Collaborative augmented reconstruction of 3D neuron morphology in mouse and human brains.

Digital reconstruction of the intricate 3D morphology of individual neurons from microscopic images is a crucial challenge in both individual laboratories and large-scale projects focusing on cell types and brain anatomy. This task often fails in both conventional manual reconstruction and state-of-the-art artificial intelligence (AI)-based automatic reconstruction algorithms. It is also challenging to organize multiple neuroanatomists to generate and cross-validate biologically relevant and mutually agreed upon reconstructions in large-scale data production. Based on collaborative group intelligence augmented by AI, we developed a collaborative augmented reconstruction (CAR) platform for neuron reconstruction at scale. This platform allows for immersive interaction and efficient collaborative editing of neuron anatomy using a variety of devices, such as desktop workstations, virtual reality headsets and mobile phones, enabling users to contribute anytime and anywhere and to take advantage of several AI-based automation tools. We tested CAR's applicability for challenging mouse and human neurons toward scaled and faithful data production.

MZT2A serves as a prognostic biomarker and promotes the progression of kidney renal clear cell carcinoma.

MZT2A is a novel core component in the γ-tubulin ring complex and aberrantly expressed in some types of tumors. However, MZT2A expression pattern across different cancers and its role in kidney renal clear cell carcinoma have not been sufficiently investigated. A thorough analysis of MZT2A expression landscape across 33 cancer types was conducted, utilizing 712 normal samples and 9807 tumor samples from TCGA (version 37.0), as well as 5112 normal samples from the GTEx databases. MZT2A's impact on KIRC cell viability and proliferation were evaluated through BrdU assays and monitored by cell imaging readers in MZT2A-expressing plasmid or siRNA-transfected cells. Additionally, the effects of MZT2A on cell apoptosis and cell cycle were detected using flow cytometry and Western blot. WGCNA analysis was employed to construct a co-expression gene network associated with MZT2A expression in KIRC, and Pearson correlation coefficient was utilized to examine the relationships between pairs of genes. MZT2A is overexpressed in 25 out of 33 types of cancer, including KIRC. In KIRC, high level of MZT2A was associated with higher clinical stage progression and poorer patients' survival. Downregulation of MZT2A decreased KIRC cell proliferation, retarded cell cycle and promoted apoptosis, while upregulation of MZT2A produced the opposite effects. WGCNA analysis and in vitro experiments revealed that MZT2A activated PI3K/AKT signaling pathway in KIRC. In all, MZT2A was overexpressed in most types of tumors. MZT2A served as an oncogene in KIRC and might be a potential target for guiding future treatments.

Chiglitazar attenuates high-fat diet-induced nonalcoholic fatty liver disease by modulating multiple pathways in mice.

Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide; however, effective intervention strategies for NAFLD are still unavailable. The present study sought to investigate the efficacy of chiglitazar, a pan-PPAR agonist, in protecting against NAFLD in mice and its underlying molecular mechanism. Male C57BL/6 J mice were fed a high-fat diet (HFD) for 8 weeks to generate NAFLD and the HFD was continued for an additional 10 weeks in the absence or presence of 5 mg/kg/d or 10 mg/kg/d chiglitazar by gavage. Chiglitazar significantly improved dyslipidemia and insulin resistance, ameliorated hepatic steatosis and reduced liver inflammation and oxidative stress in NAFLD mice. RNA-seq revealed that chiglitazar alleviated HFD-induced NAFLD in mice through multiple pathways, including fatty acid metabolism regulation, insulin signaling pathway, and AMPK signaling pathway. This study demonstrated the potential therapeutic effect of chiglitazar on NAFLD. Chiglitazar ameliorated NAFLD by modulating multiple pathways.

D4-Chip Reveals Impaired T Cell Function in Sepsis: Insights from Plasma Microenvironment Analysis and Mitochondrial Targeted Therapy.

