Single-cell RNA sequencing reveals the effects of high-fat diet on oocyte and early embryo development in female mice.

BACKGROUND: Obesity is a global health issue with detrimental effects on various human organs, including the reproductive system. Observational human data and several lines of animal experimental data suggest that maternal obesity impairs ovarian function and early embryo development, but the precise pathogenesis remains unclear. METHODS: We established a high-fat diet (HFD)-induced obese female mouse model to assess systemic metabolism, ovarian morphology, and oocyte function in mice. For the first time, this study employed single-cell RNA sequencing to explore the altered transcriptomic landscape of preimplantation embryos at different stages in HFD-induced obese mice. Differential gene expression analysis, enrichment analysis and protein-protein interactions network analysis were performed. RESULTS: HFD-induced obese female mice exhibited impaired glucolipid metabolism and insulin resistance. The ovaries of HFD mice had a reduced total follicle number, an increased proportion of atretic follicles, and irregular granulosa cell arrangement. Furthermore, the maturation rate of embryonic development by in vitro fertilization of oocytes was significantly decreased in HFD mice. Additionally, the transcriptional landscapes of preimplantation embryos at different stages in mice induced by different diets were significantly distinguished. The maternal-to-zygotic transition was also affected by the failure to remove maternal RNAs and to turn off zygotic genome expression. CONCLUSIONS: HFD-induced obesity impaired ovarian morphology and oocyte function in female mice and further led to alterations in the transcriptional landscape of preimplantation embryos at different stages of HFD mice.

Endoplasmic reticulum stress-mediated ferroptosis in granulosa cells contributes to follicular dysfunction of polycystic ovary syndrome driven by hyperandrogenism.

RESEARCH QUESTION: Does hyperandrogenaemia affect the function of ovarian granulosa cells by activating ferroptosis, and could this process be regulated by endoplasmic reticulum stress? DESIGN: Levels of ferroptosis and endoplasmic reticulum stress in granulosa cells were detected in women with and without polycystic ovary syndrome (PCOS) undergoing IVF. Ferroptosis and endoplasmic reticulum stress levels of ovarian tissue and follicle development were detected in control mice and PCOS-like mice models, induced by dehydroepiandrosterone. An in-vitro PCOS model of KGN cells was constructed with testosterone and ferroptosis inhibitor Fer-1. Endoplasmic reticulum stress inhibitor, tauroursodeoxycholate (TUDCA), determined the potential mechanism associated with excessive induction of ferroptosis in granulosa cells related to PCOS, and levels of ferroptosis and endoplasmic reticulum stress were detected. RESULTS: Activation of ferroptosis and endoplasmic reticulum stress occurred in granulosa cells of women with PCOS and the varies of PCOS-like mice. The findings in KGN cells demonstrated that testosterone treatment results in elevation of oxidative stress levels, particularly lipid peroxidation, and intracellular iron accumulation in granulosa cells. The expression of genes and proteins associated with factors related to ferroptosis, mitochondrial membrane potential and ultrastructure showed that testosterone activated ferroptosis, whereas Fer-1 reversed these alterations. During in-vitro experiments, activation of endoplasmic reticulum stress induced by testosterone treatment was detected in granulosa cells. In granulosa cells, TUDCA, an inhibitor of endoplasmic reticulum stress, significantly mitigated testosterone-induced ferroptosis. CONCLUSIONS: Ferroptosis plays a part in reproductive injury mediated by hyperandrogens associated with PCOS, and may be regulated by endoplasmic reticulum stress.

Capping Ligand Engineering Enables Stable CsPbBr3 Perovskite Quantum Dots toward White-Light-Emitting Diodes.

All-inorganic perovskite quantum dots (PeQDs) have sparked extensive research focus on white-light-emitting diodes (WLEDs), but stability and photoluminescence efficiency issues are still remain obstacles impeding their practical application. Here, we reported a facile one-step method to synthesize CsPbBr3 PeQDs at room temperature using branched didodecyldimethylammonium fluoride (DDAF) and short-chain-length octanoic acid as capping ligands. The obtained CsPbBr3 PeQDs have a near-unity photoluminescence quantum yield of 97% due to the effective passivation of DDAF. More importantly, they exhibit much improved stability against air, heat, and polar solvents, maintaining >70% of initial PL intensity. Making use of these excellent optoelectronic properties, WLEDs based on CsPbBr3 PeQDs, CsPbBr1.2I1.8 PeQDs, and blue LEDs were fabricated, which show a color gamut of 122.7% of the National Television System Committee standard, a luminous efficacy of 17.1 lm/W, with a color temperature of 5890 K, and CIE coordinates of (0.32, 0.35). These results indicate that the CsPbBr3 PeQDs have great practical potential in wide-color-gamut displays.

