is predominantly expressed in hepatocytes, was substantially elevated in the DCD rat liver, followed by air-ventilated NMP (p < .05), and in vitro, this increase was induced by decreased GCDC and hypoxia-reoxygenation in the hepatic cells HepG2 and L02 (p < .05). Knockdown of UGT1A1 in hepatic cells by siRNA aggravated hepatic injury caused by GCDC and hypoxia-reoxygenation, as indicated by the ALT and AST levels in the supernatant. Mechanistically, UGT1A1 is transcriptionally regulated by peroxisome proliferator-activator receptor-γ (PPAR-γ) under hypoxia-physoxia. Taken together, our data revealed that air-ventilated NMP could alleviate DCD- and cold preservation-induced cholestatic liver injury through PPAR-γ/UGT1A1 axis. Based on the results from this study, air-ventilated NMP confers a promising approach for predicting and alleviating cholestatic liver injury through PPAR-γ/UGT1A1 axis., (© 2024 Federation of American Societies for Experimental Biology.)

Background: Phosphatidylinositol 3-kinase (PI3K) regulates cellular development and energy homeostasis. However, the roles of its subunits in organ development remain largely unknown., Methods: We explored the roles of PI3K catalytic subunits in steroidogenic factor 1 (SF1)-expressing cells through knockout (KO) of the p110α and p110β subunits., Results: We examined mice with a double KO of p110α and p110β in SF1-expressing cells (p110αβ KOSF1). Although these animals exhibited no significant changes in the development of the ventromedial hypothalamus, we noted pronounced hypotrophy in the adrenal cortex, testis, and ovary. Additionally, corticosterone and aldosterone levels were significantly reduced. The absence of these subunits also resulted in decreased body weight and survival rate, along with impaired glucose homeostasis, in p110αβ KOSF1 mice., Conclusion: The data demonstrate the specific roles of PI3K catalytic subunits in the development and function of SF1-expressing organs.

Background: High expression of ubiquitin ligase MDM2 is a primary cause of p53 inactivation in many tumors, making it a promising therapeutic target. However, MDM2 inhibitors have failed in clinical trials due to p53-induced feedback that enhances MDM2 expression. This underscores the urgent need to find an effective adaptive genotype or combination of targets., Methods: Kinome-wide CRISPR/Cas9 knockout screen was performed to identify genes that modulate the response to MDM2 inhibitor using TP53 wild type cancer cells and found ULK1 as a candidate. The MTT cell viability assay, flow cytometry and LDH assay were conducted to evaluate the activation of pyroptosis and the synthetic lethality effects of combining ULK1 depletion with p53 activation. Dual-luciferase reporter assay and ChIP-qPCR were performed to confirm that p53 directly mediates the transcription of GSDME and to identify the binding region of p53 in the promoter of GSDME. ULK1 knockout / overexpression cells were constructed to investigate the functional role of ULK1 both in vitro and in vivo. The mechanism of ULK1 depletion to activate GSMDE was mainly investigated by qPCR, western blot and ELISA., Results: By using high-throughput screening, we identified ULK1 as a synthetic lethal gene for the MDM2 inhibitor APG115. It was determined that deletion of ULK1 significantly increased the sensitivity, with cells undergoing typical pyroptosis. Mechanistically, p53 promote pyroptosis initiation by directly mediating GSDME transcription that induce basal-level pyroptosis. Moreover, ULK1 depletion reduces mitophagy, resulting in the accumulation of damaged mitochondria and subsequent increasing of reactive oxygen species (ROS). This in turn cleaves and activates GSDME via the NLRP3-Caspase inflammatory signaling axis. The molecular cascade makes ULK1 act as a crucial regulator of pyroptosis initiation mediated by p53 activation cells. Besides, mitophagy is enhanced in platinum-resistant tumors, and ULK1 depletion/p53 activation has a synergistic lethal effect on these tumors, inducing pyroptosis through GSDME directly., Conclusion: Our research demonstrates that ULK1 deficiency can synergize with MDM2 inhibitors to induce pyroptosis. p53 plays a direct role in activating GSDME transcription, while ULK1 deficiency triggers upregulation of the ROS-NLRP3 signaling pathway, leading to GSDME cleavage and activation. These findings underscore the pivotal role of p53 in determining pyroptosis and provide new avenues for the clinical application of p53 restoration therapies, as well as suggesting potential combination strategies., (© 2024. The Author(s).)

Cyanthillium cinereum, which belongs to the family of Asteraceae, is an annual or perennial herbaceous plant with significant medicinal uses for treating colds and fever. During September to November of 2020, C. cinereum showing symptoms of witches'-broom were found in economic forests distributed in Ding'an, Hainan Province of China, with 20% incidence. The symptoms of the plant were consistent with infections by 'Candidatus Phytoplasma' species. To identify the pathogen, five symptomatic and three asymptomatic C. cinereum samples were collected. Total DNAs were extracted using 0.10 g fresh leaf tissues of symptomatic and asymptomatic C. cinereum through a CTAB DNA extraction method according to Doyle and Doyle (1990). PCR amplification were performed employing the primer pairs of R16mF2/R16mR1 (Gundersen and Lee, 1996) and secAfor1/secArev3 (Hodgetts et al., 2008) specific for the conserved gene fragments of 16S rRNA and secA from phytoplasma. The PCR products were purified and sequenced through Biotechnology (Shanghai) Co., Ltd. (Guangzhou, China), and the obtained sequences were deposited in GenBank. The phytoplasmal 16S rRNA and secA gene fragments obtained in the study were all identical with the length of 1325 bp (GenBank accession: PP098738) and 741 bp (PP072217), respectively. The phytoplasma strain was described as CcWB-hnda. A BLAST search based on 16S rRNA genes indicated that CcWB-hnda strain was identical to phytoplasmas belonging to 16SrII group like peanut witches'-broom phytoplasma strain T48 (OR239773) and 'Ca. Phytoplasma aurantifolia' strain TB2022 (CP120449). Virtual RFLP profiles based on 16S rRNA gene fragments obtained by iPhyClassifier (Zhao et al., 2009) showed that CcWB-hnda strain was a member of 16SrII-A subgroup with 1.00 similarity coefficient to the reference phytoplasma strain (L33765). A BLAST search based on secA genes indicated that CcWB-hnda had 100% sequence identity with phytoplasmas belonging to 16SrII group such as 'Ca. Phytoplasma aurantifolia' isolate TB2022 (CP120449), Vigna unguiculata witches'-broom phytoplasma (OR661282) and Emilia sonchifolia witches'-broom phytoplasma (MW353710). Phylogenetic analysis based on 16S rRNA and secA genes by MEGA 7.0 employing Neighbor-Joining method with 1000 bootstrap value (Kumar et al., 2016; Felsenstein, 1985) demonstrated that CcWB-hnda was clustered into one clade with the phytoplasmas belonging to 16SrII group, with 98% and 100% bootstrap value respectively. To our knowledge, this is the first report of C. cinereum infected by phytoplasmas belonging to 16SrII-A subgroup in China. Identification of the vector insects of the pathogens is necessary in future, revealing the epidemiology of the related diseases. Phytoplasmas belonging to same 16Sr group or subgroup can infect different plants and spread through them in nature. The finding in this study will be beneficial to epidemic monitoring and early warning of C. cinereum witches'-broom disease and the related plant diseases caused by the phytoplasmas belonging to 16SrII group.