BACKGROUND: Sepsis, a systemic inflammation syndrome initiated by infection, poses significant challenges due to its intricate pathophysiology. T cells play a crucial role in combating infections during sepsis. Despite previous observations indicating T cell dysfunction in sepsis, reliable in-vitro detection methods were lacking, and the factors influencing these impairments remained unclear. METHODS: We developed a novel method using the D4-Chip to assess sepsis T cell migration function. This microfluidic platform enabled precise analysis of migration function under controlled conditions. Additionally, We explored the impact of the plasma microenvironment on T cell behavior, along with the redox environment in sepsis, and assessed the potential efficacy of Mitoquinone mesylate (MitoQ), a mitochondrial-targeted drug. RESULTS: Our findings revealed impaired migration function in sepsis T cells compared to healthy controls. Interestingly, sepsis plasma enhanced the migration of healthy T cells, yet incubation with healthy plasma did not fully restore migration impairments in sepsis T cells. Subsequent investigations uncovered a significant increase in NADH/NAD+ levels in sepsis T cells, with healthy T cells exposed to various sepsis plasma conditions also showing elevated NADH/NAD+ levels. Importantly, MitoQ normalized abnormal intracellular NADH/NAD+ levels and enhanced the migration ability of T cells. CONCLUSIONS: Short-term incubation with sepsis plasma does not directly inhibit T cell migration but instead affects T cell function by disrupting the intracellular redox environment. Improving the intracellular redox environment of sepsis patients contributes to restoring impaired migration and proliferation, with MitoQ demonstrating therapeutic potential.

Graphene oxide inhibits the transfer of ARGs in rice by reducing the root endophytic bacterial complexity.

Antibiotic resistance genes (ARGs) as an emerging contaminant have attracted much attention for their transfer in agricultural ecosystems. Meanwhile, graphene oxide (GO), due to its high adsorption capacity and antibacterial properties, poses potential environmental ecological risks to the occurrence of ARGs, bacteria, and plant physiological ecology. However, the impact and mechanism of GO on the transfer of ARGs in host plants remain unclear. Therefore, this study selected rice as the research object and inoculated Bacillus subtilis carrying ARGs to investigate the influence of GO on the migration of ARGs into rice and its microbiological mechanism. The study found that GO had a certain inhibitory effect on the transfer of ARGs in rice. Although GO reduced the rhizosphere pH in rice, leading to a transition in endophytic bacteria from dominance by Burkholderia to dominance by Gordonia, this process did not directly affect the transfer of ARGs in rice. Further analysis of bacterial interactions revealed that GO could inhibit the transfer of ARGs in rice by reducing the network complexity of endophytic bacteria. Additionally, GO inhibited the formation of endophytic bacterial biofilms and mobile elements, which might affect ARGs' migration in rice. This study elucidated the key microbiological ecological processes of GO on the transfer of ARGs in rice, providing fundamental information for the ecological risk assessment of GO.

Maresin1 restrains chronic inflammation and Aß production to ameliorate Alzheimer's disease via modulating ADAM10/17 and its associated neuroprotective signal pathways: A pilot study.

Chronic inflammation is an important pathogenetic factor that leads to the progression of Alzheimer's disease (AD), and specialized pro-resolving lipid mediators (SPMs) play critical role in regulating inflammatory responses during AD pathogenesis. Maresin1 (MaR1) is the latest discovered SPMs, and it is found that MaR1 improves AD cognitive impairment by regulating neurotrophic pathways to protect AD synapses and reduce Aß production, which made MaR1 as candidate agent for AD treatment. Unfortunately, the underlying mechanisms are still largely known. In this study, the AD mice and cellular models were subjected to MaR1 treatment, and we found that MaR1 reduced Aß production to ameliorate AD-related symptoms and increased the expression levels of ADAM10/17, sAPPα and sAPPß to exert its anti-inflammatory role. In addition, as it was determined by Western Blot analysis, we observed that MaR1 could affected the neuroprotective signal pathways. Specifically, MaR1 downregulated p57NTR and upregulated TrkA to activate the p75NTR/TrkA signal pathway, and it could increase the expression levels of p-PI3K and p-Akt, and downregulated p-mTOR to activate the PI3K/AKT/ERK/mTOR pathway. Finally, we verified the role of ADAM10/17 in regulating AD progression, and we found that silencing of ADAM10/17 inactivated the above neuroprotective signal pathways to aggravate AD pathogenesis. In conclusion, MaR1 is verified as potential therapeutic agent for AD by eliminating Aß production, upregulating ADAM10/17, sAPPα and sAPPß, and activating the neuroprotective p75NTR/TrkA pathway and the PI3K/AKT/ERK/mTOR pathway.

