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Abstract Objective ω-3 polyunsaturated fatty acids (PUFA) are a key modifiable factor in the intervention of type 2 diabetes, yet recommendations for dietary consumption of ω-3 PUFA in type 2 diabetes remain ambiguous and controversial. Here, we revisit the subject in the light of population pharmacokinetic-pharmacodynamic (PPK-PD) modeling and propose a threshold for intake. Research design and methods Plasma levels of ω-3 PUFA and glycosylated hemoglobin (HbA1c) were measured as pharmacokinetic and pharmacodynamic indicator, respectively. The nonlinear mixed effect analysis was used to construct a PPK-PD model for ω-3 PUFA and to quantify the effects of FADS gene polymorphism, age, liver and kidney function, and other covariables. Results Data from 161 patients with type 2 diabetes in the community were modeled in a two-compartment model with primary elimination, and HDL was a statistically significant covariate. The simulation results showed that HbA1c showed a dose-dependent decrease of ω-3 PUFA plasma level. A daily intake of ω-3 PUFA at 0.4 g was sufficient to achieve an HbA1c level of 7% in more than 95% of patients. Conclusions PPK/PD modeling was proposed as a multilevel analytical framework to quantitatively investigate finer aspects of the complex relationship between ω-3 PUFA and type 2 diabetes on genetic and non-genetic influence factors. The results support a beneficial role for ω-3 PUFA in type 2 diabetes and suggested the intake threshold. This new approach may provide insights into the interaction of the two and an understanding of the context in which changes occur.

IntroductionChimeric antigen receptor natural killer (CAR-NK) cells have been found to be successful in treating hematologic malignancies and present potential for usage in solid tumors.MethodsIn this study, we created CD276-targeted CAR-expressing NK cells from pluripotent stem cells (iPSC CD276-targeted CAR-NK cells) and evaluated their cytotoxicity against esophageal squamous cell carcinoma (ESCC) using patient-specific organoid (PSO) models comprising of both CD276-positive and CD276-negative adjacent epithelium PSO models (normal control PSO, NC PSO) as well as primary culture of ESCC cell models. In addition, in vitro and in vivo models such as KYSE-150 were also examined. iPSC NK cells and NK-free media were used as the CAR-free and NK-free controls, respectively.ResultsThe positive CD276 staining was specifically detected on the ESCC membrane in 51.43% (54/105) of the patients of all stages, and in 51.35% (38/74) of stages III and IV. The iPS CD276-targeted CAR-NK cells, comparing with the iPS NK cells and the NK-free medium, exhibited specific and significant cytotoxic activity against CD276-positive ESCC PSO rather than CD276-negative NC PSO, and exhibited significant cytotoxicity against CD276-expressing cultured ESCC cells, as well as against CD276-expressing KYSE-150 in vitro and in BNDG mouse xenograft.DiscussionThe efficacy of the iPSC CD276-targeted CAR-NK cells demonstrated by their successful treatment of CD276-expressing ESCC in a multitude of pre-clinical models implied that they hold tremendous therapeutic potential for treating patients with CD276-expressing ESCC.