Vascular endothelial inflammation is crucial in hepatic ischemia-reperfusion injury (IRI). Our previous research has shown that connective tissue growth factor (CTGF), secreted by endothelial cells, protects against acute liver injury, but its upstream mechanism is unclear. We aimed to clarify the protective role of CTGF in endothelial cell inflammation during IRI and reveal the regulation between endoplasmic reticulum stress-induced activating transcription factor 6 (ATF6) and CTGF. Hypoxia/reoxygenation in endothelial cells, hepatic IRI in mice and clinical specimens were used to examine the relationships between CTGF and inflammatory factors and determine how ATF6 regulates CTGF and reduces damage. We found that activating ATF6 promoted CTGF expression and reduced liver damage in hepatic IRI. In vitro, activated ATF6 upregulated CTGF and downregulated inflammation, while ATF6 inhibition had the opposite effect. Dual-luciferase assays and chromatin immunoprecipitation confirmed that activated ATF6 binds to the CTGF promoter, enhancing its expression. Activated ATF6 increases CTGF and reduces extracellular regulated protein kinase 1/2 (ERK1/2) phosphorylation, decreasing inflammatory factors. Conversely, inhibiting ATF6 decreases CTGF and increases the phosphorylation of ERK1/2, increasing inflammatory factor levels. ERK1/2 inhibition reverses this effect. Clinical samples have shown that CTGF increases after IRI, inversely correlating with inflammatory cytokines. Therefore, ATF6 activation during liver IRI enhances CTGF expression and reduces endothelial inflammation via ERK1/2 inhibition, providing a novel target for diagnosing and treating liver IRI., 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.)

N-acetyl cysteine (NAC) is a versatile drug used in various conditions, but the limitations and toxicities are not clear. The acute toxicity and toxicological mechanisms of an intraperitoneal injection of NAC in normal mice were deciphered. The LD50 for male and female BALB/cByJNarl mice were 800 mg/kg and 933 mg/kg. The toxicological mechanisms of 800 mg/kg NAC (N800) were investigated. The serum biomarkers of hepatic and renal indices dramatically increased, followed by hepatic microvesicular steatosis, renal tubular injury and necrosis, and splenic red pulp atrophy and loss. Thus, N800 resulted in mouse mortality mainly due to acute liver, kidney, and spleen damages. The safe dose (275 mg/kg) of NAC (N275) increased hepatic antioxidant capacity by increasing glutathione levels and catalase activity. N275 elevated the hepatic gene expressions of lipid transporter, lipid synthesis, β-oxidation, and ketogenesis, suggesting a balance between lipid production and consumption, and finally, increased ATP production. In contrast, N800 increased hepatic oxidative stress by decreasing glutathione levels through suppressing Gclc, and reducing catalase activity. N800 decreased the hepatic gene expressions of lipid transporter, lipid synthesis, and interferred β-oxidation, leading to lipid accumulation and increasing Cyp2E1 expression, and finally, decreased ATP production. Therefore, NAC doses are limited for normal individuals, especially via intraperitoneal injection or similar means.

Background: In rhinoplasty, calcification around silicone implants is frequently observed in the tip dorsum (TD) area. Additionally, based on a review of various literature, it is presumed that calcification in silicone implants occurs due to both inflammatory chemical reactions and physical friction against the tissue. The calcification of nasal silicone implants not only results in the functional loss of the implants, but also leads to material deformation. However, there is a lack of research on calcification of nasal silicone implants in the current literature., Aim: To elucidate various clinical characteristics of calcification around nasal silicone implants, using histological and radiological analysis., Methods: This study analyzed data from 16 patients of calcified nasal implants, who underwent revision rhinoplasty for various reasons after undergoing augmentation rhinoplasty with silicone implants. The collected data included information on implant duration, implant types, location of calcification, presence of inflammatory reactions, and computed tomography (CT) scans., Results: The most common location of calcification, as visually analyzed, was in the TD area, accounting for 56%. Additionally, the analysis of CT scans revealed a trend of increasing Hounsfield Unit values for calcification with the duration of implantation, although this trend was not statistically significant ( P = 0.139)., Conclusion: Our study shows that reducing the frequency of calcification may be achievable by using softer silicone implants and by minimizing the damage to perioperative tissues., Competing Interests: Conflict-of-interest statement: The authors declare no conflict of interest., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

This study explored the assembly mechanisms and physicochemical dynamics of microbial communities within atmospheric bioaerosols, focusing on the influence of different aerial trajectories. Over two years, samples near Seoul were classified into 'North', 'Southwest', and 'Others' categories based on their aerial trajectories. Physicochemical analysis of the PM 2.5 particles revealed distinct ion compositions for each cluster, reflecting diverse environmental influences. Microbial community analysis revealed that shared dominant bacterial phyla were present in all clusters. However, distinct taxonomic profiles and biomarkers were also evident, such as coastal bacteria in the 'Southwest' cluster correlating with wind speed, and arid soil-originated bacteria in the 'North' cluster correlating with cations. These findings demonstrate that biomarkers in each cluster are representative of the distinct environments associated with their aerial trajectories. Notably, cluster 'Southwest' the highest microbial diversity and a strong alignment with the neutral community model, suggesting a large influence of passive dispersal from marine environments. Contrarily, 'North' and 'Others' were more influenced by niche-dependent factors. This study highlights the complex interplay between environmental factors and microbial dynamics in bioaerosols and provides important insights for environmental monitoring and public health risk assessment., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Screening for osteoporosis is crucial for early detection and prevention, yet it faces challenges due to the low accuracy of calcaneal quantitative ultrasound (QUS) and limited access to dual-energy X-ray absorptiometry (DXA) scans. Recent advances in AI offer a promising solution through opportunistic screening using existing medical images. This study aims to utilize deep learning techniques to develop a model that analyzes chest X-ray (CXR) images for osteoporosis screening. This study included the AI model development stage and the clinical validation stage. In the AI model development stage, the combined dataset of 5122 paired CXR images and DXA reports from the patients aged 20 to 98 years at a medical center was collected. The images were enhanced and filtered for hardware retention such as pedicle screws, bone cement, artificial intervertebral discs or severe deformity in target level of T12 and L1. The dataset was then separated into training, validating, and testing datasets for model training and performance validation. In the clinical validation stage, we collected 440 paired CXR images and DXA reports from both the TCVGH and Joy Clinic, including 304 pared data from TCVGH and 136 paired data from Joy Clinic. The pre-clinical test yielded an area under the curve (AUC) of 0.940, while the clinical validation showed an AUC of 0.946. Pearson's correlation coefficient was 0.88. The model demonstrated an overall accuracy, sensitivity, and specificity of 89.0%, 88.7%, and 89.4%, respectively. This study proposes an AI model for opportunistic osteoporosis screening through CXR, demonstrating good performance and suggesting its potential for broad adoption in preliminary screening among high-risk populations.

Methods for regioselective N -trideuteromethylation of tautomeric polyaza heterocycles are highly sought-after. Disclosed herein is an N -trideuterated methylation reaction of imidazoles and pyrazoles with high regioselectivity and deuterium purity using easily available CF 3 SO 3 CD 3 as the -CD 3 source. This method enables the easy synthesis of important deuterium-labeled azoles, including dimetridazole- d 3 , ipronidazole- d 3 , hydroxy dimetridazole- d 3 , and ronidazole- d 3 .

