Priority sources identification and risks assessment of heavy metal(loid)s in agricultural soils of a typical antimony mining watershed.

Heavy metal(loid) (HM) pollution in agricultural soils has become an environmental concern in antimony (Sb) mining areas. However, priority pollution sources identification and deep understanding of environmental risks of HMs face great challenges due to multiple and complex pollution sources coexist. Herein, an integrated approach was conducted to distinguish pollution sources and assess human health risk (HHR) and ecological risk (ER) in a typical Sb mining watershed in Southern China. This approach combines absolute principal component score-multiple linear regression (APCS-MLR) and positive matrix factorization (PMF) models with ER and HHR assessments. Four pollution sources were distinguished for both models, and APCS-MLR model was more accurate and plausible. Predominant HM concentration source was natural source (39.1%), followed by industrial and agricultural activities (23.0%), unknown sources (21.5%) and Sb mining and smelting activities (16.4%). Although natural source contributed the most to HM concentrations, it did not pose a significant ER. Industrial and agricultural activities predominantly contributed to ER, and attention should be paid to Cd and Sb. Sb mining and smelting activities were primary anthropogenic sources of HHR, particularly Sb and As contaminations. Considering ER and HHR assessments, Sb mining and smelting, and industrial and agricultural activities are critical sources, causing serious ecological and health threats. This study showed the advantages of multiple receptor model application in obtaining reliable source identification and providing better source-oriented risk assessments. HM pollution management, such as regulating mining and smelting and implementing soil remediation in polluted agricultural soils, is strongly recommended for protecting ecosystems and humans.

Knowledge graph construction for heart failure using large language models with prompt engineering.

Introduction: Constructing an accurate and comprehensive knowledge graph of specific diseases is critical for practical clinical disease diagnosis and treatment, reasoning and decision support, rehabilitation, and health management. For knowledge graph construction tasks (such as named entity recognition, relation extraction), classical BERT-based methods require a large amount of training data to ensure model performance. However, real-world medical annotation data, especially disease-specific annotation samples, are very limited. In addition, existing models do not perform well in recognizing out-of-distribution entities and relations that are not seen in the training phase. Method: In this study, we present a novel and practical pipeline for constructing a heart failure knowledge graph using large language models and medical expert refinement. We apply prompt engineering to the three phases of schema design: schema design, information extraction, and knowledge completion. The best performance is achieved by designing task-specific prompt templates combined with the TwoStepChat approach. Results: Experiments on two datasets show that the TwoStepChat method outperforms the Vanillia prompt and outperforms the fine-tuned BERT-based baselines. Moreover, our method saves 65% of the time compared to manual annotation and is better suited to extract the out-of-distribution information in the real world.

Mitochondrial inhibitors: a new horizon in breast cancer therapy.

Breast cancer, due to resistance to standard therapies such as endocrine therapy, anti-HER2 therapy and chemotherapy, continues to pose a major health challenge. A growing body of research emphasizes the heterogeneity and plasticity of metabolism in breast cancer. Because differences in subtypes exhibit a bias toward metabolic pathways, targeting mitochondrial inhibitors shows great potential as stand-alone or adjuvant cancer therapies. Multiple therapeutic candidates are currently in various stages of preclinical studies and clinical openings. However, specific inhibitors have been shown to face multiple challenges (e.g., single metabolic therapies, mitochondrial structure and enzymes, etc.), and combining with standard therapies or targeting multiple metabolic pathways may be necessary. In this paper, we review the critical role of mitochondrial metabolic functions, including oxidative phosphorylation (OXPHOS), the tricarboxylic acid cycle, and fatty acid and amino acid metabolism, in metabolic reprogramming of breast cancer cells. In addition, we outline the impact of mitochondrial dysfunction on metabolic pathways in different subtypes of breast cancer and mitochondrial inhibitors targeting different metabolic pathways, aiming to provide additional ideas for the development of mitochondrial inhibitors and to improve the efficacy of existing therapies for breast cancer.

Metal-ligand dual-site single-atom nanozyme mimicking urate oxidase with high substrates specificity.

