Single-nucleus RNA-sequencing Reveals a MET+ Oligodendrocyte Subpopulation that Promotes Proliferation of Radiation-Induced Gliomas.

PURPOSE: Radiation-induced gliomas (RIGs) are fatal late complications of radiotherapy, with a median survival time of 6-11 months. RIGs demonstrate unique molecular landscape and may originate from a glial lineage distinct from that of primary malignancies or diffuse midline gliomas (DMGs). This study aimed to explore the intratumoral diversity within RIGs to uncover their cellular origin and characteristics, and enhance our understanding of this uncommon tumor type. METHODS AND MATERIALS: Formalin-fixed, paraffin-embedded samples were collected from two RIGs and two DMGs for single-nucleus RNA sequencing. A detailed analysis was conducted to assess intratumoral heterogeneity and cellular interactions, including gene set enrichment, pseudotime trajectory, and cell communication analyses. Immunofluorescence staining, proliferation assay, and RNA-seq analysis were also applied to validate our findings. RESULTS: Our analysis revealed distinct heterogeneity in oligodendrocytes between the DMG and RIG samples. A unique subpopulation of oligodendrocytes in RIGs, which was characterized by gene encoding mesenchymal-epithelial transition factor (c-MET) and therefore termed MET+ ODs, exhibited characteristics typical of cancer cells, such as increased mitotic activity, cancer-related gene expression, and extensive copy number variations. Cell communication studies indicated that MET+ ODs interact vigorously with G1/S and G2/M cycling cells via the neural cell adhesion molecule (NCAM) signaling pathway, potentially enhancing the proliferation of cycling malignant cells. Integrating our results with existing RNA-seq data further supported our hypothesis. The presence of MET+ ODs in RIGs was confirmed by immunostaining, and activation of the NCAM signaling pathway in vitro significantly promoted the proliferation of RIG tumor cells. Moreover, in-vitro radiation induced the transformation of oligodendrocytes to be more similar to MET+ ODs. CONCLUSIONS: RIGs are characterized by an oligodendrocyte composition distinct from that of DMGs. A specific subpopulation of MET+ ODs in RIGs may be crucial in tumorigenesis and promote the growth of malignant cells. Identifying MET+ ODs offers a valuable target for future clinical surveillance and therapeutic strategies.

Discovery of CYP2E1 as a novel target in rheumatoid arthritis and validation by a new specific CYP2E1 inhibitor.

Considerable evidence indicates that CYP2E1 is associated with a variety of inflammatory diseases. Here we evaluated CYP2E1 as a potential therapeutic target for rheumatoid arthritis (RA) and established the protective effect of a new CYP2E1 inhibitor. Gene-expression datasets were used to analyze the change in expression of CYP2E1 in RA patients; CYP2E1 activity in collagen-induced arthritis (CIA) rats was determined by HPLC. We further evaluated the protective effects of Cyp2e1 knockout and a CYP2E1-specific inhibitor, Q11, synthesized by our group, in CIA and adjuvant-induced arthritis (AIA) rats. The expression of CYP2E1 in synovial tissue was elevated in RA patients and in CIA rats and the activity of CYP2E1 in vivo and in vitro in CIA rats was greater than that of controls. Cyp2e1 knockout significantly reduced the incidence of CIA and alleviated the severity of symptoms. Treatment with different doses of Q11 decreased paw thickness, volume and arthritis scores and reduced the serum levels of IL-6, TNF-α, IL-1ß and MDA, and increased the level of GSH in CIA rats. A similar inhibitory effect was exhibited for Q11 in the AIA rats. Moreover, Q11 significantly impeded proliferation, migration, and invasion of human rheumatoid arthritis synovial fibroblasts cells. Q11 decreased the release of ROS and enhanced Nrf2 nuclear translocation and HO-1 expression in the cell nucleus. Overall, our results indicated that CYP2E1 may be a new target for RA and Q11 has potential protective effects against RA by reducing oxidative stress and opposing the inflammatory response via the ROS/Nrf2/HO-1 signaling pathway.

Micafungin protects mouse heart against doxorubicin-induced oxidative injury via suppressing MALT1-dependent k48-linked ubiquitination of Nrf2.