Modeling soybean cultivation suitability in China and its future trends in climate change scenarios.

Soybean is an important source of oil and vegetable protein and plays a key role in agricultural production and economy. A suitability evaluation of soybean cultivation is important for identifying potential soybean planting areas. Based on the raster data of soybean harvest ratio (FSHA) and climate-soil-topography-socio-economy environmental factors, we used MaxEnt to simulate the soybean planting suitability and potential distribution in China and the future trends of soybean cultivation under climate change. Three shared socio-economic paths (SSPs) that set up in the future climate section were considered, including SSP126 (sustainable path), SSP245 (intermediate path), and SSP585 (fossil fuel dominated development path). The result shows that the suitability of soybean cultivation was primarily influenced by elevation, precipitation of warmest quarter, capacity of the clay fraction, slope, portion of primary industry, topsoil gravel content, mean diurnal temperature range and accumulated temperature ≥10 °C. High-suitability and moderate-suitability area are respectively 26.51 Mha and 41.93 Mha in China. High-suitability areas for soybean are mainly concentrated in the Northeast Plain, the North China Plain and the northern parts of the middle and lower Yangtze River plain. There were many provinces with high soybean planting potential but low development degrees, including Hebei, Henan, Shandong, Tianjin, Jilin, Liaoning, Jiangsu, Hubei and Shaanxi. From 2021 to 2060, the total area highly and moderately suitable for soybean cultivation is projected to increase first and then decrease under both SSP126 and SSP245 scenarios. However, it shows a continued upward trend under SSP585, the rising part accounting for more than 10% in the base of historical data. Specifically, under SSP585, the suitability grade in most parts of Northeast China (eastern Inner Mongolia, northern Heilongjiang and western Jilin and Liaoning) will have a general promotion, opposite to the result under SSP126. Moreover, parts of southwest China (Yunnan, Chongqing, northern Guizhou and eastern Sichuan) may be more suitable for soybean cultivation in both scenarios. This study provides a practical reference for current and future soybean planting layout and relative countermeasures.

Effects of Lactobacillus plantarum on intestinal integrity and immune responses of egg-laying chickens infected with Clostridium perfringens under the free-range or the specific pathogen free environment.

BACKGROUND: Necrotic enteritis, which is caused by Clostridium perfringens, has resulted in more than $2 billion losses in the poultry industry every year. Due to the ban of antibiotics in feed industry, alternatives like environment improvement and probiotics have been found to be effective as well. In our study, we aim to explore the protective effect of Lactobacillus plantarum supplementation on CP infected chickens in two environments. RESULTS: The results showed that the Clostridium perfringens administration led to visible and histomorphological gut lesions. In the specific pathogen free or free-range system environment, dietary supplementation with LP obvious increased the ratio of intestinal villus height to crypt depth and the expression of MUC2 mRNA in ileum mucosa, then reduced the mRNA expression level of TNF-α gene in the ileum mucosa. LP treatment significantly reduced the contents of total protein, total superoxide dismutase and glutamic oxaloacetic transaminase in serum of the chickens. CONCLUSIONS: The specific pathogen free environment contributed to the recovery of pre-inflammation of the chickens, and free-range system environment contributed to the repair of damage in the later stages of chicken inflammation. Supplementation of LP in FRS environment was more conducive to the recovery of CP infected in chickens.

The nature of status: Navigating the varied approaches to conceptualizing and measuring status.

Members of small groups fundamentally desire status as status underpins members' self-concept and dictates behavior in groups. Moreover, group members readily orient and update status perceptions that index the social standing of themselves and other members. Yet, our understanding is obscured by variability in how researchers study status. In the current review, we crystallize knowledge regarding the nature of status by characterizing variability in definitions, measures, and analytic frameworks. We advocate a definition of status that draws together attributes of respect, admiration, and voluntary deference. We also distinguish reputational and relational status operationalizations and address implications pertaining to measurement along with downstream decisions involving data management and analysis. We encourage a deliberate approach to ensure congruency in how status is defined, measured, and analyzed within a research program. This review also guides theory and hypothesis generation regarding how status-related processes may vary based on different forms of status or differing contexts.