Insulin-Like Growth Factor 1 Has the Potential to Be Used as a Diagnostic Tool and Treatment Target for Autism Spectrum Disorders.

Autism spectrum disorder (ASD), a heterogeneous group of neurodevelopmental disorders, is characterized by social impairment and repetitive and stereotypic behaviors. Because of the lack of approved laboratory diagnostic markers and effective therapeutic medications, it is one of the most challenging diseases. Therefore, it is urgent to explore potential diagnosis markers or therapeutic targets. Insulin-like growth factor 1 (IGF-1) is a neurotrophic growth factor that enhances brain development. IGF-1 levels in body fluids are lower in preschool children with ASD than in typically developing children, which may serve as a potential diagnostic marker. In various ASD models associated with genetic or environmental exposure, IGF-1 treatment can improve core symptoms or pathological changes, including neuronal development, neural cell survival, balance of synaptic excitation and inhibition, neuroimmunology, and oxidative stress status. In March 2023 an IGF-1 derivative was approved as the first drug for treating Rett syndrome, an ASD-related neurodevelopmental disorder, to improve fundamental symptoms such as social communication. Thus, in this review, we present accumulating evidence of altered IGF-1 levels in ASD patients and the possible mechanisms, as well as evidence that IGF-1 treatment improves the pathophysiology in various ASD models. IGF-1 has the potential to be an early diagnosis marker and an effective therapeutic for ASD.

Small HBV surface antigen drives regorafenib resistance in HCC via KIAA1429-dependent m6A modification of CCR9.

A substantial body of literature, including our own, points to a connection between hepatitis B virus (HBV) infection and the development of drug resistance in hepatocellular carcinoma (HCC), particularly against sorafenib. However, the influence of HBV on resistance to regorafenib, another therapeutic agent, has been less studied. In this study, we used the GEO database (GSE87630) and clinical samples to demonstrate that C-C motif chemokine receptor 9 (CCR9) was highly expressed in HBV-related HCC and predicted poor overall survival. Its overexpression correlated with HBsAg-positive HCC patients. Both univariate and multivariable Cox regression analysis elucidated CCR9 was an independent risk factor for poor overall survival in HCC patients. Our in vitro findings further revealed that HBV structural proteins, small HBV surface antigen (SHBs), triggered an upregulation of CCR9. Functional assays showed that SHBs enhanced HCC cell proliferation, migration, and invasion, increased ABCB1 and ABCC1 expression, and promoted regorafenib resistance via CCR9. Intriguingly, overexpression of HBV plasmid and an AAV-HBV mouse model both exhibited a significant elevation in global N6-methyladenosine (m6A) levels. Further investigations revealed that SHBs elevated these m6A levels, upregulated CCR9 and stabilized CCR9 mRNA through KIAA1429-mediated m6A modification, with sites 1373 and 1496 on CCR9 mRNA being critical for modification. In conclusion, SHBs promoted HCC progression and regorafenib resistance via KIAA1429-mediated m6A modification of CCR9. Our findings suggested that CCR9 could be a potential prognostic biomarker and a valuable molecular therapeutic target of regorafenib resistance in HBV-related HCC.

Diagnostic efficacy of the contrast-enhanced ultrasound thyroid imaging reporting and data system classification for benign and malignant thyroid nodules.