Background: The beneficial effects of first-line programmed death-1 (PD-1) inhibitors plus chemotherapy in patients with low programmed death-ligand 1 (PD-L1)-expressing advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma are controversial., Methods: We conducted a retrospective analysis of patients with G/GEJ adenocarcinoma who had undergone first-line treatment with PD-1 inhibitors plus chemotherapy between October 2017 and May 2022. The primary outcomes were objective response rate (ORR) and progression-free survival (PFS). SPSS software V27.0 was used for data analysis., Results: Of 345 enrolled patients, 290 had measurable lesions. The overall ORR was 59.3%. PD-L1 status was available in 171 patients, and 67.8% of them were considered as low PD-L1 expression level (combined positive score (CPS) < 5). Patients with PD-L1 CPS < 5 showed a lower response rate (51.1% vs 70.8%, P = 0.024) and a worse PFS (P = 0.009) compared to those with PD-L1 CPS ≥ 5. In the PD-L1 low-expression cohort, patients with non-diffuse type, GEJ cancer, synchronous metastasis, distant lymph node metastasis, liver metastasis, non-peritoneal metastasis, and HER2 positive were significantly associated with higher response rates to PD-1 inhibitors plus chemotherapy (P < 0.05). The presence of peritoneal metastasis (P = 0.028) and diffuse type (P = 0.046) were identified as independent predictors of poor PFS in multivariate analysis of the PD-L1 CPS < 5 subgroup. When evaluated for correlation with overall survival (OS) in the PD-L1 low-expression subgroup, peritoneal metastasis was found to be the only independent prognostic factor of an increased risk of death (hazard ratio: 2.31, 95% CI 1.09-4.90; P = 0.029)., Conclusions: PD-L1 CPS ≥ 5 is significantly associated with improved response and extended PFS in G/GEJ cancer patients treated with a combination of PD-1 inhibitors and chemotherapy. Specific subgroups within the low PD-L1-expressing population, such as those with non-diffuse-type tumors and without peritoneal metastases, may also benefit from immunotherapy combined with chemotherapy., (© 2024. The Author(s).)

Acute pancreatitis (AP) is a prevalent gastrointestinal disorder. The immune response plays a crucial role in AP progression. However, the impact of immune regulatory checkpoint PD-L1 on severe acute pancreatitis (SAP) remains uncertain. Hence, this study aimed to examine the influence of PD-L1 on SAP. We assessed PD-L1 expression in neutrophils and monocytes obtained from SAP patients. We induced SAP in C57BL/6J mice, PD-L1 gene-deficient mice, and PD-L1 humanized mice using intraperitoneal injections of cerulein plus lipopolysaccharide. Prior to the initial cerulein injection, a PD-L1 inhibitor was administered. Pancreatic tissues were collected for morphological and immunohistochemical evaluation, and serum levels of amylase, lipase, and cytokines were measured. Flow cytometry analysis was performed using peripheral blood cells. The expression of PD-L1 in neutrophils and monocytes was significantly higher in SAP patients compared to healthy individuals. Likewise, the expression of PD-L1 in inflammatory cells in the peripheral blood of SAP-induced C57BL/6J mice was notably higher than in the control group. In mice with PD-L1 deficiency, SAP model exhibited lower pancreatic pathology scores, amylase, lipase, and cytokine levels compared to wild-type mice. PD-L1 deletion resulted in reduced neutrophil apoptosis, leading to an earlier peak in neutrophil apoptosis. Furthermore, it decreased early monocyte apoptosis and diminished the peak of T lymphocyte apoptosis. Within the SAP model, administration of a PD-L1 inhibitor reduced pancreatic pathology scores, amylase, lipase, and cytokine levels in both C57BL/6J mice and PD-L1 humanized mice. These findings suggest that inhibiting PD-L1 expression can alleviate the severity of SAP., 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. Published by Elsevier B.V.)

Lonicerae japonicae (L. japonicae) flos is a medical and food homology herb. This study investigated the phenolic acid and flavonoid contents in L. japonicae flos water extract solution (LJWES) and the preventive effects of LJWES against liver fibrogenesis via FL83B cells and rats. LJWES contains many polyphenols, such as chlorogenic acid, morin, and epicatechin. LJWES increased cell viability and decreased cytotoxicity in thioacetamide (TAA)-treated FL83B cells (75 mM) (p < .05). LJWES decreased (p < .05) gene expressions of Tnf-α, Tnfr1, Bax, and cytochrome c but upregulated Bcl-2 and Bcl-xl in TAA-treated cells; meanwhile, increased protein levels of P53, cleaved caspase 3, and cleaved caspase 9 in TAA treated cells were downregulated (p < .05) by LJWES supplementation. In vivo, results indicated that TAA treatment increased serum liver damage indices (alanine aminotransferase [ALT] and alkaline phosphatase [ALP]) and cytokines (interleukin-6 and transforming growth factor-β1) levels and impaired liver antioxidant capacities (increased thiobarbituric acid reactive substance value but decreased catalase/glutathione peroxidase activities) in rats (p < .05) while LJWES supplementation amended (p < .05) them. Liver fibrosis scores, collagen deposition, and alpha-smooth muscle actin deposition in TAA-treated rats were also decreased by LJWES supplementation (p < .05). To sum up, LJWES could be a potential hepatoprotective agent against liver fibrogenesis by enhancing antioxidant ability, downregulating inflammation in livers, and reducing apoptosis in hepatocytes., (© 2024 Wiley Periodicals LLC.)

Group theory is a powerful tool to explore fundamental symmetry constraints for the physical properties of crystal structures, e.g. it is well-known that only a few components of the elastic constants are independent due to the symmetry constraint. This work further applies group theory to derive constraint relationships for high-order elastic constants with respect to the orientation angle, where the constraint relationships are more explicit than the traditional tensor transformation law. These analytic symmetry constraints are adopted to explain the molecular dynamics simulation results, which disclose that the high-order elastic constants are highly anisotropic with an anisotropy percentage of up to 25% for the hexagonal boron nitride monolayer. The elastic constant is a basic quantity in the mechanics field, so its high anisotropy shall cause strong anisotropy for other mechanical properties. Based on the anisotropic high-order elastic constants, we demonstrate that Poisson's ratio is highly anisotropic for the hexagonal boron nitride at large strains. These findings provide fundamental insights into the symmetry dependence of high-order elastic constants and other mechanical properties.

Background: Brain metastasis (BM) in gastric cancer (GC) is underestimated, and human epidermal growth factor receptor 2 (HER2) overexpression is a durable poor prognostic factor. We explored the relationship between the two and made a survival analysis., Methods: HER2 expression and BM status were collected from GC patients who were diagnosed between December 2009 and May 2021. We collected GC patients diagnosed between 2010 and 2016 from the SEER database. The primary endpoint was survival from the diagnosis of BM. Multivariable logistic regression was used to determine potential risk factors of BM at diagnosis in SEER database. Survival analysis was performed using the Kaplan-Meier method., Result: There were 513 HER2-positive GC patients, including 16 (3.1%) with BM. Among 38 brain metastasis GC patients we collected, 16 (42.1%) patients were HER2 positive. We collected 34,199 GC patients from the SEER database and there were 260 (0.76%) patients with BM at diagnosis. GC patients that are male, white, of younger age, with primary lesions located in the proximal stomach or with distant lymph nodes, liver, bone, or lung metastasis are more likely to develop BM. The median overall survival time from diagnosis of BM was 12.73 months, and the survival time from brain metastasis of HER2-positive patients was numerically shorter, though the difference was not significant (5.30 months vs.16.13 months, P = 0.28.) CONCLUSION: The incidence of BM in patients with HER2-positive gastric cancer is 4.08 times higher than that in general patients. The median overall survival time from BM is shorter for HER2-positive patients., (© 2023. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

The QuEChERS (quick, easy, cheap, effective, rugged and safe) conditions were optimized for efficient determination of the U.S. Environmental Protection Agency (US EPA) and European Union (EU) priority polycyclic aromatic hydrocarbons (PAHs) for the categories of grains, tuber & starchy vegetables, soy beans and products, fish & seafood, and poultry & meat, including raw materials and their corresponding products. The PAHs were analyzed using ultrahigh-performance liquid chromatography with temperature-controlled fluorescence detection and gas chromatography with tandem mass spectrometry. The established conditions had good accuracy, repeatability, and precision. Environmental pollution and processing methods influence the level of PAHs in samples. The low molecular weight PAHs were present in all raw materials, and processing increased high and low molecular weight PAHs in the products. The excess cancer risk for consumption of PAHs in cooked samples was mostly acceptable; a small number of samples might be of slight concern in certain age groups.