In nature, coenzyme-independent oxidases have evolved in selective catalysis using isolated substrate-binding pockets. Single-atom nanozymes (SAzymes), an emerging type of non-protein artificial enzymes, are promising to simulate enzyme active centers, but owing to the lack of recognition sites, realizing substrate specificity is a formidable task. Here we report a metal-ligand dual-site SAzyme (Ni-DAB) that exhibited selectivity in uric acid (UA) oxidation. Ni-DAB mimics the dual-site catalytic mechanism of urate oxidase, in which the Ni metal center and the C atom in the ligand serve as the specific UA and O2 binding sites, respectively, characterized by synchrotron soft X-ray absorption spectroscopy, in situ near ambient pressure X-ray photoelectron spectroscopy, and isotope labeling. The theoretical calculations reveal the high catalytic specificity is derived from not only the delicate interaction between UA and the Ni center but also the complementary oxygen reduction at the beta C site in the ligand. As a potential application, a Ni-DAB-based biofuel cell using human urine is constructed. This work unlocks an approach of enzyme-like isolated dual sites in boosting the selectivity of non-protein artificial enzymes.

STEAP2 promotes hepatocellular carcinoma progression via increased copper levels and stress-activated MAP kinase activity.

Six Transmembrane Epithelial Antigen of Prostate 2 (STEAP2) belongs to a family of metalloreductases, which indirectly aid in uptake of iron and copper ions. Its role in hepatocellular carcinoma (HCC) remains to be characterized. Here, we report that STEAP2 expression was upregulated in HCC tumors compared with paired adjacent non-tumor tissues by RNA sequencing, RT-qPCR, Western blotting, and immunostaining. Public HCC datasets demonstrated upregulated STEAP2 expression in HCC and positive association with tumor grade. Transient and stable knockdown (KD) of STEAP2 in HCC cell lines abrogated their malignant phenotypes in vitro and in vivo, while STEAP2 overexpression showed opposite effects. STEAP2 KD in HCC cells led to significant alteration of genes associated with extracellular matrix organization, cell adhesion/chemotaxis, negative enrichment of an invasiveness signature gene set, and inhibition of cell migration/invasion. STEAP2 KD reduced intracellular copper levels and activation of stress-activated MAP kinases including p38 and JNK. Treatment with copper rescued the reduced HCC cell migration due to STEAP2 KD and activated p38 and JNK. Furthermore, treatment with p38 or JNK inhibitors significantly inhibited copper-mediated cell migration. Thus, STEAP2 plays a malignant-promoting role in HCC cells by driving migration/invasion via increased copper levels and MAP kinase activities. Our study uncovered a novel molecular mechanism contributing to HCC malignancy and a potential therapeutic target for HCC treatment.

EHR coding with hybrid attention and features propagation on disease knowledge graph.

And sentences associated with these attributes and relationships have been neglected. in this paper ►We propose an end-to-end model called Knowledge Graph Enhanced neural network (KGENet) to address the above shortcomings. specifically ►We first construct a disease knowledge graph that focuses on the multi-view disease attributes of ICD codes and the disease relationships between these codes. we also use a long sequence encoder to get EHR document representation. most importantly ►KGENet leverages multi-view disease attributes and structured disease relationships for knowledge enhancement through hybrid attention and graph propagation ►Respectively. furthermore ►The above processes can provide attribute-aware and relationship-augmented explainability for the model prediction results based on our disease knowledge graph. experiments conducted on the MIMIC-III benchmark dataset show that KGENet outperforms state-of-the-art models in both model effectiveness and explainability Electronic health record (EHR) coding assigns International Classification of Diseases (ICD) codes to each EHR document. These standard medical codes represent diagnoses or procedures and play a critical role in medical applications. However, EHR is a long medical text that is difficult to represent, the ICD code label space is large, and the labels have an extremely unbalanced distribution. These factors pose challenges to automatic EHR coding. Previous studies have not explored the disease attributes (e.g., symptoms, tests, medications) of ICD codes and the disease relationships (e.g., causes, risk factors, comorbidities) between them. In addition, the important roles of medical.

Spatiotemporal variations and risk assessment of estrogens in the water of the southern Bohai Sea: A comprehensive investigation spanning three years.