Distinctions in group members' status naturally arise during group interactions. High status tends to be associated with an array of benefits, such as receiving more respect and attention, enjoying better psychological and physical health, and having greater access to valued resources and opportunities. As such, people fundamentally desire status, vigilantly attend to their own and others' status, and actively pursue status. Status also powerfully influences group functioning. Whereas a consensually formed status hierarchy may provide order and increase coordination, disputes over status rank can undermine cooperation and encourage conflict among group members. Despite the critical role status plays in social interactions, researchers continue to disagree about how status should be defined and studied. Without a consistent definition and a measurement guideline, it is difficult to produce cumulative knowledge regarding when, for whom, and why status is afforded to others, and the consequences of gaining, losing, or threats to one's status. In this review, we advocate a status definition that identifies respect, admiration, and voluntary deference as three essential attributes of status. We also distinguish status that is consensually conferred by a group (i.e., reputational status) from status conferred by a particular group member (i.e., relational status). We conclude this paper by providing a guide of measurement options and data management strategies that are suitable for studying distinctive research questions.

Correlation between ovarian follicular development and Hippo pathway in polycystic ovary syndrome.

BACKGROUND: For women of childbearing age, the biggest problem caused by polycystic ovary syndrome (PCOS) is infertility, which is mainly caused by anovulation, abnormal follicular development, proliferation of small antral follicles, and cystic follicles. The mechanism underlying its occurrence is not clear. The abnormal proliferation and development of follicles in PCOS patients is a complex process, which is affected by many factors. The objective of this study was to investigate the relationship between the Hippo pathway and follicular development in PCOS, and to further explore this relationship by using the YAP inhibitor verteporfin (VP). METHOD: 30 3-week-old BALB/C female rats were randomly divided into control group (n = 10), DHEA group (n = 10) and DHEA + VP group (n = 10). The morphology of ovary and the degree of follicular development were observed by HE staining, and the expression and location of AMH in ovarian follicles were observed by immunofluorescence. The ovarian reserve function index AMH, cell proliferation index PCNA and the ratio of Hippo pathway related proteins MST, LATS, YAP, P-YAP and P-YAP/YAP were detected by Western blot. RESULTS: After dividing 30 3-week-old female mice into control, dehydroepiandrosterone (DHEA; model of PCOS), and DHEA + VP groups, we found that the number of small follicles increased in the DHEA group compared to the control group. Additionally, in the DHEA group compared to the control group, anti-müllerian hormone (AMH; ovarian reserve index) increased, proliferating cell nuclear antigen (PCNA; cell proliferation index) decreased, and upstream (MST and LATS) and downstream (YAP and p-YAP) proteins in the Hippo pathway increased, though the p-YAP/YAP ratio decreased. VP ameliorated the increases in AMH, MST, LATS, YAP and p-YAP, but did not ameliorate the decrease in the p-YAP/YAP ratio. CONCLUSIONS: This study indicates that the increased small follicles in the ovaries and changes in ovarian reserve and cell proliferation may be closely related to Hippo pathway activation. This suggests that the Hippo pathway may be an important pathway affecting the proliferation and development of follicles and the occurrence of PCOS.

CISD2 regulates oxidative stress and mitophagy to maintain the balance of the follicular microenvironment in PCOS.

OBJECTIVES: To observe the CISD2 expression among PCOS patients and to explore its profound impact on the follicular microenvironment. Moreover, we want to elucidate the intricate mechanistic contribution of CISD2 to the onset and progression of PCOS. METHODS: Oxidase NOX2, mitophagy-related proteins, and CISD2 were detected by WB. The changes in mitochondrial structure and quantity were observed by transmission electron microscopy. Mitochondrial and lysosome colocalization was used to detect the changes of mitophagy. MDA kit, GSH and GSSG Assay kit and ROS probe were used to detect oxidative stress damage. RESULTS: We found that CISD2, mitophagy and oxidase in the GCs of PCOS patients were significantly increased. Testosterone stimulation leads to the increase of oxidase, mitophagy, and CISD2 in KGN cells. CISD2 inhibition promoted the increase of mitophagy, and the activation of mitochondria-lysosome binding, while alleviating the oxidative stress. CONCLUSIONS: Inhibition of CISD2 can improve the occurrence of oxidative stress by increasing the level of mitophagy, thus affecting the occurrence and development of PCOS diseases.