Background: Hypertensive disorders of pregnancy (HDP) is the most common cause of indicated preterm delivery, but the impact of prenatal steroid exposure on the outcomes of preterm infants born to HDP mothers, who may be at risk for intrauterine hypoxia-ischemia, remains uncertain. The study objective is to evaluate the mortality and morbidities in HDP for very preterm infants (VPIs) exposed to different course of ANS., Methods: This is a prospective cohort study comprising infants with < 32 weeks gestation born to women with HDP only from 1 Jan. 2019 to 31 Dec. 2021 within 40 participating neonatal intensive care units (NICUs) in Sino-northern network. ANS courses included completed, partial, repeated, and no ANS. Univariate and multivariable analyses were performed on administration of ANS and short-term outcomes before discharge., Results: Among 1917 VPIs born to women with HDP only, 987(51.4%) received a complete course of ANS within 48 h to 7 days before birth, 560(29.2%) received partial ANS within 24 h before delivery, 100(5.2%) received repeat ANS and 270 (14.1%) did not receive any ANS. Compared to infants who received complete ANS, infants unexposed to ANS was associated with higher odds of death (AOR 1.85; 95%CI 1.10, 3.14), Severe Neurological Injury (SNI) or death (AOR 1.68; 95%CI 1.29,3.80) and NEC or death (AOR 1.78; 95%CI 1.55, 2.89), the repeated ANS group exhibits a significant negative correlation with the duration of oxygen therapy days (correlation coefficient - 18.3; 95%CI-39.2, -2.1). However, there were no significant differences observed between the full course and partial course groups in terms of outcomes. We can draw similar conclusions in the non-SGA group, while the differences are not significant in the SGA group. From KM curve, it showed that the repeated group had the highest survival rate, but the statistical analysis did not indicate a significant difference., Conclusions: Even partial courses of ANS administered within 24 h before delivery proved to be protective against death and other morbidities. The differences mentioned above are more pronounced in the non-SGA group. Repeat courses demonstrate a trend toward protection, but this still needs to be confirmed by larger samples., (© 2024. The Author(s).)

The Lamiaceae family is renowned for its terpenoid-based medicinal components, but Leonurus, which has traditional medicinal uses, stands out for its alkaloid-rich composition. Leonurine, the principal active compound found in Leonurus, has demonstrated promising effects in reducing blood lipids and treating strokes. However, the biosynthetic pathway of leonurine remains largely unexplored. Here, we present the chromosome-level genome sequence assemblies of Leonurus japonicus, known for its high leonurine production, and Leonurus sibiricus, characterized by very limited leonurine production. By integrating genomics, RNA sequencing, metabolomics, and enzyme activity assay data, we constructed the leonurine biosynthesis pathway and identified the arginine decarboxylase (ADC), uridine diphosphate glucosyltransferase (UGT), and serine carboxypeptidase-like (SCPL) acyltransferase enzymes that catalyze key reactions in this pathway. Further analyses revealed that the UGT-SCPL gene cluster evolved by gene duplication in the ancestor of Leonurus and neofunctionalization of SCPL in L. japonicus, which contributed to the accumulation of leonurine specifically in L. japonicus. Collectively, our comprehensive study illuminates leonurine biosynthesis and its evolution in Leonurus., (Copyright © 2023 The Author. Published by Elsevier Inc. All rights reserved.)

We study the property of equal-spin Andreev reflection (ESAR) in the ferromagnet/insulator/Ising superconductor junction where Ising spin-orbit coupling is taken into account in the insulator. It is found that the ESAR exhibits a regular oscillation with the insulating barrier, the amplitude and period of which can be effectively controlled by the chemical potentials. Compared to that in the ferromagnet/Ising superconductor junction, the ESAR is greatly increased due to the resonant mode, suggesting an enhanced spin-triplet pairing. As an application, the proposed junction may work as a switch to turn on and off the ESAR. Furthermore, the insulating barrier does not change the magnetoanisotropic period of ESAR because of the invariant symmetry of the system, however, the magnetoanisotropy is strengthened., (© 2023 IOP Publishing Ltd.)

Objective: To understand the antimicrobial resistance and genome characteristics of Campylobacter isolates recovered from retailed poultry meat samples in 20 provinces in China in 2020. Methods: In 2020, 265 Campylobacter strains including 244 Campylobacter jejuni and 21 Campylobacter coli collected from retailed poultry meat samples in China were tested for antimicrobial resistance to 9 antimicrobial compounds by using the agar dilution method. Forty-two selected isolates were sent for whole genome sequencing and 38 high-quality genomes were analyzed for their antimicrobial resistance genes, virulence genes, sequence types and genetic diversity. Results: The resistance rates of Campylobacter isolates from poultry meats to tetracycline, nalidixic acid and ciprofloxacin were the highest (84%-100%), with 53.2% of the isolates showing multidrug resistance in this study. The resistance rates of C. coli to erythromycin, azithromycin, telithromycin, gentamicin and clindamycin were significantly higher than those of C. jejuni ( P <0.05). The resistance genes conferring resistance to β-lactams (100%, 38/38), quinolones (94.7%, 36/38), tetracycline (81.6%, 31/38) and aminoglycosides (50%, 19/38) were the most frequently detected among 38 Campylobacter genomes. C. jejuni carried more virulence genes than C. coli . In total, 19 and 17 sequence types (ST) were obtained from 20 sequenced C. jejuni and 18 C. coli isolates, respectively, including 5 novel STs. The isolates showed a high genetic diversity based on their sequence types. Conclusion: The phenomenon of antimicrobial resistance in Campylobacter from poultry meat sources in China is relatively serious, and resistance and virulence genes are widely distributed in Campylobacter . There is genetic diversity in Campylobacter.

The forkhead box transcription factor O1 (FoxO1) is expressed ubiquitously throughout the central nervous system, including in astrocytes, the most prevalent glial cell type in the brain. While the role of FoxO1 in hypothalamic neurons in controlling food intake and energy balance is well-established, the contribution of astrocytic FoxO1 in regulating energy homeostasis has not yet been determined. In the current study, we demonstrate the essential role of hypothalamic astrocytic FoxO1 in maintaining normal neuronal activity in the hypothalamus and whole-body glucose metabolism. Inhibition of FoxO1 function in hypothalamic astrocytes shifts the cellular metabolism from glycolysis to oxidative phosphorylation, enhancing astrocyte ATP production and release meanwhile decreasing astrocytic export of lactate. As a result, specific deletion of astrocytic FoxO1, particularly in the hypothalamus, causes a hyperactivation of hypothalamic neuropeptide Y neurons, which leads to an increase in acute feeding and impaired glucose regulation and ultimately results in diet-induced obesity and systemic glucose dyshomeostasis., (© 2023 The Authors. GLIA published by Wiley Periodicals LLC.)

