Metagenomic investigation of antibiotic resistance genes and resistant bacteria contamination in pharmaceutical plant sites in China.

Pharmaceutical plant sites play a significant role in the dissemination of antibiotic resistance genes (ARGs) into the environment. It is imperative to comprehensively monitor of ARGs across various environmental media at these sites. This study focused on three pharmaceutical plants, two located in North China and one in South China. Through metagenomic approaches, we examined the composition, mobility potential, and bacterial hosts of ARGs in diverse media such as process water, groundwater, topsoil, soil cores, and pharmaceutical fermentation residues across diverse environmental matrices, including topsoil, soil cores, process water, groundwater, and pharmaceutical fermentation residues. We identified a wide array of ARGs, comprising 21 types and 740 subtypes, with process water exhibiting the highest abundance and diversity. Treatment processes varied in their efficacy in eliminating ARGs, and the clinically relevant ARGs should also be considered when evaluating wastewater treatment plant efficiency. Geographical distinctions in groundwater ARG distribution between northern and southern regions were observed. Soil samples from the three sites showed minimal impact from pharmaceutical activity, with vancomycin-resistance genes being the most prevalent. High levels of ARGs in pharmaceutical fermentation residues underscore the necessity for improved waste management practices. Metagenomic assembly revealed that plasmid-mediated ARGs were more abundant than chromosome-mediated ARGs. Metagenome-assembled genomes (MAGs) analysis identified 166 MAGs, with 62 harboring multiple ARGs. Certain bacteria tended to carry specific types of ARGs, revealing distinct host-resistance associations. This study enhances our understanding of ARG dissemination across different environmental media within pharmaceutical plants and underscores the importance of implementing strict regulations for effluent and residue discharge to control ARG spread.

Single-cell analyses reveal evolution mimicry during the specification of breast cancer subtype.

Background: The stem or progenitor antecedents confer developmental plasticity and unique cell identities to cancer cells via genetic and epigenetic programs. A comprehensive characterization and mapping of the cell-of-origin of breast cancer using novel technologies to unveil novel subtype-specific therapeutic targets is still absent. Methods: We integrated 195,144 high-quality cells from normal breast tissues and 406,501 high-quality cells from primary breast cancer samples to create a large-scale single-cell atlas of human normal and cancerous breasts. Potential heterogeneous origin of malignant cells was explored by contrasting cancer cells against reference normal epithelial cells. Multi-omics analyses and both in vitro and in vivo experiments were performed to screen and validate potential subtype-specific treatment targets. Novel biomarkers of identified immune and stromal cell subpopulations were validated by immunohistochemistry in our cohort. Results: Tumor stratification based on cancer cell-of-origin patterns correlated with clinical outcomes, genomic aberrations and diverse microenvironment constitutions. We found that the luminal progenitor (LP) subtype was robustly associated with poor prognosis, genomic instability and dysfunctional immune microenvironment. However, the LP subtype patients were sensitive to neoadjuvant chemotherapy (NAC), PARP inhibitors (PARPi) and immunotherapy. The LP subtype-specific target PLK1 was investigated by both in vitro and in vivo experiments. Besides, large-scale single-cell profiling of breast cancer inspired us to identify a range of clinically relevant immune and stromal cell subpopulations, including subsets of innate lymphoid cells (ILCs), macrophages and endothelial cells. Conclusion: The present single-cell study revealed the cellular repertoire and cell-of-origin patterns of breast cancer. Combining single-cell and bulk transcriptome data, we elucidated the evolution mimicry from normal to malignant subtypes and expounded the LP subtype with vital clinical implications. Novel immune and stromal cell subpopulations of breast cancer identified in our study could be potential therapeutic targets. Taken together, Our findings lay the foundation for the precise prognostic and therapeutic stratification of breast cancer.

Advanced methods for gene network identification and noise decomposition from single-cell data.