The ubiquitous and adverse effects of estrogens have aroused global concerns. Natural and synthetic estrogens in 255 water samples from the southern Bohai Sea were analyzed over three years. Total estrogen concentrations were 11.0-268 ng/L in river water and 1.98-99.7 ng/L in seawater, with bisphenol A (BPA) and 17α-ethynylestradiol (EE2) being the predominant estrogens, respectively. Estrogen showed the highest concentrations in summer 2018, followed by spring 2021 and spring 2019, which was consistent with the higher estrogen flux from rivers during summer. Higher estrogen concentrations in 2021 than in 2019 were driven by the higher level of BPA, an additive used in personal protective equipment. Estrogen exhibited higher concentrations in the southern coast of the Yellow River Delta and the northeastern coast of Laizhou bay due to the riverine input and aquaculture. Estrogens could disturb the normal endocrine activities of organisms and edict high ecological risks (90th simulated RQT > 1.0) to aquatic organisms, especially to fish. EE2 was the main contributor of estrogenic potency and ecological risk, which requires special concern. This is the first comprehensive study of estrogen spatiotemporal variations and risks in the Bohai Sea, providing insights into the environmental behavior of estrogens in coastal regions.

Berberine inhibits the malignant cell phenotype by inactivating PI3K/AKT/mTOR signaling in laryngeal squamous cell carcinoma.

BACKGROUND: Berberine is an active compound found in different herbs used in Chinese medicine and is well-known for its potential anticancer properties. The study aimed to figure out the role of berberine in regulating the malignant behavior of laryngeal squamous cell carcinoma (LSCC) cells. METHODS: LSCC cell lines (SNU-899 and AMC-HN-8) were treated with different concentrations of berberine (0-200 µM) to determine its cytotoxicity. The migration, invasion, and apoptosis of LSCC cells were measured by wound healing assays, Transwell assays, and flow cytometry. Western blot was performed for the quantification of proteins involved in PI3K/AKT/mTOR signaling. RESULTS: The viability of LSCC cells was dose-dependently reduced by berberine. Berberine dampened LSCC cell migration and invasion while augmenting cell apoptosis, as evidenced by a reduced wound closure rate, a decrease in invaded cell number, and a surge in cell apoptosis in the context of berberine stimulation. Importantly, the effects of berberine on the cancer cell process were enhanced by LY294002 (an inhibitor for PI3K) treatment. Moreover, the protein levels of phosphorylated PI3K, AKT, and mTOR were markedly reduced in response to berberine treatment. CONCLUSION: Berberine inhibits cell viability, migration, and invasion but augments cell apoptosis by inactivating PI3K/AKT/mTOR signaling in LSCC.

Integrative multi-omics characterization of hepatocellular carcinoma in Hispanic patients.

Background: The incidence and mortality rates of hepatocellular carcinoma (HCC) among Hispanics in the United States are much higher than those of non-Hispanic whites. We conducted comprehensive multi-omics analyses to understand molecular alterations in HCC among Hispanic patients. Methods: Paired tumor and adjacent non-tumor samples were collected from 31 Hispanic HCC in South Texas (STX-Hispanic) for genomic, transcriptomic, proteomic, and metabolomic profiling. Additionally, serum lipids were profiled in 40 Hispanic and non-Hispanic patients with or without clinically diagnosed HCC. Results: Exome sequencing revealed high mutation frequencies of AXIN2 and CTNNB1 in STX Hispanic HCCs, suggesting a predominant activation of the Wnt/ß-catenin pathway. The TERT promoter mutation frequency was also remarkably high in the Hispanic cohort. Cell cycles and liver functions were identified as positively- and negatively-enriched, respectively, with gene set enrichment analysis. Gene sets representing specific liver metabolic pathways were associated with dysregulation of corresponding metabolites. Negative enrichment of liver adipogenesis and lipid metabolism corroborated with a significant reduction in most lipids in the serum samples of HCC patients. Two HCC subtypes from our Hispanic cohort were identified and validated with the TCGA liver cancer cohort. The subtype with better overall survival showed higher activity of immune and angiogenesis signatures, and lower activity of liver function-related gene signatures. It also had higher levels of immune checkpoint and immune exhaustion markers. Conclusions: Our study revealed some specific molecular features of Hispanic HCC and potential biomarkers for therapeutic management of HCC and provides a unique resource for studying Hispanic HCC.

Purine-Doped g-C3N4-Modified Fabrics for Personal Protective Masks with Rapid and Sustained Antibacterial Activity.