Materials exhibiting a negative Poisson's ratio have garnered considerable attention due to the improved toughness, shear resistance, and vibration absorption properties commonly found in auxetic materials. In this work, the nonlinear effect on the Poisson's ratio was derived theoretically and verified by first-principle calculations and molecular dynamics simulations of two-dimensional nanomaterials including graphene and hexagonal boron nitride. The analytic formula explicitly shows that the Poisson's ratio depends on the applied strain and can be negative for large applied strains, owing to the nonlinear interaction. Both first-principle calculations and molecular dynamics simulations show that the nonlinear effect is highly anisotropic for graphene, where the nonlinearity-induced negative Poisson's ratio is much stronger for the strain applied along the armchair direction. These findings provide valuable insights into the behavior of materials with negative Poisson's ratios and emphasize the importance of considering nonlinear effects in the study of the Poisson's ratio of two-dimensional materials., (© 2023 IOP Publishing Ltd.)

α-particle targeted radionuclide therapy has shown promise for optimal cancer management, an exciting new era for brachytherapy. Alpha-emitting nuclides can have significant advantages over gamma- and beta-emitters due to their high linear energy transfer (LET). While their limited path length results in more specific tumor 0kill with less damage to surrounding normal tissues, their high LET can produce substantially more lethal double strand DNA breaks per radiation track than beta particles. Over the last decade, the physical and chemical attributes of Actinium-225 ( 225 Ac) including its half-life, decay schemes, path length, and straightforward chelation ability has peaked interest for brachytherapy agent development. However, this has been met with challenges including source availability, accurate modeling for standardized dosimetry for brachytherapy treatment planning, and laboratory space allocation in the hospital setting for on-demand radiopharmaceuticals production. Current evidence suggests that a simple empirical approach based on 225 Ac administered radioactivity may lead to inconsistent outcomes and toxicity. In this review article, we highlight the recent advances in 225 Ac source production, dosimetry modeling, and current clinical studies., (Copyright © 2023 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Orbital angular momentum (OAM) of light has the potential to induce high-order transitions of electrons in atoms by compensating for the OAM required. However, due to the dark spot situating at the focal center of the OAM beam, high-order transitions are typically weak. In this study, we demonstrate efficient and selective high-order resonances in symmetric and asymmetric plasmonic nanoparticles that are comparable in size to the waist radius of the OAM beam. In a symmetric nanoparticle configured with a complete nanoring lying on the focal center, there is a pure high-order resonance obeying the law of conservation of angular momentum during the interaction between OAM light and the nanosystem. In an asymmetric nanoparticle configured with an complete ring off the beam center or a splitting nanoring, there are multiple resonances whose resonance orders are influenced by the ring's geometry, position, orientation, and photon OAM. Thus, high-order resonances in the symmetric and asymmetric plasmonic nanostructures are selectively stimulated using vortex beams. Our results may help to understand and control OAM-involved light-material interactions of asymmetric nanosystems.

Early detection of histamine in foodstuffs/beverages could be useful in preventing various diseases. In this work, we have prepared a free-standing hybrid mat based on manganese cobalt (2-methylimodazole)-metal organic frameworks (Mn-Co(2-MeIm)MOF) and carbon nanofibers (CNFs) and explored as a non-enzymatic electrochemical sensor for determining the freshness of fish and bananas based on histamine estimation. As-developed hybrid mat possesses high porosity with a large specific surface area and excellent hydrophilicity those allow easy access of analyte molecules to the redox-active metal sites of MOF. Furthermore, the multiple functional groups of the MOF matrix can act as active adsorption sites for catalysis. The Mn-Co(2-MeIm)MOF@CNF mat-modified GC electrode demonstrated excellent electrocatalytic activities toward the oxidation of histamine under acidic conditions (pH = 5.0) with a faster electron transfer kinetics and superior fouling resistance. The Co(2-MeIm)MOF@CNF/GCE sensor exhibited a wide linear range from 10 to 1500 µM with a low limit of detection (LOD) of 89.6 nM and a high sensitivity of 107.3 µA mM -1  cm -2 . Importantly, as-developed Nb(BTC)MOF@CNF/GCE sensor is enabled to detect histamine in fish and banana samples stored for different periods of time, which thus indicates its practical viability as analytical histamine detector., (© 2023. Springer-Verlag GmbH Germany, part of Springer Nature.)

The optimal conditions for simultaneous determination of the U.S. Environmental Protection Agency (US EPA) and European Union (EU) priority polycyclic aromatic hydrocarbons (PAHs) in coffee beans and coffee brews were developed. The QuEChERS (quick, easy, cheap, effective, rugged and safe) technology combined with high performance liquid chromatography - temperature-controlled fluorescence detection and gas chromatography - tandem mass spectrometry were used in the investigation. PAHs could be determined in commercially available green coffee beans (possibly caused by environmental contamination), and their PAHs content increased with the degree of roasting. Coffee beans brewed with the coffee machine released more PAHs into their brews than those brewed with the drip bag. The PAHs consumption risk of the brewed coffee samples was not high due to their low PAH level. Nevertheless, the methods of roasting and brewing and the amount of drinking could still be considered to reduce the intake of PAHs., 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 Ltd. All rights reserved.)

Background: Guidelines widely recommend thyrotropin suppression to reduce the risk of recurrence in intermediate- and high-risk papillary thyroid cancer (PTC) after total thyroidectomy. However, an insufficient or excessive dosage may result in a number of symptoms/complications especially in older patients., Patients and Methods: We constructed a retrospective cohort including 551 PTC patient encounters. Using propensity score matching and logistic regression models, we determined the independent risk factors affecting levothyroxine therapy at different ages. Our outcomes included: expected TSH level and an unexpected TSH level, which was based on the initial thyroid-stimulating hormone (TSH) goal< 0.1 mIU/L with usual dosage of L-T4 (1.6 μg/kg/day)., Results: From our analysis, more than 70% of patients undergoing total thyroidectomy did not achieve the expected TSH level using an empirical medication regimen, and the effect of the drug was affected by age (odds ratio [OR], 1.063; 95% CI, 1.032-1.094), preoperative TSH level (OR, 0.554; 95% CI, 0.436-0.704) and preoperative fT3 level (OR, 0.820; 95% CI, 0.727-0.925). In patients with age < 55 years old, preoperative TSH level (OR, 0.588; 95% CI, 0.459-0.753), and preoperative fT3 level (OR, 0.859; 95% CI, 0.746-0.990) were two independent protective factors, while, in patients with age ≥ 55 years old, only preoperative TSH level (OR, 0.490; 95% CI, 0.278-0.861) was the independent protective factors to achieve expected TSH level., Conclusion: Our retrospective analysis suggested the following significant risk factors of getting TSH suppression in PTC patients: age (≥55 years), lower preoperative TSH and fT3 levels., 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 Zhou, Li, Tan, Tang, Chen, Liu, Ou-Yang, Qin, Ai, Wei, Zhao, Chang and Huang.)