Nanotechnology based gas delivery system: a "green" strategy for cancer diagnosis and treatment.

Gas therapy, a burgeoning clinical treatment modality, has garnered widespread attention to treat a variety of pathologies in recent years. The advent of nanoscale gas drug therapy represents a novel therapeutic strategy, particularly demonstrating immense potential in the realm of oncology. This comprehensive review navigates the landscape of gases endowed with anti-cancer properties, including hydrogen (H2), carbon monoxide (CO), carbon dioxide (CO2), nitric oxide (NO), oxygen (O2), sulfur dioxide (SO2), hydrogen sulfide (H2S), ozone (O3), and heavier gases. The selection of optimal delivery vectors is also scrutinized in this review to ensure the efficacy of gaseous agents. The paper highlights the importance of engineering stimulus-responsive delivery systems that enable precise and targeted gas release, thereby augmenting the therapeutic efficiency of gas therapy. Additionally, the review examines the synergistic potential of integrating gas therapy with conventional treatments such as starvation therapy, ultrasound (US) therapy, chemotherapy, radiotherapy (RT), and photodynamic therapy (PDT). It also discusses the burgeoning role of advanced multimodal and US imaging in enhancing the precision of gas therapy applications. The insights presented are pivotal in the strategic development of nanomedicine platforms designed for the site-specific delivery of therapeutic gases, heralding a new era in cancer therapeutics.

Oxidative stress promotes liver fibrosis by modulating the microRNA-144 and SIN3A-p38 pathways in hepatic stellate cells.

Background & Aims: Reactive oxygen species (ROS) act as modulators triggering cellular dysfunctions and organ damage including liver fibrosis in which hepatic stellate cell (HSC) activation plays a key role. Previous studies suggest that microRNA-144 (miR-144) acts as a pro-oxidant molecule; however, whether and how miR-144 affects HSC activation and liver fibrosis remain unknown. Methods: Carbon tetrachloride (CCl4) and bile duct ligation (BDL)-induced experimental liver fibrosis models were used. Hepatic miR-144 expression was analyzed by miRNA in situ hybridization with RNAscope probe. The in vivo effects of silencing or overexpressing miR-144 were examined with an adeno-associated virus 6 (AAV6) carrying miR-144 inhibitor or mimics in fibrotic mouse experimental models. Results: In this study, we demonstrated that ROS treatment significantly upregulated miR-144 in HSCs, which further promoted HSC activation in vitro. Interestingly, miR-144 was preferentially elevated in HSCs of experimental liver fibrosis in mice and in human liver fibrotic tissues. Furthermore, in vivo loss or gain-of-function experiments via AAV6 carrying miR-144 antagomir or agomir revealed that blockade of miR-144 in HSCs mitigated, while overexpression of miR-144 in HSCs accelerated the development of experimental liver fibrosis. Mechanistically, SIN3 transcription regulator family member A (SIN3A), a transcriptional repressor, was identified to be the target of miR-144 in HSCs. MiR-144 downregulated Sin3A, and in line with this result, specific knockdown of Sin3a in HSCs remarkedly activated p38 MAPK signaling pathway to promote HSC activation, eventually exacerbating liver fibrosis. Conclusions: Oxidative stress-driven miR-144 fuels HSC activation and liver fibrogenesis by limiting the SIN3A-p38 axis. Thus, a specific inhibition of miR-144 in HSCs could be a novel therapeutic strategy for the treatment of liver fibrosis.

Preparation and comparison of two medical dressings made from the collagens from fish and bovine.