Oxidative stress contributes greatly to doxorubicin (DOX)-induced cardiotoxicity. Down-regulation of nuclear factor erythroid 2-related factor 2 (Nrf2) is a key factor in DOX-induced myocardial oxidative injury. Recently, we found that mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1)-dependent k48-linked ubiquitination was responsible for down-regulation of myocardial Nrf2 in DOX-treated mice. Micafungin, an antifungal drug, was identified as a potential MALT1 inhibitor. This study aims to explore whether micafungin can reduce DOX-induced myocardial oxidative injury and if its anti-oxidative effect involves a suppression of MALT1-dependent k48-linked ubiquitination of Nrf2. To establish the cardiotoxicity models in vivo and in vitro, mice were treated with a single dose of DOX (15 mg/kg, i.p.) and cardiomyocytes were incubated with DOX (1 µM) for 24 h, respectively. Using mouse model of DOX-induced cardiotoxicity, micafungin (10 or 20 mg/kg) was shown to improve cardiac function, concomitant with suppression of oxidative stress, mitochondrial dysfunction, and cell death in a dose-dependent manner. Similar protective roles of micafungin (1 or 5 µM) were observed in DOX-treated cardiomyocytes. Mechanistically, micafungin weakened the interaction between MALT1 and Nrf2, decreased the k48-linked ubiquitination of Nrf2 while elevated the protein levels of Nrf2 in both DOX-treated mice and cardiomyocytes. Furthermore, MALT1 overexpression counteracted the cardioprotective effects of micafungin. In conclusion, micafungin reduces DOX-induced myocardial oxidative injury via suppression of MALT1, which decreases the k48-linked ubiquitination of Nrf2 and elevates Nrf2 protein levels. Thus, micafungin may be repurposed for treating DOX-induced cardiotoxicity.

[Effects of Replacing Chemical Nitrogen Fertilizer with Organic Fertilizer on Active Organic Carbon Fractions, Enzyme Activities, and Crop Yield in Yellow Soil].

Taking the typical yellow soil in Guizhou as the research object, four treatments were set up： no fertilization （CK）, single application of chemical fertilizer （NP）, 50% organic fertilizer instead of chemical nitrogen fertilizer [1/2（NPM）], and 100% organic fertilizer instead of chemical nitrogen fertilizer （M）. The effects of organic fertilizer instead of chemical nitrogen fertilizer on organic carbon and its active components, soil carbon pool management index, soil enzyme activity, and maize and soybean yield in yellow soil were studied in order to provide theoretical basis for scientific fertilization and soil quality improvement in this area. The results showed that the replacement of chemical nitrogen fertilizer by organic fertilizer significantly increased soil pH, organic carbon （SOC）, total nitrogen （TN） content, and C/N ratio. Compared with those in the CK and NP treatments, the content and distribution ratio of soil active organic carbon components and soil carbon pool management index （CPMI） were improved by replacing chemical nitrogen fertilizer with organic fertilizer, and the effect of replacing chemical nitrogen fertilizer with 50% organic fertilizer was the best. Compared with those in the NP treatment, the 1/2 （NPM） treatment significantly increased the contents of soil readily oxidizable organic carbon （ROC333, ROC167）, dissolved organic carbon （DOC）, and microbial biomass carbon （MBC） by 22.90%, 8.10%, 29.32%, and 23.22%, respectively. Compared with those under the CK and NP treatments, organic fertilizer instead of chemical nitrogen fertilizer increased soil enzyme activities. The activities of catalase, urease, sucrase, and phosphatase in the 1/2 （NPM） treatment were significantly increased by 21.89%, 8.24%, 34.91%, and 18.78%, respectively, compared with those in the NP treatment. Compared with that of the NP treatment, the maize yield of the 1/2 （NPM） and M treatments was significantly increased by 44.15% and 17.39%, respectively. There was no significant difference in soybean yield among different fertilization treatments. Correlation analysis showed that soil SOC was significantly positively correlated with ROC333, ROC167, ROC33, DOC, MBC, and soil active organic carbon components, and CPMI was significantly positively correlated with soil organic carbon and its active components （P<0.01）. Corn yield was significantly positively correlated with soil enzyme activity, CPMI, total organic carbon, and its active components （P<0.05）. Therefore, from the perspective of yield increase and soil fertility, 50% organic fertilizer instead of chemical nitrogen fertilizer was conducive to improving soil quality and soil fertility, which is the key fertilization technology to achieve a high yield of crops in the yellow soil area of Anshun, Guizhou.