Central to analyzing noisy gene expression systems is solving the Chemical Master Equation (CME), which characterizes the probability evolution of the reacting species' copy numbers. Solving CMEs for high-dimensional systems suffers from the curse of dimensionality. Here, we propose a computational method for improved scalability through a divide-and-conquer strategy that optimally decomposes the whole system into a leader system and several conditionally independent follower subsystems. The CME is solved by combining Monte Carlo estimation for the leader system with stochastic filtering procedures for the follower subsystems. We demonstrate this method with high-dimensional numerical examples and apply it to identify a yeast transcription system at the single-cell resolution, leveraging mRNA time-course experimental data. The identification results enable an accurate examination of the heterogeneity in rate parameters among isogenic cells. To validate this result, we develop a noise decomposition technique exploiting time-course data but requiring no supplementary components, e.g., dual-reporters.

Ferrocene Derivatives for Photothermal Applications.

Ferrocene (Fc) and Fc derivatives have gained popularity in recent years due to their unique structure and characteristics. Among Fc's diverse performances, photothermal conversion, as a primary source of energy conversion, has sparked substantial study attention. This review summaries Fc and Fc derivatives with photothermal characteristics, as well as their applications developed recently. First, methods for the synthesis of Fc-based materials are systematically discussed. Then, the photothermal conversion mechanism based on nonradiative relaxation is summarized. Furthermore, the most recent advances in Fc-based materials in photothermal applications are described, including photothermal degradation, photothermal antibacterial, photothermal therapies, photothermal catalysis, solar-driven water production, and photothermal CO2 separation. Finally, a summary and insights on the photothermal application of Fc-based materials are provided. This paper seeks to provide researchers with a better knowledge of photothermal behavior while also highlighting the potential of Fc and its derivatives in photothermal fields.

Composite water value: A way forward to balance the development and protection of transboundary lakes.

Transboundary lakes are shared by multiple administrative regions. The key to balance the development and protection of transboundary lakes is to properly measure the value of water resources. Most of previous studies on the measurement of lake water resources value have not fully considered the ecosystem service function. This paper proposes a new concept "composite water value" to measure the value of transboundary lakes by integrating the external runoff value and the internal runoff value of water resources. The study constructs a composite water value measurement system for transboundary lakes, further analyzes its influencing factors,and applies the system to the case of Nansi Lake, a representative transboundary lake in eastern China. The results show that: (1) The composite water value of lakes is influenced by various factors, including industrial structure, water withdrawal, and water use methods, which impact the external runoff water value; meanwhile, the composite water quality and fluctuations in lake level are closely associated with the internal runoff water value. From 2008 to 2021, the average annual composite water value of Nansi Lake was 39.628 billion yuan, exhibiting a "rising-falling-fluctuating rising" trend due to pollution control policies, reduced precipitation, and enhanced water-saving technologies successively. (2) From a long-term perspective, it is necessary to focus on the internal runoff water use value of lakes. The internal runoff water value of Nansi Lake has been over 75% of the composite water value, and flood storage and water conservation are important manifestations of its ecosystem service value. (3) The external runoff water value of lake is closely related to the internal runoff water value, and relevant departments need to consider the balance between the water withdrawal of multiple cities along the lake and the retained water volume of the lake to achieve the maximum benefit of composite water value.

Comprehensive single-cell and bulk RNA-seq analyses reveal a novel CD8+ T cell-associated prognostic signature in ovarian cancer.

CD8+ T cells play pivotal roles in combating intracellular pathogens and eliminating malignant cells in cancer. However, the prognostic role of CD8+ T cells in ovarian carcinoma is insufficiently exploited. Herein, through univariate Cox regression along with least absolute shrinkage and selection operator (LASSO) regression analyses, we developed a novel prognostic model based on CD8+ T cell markers identified by single-cell sequencing (scRNA-seq) analyses. Patient grouping by the median risk score reveals an excellent prognostic efficacy of this model in both training and validation cohorts. Of note, patients classified as low-risk group exhibit a dramatically improved prognosis. In addition, higher enrichment level of immune-related pathways and increased infiltration level of multiple immune cells are found in patients with lower risk score. Importantly, low-risk patients also exhibited higher response rate to immunotherapies. Summarily, this developed CD8+ T cell-associated prognostic model serves as an excellent predictor for clinical outcomes and aids in guiding therapeutic strategy choices for ovarian cancer patients.

One-step chemical vapor deposition synthesis of Si NWs@C core/shell anodes without additional catalysts by the oxide-assisted growth mechanism for lithium-ion batteries.