Protective masks are critical to impeding microorganism transmission but can propagate infection via pathogen buildup and face touching. To reduce this liability, we integrated electrospun photocatalytic graphitic carbon nitride (g-C3N4) nanoflakes into standard surgical masks to confer a self-sanitization capacity. By optimizing the purine/melamine precursor ratio during synthesis, we reduced the g-C3N4 band gap from 2.92 to 2.05 eV, eliciting a 4× increase in sterilizing hydrogen peroxide production under visible light. This narrower band gap enables robust photocatalytic generation of reactive oxygen species from environmental and breath humidity to swiftly eliminate accumulated microbes. Under ambient sunlight, the g-C3N4 nanocomposite mask layer achieved a 97% reduction in the bacterial viability during typical use. Because the optimized band gap also allows photocatalytic activity under shadowless lamp illumination, the self-cleaning functionality could mitigate infection risk from residual pathogens in routine hospital settings. Both g-C3N4 and polycaprolactone demonstrate favorable biocompatibility and biodegradability, making this approach preferable over current commercially available metal-based options. Given the abundance and low cost of these components, this scalable approach could expand global access to reusable self-sanitizing protective masks, serving as a sustainable public health preparedness measure against future pandemics, especially in resource-limited settings.

Spatiotemporal expression of AP-2/myosin â ¥ in mouse cochlear IHCs and correlation with auditory function.

BACKGROUND: Recycling of synaptic vesicles plays an important role in vesicle pool replenishment, neurotransmitter release and synaptic plasticity. Clathrin-mediated endocytosis (CME) is considered to be the main mechanism for synaptic vesicle replenishment. AP-2 (adaptor-related protein complex 2) and myosin Ⅵ are known as key proteins that regulate the structure and dynamics of CME. OBJECTIVE: This study aims to reveal the spatiotemporal expression of AP-2/myosin Ⅵ in inner hair cells (IHCs) of the mouse cochlea and its correlation with auditory function. MATERIAL AND METHODS: Immunofluorescence was used to detect the localization and expression of AP-2 and myosin Ⅵ in cochlear hair cells (HCs) of CBA/CaJ mice of various ages. qRT-PCR was used to verify the differential expression of AP-2 and myosin Ⅵ mRNA in the mouse cochlea, and ABR tests were administered to mice of various ages. A preliminary analysis of the correlation between AP-2/myosin Ⅵ levels and auditory function was conducted. RESULTS: AP-2 was located in the cytoplasmic region of IHCs and was mainly expressed in the basal region of IHCs and the area near ribbon synapses, while myosin Ⅵ was expressed in the cytoplasmic region of IHCs and OHCs. Furthermore, AP-2 and myosin Ⅵ were not significant detected in the cochleae of P7 mice; the expression level reached a peak at P35 and then decreased significantly with age. The expression patterns and expression levels of AP-2 and myosin Ⅵ in the cochleae of the mice were consistent with the development of the auditory system. CONCLUSIONS AND SIGNIFICANCE: AP-2 and myosin Ⅵ protein expression may differ in mice of different ages, and this variation probably leads to a difference in the efficiency in CME; it may also cause a defect in IHC function.

Effects of COVID-19 on coastal and marine environments: Aggravated microplastic pollution, improved air quality, and future perspective.

The COVID-19 pandemic during 2020-2023 has wrought adverse impacts on coastal and marine environments. This study conducts a comprehensive review of the collateral effects of COVID-19 on these ecosystems through literature review and bibliometric analysis. According to the output and citation analysis of these publications, researchers from the coastal countries in Asia, Europe, and America payed more attentions to this environmental issue than other continents. Specifically, India, China, and USA were the top three countries in the publications, with the proportion of 19.55%, 18.99%, and 12.01%, respectively. The COVID-19 pandemic significantly aggravated the plastic and microplastic pollution in coastal and marine environments by explosive production and unproper management of personal protective equipment (PPE). During the pandemic, the estimated mismanaged PPE waste ranged from 16.50 t/yr in Sweden to 250,371.39 t/yr in Indonesia. In addition, the PPE density ranged from 1.13 × 10-5 item/m2 to 2.79 item/m2 in the coastal regions worldwide, showing significant geographical variations. Besides, the emerging contaminants released from PPE into the coastal and marine environments cannot be neglected. The positive influence was that the COVID-19 lockdown worldwide reduced the release of air pollutants (e.g., fine particulate matter, NO2, CO, and SO2) and improved the air quality. The study also analyzed the relationships between sustainable development goals (SDGs) and the publications and revealed the dynamic changes of SDGs in different periods the COVID-19 pandemic. In conclusion, the air was cleaner due to the lockdown, but the coastal and marine contamination of plastic, microplastic, and emerging contaminants got worse during the COVID-19 pandemic. Last but not least, the study proposed four strategies to deal with the coastal and marine pollution caused by COVID-19, which were regular marine monitoring, performance of risk assessment, effective regulation of plastic wastes, and close international cooperation.