Resting-state neural activity and cerebral blood flow alterations in type 2 diabetes mellitus: Insights from hippocampal subfields.

OBJECTIVE: In this study, multimodal magnetic resonance imaging (MRI) imaging was used to deeply analyze the changes of hippocampal subfields perfusion and function in patients with type 2 diabetes mellitus (T2DM), aiming to provide image basis for the diagnosis of hippocampal-related nerve injury in patients with T2DM. METHODS: We recruited 35 patients with T2DM and 40 healthy control subjects (HCs). They underwent resting-state functional MRI (rs-fMRI), arterial spin labeling (ASL) scans, and a series of cognitive tests. Then, we compared the differences of two groups in the cerebral blood flow (CBF) value, amplitude of low-frequency fluctuation (ALFF) value, and regional homogeneity (ReHo) value of the bilateral hippocampus subfields. RESULTS: The CBF values of cornu ammonis area 1 (CA1), dentate gyrus (DG), and subiculum in the right hippocampus of T2DM group were significantly lower than those of HCs. The ALFF values of left hippocampal CA3, subiculum, and bilateral hippocampus amygdala transition area (HATA) were higher than those of HCs in T2DM group. The ReHo values of CA3, DG, subiculum, and HATA in the left hippocampus of T2DM group were higher than those of HCs. In the T2DM group, HbAc1 and FINS were negatively correlated with imaging characteristics in some hippocampal subregions. CONCLUSION: This study indicates that T2DM patients had decreased perfusion in the CA1, DG, and subiculum of the right hippocampus, and the right hippocampus subiculum was associated with chronic hyperglycemia. Additionally, we observed an increase in spontaneous neural activity within the left hippocampal CA3, subiculum, and bilateral HATA regions, as well as an enhanced local neural coordination in the left hippocampal CA3, DG, HATA, and subiculum among patients with type 2 diabetes, which may reflect an adaptive compensation for cognitive decline. However, this compensation may decline with the exacerbation of metabolic disorders.

Entanglement Structure and Information Protection in Noisy Hybrid Quantum Circuits.

In the context of measurement-induced entanglement phase transitions, the influence of quantum noises, which are inherent in real physical systems, is of great importance and experimental relevance. In this Letter, we present a comprehensive theoretical analysis of the effects of both temporally uncorrelated and correlated quantum noises on entanglement generation and information protection. This investigation reveals that entanglement within the system follows q^{-1/3} scaling for both types of quantum noises, where q represents the noise probability. The scaling arises from the Kardar-Parisi-Zhang fluctuation with effective length scale L_{eff}∼q^{-1}. More importantly, the information protection timescales of the steady states are explored and shown to follow q^{-1/2} and q^{-2/3} scaling for temporally uncorrelated and correlated noises, respectively. The former scaling can be interpreted as a Hayden-Preskill protocol, while the latter is a direct consequence of Kardar-Parisi-Zhang fluctuations. We conduct extensive numerical simulations using stabilizer formalism to support the theoretical understanding. This Letter not only contributes to a deeper understanding of the interplay between quantum noises and measurement-induced phase transition but also provides a new perspective to understand the effects of Markovian and non-Markovian noises on quantum computation.

Palmitic acid impairs human and mouse placental function by inhibiting trophoblast autophagy through induction of acyl-coenzyme A-binding protein (ACBP) upregulation.