Background: The contrasted-enhanced ultrasound thyroid imaging reporting and data system (CEUS TI-RADS) is the first international risk stratification system for thyroid nodules based on conventional ultrasound (US) and CEUS. This study aimed to evaluate the diagnostic efficacy of CEUS TI-RADS for benign and malignant thyroid nodules and to assess the related interobserver agreement. Methods: The study recruited 433 patients who underwent thyroid US and CEUS between January 2019 and June 2023 at the Affiliated Hospital of Guangdong Medical University. A retrospective analysis of 467 thyroid nodules confirmed by fine-needle aspiration (FNA) and/or surgery was performed. Further, a CEUS TI-RADS classification was assigned to each thyroid nodule based on the CEUS TI-RADS scoring criteria for the US and CEUS features of the nodule. The nodules were grouped based on their sizes as follows: size ≤1 cm, group A; size >1 and ≤4 cm, group B; and size >4 cm, group C. Multivariate logistic regression was used to analyze independent risk factors for malignant thyroid nodules. Pathological assessment was the reference standard for establishing the sensitivity (SEN), specificity (SPE), accuracy (ACC), positive predictive value (PPV), and negative predictive value (NPV) of CEUS TI-RADS in diagnosing malignant thyroid nodules. The area under the curve (AUC) in the receiver operating characteristic (ROC) curve analysis was used to compare the diagnostic efficacy of the scoring system in predicting malignancy in three groups of nodules. The intragroup correlation coefficient (ICC) was adopted to assess the interobserver agreement of the CEUS TI-RADS score. Results: Out of the 467 thyroid nodules, 262 were malignant and 205 were benign. Logistic regression analysis revealed that the independent risk factors for malignant thyroid nodules included punctate echogenic foci (P<0.001), taller-than-wide shape (P=0.015), extrathyroidal invasion (P=0.020), irregular margins/lobulation (P=0.036), hypoechoicity on US (P=0.038), and hypoenhancement on CEUS (P<0.001). The AUC for the CEUS TI-RADS in diagnosing malignant thyroid nodules was 0.898 for all nodules, 0.795 for group A, 0.949 for group B, and 0.801 for group C, with the optimal cutoff values of the CEUS TI-RADS being 5 points, 6 points, 5 points, and 5 points, respectively. Among these groups of nodules, group B had the highest AUC, with the SEN, SPE, ACC, PPV, and NPV for diagnosing malignant nodules being 95.9%, 88.1%, 92.8%, 92.6%, and 93.2%, respectively. The ICC of the CEUS TI-RADS classification between senior and junior physicians was 0.862 (P<0.001). Conclusions: In summary, CEUS TI-RADS demonstrated significant efficacy in distinguishing thyroid nodules. Nonetheless, there were variations in its capacity to detect malignant nodules across diverse sizes, and it demonstrate optimal performance in 1- to 4-cm nodules. These findings may serve as important insights for clinical diagnoses.

Low-threshold distributed feedback laser based on holographic polymer dispersed liquid crystals through the oriented organic semiconductor films.

A specific optimized configuration for low threshold organic semiconductor laser based on a holographic polymer dispersed liquid crystal (HPDLC) transmission grating was demonstrated. Here the organic semiconductor films and phase separated liquid crystal (LC) molecules were oriented along the direction of the HPDLC grating grooves. The influence of the organic semiconductor chain orientation and the excitation polarization on the optical properties of the materials has been investigated. Especially, when polymer chain orientation, LC molecules and pump light polarization are consistent with the direction of the grating grooves, the performance of the outgoing laser is greatly improved. Up to 9.78% conversion efficiency with a threshold lower to 0.12 µJ/pulse can be obtained, indicating their potential for high-performance organic optoelectronics.

Mesothelin CAR-engineered NK cells derived from human embryonic stem cells suppress the progression of human ovarian cancer in animals.

