Discovery of novel Thymol-TPP antibiotics that eradicate MRSA persisters.

The high prevalence of methicillin-resistant Staphylococcus aureus (MRSA) strains and the formation of non-growing, dormant "persisters" subsets help bacteria evade antibiotic treatment and enhance bacterial resistance, which poses a serious threat to human life and health. It is urgent to discover novel antibacterial therapies effective against MRSA persisters. Thymol is a common nutraceutical with weak antibacterial and antitumor activities. A series of Thymol triphenylphosphine (TPP) conjugates (TPP-Thy3) was designed and synthesized. These compounds showed significantly improved inhibitory activity against Gram-positive bacteria compared with Thymol. Among them, Thy3d displayed a low probability of resistance selection and showed excellent biocompatibility. Interestingly, Thy3d elicited a rapid killing effect of MRSA persisters (99.999%) at high concentration. Fluorescence experiments, electron microscopy, molecular dynamics simulation and bilayer experiment confirmed that Thy3d conjugates exerted potent antimicrobial activity by disrupting the integrity of the membrane of bacterial even the persister. Furthermore, Thy3d exhibited considerable efficacy in a mouse model of subcutaneous murine MRSA infection. In summary, TPP-Thy3 conjugates are a series of novel antibacterial agents and could serve as a new therapeutic strategy for combating antibiotic resistance.

Design, Synthesis, and Biological Activity of Novel Phenyltriazolinone PPO Inhibitors Containing Five-Membered Heterocycles.

Protoporphyrinogen oxidase (PPO, EC 1.3.3.4) catalyzes the oxidation of protoporphyrinogen IX to protoporphyrin IX, which is a key step in the synthesis of porphyrins in vivo. PPO inhibitors use protoporphyrinogen oxidase as the target and block the biosynthesis process of porphyrin by inhibiting the activity of the enzyme, eventually leading to plant death. In this paper, phenyl triazolinone was used as the parent structure, and the five-membered heterocycle with good herbicidal activity was introduced by using the principle of substructure splicing. According to the principle of bioisosterism, the sulfur atoms on the thiophene ring were replaced with oxygen atoms. Finally, 33 phenyl triazolinones and their derivatives were designed and synthesized, and their characterizations and biological activities were investigated. The in vitro PPO inhibitory activity and greenhouse herbicidal activity of 33 target compounds were determined, and compound D4 with better activity was screened out. The crop safety determination, field weeding effect determination, weeding spectrum determination, and crop metabolism study were carried out. The results showed that compound D4 showed good safety to corn, soybean, wheat, and peanut but poor selectivity to cotton. The field weeding effect of this compound is comparable to that of the commercial herbicide sulfentrazone. The herbicidal spectrum experiment showed that compound D4 had a wide herbicidal spectrum and a good growth inhibition effect on dicotyledonous weeds. Molecular docking results showed that compound D4 forms a hydrogen bond with amino acid residue Arg-98 in the tobacco mitochondria (mtPPO)-active pocket and forms two π-π stacking interactions with Phe-392. This indicates that compound D4 has stronger PPO inhibitory activity. This indicates that compound D4 has wide prospects for development.

Treatment of MRSA Infection: Where are We?

Staphylococcus aureus is a leading cause of septicemia, endocarditis, pneumonia, skin and soft tissue infections, bone and joint infections, and hospital-acquired infections. In particular, methicillin-resistant Staphylococcus aureus (MRSA) is associated with high morbidity and mortality, and continues to be a major public health problem. The emergence of multidrug-resistant MRSA strains along with the wide consumption of antibiotics has made anti-MRSA treatment a huge challenge. Novel treatment strategies (e.g., novel antimicrobials and new administrations) against MRSA are urgently needed. In the past decade, pharmaceutical companies have invested more in the research and development (R&D) of new antimicrobials and strategies, spurred by favorable policies. All research articles were collected from authentic online databases, including Google Scholar, PubMed, Scopus, and Web of Science, by using different combinations of keywords, including 'anti-MRSA', 'antibiotic', 'antimicrobial', 'clinical trial', 'clinical phase', clinical studies', and 'pipeline'. The information extracted from articles was compared to information provided on the drug manufacturer's website and Clinical- Trials.gov (https://clinicaltrials.gov/) to confirm the latest development phase of anti- MRSA agents. The present review focuses on the current development status of new anti-MRSA strategies concerning chemistry, pharmacological target(s), indications, route of administration, efficacy and safety, pharmacokinetics, and pharmacodynamics, and aims to discuss the challenges and opportunities in developing drugs for anti-MRSA infections.

Polydopamine-Modified 2D Iron (II) Immobilized MnPS3 Nanosheets for Multimodal Imaging-Guided Cancer Synergistic Photothermal-Chemodynamic Therapy.