Si NWs@C core/shell anodes for lithium-ion batteries were synthesized via a one-step environmental-pressure chemical vapor deposition (CVD) process utilizing nano-silicon and methane as raw materials. In this structure, the silicon nanowire core is obtained by controlling the temperature above 900 °C to catalyze the growth of nano-silicon particles coated with a natural oxide layer according to the oxide-assisted growth (OAG) mechanism, while the carbon as a protective coating shell is derived from methane cracking. In contrast to the conventional nanowire catalytic approach, this method obviates the addition of metal catalysts while ensuring a straightforward and scalable process. This Si NWs@C electrode displayed excellent electrochemical performance, exhibiting high reversible capacity (745.8 mA h g-1) and excellent cycling stability (91.3% after 100 cycles at 0.5 A g-1).

METTL5 promotes gastric cancer progression via sphingomyelin metabolism.

BACKGROUND: The treatment of gastric cancer (GC) has caused an enormous social burden worldwide. Accumulating studies have reported that N6-methyladenosine (m6A) is closely related to tumor progression. METTL5 is a m6A methyltransferase that plays a pivotal role in maintaining the metabolic stability of cells. However, its aberrant regulation in GC has not been fully elucidated. AIM: To excavate the role of METTL5 in the development of GC. METHODS: METTL5 expression and clinicopathological characteristics were analyzed via The Cancer Genome Atlas dataset and further verified via immunohistochemistry, western blotting and real-time quantitative polymerase chain reaction in tissue microarrays and clinical samples. The tumor-promoting effect of METTL5 on HGC-27 and AGS cells was explored in vitro by Cell Counting Kit-8 assays, colony formation assays, scratch healing assays, transwell assays and flow cytometry. The tumor-promoting role of METTL5 in vivo was evaluated in a xenograft tumor model. The EpiQuik m6A RNA Methylation Quantification Kit was used for m6A quantification. Next, liquid chromatography-mass spectrometry was used to evaluate the association between METTL5 and sphingomyelin metabolism, which was confirmed by Enzyme-linked immunosorbent assay and rescue tests. In addition, we investigated whether METTL5 affects the sensitivity of GC cells to cisplatin via colony formation and transwell experiments. RESULTS: Our research revealed substantial upregulation of METTL5, which suggested a poor prognosis of GC patients. Increased METTL5 expression indicated distant lymph node metastasis, advanced cancer stage and pathological grade. An increased level of METTL5 correlated with a high degree of m6A methylation. METTL5 markedly promotes the proliferation, migration, and invasion of GC cells in vitro. METTL5 also promotes the growth of GC in animal models. METTL5 knockdown resulted in significant changes in sphingomyelin metabolism, which implies that METTL5 may impact the development of GC via sphingomyelin metabolism. In addition, high METTL5 expression led to cisplatin resistance. CONCLUSION: METTL5 was found to be an oncogenic driver of GC and may be a new target for therapy since it facilitates GC carcinogenesis through sphingomyelin metabolism and cisplatin resistance.

Therapeutic targeting of white adipose tissue metabolic dysfunction in obesity: mechanisms and opportunities.

White adipose tissue is not only a highly heterogeneous organ containing various cells, such as adipocytes, adipose stem and progenitor cells, and immune cells, but also an endocrine organ that is highly important for regulating metabolic and immune homeostasis. In individuals with obesity, dynamic cellular changes in adipose tissue result in phenotypic switching and adipose tissue dysfunction, including pathological expansion, WAT fibrosis, immune cell infiltration, endoplasmic reticulum stress, and ectopic lipid accumulation, ultimately leading to chronic low-grade inflammation and insulin resistance. Recently, many distinct subpopulations of adipose tissue have been identified, providing new insights into the potential mechanisms of adipose dysfunction in individuals with obesity. Therefore, targeting white adipose tissue as a therapeutic agent for treating obesity and obesity-related metabolic diseases is of great scientific interest. Here, we provide an overview of white adipose tissue remodeling in individuals with obesity including cellular changes and discuss the underlying regulatory mechanisms of white adipose tissue metabolic dysfunction. Currently, various studies have uncovered promising targets and strategies for obesity treatment. We also outline the potential therapeutic signaling pathways of targeting adipose tissue and summarize existing therapeutic strategies for antiobesity treatment including pharmacological approaches, lifestyle interventions, and novel therapies.