STUDY QUESTION: Can exposure to palmitic acid (PA), a common saturated fatty acid, modulate autophagy in both human and mouse trophoblast cells through the regulation of acyl-coenzyme A-binding protein (ACBP)? SUMMARY ANSWER: PA exposure before and during pregnancy impairs placental development through mechanisms involving placental autophagy and ACBP expression. WHAT IS KNOWN ALREADY: High-fat diets, including PA, have been implicated in adverse effects on human placental and fetal development. Despite this recognition, the precise molecular mechanisms underlying these effects are not fully understood. STUDY DESIGN, SIZE, DURATION: Extravillous trophoblast (EVT) cell line HTR-8/SVneo and human trophoblast stem cell (hTSC)-derived EVT (hTSCs-EVT) were exposed to PA or vehicle control for 24 h. Female wild-type C57BL/6 mice were divided into PA and control groups (n = 10 per group) and subjected to a 12-week dietary intervention. Afterward, they were mated with male wild-type C57BL/6 mice and euthanized on Day 14 of gestation. Female ACBPflox/flox mice were also randomly assigned to control and PA-exposed groups (each with 10 mice), undergoing the same dietary intervention and mating with ACBPflox/floxELF5-Cre male mice, followed by euthanasia on Day 14 of gestation. The study assessed the effects of PA on mouse embryonic development and placental autophagy. Additionally, the role of ACBP in the pathogenesis of PA-induced placental toxicity was investigated. PARTICIPANTS/MATERIALS, SETTING, METHODS: The findings were validated using real-time PCR, Western blot, immunofluorescence, transmission electron microscopy, and shRNA knockdown approaches. MAIN RESULTS AND THE ROLE OF CHANCE: Exposure to PA-upregulated ACBP expression in both human HTR-8/SVneo cells and hTSCs-EVT, as well as in mouse placenta. PA exposure also induced autophagic dysfunction in HTR-8/SVneo cells, hTSCs-EVT, and mouse placenta. Through studies on ACBP placental conditional knockout mice and ACBP knockdown human trophoblast cells, it was revealed that reduced ACBP expression led to trophoblast malfunction and affected the expression of autophagy-related proteins LC3B-II and P62, thereby impacting embryonic development. Conversely, ACBP knockdown partially mitigated PA-induced impairment of placental trophoblast autophagy, observed both in vitro in human trophoblast cells and in vivo in mice. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: Primary EVT cells from early pregnancy are fragile, limiting research use. Maintaining their viability is tough, affecting data reliability. The study lacks depth to explore PA diet cessation effects after 12 weeks. Without follow-up, understanding postdiet impacts on pregnancy stages is incomplete. Placental abnormalities linked to elevated PA diet in embryos lack confirmation due to absence of control groups. Clarifying if issues stem solely from PA exposure is difficult without proper controls. WIDER IMPLICATIONS OF THE FINDINGS: Consuming a high-fat diet before and during pregnancy may result in complications or challenges in successfully carrying the pregnancy to term. It suggests that such dietary habits can have detrimental effects on the health of both the mother and the developing fetus. STUDY FUNDING/COMPETING INTEREST(S): This work was supported in part by the National Natural Science Foundation of China (82171664, 82301909) and the Natural Science Foundation of Chongqing Municipality of China (CSTB2022NS·CQ-LZX0062, cstc2019jcyj-msxmX0749, and cstc2021jcyj-msxmX0236). The authors declare that they have no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

CARD11-BCL10-MALT1 Complex-Dependent MALT1 Activation Facilitates Myocardial Oxidative Stress in Doxorubicin-Treated Mice via Enhancing k48-Linked Ubiquitination of Nrf2.

Aims: Downregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) contributes to doxorubicin (DOX)-induced myocardial oxidative stress, and inhibition of mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) increased Nrf2 protein level in rat heart suffering ischemia/reperfusion, indicating a connection between MALT1 and Nrf2. This study aims to explore the role of MALT1 in DOX-induced myocardial oxidative stress and the underlying mechanisms. Results: The mice received a single injection of DOX (15 mg/kg, i.p.) to induce myocardial oxidative stress, evidenced by increases in the levels of reactive oxidative species as well as decreases in the activities of antioxidative enzymes, concomitant with a downregulation of Nrf2; these phenomena were reversed by MALT1 inhibitor. Similar phenomena were observed in DOX-induced oxidative stress in cardiomyocytes. Mechanistically, knockdown or inhibition of MALT1 notably attenuated the interaction between Nrf2 and MALT1 and decreased the k48-linked ubiquitination of Nrf2. Furthermore, inhibition or knockdown of calcium/calmodulin-dependent protein kinase II (CaMKII-δ) reduced the phosphorylation of caspase recruitment domain-containing protein 11 (CARD11), subsequently disrupted the assembly of CARD11, B cell lymphoma 10 (BCL10), and MALT1 (CBM) complex, and reduced the MALT1-dependent k48-linked ubiquitination of Nrf2 in DOX-treated mice or cardiomyocytes. Innovation and Conclusion: The E3 ubiquitin ligase function of MALT1 accounts for the downregulation of Nrf2 and aggravation of myocardial oxidative stress in DOX-treated mice, and CaMKII-δ-dependent phosphorylation of CARD11 triggered the assembly of CBM complex and the subsequent activation of MALT1.