Manganese phosphosulphide (MnPS3 ), a newly emerged and promising member of the 2D metal phosphorus trichalcogenides (MPX3 ) family, has aroused abundant interest due to its unique physicochemical properties and applications in energy storage and conversion. However, its potential in the field of biomedicine, particularly as a nanotherapeutic platform for cancer therapy, has remained largely unexplored. Herein, a 2D "all-in-one" theranostic nanoplatform based on MnPS3 is designed and applied for imaging-guided synergistic photothermal-chemodynamic therapy. (Iron) Fe (II) ions are immobilized on the surface of MnPS3 nanosheets to facilitate effective chemodynamic therapy (CDT). Upon surface modification with polydopamine (PDA) and polyethylene glycol (PEG), the obtained Fe-MnPS3 /PDA-PEG nanosheets exhibit exceptional photothermal conversion efficiency (η = 40.7%) and proficient pH/NIR-responsive Fenton catalytic activity, enabling efficient photothermal therapy (PTT) and CDT. Importantly, such nanoplatform can also serve as an efficient theranostic agent for multimodal imaging, facilitating real-time monitoring and guidance of the therapeutic process. After fulfilling the therapeutic functions, the Fe-MnPS3 /PDA-PEG nanosheets can be efficiently excreted from the body, alleviating the concerns of long-term retention and potential toxicity. This work presents an effective, precise, and safe 2D "all-in-one" theranostic nanoplatform based on MnPS3 for high-efficiency tumor-specific theranostics.

Early Diagnosing and Transformation Prediction of Alzheimer's Disease Using Multi-Scaled Self-Attention Network on Structural MRI Images with Occlusion Sensitivity Analysis.

BACKGROUND: Structural magnetic resonance imaging (sMRI) is vital for early Alzheimer's disease (AD) diagnosis, though confirming specific biomarkers remains challenging. Our proposed Multi-Scale Self-Attention Network (MUSAN) enhances classification of cognitively normal (CN) and AD individuals, distinguishing stable (sMCI) from progressive mild cognitive impairment (pMCI). OBJECTIVE: This study leverages AD structural atrophy properties to achieve precise AD classification, combining different scales of brain region features. The ultimate goal is an interpretable algorithm for this method. METHODS: The MUSAN takes whole-brain sMRI as input, enabling automatic extraction of brain region features and modeling of correlations between different scales of brain regions, and achieves personalized disease interpretation of brain regions. Furthermore, we also employed an occlusion sensitivity algorithm to localize and visualize brain regions sensitive to disease. RESULTS: Our method is applied to ADNI-1, ADNI-2, and ADNI-3, and achieves high performance on the classification of CN from AD with accuracy (0.93), specificity (0.82), sensitivity (0.96), and area under curve (AUC) (0.95), as well as notable performance on the distinguish of sMCI from pMCI with accuracy (0.85), specificity (0.84), sensitivity (0.74), and AUC (0.86). Our sensitivity masking algorithm identified key regions in distinguishing CN from AD: hippocampus, amygdala, and vermis. Moreover, cingulum, pallidum, and inferior frontal gyrus are crucial for sMCI and pMCI discrimination. These discoveries align with existing literature, confirming the dependability of our model in AD research. CONCLUSION: Our method provides an effective AD diagnostic and conversion prediction method. The occlusion sensitivity algorithm enhances deep learning interpretability, bolstering AD research reliability.

Development of membrane-targeting TPP+-chloramphenicol conjugates to combat methicillin-resistant staphylococcus aureus (MRSA) infections.

Infections caused by drug-resistant bacteria have become a new challenge in infection treatment, gravely endangering public health. Chloramphenicol (CL) is a well-known antibiotic which has lost its efficacy due to bacterial resistance. To address this issue, herein we report the design, synthesis and biological evaluations of novel triphenylphosphonium chloramphenicol conjugates (TPP+-CL). Study results indicated that compounds 39 and 42 possessed remarkable antibacterial effects against clinically isolated methicillin-resistant Staphylococcus aureus (MRSA) with MIC values ranging from 1 to 2 µg/mL, while CL was inactive to the tested MRSA strains. In addition, these conjugates exhibited rapid bactericidal properties and low toxicity, and did not readily induced bacterial resistance, obviously outperforming the parent drug CL. In a mouse model infected with a clinically isolated MRSA strain, compound 39 at a dose of 20 mg/kg exhibited a comparable or even better in vivo anti-MRSA efficacy than the golden standard drug vancomycin, while no toxicity was observed.

Defect Passivation in Quasi-2D Perovskite Light-Emitting Diodes by an Ibuprofen Additive.

It is well known that the inferior film morphology and the excessive surface/interface defect states are two obstacles to achieving high electroluminescence performance of quasi-2D perovskite light-emitting diodes (PeLEDs). To solve these problems, ibuprofen was introduced as an additive in the quasi-2D perovskite emitting layer. More efficient photoluminescence is demonstrated. Further, optimized quasi-2D PeLEDs with a current efficiency of 55.93 cd/A are confirmed and 5.7-fold enhancement in device stability is obtained. The physical mechanism of the remarkable improvement is investigated by kinds of measurements. Three aspects should be counted into it. First, the introduction of ibuprofen can passivate defects, thus making the quasi-2D perovskite emitting layer more dense and homogeneous. The reason should be that the C═O functional group and C═C bond in the benzene ring in ibuprofen can coordinate the unsaturated Pb2+ perovskite emitting layer. Meanwhile, the related exciton harvesting process is investigated. The proportion of the crystalline phases (small n and large n phase) can be tuned to benefit the energy funneling process. Finally, the analysis of the current density and voltage curves of the hole-dominated devices and the electron-dominated devices is conducted by utilizing the space charge-limited current (SCLC) methods.