CAR-NK cell therapy does not require HLA matching and has minimal side effects. However, traditional methods of engineering CARs into human tissue-derived NK cells exhibit heterogeneity, low transduction efficiency, and high manufacturing costs. Here, we provide a reliable approach for generating large-scale and cryopreserved mesothelin (MSLN) CAR-NK cells from human embryonic stem cells (hESCs) as an alternative cell source. We first constructed MSLN CAR-expressing hESCs to reduce CAR engineering costs and subsequently differentiated these stem cells into MSLN CAR-NK cells via an efficient organoid induction system. The MSLN CAR-NK cells exhibit the typical expression patterns of activating receptors, inhibitory receptors, and effector molecules of NK cells. In the presence of tumour cells, the MSLN CAR-NK cells show increased secretion of IFN-γ and TNF-α, as well as elevated CD107a expression level compared with induced NK cells. We cryopreserved the MSLN CAR-NK cells in liquid nitrogen using a clinical-grade freezing medium (CS10) for more than 6 months to mimic an off-the-shelf CAR-NK cell product. The thawed MSLN CAR-NK cells immediately recovered after 48-72-h culture and effectively eliminated ovarian tumour cells, including human primary ovarian tumour cells from patients. The thawed MSLN CAR-NK cells efficiently suppressed ovarian tumour development in vivo and prolonged the survival of tumour-bearing mice. Our study provides insights into the clinical translation of hESC-derived MSLN CAR-NK cells as a promising off-the-shelf cell product.

Yishen Tongbi decoction attenuates inflammation and bone destruction in rheumatoid arthritis by regulating JAK/STAT3/SOCS3 pathway.

Background: Yishen-Tongbi Decoction (YSTB), a traditional Chinese prescription, has been used to improve syndromes of rheumatoid arthritis (RA) for many years. Previous research has shown that YSTB has anti-inflammatory and analgesic properties. However, the underlying molecular mechanism of the anti-RA effects of YSTB remains unclear. Purpose and study design: The purpose of this research was to investigate how YSTB affected mice with collagen-induced arthritis (CIA) and RAW264.7 cells induced with lipopolysaccharide (LPS). Results: The findings show that YSTB could significantly improve the clinical arthritic symptoms of CIA mice (mitigate paw swelling, arthritis score, thymus and spleen indices, augment body weight), downregulated expression of pro-inflammatory cytokines like tumor necrosis factor-alpha (TNF-α), interleukin-1ß (IL-1ß), IL-6 and IL-17, while upregulated the level of anti-inflammatory like IL-10 and transforming growth factor-ß (TGF-ß). Meanwhile, YSTB inhibits bone erosion and reduces inflammatory cell infiltration, synovial proliferation, and joint destruction in CIA mice. In addition, we found that YSTB was able to suppress the LPS-induced inflammation of RAW264.7 cells, which was ascribed to the suppression of nitric oxide (NO) production and reactive oxygen species formation (ROS). YSTB also inhibited the production of inducible nitric oxide synthase and reduced the releases of pro-inflammatory cytokines TNF-α, IL-1ß, and IL-6 in LPS-induced RAW264.7 cells. Furthermore, the phosphorylation expression of JAK2, JAK3, STAT3, p38, ERK and p65 protein could be suppressed by YSTB, while the expression of SOCS3 could be activated. Conclusion: Taken together, YSTB possesses anti-inflammatory and prevention bone destruction effects in RA disease by regulating the JAK/STAT3/SOCS3 signaling pathway.

Population genetic structure of Culex tritaeniorhynchus in different types of climatic zones in China.

BACKGROUND: Culex tritaeniorhynchus is widely distributed in China, from Hainan Island in the south to Heilongjiang in the north, covering tropical, subtropical, and temperate climate zones. Culex tritaeniorhynchus carries 19 types of arboviruses. It is the main vector of the Japanese encephalitis virus (JEV), posing a serious threat to human health. Understanding the effects of environmental factors on Culex tritaeniorhynchus can provide important insights into its population structure or isolation patterns, which is currently unclear. RESULTS: In total, 138 COI haplotypes were detected in the 552 amplified sequences, and the haplotype diversity (Hd) value increased from temperate (0.534) to tropical (0.979) regions. The haplotype phylogeny analysis revealed that the haplotypes were divided into two high-support evolutionary branches. Temperate populations were predominantly distributed in evolutionary branch II, showing some genetic isolation from tropical/subtropical populations and less gene flow between groups. The neutral test results of HNQH (Qionghai) and HNHK(Haikou) populations were negative (P < 0.05), indicating many low-frequency mutations in the populations and that the populations might be in the process of expansion. Moreover, Wolbachia infection was detected only in SDJN (Jining) (2.24%), and all Wolbachia genotypes belonged to supergroup B. To understand the influence of environmental factors on mosquito-borne viruses, we examined the prevalence of Culex tritaeniorhynchus infection in three ecological environments in Shandong Province. We discovered that the incidence of JEV infection was notably greater in Culex tritaeniorhynchus from lotus ponds compared to those from irrigation canal regions. In this study, the overall JEV infection rate was 15.27 per 1000, suggesting the current risk of Japanese encephalitis outbreaks in Shandong Province. CONCLUSIONS: Tropical and subtropical populations of Culex tritaeniorhynchus showed higher genetic diversity and those climatic conditions provide great advantages for the establishment and expansion of Culex tritaeniorhynchus. There are differences in JEV infection rates in wild populations of Culex tritaeniorhynchus under different ecological conditions. Our results suggest a complex interplay of genetic differentiation, population structure, and environmental factors in shaping the dynamics of Culex tritaeniorhynchus. The low prevalence of Wolbachia in wild populations may reflect the recent presence of Wolbachia invasion in Culex tritaeniorhynchus.