LiCl in situ decorated metal-organic framework (MOF)-derived porous carbon for efficient solar-driven atmospheric water harvesting.

Solar-powered sorption-based atmospheric water harvesting (AWH) technology is a promising solution to the freshwater scarcity in arid regions. Existing adsorbent materials still face challenges in aspects such as cycling stability and adsorption kinetics and require further development. Herein, we presented a strategy for the in situ fabrication of high-performance adsorbents, lithium chloride (LiCl)-decorated metal-organic framework (MOF)-derived porous carbon sorbents (PCl), via high-temperature pyrolysis and hydrogen chloride (HCl) vapor treatment. The sorbents display high adsorption capacity across a wide range of humidity water adsorption capacities in a wide humidity range with the maximum adsorption capacity of 7.87 g g-1, and rapid response to the solar-driven process and excellent cyclic stability. The LiCl nanocrystals in PCl can be utilized efficiently and decorated within the porous framework stably, and demonstrate water adsorption at 20%, 40%, 60% and 80% RH, of 1.34, 1.69, 2.56 and 4.23 gH2O·gLiCl-1, respectively, and significantly higher water uptake and release rates than bulk LiCl. This may provide new guides for designing efficient solar-driven AWH.

Cancer-associated fibroblast-derived gene signature discriminates distinct prognoses by integrated single-cell and bulk RNA-seq analyses in breast cancer.

BACKGROUND: Cancer-associated fibroblasts (CAFs) are one of the most predominant cellular subpopulations in the tumor stroma and play an integral role in cancer occurrence and progression. However, the prognostic role of CAFs in breast cancer remains poorly understood. METHODS: We identified a number of CAF-related biomarkers in breast cancer by combining single-cell and bulk RNA-seq analyses. Based on univariate Cox regression as well as Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis, a novel CAF-associated prognostic model was developed. Breast cancer patients were grouped according to the median risk score and further analyzed for outcome, clinical characteristic, pathway activity, genomic feature, immune landscape, and drug sensitivity. RESULTS: A total of 341 CAF-related biomarkers were identified from single-cell and bulk RNA-seq analyses. We eventually screened eight candidate prognostic genes, including CERCAM, EMP1, SDC1, PRKG1, XG, TNN, WLS, and PDLIM4, and constructed the novel CAF-related prognostic model. Grouped by the median risk score, high-risk patients showed a significantly worse prognosis and exhibited distinct pathway activities such as uncontrolled cell cycle progression, angiogenesis, and activation of glycolysis. In addition, the combined risk score and tumor mutation burden significantly improved the ability to predict patient prognosis. Importantly, patients in the high-risk group had a higher infiltration of M2 macrophages and a lower infiltration of CD8+ T cells and activated NK cells. Finally, we calculated the IC50 for a range of anticancer drugs and personalized the treatment regimen for each patient. CONCLUSION: Integrating single-cell and bulk RNA-seq analyses, we identified a list of compositive CAF-associated biomarkers and developed a novel CAF-related prognostic model for breast cancer. This robust CAF-derived gene signature acts as an excellent predictor of patient outcomes and treatment responses in breast cancer.

Construction of CDKN2A-related competitive endogenous RNA network and identification of GAS5 as a prognostic indicator for hepatocellular carcinoma.

BACKGROUND: Competitive endogenous RNA (ceRNA) is an innovative way of gene expression modulation, which plays a crucial part in neoplasia. However, the intricacy and behavioral characteristics of the ceRNA network in hepatocellular carcinoma (HCC) remain dismal. AIM: To establish a cyclin dependent kinase inhibitor 2A (CDKN2A)-related ceRNA network and recognize potential prognostic indicators for HCC. METHODS: The mutation landscape of CDKN2A in HCC was first explored using the cBioPortal database. Differential expression analysis was implemented between CDKN2Ahigh and CDKN2Alow expression HCC samples. The targeted microRNAs were predicted by lncBasev3.0, and the targeted mRNAs were predicted by miRDB, and Targetscan database. The univariate and multivariate analysis were utilized to identify independent prognostic indicators. RESULTS: CDKN2A was frequently mutated and deleted in HCC. The single-cell RNA-sequencing analysis revealed that CDKN2A participated in cell cycle pathways. The CDKN2A-related ceRNA network-growth arrest specific 5 (GAS5)/miR-25-3p/SRY-box transcription factor 11 (SOX11) was successfully established. GAS5 was recognized as an independent prognostic biomarker, whose overexpression was correlated with a poor prognosis in HCC patients. The association between GAS5 expression and methylation, immune infiltration was explored. Besides, traditional Chinese medicine effective components targeting GAS5 were obtained. CONCLUSION: This CDKN2A-related ceRNA network provides innovative insights into the molecular mechanism of HCC formation and progression. Moreover, GAS5 might be a significant prognostic biomarker and therapeutic target in HCC.