Novel insights into TCR-T cell therapy in solid neoplasms: optimizing adoptive immunotherapy.

Adoptive immunotherapy in the T cell landscape exhibits efficacy in cancer treatment. Over the past few decades, genetically modified T cells, particularly chimeric antigen receptor T cells, have enabled remarkable strides in the treatment of hematological malignancies. Besides, extensive exploration of multiple antigens for the treatment of solid tumors has led to clinical interest in the potential of T cells expressing the engineered T cell receptor (TCR). TCR-T cells possess the capacity to recognize intracellular antigen families and maintain the intrinsic properties of TCRs in terms of affinity to target epitopes and signal transduction. Recent research has provided critical insight into their capability and therapeutic targets for multiple refractory solid tumors, but also exposes some challenges for durable efficacy. In this review, we describe the screening and identification of available tumor antigens, and the acquisition and optimization of TCRs for TCR-T cell therapy. Furthermore, we summarize the complete flow from  laboratory to clinical applications of TCR-T cells. Last, we emerge future prospects for improving therapeutic efficacy in cancer world with combination therapies or TCR-T derived products. In conclusion, this review depicts our current understanding of TCR-T cell therapy in solid neoplasms, and provides new perspectives for expanding its clinical applications and improving therapeutic efficacy.

Occurrence, bioaccumulation and trophodynamics of organophosphate esters in the marine biota web of Laizhou Bay, Bohai Sea.

The trophodynamic of organophosphate esters (OPEs) has not been known well despite their widespread occurrence in the aquatic environments. In this study, ten species of crustacean, seven species of mollusk, and 22 species of fish were collected in the Laizhou Bay (LZB) to examine the occurrence, bioaccumulation, and trophic transfer, and health risk of eight traditional OPEs and three emerging oligomeric OPEs. The results showed that total concentration of OPEs was 2.04 to 28.6 ng g-1 ww in the muscle of crustacean, mollusk, and fish and 2.62 to 60.6 ng g-1 ww in the fish gill. Chlorinated OPEs averagely contributed to over 85% of total OPEs while oligomeric OPEs averagely accounted for approximate 4%. The average log apparent bioaccumulation factor (ABAF) ranged from - 0.4 L kg-1 ww for triethyl phosphate to 2.4 L kg-1 ww for resorcinol-bis (diphenyl) phosphate. Apparent trophic magnification factors (ATMF) of individual OPE were generally less than 1, demonstrating the biodilution effect of the OPEs in the organism web of LZB. Additionally, the log ABAF and ATMF of OPEs were significantly positively correlated to their log Kow but negatively correlated to their biotransformation rate constant (BRC). Therefore, the OPEs with high Kow and low BRC tend to more accumulate in the marine organisms. The health risks associated with OPEs through the consumption of the seafood from the bay were low, even at high exposure scenario.

Illuminating the immunological landscape: mitochondrial gene defects in pancreatic cancer through a multiomics lens.

This comprehensive review delves into the complex interplay between mitochondrial gene defects and pancreatic cancer pathogenesis through a multiomics approach. By amalgamating data from genomic, transcriptomic, proteomic, and metabolomic studies, we dissected the mechanisms by which mitochondrial genetic variations dictate cancer progression. Emphasis has been placed on the roles of these genes in altering cellular metabolic processes, signal transduction pathways, and immune system interactions. We further explored how these findings could refine therapeutic interventions, with a particular focus on precision medicine applications. This analysis not only fills pivotal knowledge gaps about mitochondrial anomalies in pancreatic cancer but also paves the way for future investigations into personalized therapy options. This finding underscores the crucial nexus between mitochondrial genetics and oncological immunology, opening new avenues for targeted cancer treatment strategies.