Collagen is used in medical dressings because of its high hydrophilicity, low immunogenicity, excellent biocompatibility, and degradability. These features can promote cell proliferation and platelet agglomeration. Herein, we studied the preparation of gel dressing by using silver carp skin collagen and bovine collagen as raw materials. Their properties and the application effects of collagen gel dressing were evaluated and compared. The centrifugal stability, rheology, and water-loss rate of silver carp skin collagen gel (SCG) and bovine tendon collagen gel (CTG) were determined. Results showed that the two gels were stable, and SCG had better rheology and ductility than CTG. However, the denaturation temperature and water-retention rate of SCG were slightly lower than those of CTG. Two collagen gels were used in the burn-repair experiment of KM mice. Results showed that the SCG and CTG were consistent with the wound-repair effect of commercially available products for shallow II-degree scald and deep II-degree scald. In the superficial shallow II scald experiment, SCG had a faster healing rate in the first 8 days and a shorter recovery time than CTG. In the deep II-degree scald experiment, the wound-healing rate of SCG on the 14th day reached 94.24%, which was 2 days faster than the recovery time of CTG. Moreover, the skin after wound healing was shallower than the scar produced after CTG treatment. Therefore, SCG had the potential to be used as the medical dressing.

Hyperandrogenism drives ovarian inflammation and pyroptosis: A possible pathogenesis of PCOS follicular dysplasia.

Hyperandrogenemia and persistent chronic inflammation, two main striking features of polycystic ovary syndrome (PCOS), have been proven involved in follicular dysgenesis in PCOS. However, the association between hyperandrogenism and inflammation activation in PCOS is not fully understood. Excess testosterone（T） induces inflammation and pyroptosis activation in a mouse model of PCOS, leading to ovarian dysfunction and fibrosis. Excessive endoplasmic reticulum (ER) stress is present in ovarian granulosa cells (GCs), testosterone-induced PCOS mouse and cellular models. This study found higher levels of interleukin (IL)-1ß, IL-8, IL-17, and IL-18 in the follicular fluid of PCOS patients with hyperandrogenemia undergoing IVF treatment. In addition, pyroptosis in GCs was demonstrated, which was significantly elevated in PCOS patients. To clarify the association of hyperandrogenism, inflammation, and pyroptosis activation in PCOS, dehydroepiandrosterone(DHEA)-treated mouse PCOS model and T-treated KGN cell line were explored for PCOS mechanism. Markers of inflammatory activation and pyroptosis were significantly increased after DHEA treatment in mice and T treatment in KGN cells. In addition, ER stress sensor proteins were increased simultaneously. However, suppression of inflammation by genipin(GP) led to decreased pyroptosis in KGN cells but no variation in ER stress sensor proteins. In contrast, when treated with tauroursodeoxycholic acid(TUDCA) to attenuate ER stress, the markers of inflammatory factors were significantly reduced, accompanied by a reduction in pyroptosis. Our results suggest that persistent hyperandrogenemia of PCOS promotes local inflammatory activation of the ovary, and the imbalanced inflammatory microenvironment leads to pyroptosis of GCs, which is mediated by ER stress activation.

Modulating the tumor immune microenvironment with nanoparticles: A sword for improving the efficiency of ovarian cancer immunotherapy.

With encouraging antitumor effects, immunotherapy represented by immune checkpoint blockade has developed into a mainstream cancer therapeutic modality. However, only a minority of ovarian cancer (OC) patients could benefit from immunotherapy. The main reason is that most OC harbor a suppressive tumor immune microenvironment (TIME). Emerging studies suggest that M2 tumor-associated macrophages (TAMs), T regulatory cells (Tregs), myeloid-derived suppressor cells (MDSCs), and cancer-associated fibroblasts (CAFs) are enriched in OC. Thus, reversing the suppressive TIME is considered an ideal candidate for improving the efficiency of immunotherapy. Nanoparticles encapsulating immunoregulatory agents can regulate immunocytes and improve the TIME to boost the antitumor immune response. In addition, some nanoparticle-mediated photodynamic and photothermal therapy can directly kill tumor cells and induce tumor immunogenic cell death to activate antigen-presenting cells and promote T cell infiltration. These advantages make nanoparticles promising candidates for modulating the TIME and improving OC immunotherapy. In this review, we analyzed the composition and function of the TIME in OC and summarized the current clinical progress of OC immunotherapy. Then, we expounded on the promising advances in nanomaterial-mediated immunotherapy for modulating the TIME in OC. Finally, we discussed the obstacles and challenges in the clinical translation of this novel combination treatment regimen. We believe this resourceful strategy will open the door to effective immunotherapy of OC and benefit numerous patients.

Fungus Pichia kudriavzevii XTY1 and heterotrophic nitrifying bacterium Enterobacter asburiae GS2 cannot efficiently transform organic nitrogen via hydroxylamine and nitrite.