Fluorescein-guided surgery in high-grade gliomas: focusing on the eloquent and deep-seated areas.

PURPOSE: The vital function of eloquent and deep brain areas necessitates precise treatment for tumors located in these regions. Fluorescein-guided surgery (FGS) has been widely used for high-grade gliomas (HGGs) resection. Nevertheless, the safety and efficacy of utilizing this technique for resecting brain tumors located in eloquent and deep-seated areas remain uncertain. This study aims to assess the safety and extent of resection of HGGs in these challenging tumors with fluorescein and explore its impact on patient survival. METHODS: A retrospective analysis was conducted on the clinical and radiological data of 67 consecutive patients with eloquent or deep-seated HGGs who underwent surgery between January 2020 and June 2023. Lacroix functional location grade was used to determine the eloquence of the tumors. The comparison between the fluorescence-guided surgery group (FGS, n = 32) and the conventional white-light microscopic surgery group (non-FGS, n = 35) included assessments of extent of resection (EOR), rates of gross total resection (GTR, 100%) and near-total resection (NTR, 99 to 98%), postoperative Neurologic Assessment in Neuro-Oncology (NANO) scores, overall survival (OS), and progression-free survival (PFS), to evaluate the safety and efficacy of fluorescein-guided technology in tumor resection at these specific locations. RESULTS: Baseline of demographics, lesion location, and pathology showed no significant difference between the two groups. GTR of the FGS group was higher than the non-FGS group (84.4% vs. 60.0%, OR 3.60, 95% CI 1.18-10.28, p < 0.05). The FGS group also showed higher GTR + NTR (EOR ≥ 98%) than the non-FGS group (93.8% vs. 65.7%, OR 7.83, 95% CI 1.86-36.85, p < 0.01). 87.0% of eloquent tumors (Lacroix grade III) in the FGS group achieved GTR + NTR, compared to 52.2% of control group (OR 6.11, 95% CI 1.50-22.78, p < 0.05). For deep-seated tumors, the rate of GTR + NTR in the two groups were 91.7% and 53.3%, respectively (OR 9.62, 95% CI 1.05-116.50, p < 0.05). No significant difference of the preoperative NANO score of the two groups was found. The postoperative NANO score of the FGS group was significantly lower than the non-FGS group (2.56 ± 1.29 vs. 3.43 ± 1.63, p < 0.05). Median OS of the FGS group was 4.2 months longer than the non-FGS group despite no statistical difference (18.2 months vs. 14.0 months, HR 0.63, 95% CI 0.36-1.11, p = 0.112), while PSF was found significantly longer in FGS patients than those of the non-FGS group (11.2 months vs. 7.7 months, HR 0.59, 95% CI 0.35-0.99, p < 0.05). CONCLUSION: Sodium fluorescein-guided surgery for high-grade gliomas in eloquent and deep-seated brain regions enables more extensive resection while preserving neurologic function and improve patient survival.

Incorporation of Lactococcus lactis and Chia Mucilage for Improving the Physical and Biological Properties of Gelatin-Based Coating: Application for Strawberry Preservation.

In this work, a gelatin/chia mucilage (GN/CM) composite coating material doped with Lactococcus lactis (LS) was developed for strawberry preservation applications. The results of the scanning electron microscope and Fourier transform infrared spectroscopy stated that the enhanced molecular interaction between the CM and GN matrix strengthened the density and compactness of the GN film. Antifungal results indicated that the addition of LS significantly (p < 0.05) improved the ability of the GN coating to inhibit the growth of Botrytis cinerea (inhibition percentage = 62.0 ± 4.6%). Adding CM significantly (p < 0.05) decreased the water vapour permeability and oxygen permeability of the GN coating by 32.7 ± 4.0% and 15.76 ± 1.89%, respectively. In addition, the incorporated CM also significantly (p < 0.05) improved the LS viability and elongation at break of the film by 13.11 ± 2.05% and 42.58 ± 1.21%, respectively. The GN/CM/LS composite coating material also exhibited an excellent washability. The results of this study indicated that the developed GN/CM/LS coating could be used as a novel active material for strawberry preservation.