Balancing river water pollution and agricultural development: A tradeoff threshold approach.

Balancing environmental protection and social-economic development in agricultural land use management is a dilemma for decision-makers. Based on the modelling of the impacts of land use changes on river water pollution by SWAT model, the tradeoff between tea plantation expansion and river water quality was detected. SWAT model performs well in simulating the non-point source (NPS) pollution in agricultural watershed. The results showed that the tea plantation area expanded dramatically from 44 km2 in 2000 to 169 km2 in 2020 at the high cost of forest land. Consequently, the mean contents of NO3--N and TN have significantly increased by 100% and 91% respectively in the past 20 years. And the NO3--N in river water accounted for over 80% of TN in the tea plantation area. The NO3--N and TN concentrations were positively related with the proportions of tea plantation area (Tea%) at different periods. The high pollution levels of NO3--N and TN are priority control targets for river water quality management. The results indicated that the proportion of tea plantation thresholds lead to abrupt changes in river water quality. When the Tea% exceeded 3.0% in 2000, the probability of N pollution increased sharply. Whereas in 2020, it is suggested that the Tea% should not exceeds 18% to avoid sudden deterioration of water quality. The critical interval value of the Tea% for sudden change in N pollution showed an obvious increase tendency. The accelerating of nutrient pollution in rivers reduced the sensitivity of water quality to tea plantation expansion. Our results can provide new insights and empirical evidence for balancing the tradeoff between agricultural development and river water quality protection by demonstrating the carrying capacity threshold of river water environment for the expansion tea plantation.

Design and Research of a Strain Elastic Element with a Double-Layer Cross Floating Beam for Strain Gauge Wireless Rotating Dynamometers.

Cutting force is one of the most basic signals that can reflect the information of the cutting process, so it is very necessary to study the strain elastic element of strain gauge wireless rotating dynamometers. This paper proposes a strain elastic element with a double-layer cross floating beam that can be applied to the strain gauge wireless rotating dynamometer, which can simultaneously obtain the four-component cutting force/torque information of FX, FY, FZ, and MZ. Based on the proposed strain elastic element, a compact strain gauge wireless rotating dynamometer is designed, which is composed of a tool holder, upper connection flange, strain elastic element, lower connection flange, tool base, and data acquisition and wireless transmission system. The static model of the double-layer cross floating beam on the strain elastic element is established by the segmented rigid body method, and the relationships between the material, force, structural parameters, and the strain and deformation of the floating beam are obtained. The static model is consistent with the finite element solution, which proves the rationality of the static model. Based on the established static model, the sequential quadratic programming algorithm is used to optimize the structural parameters of the double-layer cross floating beam to maximize the sensitivity of the floating beam. The overall structure of the strain elastic element is analyzed by finite element software, and the strain of the structure under simulation conditions is obtained, which provides a reference for subsequent calibration tests and circuit design. The calibration matrix and dynamic performance of the strain elastic element are obtained by the static calibration test, dynamic calibration test, and cutting test. The results show that the proposed strain elastic element has high sensitivity and low cross-sensitivity error, and can be applied to the strain gauge wireless rotating dynamometer to measure medium- and low-speed cutting forces.