Heterotrophic nitrification is a process of organic nitrogen degradation completed by the participation of heterotrophic nitrifying microorganisms, which can accelerate the nitrogen transformation process. However, the current research mainly focuses on heterotrophic nitrifying bacteria and their ammonium degradation capacities. And there is little accumulation of research on fungi, the main force of heterotrophic nitrification, and their capacities to transform organic nitrogen. In this study, novel heterotrophic nitrifying fungus (XTY1) and bacterium (GS2) were screened and isolated from upland soil, and the strains were identified and registered through GenBank comparison. After 24 h single nitrogen source tests and 15N labeling tests, we compared and preliminarily determined the heterotrophic nitrification capacities and pathways of the two strains. The results showed that XTY1 and GS2 had different transformation capacities to different nitrogen substrates and could efficiently transform organic nitrogen. However, the transformation capacity of XTY1 to ammonium was much lower than that of GS2. The two strains did not pass through NH2OH and NO2 - during the heterotrophic nitrification of organic nitrogen, and mainly generated intracellular nitrogen and low N2O. Other novel organic nitrogen metabolism pathways may be existed, but they remain to be further validated.

Phenotypic and genomic characterization of pathogenic Providencia rettgeri from kuruma shrimp Marsupenaeus japonicus.

Providencia rettgeri has been recognized as a zoonotic pathogen of humans and aquaculture animals and has become a global public health concern. However, scarce information is available on the characterization of pathogenic P. rettgeri from kuruma shrimp Marsupenaeus japonicus. In the present study, a P. rettgeri isolate (KM4) was confirmed as a causative agent of red leg disease in cultured M. japonicus, which showed a median lethal dose (LD50 ) value of 5.01 × 105 CFU·ml-1 and had multiple resistances to aminoglycosides, sulfonamides, and tetracycline antimicrobials used in aquaculture. In addition, the whole genome of isolate KM4 was sequenced and found to consist of a single circular chromosome of 4,378,712 bp and a circular plasmid of 171,394 bp. The genome sequence analysis further revealed the presence of potential virulence and antibiotic resistance genes in isolate KM4, which probably rendered this isolate particularly virulent. To our knowledge, this is the first study to characterize P. rettgeri pathogens from kuruma shrimp infected with red leg disease. The findings of this study can provide novel insights into the presence and distribution of pathogenicity-associated genes in shrimp-pathogenic P. rettgeri.

Non-destructive monitoring of amylose content in rice by UAV-based hyperspectral images.

Amylose content (AC) is an important indicator for rice quality grading. The rapid development of unmanned aerial vehicle (UAV) technology provides rich spectral and spatial information on observed objects, making non-destructive monitoring of crop quality possible. To test the potential of UAV-based hyperspectral images in AC estimation, in this study, observations on five rice cultivars were carried out in eastern China (Zhejiang province) for four consecutive years (from 2017 to 2020). The correlations between spectral and textural variables of UAV-based hyperspectral images at different growth stages (booting, heading, filling, and ripening) and AC (%) were analyzed, and the linear regression models based on spectral variables alone, textural variables alone, and combined spectral and textural variables were established. The results showed that the sensitive bands (P< 0.001) to AC were mainly centered in the green (536∽568 nm) and red regions (630∽660nm), with spectral and textural variables at the ripening stage giving the highest negative correlation coefficient of -0.868 and -0.824, respectively. Models based on combined spectral and textural variables give better estimation than those based on spectral or textural variables alone, characterized by less variables and higher accuracy. The best models using spectral or textural variables alone both involved three growth stages (heading, filling, and ripening), with root mean square error (RMSE) of 1.01% and 1.04%, respectively, while the models based on combined spectral and textural variables have RMSE of 1.04% 0.844% with only one (ripening stage) or two (ripening and filling stages) growth stages involved. The combination of spectral and textural variables of UAV-based hyperspectral images is expected to simplify data acquisition and enhance estimation accuracy in remote sensing of rice AC.

Improvement of TNBC immune checkpoint blockade with a microwave-controlled ozone release nanosystem.