HMGB1 regulates autophagy of placental trophoblast through ERK signaling pathway†.

OBJECTIVE: The purpose of this study is to investigate the role of high mobility group protein B1 (HMGB1) in placental development and fetal growth. METHODS: We employed the Cre-loxP recombination system to establish a placenta-specific HMGB1 knockout mouse model. Breeding HMGB1flox/flox mice with Elf5-Cre mice facilitated the knockout, leveraging Elf5 expression in extra-embryonic ectoderm, ectoplacental cone, and trophoblast giant cells at 12.5 days of embryonic development. The primary goal of this model was to elucidate the molecular mechanism of HMGB1 in placental development, assessing parameters such as placental weight, fetal weight, and bone development. Additionally, we utilized lentiviral interference and overexpression of HMGB1 in human trophoblast cells to further investigate HMGB1's functional role. RESULTS: Our findings indicate that the HMGB1flox/floxElf5cre/+ mouse displays fetal growth restriction, characterized by decreased placental and fetal weight and impaired bone development. The absence of HMGB1 inhibits autophagosome formation, impairs lysosomal degradation, and disrupts autophagic flux. Depletion of HMGB1 in human trophoblast cells also suppresses cell viability, proliferation, migration, and invasion by inhibiting the ERK signaling pathway. Overexpression of HMGB1 observed the opposite phenotypes. CONCLUSIONS: HMGB1 participates in the regulation of autophagy through the ERK signaling pathway and affects placental development.

Role of deubiquitinase JOSD2 in the pathogenesis of esophageal squamous cell carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a deadly malignancy with limited treatment options. Deubiquitinases (DUBs) have been confirmed to play a crucial role in the development of malignant tumors. JOSD2 is a DUB involved in controlling protein deubiquitination and influencing critical cellular processes in cancer. AIM: To investigate the impact of JOSD2 on the progression of ESCC. METHODS: Bioinformatic analyses were employed to explore the expression, prognosis, and enriched pathways associated with JOSD2 in ESCC. Lentiviral transduction was utilized to manipulate JOSD2 expression in ESCC cell lines (KYSE30 and KYSE150). Functional assays, including cell proliferation, colony formation, drug sensitivity, migration, and invasion, were performed, revealing the impact of JOSD2 on ESCC cell lines. JOSD2's role in xenograft tumor growth and drug sensitivity in vivo was also assessed. The proteins that interacted with JOSD2 were identified using mass spectrometry. RESULTS: Preliminary research indicated that JOSD2 was highly expressed in ESCC tissues, which was associated with poor prognosis. Further analysis demonstrated that JOSD2 was upregulated in ESCC cell lines compared to normal esophageal cells. JOSD2 knockdown inhibited ESCC cell activity, including proliferation and colony-forming ability. Moreover, JOSD2 knockdown decreased the drug resistance and migration of ESCC cells, while JOSD2 overexpression enhanced these phenotypes. In vivo xenograft assays further confirmed that JOSD2 promoted tumor proliferation and drug resistance in ESCC. Mechanistically, JOSD2 appears to activate the MAPK/ERK and PI3K/AKT signaling pathways. Mass spectrometry was used to identify crucial substrate proteins that interact with JOSD2, which identified the four primary proteins that bind to JOSD2, namely USP47, IGKV2D-29, HSP90AB1, and PRMT5. CONCLUSION: JOSD2 plays a crucial role in enhancing the proliferation, migration, and drug resistance of ESCC, suggesting that JOSD2 is a potential therapeutic target in ESCC.

Synthesis of axially chiral diaryl ethers via NHC-catalyzed atroposelective esterification.

Axially chiral diaryl ethers bearing two potential axes find unique applications in bioactive molecules and catalysis. However, only very few catalytic methods have been developed to construct structurally diverse diaryl ethers. We herein describe an NHC-catalyzed atroposelective esterification of prochiral dialdehydes, leading to the construction of enantioenriched axially chiral diaryl ethers. Mechanistic studies indicate that the matched kinetic resolutions play an essential role in the challenging chiral induction of flexible dual-axial chirality by removing minor enantiomers via over-functionalization. This protocol features mild conditions, excellent enantioselectivity, broad substrate scope, and applicability to late-stage functionalization, and provides a modular platform for the synthesis of axially chiral diaryl ethers and their derivatives.