Multiscale Structural Engineering Boosts Piezoelectricity in Na0.5Bi2.5Nb2O9-Based High-Temperature Piezoceramics.

High-temperature piezoelectric materials, which enable the accurate and reliable sensing of physical parameters to guarantee the functional operation of various systems under harsh conditions, are highly demanded. To this end, both large piezoelectricity and high Curie temperature are pivotal figures of merit (FOMs) for high-temperature piezoceramics. Unfortunately, despite intensive pursuits, it remains a formidable challenge to unravel the inverse correlation between these FOMs. Herein, a conceptual material paradigm of multiscale structural engineering was proposed to address this dilemma. The synergistic effects of phase structure reminiscent of a polymorphic phase boundary and refined domain morphology simultaneously contribute to a large piezoelectric coefficient d33 of 30.3 pC/N and a high Curie temperature TC of 740 °C in (LiCeNd) codoped Na0.5Bi2.5Nb2O9 (NBN-LCN) ceramics. More encouragingly, the system has exceptional thermal stability and is nonsusceptible to mechanical loading. This study not only demonstrates that the high-performance and robust NBN-LCN high-temperature piezoceramics hold great potential for implements under harsh conditions but also opens an avenue for integrating antagonistic properties for the enhancement of the collective performance in functional materials.

Airborne antibiotic resistome and microbiome in pharmaceutical factories.

Antimicrobial resistance is considered to be one of the biggest public health problems, and airborne transmission is an important but under-appreciated pathway for the spread of antibiotic resistance genes (ARGs) in the environment. Previous research has shown pharmaceutical factories to be a major source of ARGs and antibiotic resistant bacteria (ARB) in the surrounding receiving water and soil environments. Pharmaceutical factories are hotspots of antibiotic resistance, but the atmospheric transmission and its environmental risk remain more concerns. Here, we conducted a metagenomic investigation into the airborne microbiome and resistome in three pharmaceutical factories in China. Soil (average: 38.45%) and wastewater (average: 28.53%) were major contributors of airborne resistome. ARGs (vanR/vanS, blaOXA, and CfxA) conferring resistance to critically important clinically used antibiotics were identified in the air samples. The wastewater treatment area had significantly higher relative abundances of ARGs (average: 0.64 copies/16S rRNA). Approximately 28.2% of the detected airborne ARGs were found to be associated with plasmids, and this increased to about 50% in the wastewater treatment area. We have compiled a list of high-risk airborne ARGs found in pharmaceutical factories. Moreover, A total of 1,043 viral operational taxonomic units were identified and linked to 47 family-group taxa. Different CRISPR-Cas immune systems have been identified in bacterial hosts in response to phage infection. Similarly, higher phage abundance (average: 2451.70 PPM) was found in the air of the wastewater treatment area. Our data provide insights into the antibiotic resistance gene profiles and microbiome (bacterial and non-bacterial) in pharmaceutical factories and reveal the potential role of horizontal transfer in the spread of airborne ARGs, with implications for human and animal health.

SUMOylation of zebrafish transcription factor Zbtb21 affects its transcription activity.