Despite revolutionary achievements have been made in clinical cancer therapy, the immune checkpoint blockade regimen still presents limited efficacy on tumors lack of neoantigens exposure. Here, we designed and synthesized an on-demand microwave-controlled ozone release nanosystem to specifically generate reactive oxygen species in tumor mass. By taking advantage of iRGD modification, the synthesized nanosystem can be specifically enriched in the tumor microenvironment and subsequently internalized by tumor cells. Triggered by the low-power microwave, ozone was released from the nanocarriers and inhibited tumor cell growth in vitro and in vivo. Molecular mechanism investigation further unraveled that the released-ozone induced cytolytic cell death through the rapid generation of reactive oxygen species such as hydroxyl radical. The tumor-specific neoantigen derived from this immunogenic cell death promoted cytotoxic T-lymphocytes infiltration, which provided a fundament for immune checkpoint blockade therapy. In the triple-negative breast cancer animal model, tumor-specific delivery of ozone significantly improved the systematical anti-tumor efficacy of the PD-1 blockade antibody. Notably, tumor-locally confined microwave-controlled release avoided systematic toxicity in the tested animals. Collectively, our nanosystem provides a novel controllable strategy for promoting immune checkpoint blockade therapy, especially in tumor types deficient in infiltrated T-lymphocytes.

Access to Bromo-γ-butenolides via Zwitterion-Catalyzed Rearrangement of Cyclopropene Carboxylic Acids.

γ-Butenolides are useful structural motifs in many pharmaceutically relevant compounds. In particular, halogenated γ-butenolides are attractive building blocks because the halogen handles can readily be manipulated to give various functional molecules. In this study, a catalytic synthesis of halogenated γ-butenolides from cyclopropene carboxylic acids was developed using zwitterionic catalysts and N-haloamides as the halogen sources. The catalytic protocol could also be applied to the synthesis of halogenated pyrrolones by using cyclopropene amides as the starting materials.

Microbiota and metabolome responses in the cecum and serum of broiler chickens fed with plant essential oils or virginiamycin.

This study investigated the cecal microbiota and serum metabolite profile of chickens fed with plant essential oils (PEO) or virginiamycin (VIRG) using high-throughput 16S rRNA gene sequencing and untargeted metabolomics approach. The main aim of this work was to explore the biochemical mechanisms involved in the improved growth performance of antibiotics and their alternatives in animal production. The results showed that both PEO and VIRG treatment significantly increased the relative abundance of phyla Bacteroidetes and decreased the abundance of phyla Firmicutes and genus of Lactobacillus in cecal microbiota of chickens. Compared to the control group (CT group), the relative abundance of genus of Alistipes, unclassified Rikenellaceae, Roseburia, and Anaeroplasma was enriched in the PEO group; that of genus Bacteroides, Lachnospiraceae, and unclassified Enterobacteriaceae was enriched in the cecal microbiota of the VIRG group. Untargeted metabolomics analyses revealed that the PEO treatment modified 102 metabolites and 3 KEGG pathways (primary bile acid biosynthesis and phenylalanine metabolism) in the cecal microbiota, and 81 metabolites and relevant KEGG pathways (fructose and mannose metabolism, biosynthesis of unsaturated fatty acids, and linoleic acid.) in the serum of the chicken. Compared to the CT group, VIRG treatment group differed 217 metabolites and 10 KEGG pathways in cecal contents and 142 metabolites and 7 KEGG pathways in serum of chickens. Pearson's correlation analysis showed that phyla Bacteroidetes and genus of Bacteroides, Alistipes, and unclassified Rikenellaceae (in the VIRG and PE group) were positively correlated with many lipid metabolites. However, phyla Firmicutes and genera Lactobacillus (higher in the CT group) were negatively correlated with the lipid and thymine metabolism, and positively correlated with hydroxyisocaproic acid, cytosine, and taurine. This study shows that dietary supplementation with PEO and VIRG altered the composition and metabolism profile of the cecal microbiota, modified the serum metabolism profile.

Synthesis of the Core Structure of Daphnimacropodines.

Daphniphyllum alkaloids daphnimacropodines A-C possess a highly congested ring system and share a common tetracyclic ring skeleton. To access the challenging chemical structure of daphnimacropodines, a divergent synthetic approach toward their total synthesis is described. A stereoselective synthesis of the core structure of daphnimacropodines has been achieved from a simple diketone building block. Our approach features an intramolecular carbamate aza-Michael addition and a hydropyrrole synthesis via a Au-catalyzed alkyne hydration followed by an aldol condensation, whereas all the other attempts failed.