Network-based analysis identifies potential therapeutic ingredients of Chinese medicines and their mechanisms toward lung cancer.

Lung cancer is one of the most common malignant tumors around the world, which has the highest mortality rate among all cancers. Traditional Chinese medicine (TCM) has attracted increased attention in the field of lung cancer treatment. However, the abundance of ingredients in Chinese medicines presents a challenge in identifying promising ingredient candidates and exploring their mechanisms for lung cancer treatment. In this work, two network-based algorithms were combined to calculate the network relationships between ingredient targets and lung cancer targets in the human interactome. Based on the enrichment analysis of the constructed disease module, key targets of lung cancer were identified. In addition, molecular docking and enrichment analysis of the overlapping targets between lung cancer and ingredients were performed to investigate the potential mechanisms of ingredient candidates against lung cancer. Ten potential ingredients against lung cancer were identified and they may have similar effect on the development of lung cancer. The results obtained from this study offered valuable insights and provided potential avenues for the development of novel drugs aimed at treating lung cancer.

Effect of bromodomain PHD-finger transcription factor (BPTF) on trophoblast epithelial-to-mesenchymal transition.

The trophoblast epithelial-to-mesenchymal transition (EMT) is a procedure related to embryo implantation, spiral artery establishment and fetal-maternal communication, which is a key event for successful pregnancy. Inadequate EMT is one of the pathological mechanisms of recurrent miscarriage (RM). Whole-exome sequencing revealed that the mutation of bromodomain PHD-finger transcription factor (BPTF) was strongly associated with RM. In the present study, the effects of BPTF on EMT and the underlying mechanism were investigated. We found that the expression of BPTF in the villi of RM patients was significantly downregulated. Gene Ontology (GO) analysis revealed that BPTF participated in cell adhesion. The knockdown of BPTF prevented EMT and attenuated trophoblast invasion in vitro. BPTF activated Slug transcription by binding directly to the promoter region of the Slug gene. Interestingly, the protein levels of both Slug and BPTF were decreased in the villous cytotrophoblasts (VCTs) of RM villi. In conclusion, BPTF participates in the regulation of trophoblast EMT by activating Slug expression, suggesting that BPTF defects are an important factor in RM pathogenesis.

Ecological Risk Assessment of Organochlorine Pesticides and Polychlorinated Biphenyls in Coastal Sediments in China.

Although the ecological risk of emerging contaminants is currently a research hotspot in China and abroad, few studies have investigated the ecological risk of pesticide pollutants in Chinese coastal sediments. In this study, nine pesticide pollutants included in the "List of New Key Pollutants for Control (2023 Edition)" issued by the Chinese government were used as the research objects, and the environmental exposure of pesticide pollutants in China's coastal sediments was analyzed. The baseline sediment quality criteria were deduced using the balanced distribution method, and a multi-level ecological risk assessment of pesticides in sediment was performed. The results showed that the nine pesticide pollutants were widespread in Chinese coastal sediments, with concentrations ranging from 0.01 ng·g-1 to 330 ng·g-1. The risk quotient assessment showed that endosulfan and DDT posed medium environmental risks to the Chinese coastal sediment environment, and PCBs posed medium risks in some bays of the East China Sea. The semi-probabilistic, optimized semi-probability evaluation and joint probability curve (JPC) assessments all show that endosulfan and DDT pose a certain degree of risk to the environment.

Novel l-Cysteine Incomplete Degradation Method for Preparation of Procyanidin B2-3'-O-Gallate and Exploration of its in Vitro Anti-inflammatory Activity and in Vivo Tissue Distribution.