Abstract Background Keystone taxa are drivers of microbiome structure and functioning, which may play critical roles in microbiome-level responses to recalcitrant pollution and are a key to bioremediation. However, the characterization and manipulation of such taxa is a major challenge due to the complexity of microbial communities and rapid turnover in both time and space. Here, microcosms were set up with benzo[a]-pyrene (BaP) and/or nitrate based on C-rich, S-rich, and N-limited mangrove sediments as reductive experimental models to trigger and track the turnover of keystone taxa to address this challenge. Results Based on microbial co-occurrence network analysis, two keystone taxa, Sulfurovum and Sulfurimonas, were found to exhibit significant role transitions in different microcosms, where these two taxa played nonkeystone roles with neutral relationships in in situ mangrove sediments. However, Sulfurimonas transitioned to be keystone taxa in nitrate-replenished microcosms and formed a keystone guild with Thioalkalispira. Sulfurovum stood out in BaP-added microcosms and mutualized in a densely polycyclic aromatic hydrocarbon (PAH)-degrader-centric keystone guild with Novosphingobium and Robiginitalea, where 63.25% of added BaP was removed. Under the occurrence of nitrate and BaP, they simultaneously played roles as keystone taxa in their respective guilds but exhibited significant competition. Comparative genomics and metagenome-assembled genome (MAG) analysis was then performed to reveal the metabolic potential of those keystone taxa and to empirically deduce their functional role in keystone guilds. Sulfurimonas possesses a better sense system and motility, indicative of its aggressive role in nitrate acquisition and conversion; Sulfurovum exhibited a better ability for oxidation resistance and transporting nutrients and electrons. High-efficiency thermal asymmetric interlaced polymerase reaction (hiTAIL-PCR) and enhanced green fluorescent protein (eGFP)-labeling approaches were employed to capture and label the BaP key degrader to further experimentally verify the roles of keystone taxa Sulfurovum in the keystone guilds. Observations of the enhancement in reactive oxygen species (ROS) removal, cell growth, and degradation efficiency by co-culture of isolated keystone taxa strains experimentally demonstrated that Sulfurovum contributes to the BaP degradative microbiome against BaP toxicity. Conclusions Our findings suggest that the combined use of co-occurrence network analysis, comparative genomics, and co-culture of captured keystone taxa (3C-strategy) in microbial communities whose structure is strongly shaped by changing environmental factors can characterize keystone taxa roles in keystone guilds and may provide targets for manipulation to improve the function of the microbiome. Video Abstract

IntroductionThe clinical efficacy of CAR-NK cells against CD19-expressing blood cancers has been demonstrated, and they have shown potential for treating solid tumors as well. However, the efficacy of CAR-NK cells for treating human oral tongue squamous cell carcinoma (OTSCC) has not been examined. MethodsWe assessed MUC1 expression in human OTSCC tissue and a cell line using immunohistochemistry and immunofluorescence. We constructed NK cells that express CAR targeted to MUC1 from pluripotent stem cells (iPSC-derived MUC1-targeted CAR-NK cells) and evaluated their effectiveness against OTSCC in vitro using the xCELLigence Real-Time Cell Analysis system and CCK8 assay, and in vivo by measuring xenograft growth daily in BNDG mice treated with MUC1-targeted CAR-NK cells. As controls, we used iPSC-derived NK cells and NK-free media, which were CAR-free and blank, respectively.ResultsMUC1 expression was detected in 79.5% (66/83) of all OTSCC patients and 72.7% (24/33) of stage III and IV. In stage III and IV MUC1 positive OTSCC, 63.6% (21/33) and 48.5% (16/33) patients had a MUC1-positive cancer cell rate of more than 50% and 80%, respectively. The iPSC-derived MUC1-targeted CAR-NK cells exhibited significant cytotoxicity against MUC1-expressing OTSCC cells in vitro, in a time- and dose-dependent manner, and showed a significant inhibitory effect on xenograft growth compared to both the iPSC-derived NK cells and the blank controls. We observed no weight loss, severe hematological toxicity or NK cell-mediated death in the BNDG mice. ConclusionThe MUC1-targeted CAR-NK cells had significant efficacy against human OTSCC, and their promising therapeutic response warrants further clinical trials.