Normothermic machine perfusion (NMP) could provide a curative treatment to reduce biliary injury in donation after cardiac death (DCD) donor livers; however, the underlying mechanisms remain poorly understood. In a rat model, our study compared air-oxygenated NMP to hyperoxygenated NMP and found that air-oxygenated NMP improved DCD functional recovery. Here, we found that the charged multivesicular body protein 2B (CHMP2B) expression was substantially elevated in the intrahepatic biliary duct endothelium of the cold-preserved rat DCD liver after air-oxygenated NMP or in biliary endothelial cells under hypoxia/physoxia. CHMP2B knockout (CHMP2B -/- ) rat livers showed increased biliary injury after air-oxygenated NMP, indicated by decreased bile production and bilirubin level, elevated biliary levels of lactate dehydrogenase and gamma-glutamyl transferase. Mechanically, we demonstrated that CHMP2B was transcriptionally regulated by Kruppel-like transcription factor 6 (KLF6) and alleviated biliary injury through decreasing autophagy. Collectively, our results suggested that air-oxygenated NMP regulates CHMP2B expression through the KLF6, which reduces biliary injury by inhibiting autophagy. Targeting the KLF6-CHMP2B autophagy axis may provide a solution to reducing biliary injury in DCD livers undergoing NMP., 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 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: We aimed to evaluate the risk factors for moderate-to-severe bronchopulmonary dysplasia (BPD) and focus on discussing its relationship with the duration of initial invasive mechanical ventilation (IMV) in very preterm neonates less than 32 weeks of gestational age (GA)., Methods: We performed a prospective cohort study involving infants born at 23-31 weeks of GA who were admitted to 47 different neonatal intensive care unit (NICU) hospitals in China from January 2018 to December 2021. Patient data were obtained from the Sina-northern Neonatal Network (SNN) Database., Results: We identified 6538 very preterm infants, of whom 49.5% (3236/6538) received initial IMV support, and 12.6% (823/6538) were diagnosed with moderate-to-severe BPD symptoms. The median duration of initial IMV in the moderate-to-severe BPD group was 26 (17-41) days, while in the no or mild BPD group, it was 6 (3-10) days. The incidence rate of moderate-to-severe BPD and the median duration of initial IMV were quite different across different GAs. Multivariable logistic regression analysis showed that the onset of moderate-to-severe BPD was significantly associated with the duration of initial IMV [adjusted odds ratio (AOR): 1.97; 95% confidence interval (CI): 1.10-2.67], late-onset neonatal sepsis (LONS), and patent ductus arteriosus (PDA)., Conclusion: In this multicenter cohort study, the duration of initial IMV was still relatively long in very premature infants, and the longer duration of initial IMV accounts for the increased risk of moderate-to-severe BPD., (© 2023. The Author(s).)

Background: Published guidelines on decision-making and resuscitation of extremely preterm infants primarily focus on high-income countries. For rapidly industrializing ones like China, there is a lack of population-based data for informing prenatal management and practice guidelines., Methods: The Sino-northern Neonatal Network conducted a prospective multi-centre cohort study between 1 January 2018 and 31 December 2021. Infants with a gestational age (GA) between 22 (postnatal age in days = 0) and 28 (postnatal age in days = 6) admitted to 40 tertiary NICUs in northern China were included and evaluated for death or severe neurological injury before discharge., Results: For all extremely preterm infants (n = 5838), the proportion of admission to the neonatal was 4.1% at 22-24 weeks, 27.2% at 25-26 weeks, and 75.2% at 27 and 28 weeks. Among 2228 infants admitted to the NICU, 216 (11.1%) were still elected for withdrawal of care (WIC) due to non-medical factors. Survival rates without severe neurological injury were 6.7% for infants at 22-23 weeks, 28.0% at 24 weeks, 56.7% at 24 weeks, 61.7% at 25 weeks, 79.9% at 26 weeks, and 84.5% at 27 and 28 weeks. Compared with traditional criterion at 28 weeks, the relative risk for death or severe neurological injury were 1.53 (95% confidence interval (CI) = 1.26-1.86) at 27 weeks, 2.32 (95% CI = 1.73-3.11) at 26 weeks, 3.62 (95% CI = 2.43-5.40) at 25 weeks, and 8.91 (95% CI = 4.69-16.96) at 24 weeks. The NICUs with higher proportion of WIC also had a higher rate of death or severe neurological injury after maximal intensive care (MIC)., Conclusions: Compared to the traditional threshold of 28 weeks, more infants received MIC after 25 weeks, leading to significant increases in survival rates without severe neurological injury. Therefore, the resuscitation threshold should be gradually adjusted from 28 to 25 weeks based on reliable capacity., Registration: China Clinical Trials Registry. ID: ChiCTR1900025234., Competing Interests: Disclosure of interest: The authors completed the ICMJE Disclosure of Interest Form (available upon request from the corresponding author) and disclose no relevant interests., (Copyright © 2023 by the Journal of Global Health. All rights reserved.)

Although activin receptor IIB (ACVR2B) is emerging as a novel pathogenic receptor, its ligand and assembled components (or assembly) are totally unknown in the context of osteoarthritis (OA) pathogenesis. The present results suggest that upregulation of ACVR2B and its assembly could affect osteoarthritic cartilage destruction. It is shown that the ACVR2B ligand, activin A, regulates catabolic factor expression through ACVR2B in OA development. Activin A Tg mice (Col2a1-Inhba) exhibit enhanced cartilage destruction, whereas heterozygous activin A KO mice (Inhba +/- ) show protection from cartilage destruction. In silico analysis suggests that the Activin A-ACVR2B axis is involved in Nox4-dependent ROS production. Activin A Tg:Nox4 KO (Col2a1-Inhba:Nox4 -/- ) mice show inhibition of experimental OA pathogenesis. NOX4 directly binds to the C-terminal binding site on ACVR2B-ACVR1B and amplifies the pathogenic signal for cartilage destruction through SMAD2/3 signaling. Together, the findings reveal that the ACVR2B assembly, which comprises Activin A, ACVR2B, ACVR1B, Nox4, and AP-1-induced HIF-2α, accelerates OA development. Furthermore, it is shown that shRNA-mediated ACVR2B knockdown or trapping ligands of ACVR2B abrogate OA development by competitively disrupting the ACVR2B-Activin A interaction. These results suggest that the ACVR2B assembly is required to amplify osteoarthritic cartilage destruction and could be a potential therapeutic target in efforts to treat OA., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Objective: To investigate the antimicrobial resistance of food-borne diarrheagenic Escherichia coli (DEC) and the prevalence of mcr genes that mediates mobile colistin resistance in parts of China, 2020. Methods: For 91 DEC isolates recovered from food sources collected from Fujian province, Hebei province, Inner Mongolia Autonomous Region and Shanghai city in 2020, Vitek2 Compact biochemical identification and antimicrobial susceptibility testing platform was used for the detection of antimicrobial susceptibility testing (AST) against to 18 kinds of antimicrobial compounds belonging to 9 categories, and multi-polymerase chain reaction (mPCR) was used to detect the mcr-1 - mcr-9 genes, then a further AST, whole genome sequencing (WGS) and bioinformatics analysis were platformed for these DEC isolates which were PCR positive for mcr genes. Results: Seventy in 91 isolates showed different antimicrobial resistance levels to the drugs tested with a resistance rate of 76.92%. The isolates showed the highest antimicrobial resistance rates to ampicillin (69.23%, 63/91) and trimethoprim-sulfamethoxazole (59.34%, 54/91), respectively. The multiple drug-resistant rate was 47.25% (43/91). Two mcr-1 gene and ESBL (extended-spectrum beta-lactamase) positive EAEC (enteroaggregative Escherichia coli ) strains were detected. One of them was identified as serotype of O11:H6, which showed a resistance profile to 25 tested drugs referring to 10 classes, and 38 drug resistance genes were predicted by genome analysis. The other one was O16:H48 serotype, which was resistant to 21 tested drugs belonging to 7 classes and carried a new variant of mcr-1 gene ( mcr-1.35 ). Conclusion: An overall high-level antimicrobial resistance was found among foodborne DEC isolates recovered from parts of China in 2020, and so was the MDR (multi-drug resistance) condition. MDR strains carrying multiple resistance genes such as mcr-1 gene were detected, and a new variant of mcr-1 gene was also found. It is necessary to continue with a dynamic monitoring on DEC contamination and an ongoing research into antimicrobial resistance mechanisms.