Bioinspired Nanozymes as Nanodecoys for Urinary Tract Infection Treatment.

Urinary tract infections (UTIs), common bacterial infections in communities and medical facilities, are mainly mediated by FimH. The glycan sites of the uromodulin protein play a crucial role in protecting against UTIs by interacting with FimH. A bioinspired approach using glycan-FimH interactions may effectively reduce bacteria through an antiadhesive mechanism, thereby curbing bacterial resistance. However, typical antiadhesive therapy alone fails to address the excessive reactive oxygen species and inflammatory response during UTIs. To bridge this gap, antioxidant nanozymes with antiadhesive ability were developed as nanodecoys to counter bacteria and inflammation. Specifically, ultrasmall dextran-coated ceria (DEC) was engineered to address UTIs, with dextran blocking FimH adhesion and ceria exhibiting anti-inflammatory properties. DECs, metabolizable by the kidneys, reduced bacterial content in the urinary tract, mitigating inflammation and tissue damage. In murine models, DECs successfully treated acute UTIs, repeated infections, and catheter-related UTIs. This dual approach not only highlights the potential of nanozymes for UTIs but also suggests applicability to other FimH-induced infections in the lungs and bowels, marking a significant advancement in nanozyme-based clinical approaches.

Metabolism-associated molecular classification and prognosis signature of head and neck squamous cell carcinoma.

Although the fundamental processes and chemical changes in metabolic programs have been elucidated in many cancers, the expression patterns of metabolism-related genes in head and neck squamous cell carcinoma (HNSCC) remain unclear. The mRNA expression profiles from the Cancer Genome Atlas included 502 tumour and 44 normal samples were extracted. We explored the biological functions and prognosis roles of metabolism-associated genes in patients with HNSCC. The results indicated that patients with HNSCC could be divided into three molecular subtypes (C1, C2 and C3) based on 249 metabolism-related genes. There were markedly different clinical characteristics, prognosis outcomes, and biological functions among the three subtypes. Different molecular subtypes also have different tumour microenvironments and immune infiltration levels. The established prognosis model with 17 signature genes could predict the prognosis of patients with HNSCC and was validated using an independent cohort dataset. An individual risk scoring tool was developed using the risk score and clinical parameters; the risk score was an independent prognostic factor for patients with HNSCC. Different risk stratifications have different clinical characteristics, biological features, tumour microenvironments and immune infiltration levels. Our study could be used for clinical risk management and to help conduct precision medicine for patients with HNSCC.

Dimethyl Carbonate Synthesis from CO2 over CeO2 with Electron-Enriched Lattice Oxygen Species.

Direct synthesis of dimethyl carbonate (DMC) from CO2 plays an important role in carbon neutrality, but its efficiency is still far from the practical application, due to the limited understanding of the reaction mechanism and rational design of efficient catalyst. Herein, abundant electron-enriched lattice oxygen species were introduced into CeO2 catalyst by constructing the point defects and crystal-terminated phases in the crystal reconstruction process. Benefitting from the acid-base properties modulated by the electron-enriched lattice oxygen, the optimized CeO2 catalyst exhibited a much higher DMC yield of 22.2 mmol g-1 than the reported metal-oxide-based catalysts at the similar conditions. Mechanistic investigations illustrated that the electron-enriched lattice oxygen can provide abundant sites for CO2 adsorption and activation, and was advantageous of the formation of the weakly adsorbed active methoxy species. These were facilitating to the coupling of methoxy and CO2 for the key *CH3OCOO intermediate formation. More importantly, the weakened adsorption of *CH3OCOO on the electron-enriched lattice oxygen can switch the rate-determining-step (RDS) of DMC synthesis from *CH3OCOO formation to *CH3OCOO dissociation, and lower the corresponding activation barriers, thus giving rise to a high performance. This work provides insights into the underlying reaction mechanism for DMC synthesis from CO2 and methanol and the design of highly efficient catalysts.

Engineered bone marrow mesenchymal stem cell-derived exosomes loaded with miR302 through the cardiomyocyte specific peptide can reduce myocardial ischemia and reperfusion (I/R) injury.