Background: Post-translational modification by Small Ubiquitin-like MOdifier (SUMO) is an important mechanism to regulate protein activity, protein stability, and localization of substrates. Zbtb21 is a zinc finger and BTB (Broad-complex, Tram-track and Bric à brac) domain-containing transcription factor. Bioinformatic prediction suggests several putative SUMOylated sites in Zbtb21 protein. Methods: Two evolutionarily conserved lysine residues in Zbtb21 protein were mutated alone or in combination to disrupt the binding with SUMO molecules. Western blot and co-immunoprecipitation analyses were performed to detect the SUMOylation state of wild type and mutant Zbtb21 proteins, respectively. Luciferase reporter assays were conducted to evaluate their transcription activities. Meanwhile, immunofluorescence staining was carried out to show their sub-nuclear localizations. Finally, co-immunoprecipitation was performed to detect the interaction between Zbtb21 and its partners. Results: Phylogenetically conserved lysines 419 and 845 of zebrafish Zbtb21 protein can be conjugated with SUMO molecules. SUMOylation does not affect the subcellular localization and protein stability of Zbtb21, as well as the interaction with Zbtb14 or Zbtb21. Nevertheless, luciferase reporter assays revealed that Zbtb21 is a dual-function transcription factor which exerts activation or repression effect on different promoters, and SUMOylation can modulate the transcriptional activity of Zbtb21 in regulating downstream target genes. Hence, Zbtb21 is identified as a novel substrate of SUMOylation, which would be important for its function. Conclusions: Zebrafish Zbtb21 protein can be SUMOylated on lysines 419 and 845, which is evolutionary conserved. SUMOylation affects the dual role of Zbtb21 on transcription.

"Two Mountains concept" leading the green transformation of China's economic society.

The rapid urbanization are serious threats to global sustainable development, making the green transformation of socio-economy and industry a must for global efforts. The theory of ecological and economic harmonization in ecological economics has gained attention. However the Two Mountains concept, i.e., "Lucid waters and lush mountains are invaluable assets", has been mostly neglected as a practical demonstration of the theory. In this study an equal weights method is used to construct an index system for testing the effectiveness of the ongoing practices and demonstrations of the Two Mountains concept, and whether it can achieve the expected green transformation objectives. A total of 421 pilot cases and 208 surrounding non-pilot cases in China from 2010 to 2020 are selected for analysis. The results indicate that: (1) From 2010 to 2020, overall 98.33% of pilots show positive improvement in comprehensive effectiveness; (2) Strong evidence indicate that the positive externality of the demonstrations extends to their surrounding region, mainly manifested in the impact of industrial structure change, inspiring collaboration between cities; (3) Such ambitious green transformation has a significant impact on landscape characteristics, which emphasizes the role of landscape management and monitoring. Therefore, this study proposes an industrial integration framework to enhance the transformation of ecosystem service values, to facilitate transition to a green economy in various regions globally. It provides significant managerial insights and practical expertise. The demonstration of China's Two Mountains concept can offer reliable empirical cases to enrich the theory of ecological economics and global sustainable development.

Role of extracellular vesicles in insulin resistance: Signaling pathways, bioactive substances, miRNAs, and therapeutic potential.

Extracellular vesicles are small lipid bilayer particles that resemble the structure of cells and range in size from 30 to 1000 nm. They transport a variety of physiologically active molecules, such as proteins, lipids, and miRNAs. Insulin resistance (IR) is a pathological disease in which insulin-responsive organs or components become less sensitive to insulin's physiological effects, resulting in decreased glucose metabolism in target organs such as the liver, muscle, and adipose tissue. Extracellular vesicles have received a lot of attention as essential intercellular communication mediators in the setting of IR. This review looks at extracellular vesicles' role in IR from three angles: signaling pathways, bioactive compounds, and miRNAs. Relevant publications are gathered to investigate the induction, inhibition, and bidirectional regulation of extracellular vesicles in IR, as well as their role in insulin-related illnesses. Furthermore, considering the critical function of extracellular vesicles in regulating IR, the study analyzes the practicality of employing extracellular vesicles for medication delivery and the promise of combination therapy for IR.

A fully biodegradable spherical nucleic acid nanoplatform for self-codelivery of doxorubicin and miR122 for innate and adaptive immunity activation.