Chicken-liver hydrolysates (CLHs) have been characterized as performing several biofunctions by our team. This study aimed to investigate if a CLH-based supplement (GBHP01 TM ) can ameliorate liver fibrogenesis induced by thioacetamide (TAA) treatment. Our results showed that the TAA treatment caused lower body weight gains and enlarged livers, as well as higher serum ALT, AST, and ALP levels ( p < 0.05). This liver inflammatory and fibrotic evidence was ameliorated ( p < 0.05) by supplementing with GBHP01 TM ; this partially resulted from its antioxidant abilities, including decreased TBARS values but increased TEAC levels, reduced GSH contents and catalase/GPx activities in the livers of TAA-treated rats ( p < 0.05). Additionally, fewer nodules were observed in the appearance of the livers of TAA-treated rats after supplementing with GBHP01 TM . Similarly, supplementing GBHP01 TM decreased fibrotic scars and the fibrotic score in the livers of TAA-treated rats ( p < 0.05). Moreover, the increased hepatic IL-6, IL-1β, and TNF-α levels after TAA treatment were also alleviated by supplementing with GBHP01 TM ( p < 0.05). Meanwhile, GBHP01 TM could decrease the ratio of LC3B II/LC3B I, but upregulated P62 and Rab7 in the livers of TAA-treated rats ( p < 0.05). Taking these results together, the CLH-based supplement (GBHP01 TM ) can be characterized as a natural agent against liver fibrogenesis.

The prognosis and overall survival of castration-resistant prostate cancer (CRPC) patients are poor. The search for novel and efficient anti-CRPC agents is therefore extremely important. WM-3835 is a cell-permeable, potent and first-in-class HBO1 (KAT7 or MYST2) inhibitor. Here in primary human prostate cancer cells-derived from CRPC patients, WM-3835 potently inhibited cell viability, proliferation, cell cycle progression and in vitro cell migration. The HBO1 inhibitor provoked apoptosis in the prostate cancer cells. It failed to induce significant cytotoxicity and apoptosis in primary human prostate epithelial cells. shRNA-induced silencing of HBO1 resulted in robust anti-prostate cancer cell activity as well, and adding WM-3835 failed to induce further cytotoxicity in the primary prostate cancer cells. Conversely, ectopic overexpression of HBO1 further augmented primary prostate cancer cell proliferation and migration. WM-3835 inhibited H3-H4 acetylation and downregulated several pro-cancerous genes (CCR2, MYLK, VEGFR2, and OCIAD2) in primary CRPC cells. Importantly, HBO1 mRNA and protein levels are significantly elevated in CRPC tissues and cells. In vivo, daily intraperitoneal injection of WM-3835 potently inhibited pPC-1 xenograft growth in nude mice, and no apparent toxicities detected. Moreover, intratumoral injection of HBO1 shRNA adeno-associated virus (AAV) suppressed the growth of primary prostate cancer xenografts in nude mice. H3-H4 histone acetylation and HBO1-dependent genes (CCR2, MYLK, VEGFR2, and OCIAD2) were remarkably decreased in WM-3835-treated or HBO1-silenced xenograft tissues. Together, targeting HBO1 by WM-3835 robustly inhibits CRPC cell growth., (© 2023. The Author(s).)

Enterocytozoon bieneusi is a common pathogen in humans and various animals, threatening the breeding industry and public health. However, there is limited information on the molecular characteristics of E. bieneusi in yaks, an economically important animal mainly domesticated in the Qinghai Tibet Plateau in China. In the present study, nested PCR targeting the ITS gene region was applied to investigate the positive rates and genetic diversity of E. bieneusi in 223 faecal samples of yaks from three locations in Ganzi Tibetan Autonomous Prefecture, Sichuan Province. The total positive rate of E. bieneusi was 23.8% (53/223). Significant differences in positive rates were identified among yaks from three locations (χ 2  = 8.535, p = 0.014) and four age groups (χ 2  = 17.259, p = 0.001), with the highest positive rates in yaks from Yajiang and aged < 6 months, respectively. Sequence analysis identified seven known (EbpC, LW1, LQ10, PigEBITS5, ESH-01, J and BEB4) and five novel (Ganzi1-5) ITS genotypes. Phylogenetic analysis showed eight genotypes (EbpC, LW1, LQ10, PigEBITS5, ESH-01, Ganzi1, Ganzi2 and Ganzi4) in group 1 and three genotypes (J, BEB4 and Ganzi3) in group 2, indicating high genotype diversity and zoonotic potential of E. bieneusi in yaks from Ganzi. Considering the increasing zoonotic genotypes in yaks in the present study compared with previous findings, interventions should be developed to reduce the potential transmission of E. bieneusi between humans and animals., (© X. Yang et al., published by EDP Sciences, 2023.)

Lacticaseibacillus paracasei strain PS23 (PS23) exhibits some probiotic properties. In this study, a genomic analysis of PS23 revealed no genes related to virulence or antibiotic resistance. Moreover, ornithine decarboxylase activity was not detected in vitro. In addition, PS23 was sensitive to the tested antibiotics. Genotoxicity tests for PS23 including the Ames test and chromosomal aberrations in vitro using Chinese hamster ovary cells and micronuclei in immature erythrocytes of ICR mice were all negative. Moreover, following a 28-day study involving repeated oral dose toxicity tests (40, 400, and 4000 mg/kg equal 1.28 × 10 10 , 1.28 × 10 11 , and 1.28 × 10 12 CFU/kg body weight, respectively) using an ICR mouse model, no adverse effects were observed from any doses. In addition, supplementation with live or heat-killed PS23 ameliorates DSS-induced colonic inflammation in mice. Our findings suggest that PS23 is safe and has anti-inflammatory effects and may therefore have therapeutic implications.

The good performance conditions for determination of EU priority PAHs in coffee samples were established to evaluate the effects of roasting degree on the PAHs in coffee beans and the brewing methods on the PAHs transfer from coffee beans to their brews. The consumption risk of the PAHs in coffee products was also assessed. The PAHs levels of the roasted coffee beans were in the order: 923.65 ng/g (dark roast) > 132.20 ng/g (medium roast) > 69.28 ng/g (light roast). Compared with general brewing with the drip bag (PAHs content, 0.30-0.62 ng/mL in coffee brews), the coffee machine brewing (set at 4 bar) induced higher PAHs release into coffee brews (PAHs content, 0.36-2.14 ng/g). The PAHs amounts of the commercial brewed and canned coffee products were 0.32-1.23 ng/g and 0.16-0.46 ng/g, respectively. The consumption risk of the PAHs in the coffee brews and products is a low level of concern.

Surface plasmons usually take two forms: surface plasmon polaritons (SPP) and localized surface plasmons (LSP). Recent experiments demonstrate an interesting plasmon mode within plasmonic gaps, showing distinct characters from the two usual forms. In this investigation, by introducing a fundamental concept of SPP standing wave and an analytical model, we reveal the nature of the recently reported plasmon modes. The analytical model includes SPP propagating and SPP reflection within a metal-insulator-metal (MIM) cavity, which is rechecked and supplemented by numerical simulations. We systematically analyze SPP standing waves within various nanocavities. During the discussion, some unusual phenomena have been explained. For example, the hot spot of a nanodimer could be off-tip, depending on the order of standing wave mode; and that a nanocube on metal film can be viewed as a nanocube dimer with the same separation. And many other interesting phenomena have been discussed, such as dark mode of SPP standing wave and extraordinary optical transmission. The study gives a comprehensive understanding of SPP standing waves, and may promote the applications of cavity plasmons in ultrasensitive bio-sensings.