Pollution level and ecological risk assessment of triazine herbicides in Laizhou Bay and derivation of seawater quality criteria.

Triazine herbicides are widely used in agriculture and have become common pollutants in marine environments. However, the spatiotemporal distribution characteristics and water quality criteria (WQC) of triazine herbicides are still unclear. This study found that triazine herbicides had a high detection rate of 100 % in surface seawater of Laizhou Bay, China, with average concentrations of 217.61, 225.13, 21.97, and 1296.72 ng/L in March, May, August, and October, respectively. Moreover, estuaries were important sources, and especially the Yellow River estuary exhibited the highest concentrations of 16,115.86 ng/L in October. The 10 triazine herbicides were detected in the sediments of Laizhou Bay, with a concentration ranging from 0.14-1.68 µg/kg. Atrazine and prometryn accounted for 33.41 %-59.10 % and 28.93 %-50.06 % of the total triazine herbicides in the seawater, and prometryn had the highest proportion (63.50 %) in the sediments. Correlation analysis revealed that triazine herbicides led to the loss of plankton biodiversity, which further decreased the dissolved oxygen. In addition, this study collected 45 acute toxicity data and 22 chronic toxicity data of atrazine, 16 acute toxicity data of prometryn, and supplemented with toxicity experiments of prometryn on marine organisms. Based on the toxicity database, the WQCs of atrazine and prometryn were derived using species sensitivity distribution. The overall risk probability of atrazine and prometryn were both less than 1.75 % in the Laizhou Bay, indicating an acceptable risk. This study not only clarified the pollution status and ecological risk of triazine herbicides, but also provided scientific basis for their environmental management standards.

Visual and photoelectrochemical analysis of antibiotic resistance genes enabled by surface-engineered ZIF-8@Au cascade nanozymes.

The aggravation of antibiotic resistance genes (ARGs) in the environment has posed a significant global health crisis. Accurate evaluation of ARGs levels in a facile manner is a pressing issue for environmental surveillance. Here, we demonstrate a unique dumbbell-shaped cascade nanozyme for visual/photoelectrochemical (PEC) dual-mode detection of ARGs. Gold nanoparticles (AuNPs) with tunable exposed facets are controllably anchored onto ZIF-8 dodecahedrons, exhibiting glucose oxidase (GOx)-like (ZIF-8@Au/G) and peroxidase (POD)-like (ZIF-8@Au/P) activities. Upon the occurrence of ARGs, an asymmetric cascade-amplified "dumbbell" configuration is spontaneously generated via target-induced DNA hybridization, comprising GOx-like ZIF-8@Au/G with capture DNA on one side and POD-like ZIF-8@Au/P with signal DNA on the opposite side. Such a cascade nano-system can efficiently oxidize colorless 2, 2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) into its green oxidation state and synergistically decompose H2O2, realizing colorimetric/PEC dual-mode ARGs detection with a detection limit of 0.112 nM. The applicability of the present bioassay is validated through measuring ARGs in real sludge samples. This work suggests the possibility to rationally design task-specific nanozymes and develop target-responsive nano-cascade assays for environmental monitoring.

Discovery of novel quinoline scaffold selective estrogen receptor degraders (SERDs) for treatment of ER positive breast cancer with enhanced antiproliferative bioactivity through immunogenic cell death (ICD) effects.

Combination therapy proven to be an effective therapeutic approach for estrogen receptor (ER)-positive breast cancer. Currently, cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are combined with aromatase inhibitors (AIs) or selective estrogen receptor degraders (SERDs) as first-line therapy for advanced ER-positive breast cancer. Herein, a new family of quinoline scaffold SERDs was synthesized and evaluated in MCF-7 cells. Among them, compounds 18j and 24d exhibited remarkable MCF-7 inhibition, both alone and in combination with ribociclib (CDK4/6 inhibitor), in vitro and in vivo. Meanwhile, compounds 18j and 24d effectively degraded ER and inhibited ER downstream signaling pathways. Interestingly, compounds 18j and 24d induced endoplasmic reticulum stress (ERS) and triggered immunogenic cell death (ICD) via damage-associated molecular patterns (DAMPs) in MCF-7 cells. These findings highlight the immune-related and enhanced antiproliferative effects of oral SERDs in ER positive breast cancer treatment.