BACKGROUND: MicroRNA (miRNA)-based therapies have shown great potential in myocardial repair following myocardial infarction (MI). MicroRNA-302 (miR302) has been reported to exert a protective effect on MI. However, miRNAs are easily degraded and ineffective in penetrating cells, which limit their clinical applications. Exosomes, which are small bioactive molecules, have been considered as an ideal vehicle for miRNAs delivery due to their cell penetration, low immunogenicity and excellent stability potential. Herein, we explored cardiomyocyte-targeting exosomes as vehicles for delivery of miR302 into cardiomyocyte to potentially treat MI. METHODS: To generate an efficient exosomal delivery system that can target cardiomyocytes, we engineered exosomes with cardiomyocyte specific peptide (CMP, WLSEAGPVVTVRALRGTGSW). Afterwards, the engineered exosomes were characterized and identified using transmission electron microscope (TEM) and Nanoparticle Tracking Analysis (NTA). Later on, the miR302 mimics were loaded into the engineered exosomes via electroporation technique. Subsequently, the effect of the engineered exosomes on myocardial ischemia and reperfusion (I/R) injury was evaluated in vitro and in vivo, including MTT, ELISA, real-time quantitative polymerase chain reaction (PCR), western blot, TUNNEL staining, echocardiogram and hematoxylin and eosin (HE) staining. RESULTS: Results of in vitro experimentation showed that DSPE-PEG-CMP-EXO could be more efficiently internalized by H9C2 cells than unmodified exosomes (blank-exosomes). Importantly, compared with the DSPE-PEG-CMP-EXO group, DSPE-PEG-CMP-miR302-EXO significantly upregulated the expression of miR302, while exosomes loaded with miR302 could enhance proliferation of H9C2 cells. Western blot results showed that the DSPE-PEG-CMP-miR302-EXO significantly increased the protein level of Ki67 and Yap, which suggests that DSPE-PEG-CMP-miR302-EXO enhanced the activity of Yap, the principal downstream effector of Hippo pathway. In vivo, DSPE-PEG-CMP-miR302-EXO improved cardiac function, attenuated myocardial apoptosis and inflammatory response, as well as reduced infarct size significantly. CONCLUSION: In conclusion, our findings suggest that CMP-engineered exosomes loaded with miR302 was internalized by H9C2 cells, an in vitro model for cardiomyocytes coupled with potential enhancement of the therapeutic effects on myocardial I/R injury.

Expanding Olefin-Linked Covalent Organic Frameworks toward Selective Photocatalytic Oxidation of Organic Sulfides.

Olefin-linked covalent organic frameworks (COFs) have exhibited great potential in visible-light photocatalysis. In principle, expanding fully conjugated COFs can facilitate light absorption and charge transfer, leading to improved photocatalysis. Herein, three olefin-linked COFs with the same topology are synthesized by combining 2,4,6-trimethyl-1,3,5-triazine (TMT) with 1,3,5-triformylbenzene (TFB), 1,3,5-tris(4-formylphenyl)benzene (TFPB), and 1,3,5-tris(4-formylphenylethynyl)benzene (TFPEB), namely, TMT-TFB-COF, TMT-TFPB-COF, and TMT-TFPEB-COF, respectively. From TMT-TFB-COF to TMT-TFPB-COF, expanding phenyl rings provides only limited expansion for π-conjugation due to the steric effect of structural twisting. However, from TMT-TFPB-COF to TMT-TFPEB-COF, the insertion of acetylenes eliminates the steric effect and provides more delocalized π-electrons. As such, TMT-TFPEB-COF exhibits the best optoelectronic properties among these three olefin-linked COFs. Consequently, the photocatalytic performance of TMT-TFPEB-COF is much better than those of TMT-TFB-COF and TMT-TFPB-COF on the oxidation of organic sulfides into sulfoxides with oxygen. The desirable reusability and substrate compatibility of the TMT-TFPEB-COF photocatalyst are further confirmed. The selective formation of organic sulfoxides over TMT-TFPEB-COF under blue light irradiation proceeds via both electron- and energy-transfer pathways. This work highlights a rational design of expanding the π-conjugation of fully conjugated COFs toward selective visible-light photocatalysis.