ABSTRACT As an important coastal “blue carbon sink,” mangrove ecosystems contain microbial communities with an as-yet-unknown high species diversity. Exploring the assemblage and structure of sediment microbial communities therein can aid in a better understanding of their ecosystem functioning, such as carbon sequestration and other biogeochemical cycles in mangrove wetlands. However, compared to other biomes, the study of mangrove sediment microbiomes is limited, especially in diverse mangrove ecosystems at a large spatial scale, which may harbor microbial communities with distinct compositions and functioning. Here, we analyzed 380 sediment samples from 13 and 8 representative mangrove ecosystems, respectively, in China and South America and compared their microbial features. Although the microbial community compositions exhibited strong distinctions, the community assemblage in the two locations followed analogous patterns: the assemblages of the entire community, abundant taxa, rare taxa, and generalists were predominantly driven by stochastic processes with significant distance-decay patterns, while the assembly of specialists was more likely related to the behaviors of other organisms in or surrounding the mangrove ecosystems. In addition, co-occurrence and topological network analysis of mangrove sediment microbiomes underlined the dominance of sulfate-reducing prokaryotes in both the regions. Moreover, we found that more than 70% of the keystone and hub taxa were sulfate-reducing prokaryotes, implying their important roles in maintaining the linkage and stability of the mangrove sediment microbial communities. This study fills a gap in the large-scale analysis of microbiome features covering distantly located and diverse mangrove ecosystems. Here, we propose a suggestion to the Mangrove Microbiome Initiative that 16S rRNA sequencing protocols should be standardized with a unified primer to facilitate the global-scale analysis of mangrove microbiomes and further comparisons with the reference data sets from other biomes. Importance Mangrove wetlands are important ecosystems possessing valuable ecological functions for carbon storage, species diversity maintenance, and coastline stabilization. These functions are greatly driven or supported by microorganisms that make essential contributions to biogeochemical cycles in mangrove ecosystems. The mechanisms governing the microbial community assembly, structure, and functions are vital to microbial ecology but remain unclear. Moreover, studying these mechanisms of mangrove microbiomes at a large spatial scale can provide a more comprehensive insight into their universal features and can help untangle microbial interaction patterns and microbiome functions. In this study, we compared the mangrove microbiomes in a large spatial range and found that the assembly patterns and key functional guilds of the Chinese and South American mangrove microbiomes were analogous. The entire communities exhibited significant distance-decay patterns and were strongly governed by stochastic processes, while the assemblage of specialists may be merely associated with the behaviors of the organisms in mangrove ecosystems. Furthermore, our results highlight the dominance of sulfate-reducing prokaryotes in mangrove microbiomes and their key roles in maintaining the stability of community structure and functions.

Objectives: To investigate the prevalence of post-traumatic stress disorder in intensive care unit survivors, and disorder’s correlation with analgesia use. Method: The single-centre retrospective cohort study was conducted at the First Affiliated Hospital of Jinan University, China, and comprised data from February 2021 to January 2022 related to patients of either gender aged 18 years who were admitted to the intensive care unit and were successfully transferred out to the general ward. Post-traumatic stress disorder Checklist-Civilian Version scale was used for follow-up within one month of getting transferred out of intensive care. Data was analysed using Empower Stats. Results: Of the 121 patients with mean age 54.34±18.19 years, 52(43percent) were positive for post-traumatic stress disorder; 32(61.5percent) males and 20(38.5percent) females with mean age 54.48 ± 19.56 years. The remaining 69(57percent) patients were negative; 40(58percent) males and 29(42percent) females with mean age 54.23±17.24 years (p 0.05). The positive rate of re-experiencing symptoms was noted in 68(56.20percent) patients. Analgesia usage was positive in 61(50.4percent) cases and negative in 60(49.6percent) cases. Compared to the non-analgesic group, the risk of post-traumatic stress disorder occurrence in the analgesic group was significantly high (p=0.018). The duration of analgesia usage 24-48h was also significant (p=0.017). Conclusions: There was a high prevalence of post-traumatic stress disorder in intensive care unit survivors, which was affected by the use of analgesics in intensive care settings. Key Words: Post-traumatic stress disorder, PTSD, Analgesics, Intensive care unit.

Gibberellic acids had been proven to improve the fruit quality and storability by delaying deterioration and maintaining the antioxidant system. In this study, the effect of GA3 spraying at different concentrations (10, 20, and 50 mg L−1) on the quality of on-tree preserved ‘Shixia’ longan was examined. Only 50 mg L−1 GA3 significantly delayed the decline of soluble solids (22.0% higher than the control) and resulted in higher total phenolics content (TPC), total flavonoid content (TFC), and phenylalanine ammonia-lyase activity in pulp at the later stages. The widely targeted metabolome analysis showed that the treatment reprogrammed secondary metabolites and up-regulated many tannins, phenolic acids, and lignans during the on-tree preservation. More importantly, the preharvest 50 mg L−1 GA3 spraying (at 85 and 95 days after flowering) led to significantly delayed pericarp browning and aril breakdown, as well as lower pericarp relative conductivity and mass loss at the later stages of room-temperature storage. The treatment also resulted in higher antioxidants in pulp (vitamin C, phenolics, and reduced glutathione) and pericarp (vitamin C, flavonoids, and phenolics). Therefore, preharvest 50 mg L−1 GA3 spraying is an effective method for maintaining the quality and up-regulating antioxidants of longan fruit during both on-tree preservation and room-temperature storage.