CircHIPK3/miR-124 affects angiogenesis in early-onset preeclampsia via CPT1A-mediated fatty acid oxidation.

Multiple theories have been proposed to explain the pathogenesis of early-onset preeclampsia (EOPE), and angiogenic dysfunction is an important part of this pathogenesis. Carnitine palmitoyltransferase (CPT1A) is a key rate-limiting enzyme in the metabolic process of fatty acid oxidation (FAO). FAO regulates endothelial cell (EC) proliferation during vascular germination and is also essential for ab initio deoxyribonucleotide synthesis, but its role in EOPE needs to be further elucidated. In the present study, we investigated its functional role in EOPE by targeting the circHIPK3/miR-124-3p/CPT1A axis. In our study, reduced expression of circHIPK3 and CPT1A and increased expression of miR-124-3p in placental tissues from patients with EOPE were associated with EC dysfunction. Here, we confirmed that CPT1A regulates fatty acid oxidative activity, cell proliferation, and tube formation in ECs by regulating FAO. Functionally, knockdown of circHIPK3 suppressed EC angiogenesis by inhibiting CPT1A-mediated fatty acid oxidative activity, which was ameliorated by CPT1A overexpression. In addition, circHIPK3 regulates CPT1A expression by sponging miR-124-3p. Hence, circHIPK3 knockdown reduced fatty acid oxidation in ECs by sponging miR-124-3p in a CPT1A-dependent manner and inhibited EC proliferation and tube formation, which may have led to aberrant angiogenesis in EOPE. Thus, strategies targeting CPT1A-driven FAO may be promising approaches for the treatment of EOPE. KEY MESSAGES: Decreased Carnitine palmitoyltransferase (CPT1A) expression in preeclampsia(PE). CPT1A overexpression promotes FAO activity and tube formation in ECs. CircHIPK3 can affect CPT1A expression and impaire angiogenesis of EOPE. CircHIPK3 regulates CPT1A expression by acting as a ceRNA of miR-124-3p in HUVECs. Confirming the effect of circHIPK3/miR-124-3p/CPT1A axis on EOPE.

Systematic identification and functional characterization of the CFEM proteins in fishscale bamboo rhombic-spot pathogen Neostagonosporella sichuanensis.

Fungal effectors play a crucial role in the interaction between pathogenic fungi and their hosts. These interactions directly influence the invasion and spread of pathogens, and the development of diseases. Common in fungal extracellular membrane (CFEM) effectors are closely associated with the pathogenicity, cell wall stability, and pathogenic processes of pathogenic fungi. The aim of this study was to investigate the role of CFEM proteins in Neostagonosporella sichuanensis in pathogen-host interactions. We retrieved 19 proteins containing CFEM structural domains from the genome of N. sichuanensis. By systematic analysis, five NsCFEM proteins had signal peptides but lacked transmembrane structural domains, and thus were considered as potential effectors. Among them, NsCFEM1 and NsCFEM2 were successfully cloned and their functions were further investigated. The validation results show that NsCFEM1 was localized in the cell membrane and nucleus, whereas NsCFEM2 was exclusively observed in the cell membrane. Both were identified as secreted proteins. Additionally, NsCFEM1 inhibited Bax-induced programmed cell death in Nicotiana benthamiana, whereas NsCFEM2 did not induce or inhibit this response. NsCFEM1 was implicated as a virulence factor that contributes to fungal growth, development, stress response, and pathogenicity. NsCFEM2 was implicated in maintenance of cell wall stability. This study lays a foundation for elucidating the role of CFEM proteins in the pathogen of fishscale bamboo rhombic-spot caused by N. sichuanensis. In particular, the functional studies of NsCFEM1 and NsCFEM2 revealed their potential roles in the interaction between N. sichuanensis and the host Phyllostachys heteroclada.