In this study, an effective method for preparation of bioactive galloylated procyanidin B2-3'-O-gallate (B2-3'-G) was first developed by incomplete depolymerization of grape seed polymeric procyanidins (PPCs) using l-cysteine (Cys) in the presence of citric acid. The structure-activity relationship of B2-3'-G was further evaluated in vitro through establishing lipopolysaccharide (LPS)-induced inflammation in RAW264.7 cells. The results suggested that the better protective effects of B2-3'-G against inflammation were attributed to its polymerization degree and the introduction of the galloyl group, compared to its four corresponding structural units. In vivo experiments demonstrated that the B2-3'-G prototype was distributed in plasma, small intestine, liver, lung, and brain. Remarkably, B2-3'-G was able to penetrate the blood-brain barrier and appeared to play an important role in improving brain health. Furthermore, a total of 18 metabolites were identified in tissues. Potential metabolic pathways, including reduction, methylation, hydration, desaturation, glucuronide conjugation, and sulfation, were suggested.

Porous borders at the wild-crop interface promote weed adaptation in Southeast Asia.

High reproductive compatibility between crops and their wild relatives can provide benefits for crop breeding but also poses risks for agricultural weed evolution. Weedy rice is a feral relative of rice that infests paddies and causes severe crop losses worldwide. In regions of tropical Asia where the wild progenitor of rice occurs, weedy rice could be influenced by hybridization with the wild species. Genomic analysis of this phenomenon has been very limited. Here we use whole genome sequence analyses of 217 wild, weedy and cultivated rice samples to show that wild rice hybridization has contributed substantially to the evolution of Southeast Asian weedy rice, with some strains acquiring weed-adaptive traits through introgression from the wild progenitor. Our study highlights how adaptive introgression from wild species can contribute to agricultural weed evolution, and it provides a case study of parallel evolution of weediness in independently-evolved strains of a weedy crop relative.

Endoplasmic Reticulum-Targeting Self-Assembly Nanosheets Promote Autophagy and Regulate Immunosuppressive Tumor Microenvironment for Efficient Photodynamic Immunotherapy.

The poor efficiency and low immunogenicity of photodynamic therapy (PDT), and the immunosuppressive tumor microenvironment (ITM) lead to tumor recurrence and metastasis. In this work, TCPP-TER-Zn@RSV nanosheets (TZR NSs) that co-assembled from the endoplasmic reticulum (ER)-targeting photosensitizer TCPP-TER-Zn nanosheets (TZ NSs for short) and the autophagy promoting and indoleamine-(2, 3)-dioxygenase (IDO) inhibitor-like resveratrol (RSV) are fabricated to enhance antitumor PDT. TZR NSs exhibit improved therapeutic efficiency and amplified immunogenic cancer cell death (ICD) by ER targeting PDT and ER autophagy promotion. TZR NSs reversed the ITM with an increase of CD8+ T cells and reduce of immunosuppressive Foxp3 regulatory T cells, which effectively burst antitumor immunity thus clearing residual tumor cells. The ER-targeting TZR NSs developed in this paper presents a simple but valuable reference for high-efficiency tumor photodynamic immunotherapy.

An Efficient Strategy for Constructing Fluorescent Nanoprobes for Prolonged and Accurate Tumor Imaging.

Activatable near-infrared (NIR) fluorescent probes possess advantages of high selectivity, sensitivity, and deep imaging depth, holding great potential in the early diagnosis and prognosis assessment of tumors. However, small-molecule fluorescent probes are largely limited due to the rapid diffusion and metabolic clearance of activated fluorophores in vivo. Herein, we propose an efficient and reproducible novel strategy to construct activatable fluorescent nanoprobes through bioorthogonal reactions and the strong gold-sulfur (Au-S) interactions to achieve an enhanced permeability and retention (EPR) effect, thereby achieving prolonged and high-contrast tumor imaging in vivo. To demonstrate the merits of this strategy, we prepared an activatable nanoprobe, hCy-ALP@AuNP, for imaging alkaline phosphatase (ALP) activity in vivo, whose nanoscale properties facilitate accumulation and long-term retention in tumor lesions. Tumor-overexpressed ALP significantly increased the fluorescence signal of hCy-ALP@AuNP in the NIR region. More importantly, compared with the small-molecule probe hCy-ALP-N3, the nanoprobe hCy-ALP@AuNP significantly improved the distribution and retention time in the tumor, thus improving the imaging window and accuracy. Therefore, this nanoprobe platform has great potential in the efficient construction of biomarker-responsive fluorescent nanoprobes to realize precise tumor diagnosis in vivo.