Background: With uncontrolled inflammatory progression, acute pancreatitis (AP) can progress to severe acute pancreatitis (SAP). Inflammation and parenchymal cell death are key pathologic responses of AP. Toll-like receptor 4 (TLR4) plays a pro-inflammatory role in AP. Myeloid differentiation primary response protein 88 (MyD88) is the most essential utilized adaptor of TLR4, but its role in AP remains unclear. We investigated the potential role of MyD88 in the pathogenesis of AP., Methods: An AP model was induced by administering either cerulein or L-arginine to wild-type or MyD88-deficient mice. Additionally, receptor-interacting protein kinase 1 (RIP1) inhibitor necrostatin-1 (Nec-1) was administered to the MyD88 -/- mice. The severity of AP was determined by measuring serum amylase and lipase activities, quantifying pancreatic myeloperoxidase (MPO) activity, and histological examination. The effects of MyD88 deletion on cell death and the inflammatory response were determined by measuring apoptosis, necrosis, and inflammatory cytokines. Western blot was used to assess the necrotic mediators, RIP1 and RIP3., Results: The deletion of MyD88 resulted in more severe acute experimental pancreatitis as assessed by increased amylase and lipase activities, increased pancreatic MPO activity, a reduced anti-inflammatory response, reduced apoptosis, and increased necrosis. Additionally, Nec-1 treatment significantly reduced necrosis in the MyD88 -/- mice., Conclusions: The deletion of MyD88 inhibited the TLR4/MyD88-dependent pathway mediated protective immune defense response and enhanced TLR4/MyD88-independent TRIF pathway-mediated pancreatic necrosis, which in turn aggravated the severity of AP. The critical role of MyD88 in immune defense response and cell death indicates that MyD88 represents a potential therapeutic target in the management of AP., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-5134/coif). The authors have no conflicts of interest to declare., (2022 Annals of Translational Medicine. All rights reserved.)

Colon cancer is the third most common cancer and the second leading cause of cancer-related death worldwide. Dysregulated RNA splicing factors have been reported to be associated with tumorigenesis and development in colon cancer. In this study, we interrogated clinical and RNA expression data of colon cancer patients from The Cancer Genome Atlas (TCGA) dataset and the Gene Expression Omnibus (GEO) database. Genes regulating RNA splicing correlated with survival in colon cancer were identified and a risk score model was constructed using Cox regression analyses. In the risk model, RNA splicing factor peroxisome proliferator-activated receptor-γ coactivator-1α (PPARGC1) is correlated with a good survival outcome, whereas Cdc2-like kinase 1(CLK1), CLK2, and A-kinase anchor protein 8-like (AKAP8L) with a bad survival outcome. The risk model has a good performance for clinical prognostic prediction both in the TCGA cohort and the other two validation cohorts. In the tumor microenvironment (TME) analysis, the immune score was higher in the low-risk group, and TME-related pathway gene expression was also higher in low-risk group. We further verified the mRNA and protein expression levels of these four genes in the adjacent nontumor, tumor, and liver metastasis tissues of colon cancer patients, which were consistent with bioinformatics analysis. In addition, knockdown of AKAP8L can suppress the proliferation and migration of colon cancer cells. Animal studies have also shown that AKAP8L knockdown can inhibit tumor growth in colon cancer in vivo. We established a prognostic risk model for colon cancer based on genes related to RNA splicing regulation and uncovered the role of AKAP8L in promoting colon cancer progression., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Male-specific wing spots are usually associated with wing displays in the courtship behavior of Drosophila and may play important roles in sexual selection. Two closely related species, D. nepalensis and D. trilutea, differ in wing spots and scissoring behavior. Here, we compare male morphological characters, pigmentation intensity of male wing spots, wing-scissoring behavior, courtship songs, and reproductive isolation between 2 species. F1 fertile females and sterile males result from the cross between females of D. nepalensis and males of D. trilutea. The pigmentation of wing spots is significantly weaker in D. trilutea than in D. nepalensis and the F1 hybrid. Males scissor both wings in front of the female during courtship, with a posture spreading wings more widely, and at a faster frequency in D. nepalensis than in D. trilutea and the F1s. Males of D. trilutea vibrate wings to produce 2 types (A and B) of pulse songs, whereas D. nepalensis and the F1s sing only type B songs. The incidence of wing vibration and scissoring during courtship suggests that wing vibration is essential but scissoring is a facultative courtship element for successful mating in both species. The association between the darker wing spots with more elaborate scissoring might be the consequence of correlated evolution of these traits in D. nepalensis; however, D. trilutea retains wing scissoring during courtship despite having weaker pigmentation of wing spots. The genetic architecture of 2 traits differs in the F1s, consistent with maternal or sex-linked effects for spots but nonadditive effects for scissoring., (© 2021 Institute of Zoology, Chinese Academy of Sciences.)

Deciphering the crosstalk between RNA-binding proteins and corresponding RNAs will provide a better understanding of gastric cancer (GC) progression. The comprehensive bioinformatics study identified cytoplasmic polyadenylation element-binding protein 3 (CPEB3) might play a vital role in GC progression. Then we found CPEB3 was downregulated in GC and correlated with prognosis. In addition, CPEB3 suppressed GC cell proliferation, invasion and migration in vitro, as well as tumor growth and metastasis in vivo. Mechanistic study demonstrated CPEB3 interacted with 3'-UTR of ADAR1 mRNA through binding to CPEC nucleotide element, and then inhibited its translation by localizing it to processing bodies (P bodies), eventually leading to the suppression of ADAR1-mediated RNA editing. Microscale thermophoresis assay further revealed that the direct interaction between CPEB3 and GW182, the P-body's major component, was through the 440-698AA region of CPEB3 binding to the 403-860AA region of GW182. Finally, AAV9-CPEB3 was developed and administrated in mouse models to assess its potential value in gene therapy. We found AAV9-CPEB3 inhibited GC growth and metastasis. Besides, AAV9-CPEB3 induced hydropic degeneration in mouse liver, but did not cause kidney damage. These findings concluded that CPEB3 suppresses GC progression by inhibiting ADAR1-mediated RNA editing via localizing ADAR1 mRNA to P bodies., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Objective: Neuronal primary cilia are known to be a required organelle for energy balance and leptin action. However, whether primary cilia directly mediate adaptive responses during starvation is yet unknown. Therefore, we investigated the counterregulatory roles of primary cilia, and their related leptin action in energy-depleted condition., Method: We generated leptin receptor (LepR) neuron-specific primary cilia knockout (Ift88 KO LepR ) mice. Leptin-mediated electrophysiological properties of the neurons in fasting condition were assessed using patch-clamp technique. Adaptive responses and neuroendocrine reflexes were measured by monitoring counterregulatory hormones., Results: In fasting state, the leptin-induced neuronal excitability and leptin homeostasis were impaired in Ift88 KO LepR . In addition, the Ift88 KO LepR exhibited aberrant fasting responses including lesser body weight loss, decreased energy expenditure, and lower heat generation compared to wild-type littermates. Furthermore, the primary cilia in LepR neurons are necessary for counterregulatory responses and leptin-mediated neuroendocrine adaptation to starvation., Conclusion: Our results demonstrated that the neuronal primary cilia are crucial neuronal components mediating the adaptive counterregulatory responses to starvation., Competing Interests: Declaration of competing interest All authors declare no competing financial or other interests in relation to this study., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)