Although the effects of phytohormones (mainly salicylic acid) on the storability of longan fruit have been reported, the relationship between postharvest hormone variation and signal transduction and storability remains unexplored. The basis of physiology, biochemistry, hormone content and signalling for the storability difference at room-temperature between ‘Shixia’ and ‘Luosanmu’ longan fruit were examined. ‘Luosanmu’ longan exhibited faster pericarp browning, aril breakdown and rotting during storage. ‘Luosanmu’ pericarp exhibited higher malondialdehyde but faster decreased total phenolics, flavonoid, glutathione, vitamin C, catalase activity and gene expression. Higher H2O2 and malondialdehyde but lower glutathione, glutathione-reductase and peroxidase activities, while higher activities and gene expressions of polygalacturonase, β-galactosidase and cellulose, lower covalent-soluble pectin, cellulose and hemicellulose but higher water-soluble pectin were observed in ‘Luosanmu’ aril. Lower abscisic acid and methyl jasmonate but higher expressions of LOX2, JAZ and NPR1 in pericarp, while higher abscisic acid, methyl jasmonate and salicylic acid together with higher expressions of ABF, JAZ, NPR1 and PR-1 in ‘Luosanmu’ aril were observed. In conclusion, the imbalance between the accumulation and scavenging of active oxygen in ‘Luosanmu’ longan might induce faster lipid peroxidation and senescence-related hormone signalling and further the polymerization of phenolics in pericarp and polysaccharide degradation in aril.

Introduction: The clinical efficacy of CAR-NK cells against CD19-expressing blood cancers has been demonstrated, and they have shown potential for treating solid tumors as well. However, the efficacy of CAR-NK cells for treating human oral tongue squamous cell carcinoma (OTSCC) has not been examined. Methods: We assessed MUC1 expression in human OTSCC tissue and a cell line using immunohistochemistry and immunofluorescence. We constructed NK cells that express CAR targeted to MUC1 from pluripotent stem cells (iPSCderived MUC1-targeted CAR-NK cells) and evaluated their effectiveness against OTSCC in vitro using the xCELLigence Real-Time Cell Analysis system and CCK8 assay, and in vivo by measuring xenograft growth daily in BNDG mice treated with MUC1-targeted CAR-NK cells. As controls, we used iPSC-derived NK cells and NK-free media, which were CAR-free and blank, respectively. Results: MUC1 expression was detected in 79.5% (66/83) of all OTSCC patients and 72.7% (24/33) of stage III and IV. In stage III and IV MUC1 positive OTSCC, 63.6% (21/33) and 48.5% (16/33) patients had a MUC1-positive cancer cell rate of more than 50% and 80%, respectively. The iPSC-derived MUC1-targeted CARNK cells exhibited significant cytotoxicity against MUC1-expressing OTSCC cells in vitro, in a time- and dose-dependent manner, and showed a significant inhibitory effect on xenograft growth compared to both the iPSC-derived NK cells and the blank controls. We observed no weight loss, severe hematological toxicity or NK cell-mediated death in the BNDG mice. Conclusion: The MUC1-targetedCAR-NK cells had significant efficacy against human OTSCC, and their promising therapeutic response warrants further clinical trials. [ABSTRACT FROM AUTHOR]

Bacterial membrane vesicles (BMVs) are crucial biological vehicles for facilitating interspecies and interkingdom interactions. However, the extent and mechanisms of BMV involvement in bacterial-algal communication remain elusive. This study provides evidence of BMVs delivering cargos to targeted microalgae. Membrane vesicles (MVs) from Chitinimonas prasina LY03 demonstrated an algicidal profile similar to strain LY03. Further investigation revealed Tambjamine LY2, an effective algicidal compound, selectively packaged into LY03-MVs. Microscopic imaging demonstrated efficient delivery of Tambjamine LY2 to microalgae Heterosigma akashiwo and Thalassiosira pseudonana through membrane fusion. In addition, the study demonstrated the versatile cargo delivery capabilities of BMVs to algae, including the transfer of MV-carried nucleic acids into algal cells and the revival of growth in iron-depleted microalgae by MVs. Collectively, our findings reveal a previously unknown mechanism by which algicidal bacteria store hydrophobic algicidal compounds in MVs to trigger target microalgae death and highlight BMV potency in understanding and engineering bacterial-algae cross-talk. [ABSTRACT FROM AUTHOR]