Facile construction of a fully biodegradable spherical nucleic acid (SNA) nanoplatform is highly desirable for clinical translations but remains rarely explored. We developed herein the first polycarbonate-based biodegradable SNA nanoplatform for self-codelivery of a chemotherapeutic drug, doxorubicin (DOX), and a human liver-specific miR122 for synergistic chemo-gene therapy of hepatocellular carcinoma (HCC). Ring-opening polymerization (ROP) of a carbonate monomer leads to a well-defined polycarbonate backbone for subsequent DOX conjugation to the pendant side chains via acidic pH-cleavage Schiff base links and miR122 incorporation to the chain termini via click coupling, affording an amphiphilic polycarbonate-DOX-miR122 conjugate, PBis-Mpa30-DOX-miR122 that can self-assemble into stabilized SNA. Besides the desired biodegradability, another notable merit of this nanoplatform is the use of miR122 not only for gene therapy but also for enhanced innate immune response. Together with the ICD-triggering effect of DOX, PBis-Mpa30-DOX-miR122 SNA-mediated DOX and miR122 codelivery leads to synergistic immunogenicity enhancement, resulting in tumor growth inhibition value (TGI) of 98.1 % significantly higher than those of the groups treated with only drug or gene in a Hepa1-6-tumor-bearing mice model. Overall, this study develops a useful strategy toward biodegradable SNA construction, and presents a drug and gene-based self-codelivery SNA with synergistic immunogenicity enhancement for efficient HCC therapy. STATEMENT OF SIGNIFICANCE: Facile construction of a fully biodegradable SNA nanoplatform is useful for in vivo applications but remains relatively unexplored likely due to the synthetic challenge. We report herein construction of a polycarbonate-based SNA nanoplatform for co-delivering a chemotherapeutic drug, DOX, and a human liver-specific miR-122 for synergistic HCC treatment. In addition to the desired biodegradability properties, this SNA nanoplatform integrates DOX-triggered ICD and miR-122-enhanced innate immunity for simultaneously activating adaptive and innate immunities, which leads to potent antitumor efficiency with a TGI value of 98.1 % in a Hepa1-6-tumor-bearing mice model.

The azole biocide climbazole induces oxidative stress, inflammation, and apoptosis in fish gut.

Climbazole is an azole biocide that has been widely used in formulations of personal care products. Climbazole can cause developmental toxicity and endocrine disruption as well as gut disturbance in aquatic organisms. However, the mechanisms behind gut toxicity induced by climbazole still remain largely unclear in fish. Here, we evaluate the gut effects by exposing grass carp (Ctenopharyngodon idella) to climbazole at levels ranging from 0.2 to 20 µg/L for 42 days by evaluating gene transcription and expression, biochemical analyses, correlation network analysis, and molecular docking. Results showed that climbazole exposure increased cyp1a mRNA expression and ROS level in the three treatment groups. Climbazole also inhibited Nrf2 and Keap1 transcripts as well as proteins, and suppressed the transcript levels of their subordinate antioxidant molecules (cat, sod, and ho-1), increasing oxidative stress. Additionally, climbazole enhanced NF-κB and iκBα transcripts and proteins, and the transcripts of NF-κB downstream pro-inflammatory factors (tnfα, and il-1ß/6/8), leading to inflammation. Climbazole increased pro-apoptosis-related genes (fadd, bad1, and caspase3), and decreased anti-apoptosis-associated genes (bcl2, and bcl-xl), suggesting a direct reaction to apoptosis. The molecular docking data showed that climbazole could form stable hydrogen bonds with CYP1A. Mechanistically, our findings suggested that climbazole can induce inflammation and oxidative stress through CYP450s/ROS/Nrf2/NF-κB pathways, resulting in cell apoptosis in the gut of grass carp.

Mental health in China: exploring the impacts of built environment, work environment, and subjective perception.

Introduction: The shifting living and working conditions have profound impacts on the residents' mental health. However, current research in this field has not remarkable investigated. Methods: This study used the China Labor-force Dynamic Survey (CLDS) dataset from 2018 and relied on a regression model to examine the effects of the built environment, work environment, and subjective perception on the mental health of Chinese citizens. It also considers the circumstances of both migrants and local residents. Results: This study revealed significant correlations between mental health and greening space rate, road network density, commuting time, work feelings, community trust, economic satisfaction, and other factors. Additionally, the mental health of local residents was shown to be significantly affected by community security, while it shows no significance in migrants. Furthermore, a significant spatial autocorrelation was found in terms of mental health within the central and eastern regions of China. Discussion: The findings of this study offer valuable insights that can be used to facilitate measures aimed at improving the mental health of residents and promoting the development of healthy cities.