LINC00958 promotes the malignant biological behaviors of cervical cancer cells and lymph node metastasis in mouse models by upregulating VEGF-C expression / 中国肿瘤生物治疗杂志

@#目的：探讨LINC00958/血管内皮生长因子C（VEGF-C）信号通路在宫颈癌的淋巴管生成和淋巴转移中的作用。方法：从2020年9月至2022年9月期间在河南省人民医院接受手术的患者中收集了42例宫颈癌组织标本，通过qPCR检测宫颈癌组织和宫颈癌细胞（Hela、C33A、SiHa、Caski）中LINC00958的表达情况。将LINC00958过表达载体（LINC00958组）或对照载体（CMV组）转染Caski细胞，敲减LINC00958（shLINC00958组）、VEGF-C（shVEGF-C组）的shRNA序列或阴性对照shRNA（shNC组）转染SiHa细胞。分别通过CCK-8法、Transwell实验检测过表达或敲减LINC00958对宫颈癌细胞增殖、迁移和侵袭的影响。观察转染后细胞的培养上清液对人淋巴管内皮细胞（HLEC）淋巴管形成能力的影响。建立小鼠腘淋巴结转移模型，观察过表达LINC00958或同时敲减VEGF-C对宫颈癌淋巴结转移的影响。结果：LINC00958在宫颈癌组织中呈高表达（P<0.001），高水平的LINC00958与大肿瘤、晚期肿瘤分级、浸润深度和淋巴转移有关联（P<0.05或P<0.01）。与正常人宫颈上皮细胞ende1617相比，宫颈癌细胞中LINC00958水平均显著升高（P<0.01或P<0.001）。shLINC00958组SiHa细胞的增殖、迁移、侵袭能力及其培养上清液的促HLEC淋巴管形成能力均显著低于shNC组（P<0.05、P<0.01或P<0.001），LINC00958组Caski细胞的增殖、迁移、侵袭能力及其培养上清液的促HLEC淋巴管形成能力显著高于CMV组（P<0.05、P<0.01或P<0.001）。通过RNA下拉、RNA免疫沉淀实验发现宫颈癌细胞中LINC00958能够特异性结合VEGF-C。LINC00958+shVEGF-C组Caski细胞的增殖、迁移、侵袭能力及其培养上清液的促淋巴管形成能力显著低于LINC00958组（P<0.01或P<0.001）；在小鼠腘淋巴结转移模型中，LINC00958+shVEGF-C组中小鼠腘窝淋巴结的体积和VEGF-C蛋白、N-cadherin蛋白以及LYVE-1的阳性细胞比例均显著低于LINC00958组（均P<0.001）。结论：LINC00958通过直接与VEGF-C蛋白相互作用增强宫颈癌细胞的增殖、侵袭、淋巴管生成能力，促进小鼠腘淋巴结转移模型的淋巴结转移。

Association between serum ferritin and uric acid levels and nonalcoholic fatty liver disease in the Chinese population.

Background: The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide. Accumulating evidence suggests that serum ferritin and uric acid (UA) are strongly associated with the risk of NAFLD, but no consensus has been reached. Objective: We sought to demonstrate the association between serum ferritin, UA levels, and NAFLD risk in a large cohort study. Methods: We separated 2,049 patients into non-NAFLD and NAFLD groups. The NAFLD group had four subgroups based on serum ferritin and four subgroups based on UA quartile levels. We used binary logistic regression to evaluate the correlation between serum ferritin, UA, and NAFLD. Additionally, an area under the curve (AUC) of receiver operating characteristic analysis (ROC) was used to predict the diagnostic value of combined serum ferritin and UA for NAFLD. Results: Serum ferritin and UA levels were higher in the NAFLD group compared with the non-NAFLD group. Serum lipid and liver transaminase concentrations were elevated with the increase of serum ferritin and UA. The logistic regression results showed an independent correlation between serum ferritin, UA, and NAFLD. In the NAFLD group, the AUC value of serum ferritin and UA was 0.771. Conclusions: Increased serum ferritin and UA levels are independent risk factors for NAFLD. Increased serum UA is a stronger risk factor for NAFLD than elevated serum ferritin. Serum ferritin and UA can be important predictors of NAFLD risk.

2,4-Diacetylphloroglucinol (DAPG) derivatives rapidly eradicate methicillin-resistant staphylococcus aureus without resistance development by disrupting membrane.

Methicillin-resistant Staphylococcus aureus (MRSA) causes severe public health challenges throughout the world, and the multi-drug resistance (MDR) of MRSA to antibiotics necessitates the development of more effective antibiotics. Natural 2,4-diacetylphloroglucinol (DAPG), produced by Pseudomonas, displays moderate inhibitory activity against MRSA. A series of DAPG derivatives was synthesized and evaluated for their antibacterial activities, and some showed excellent activities (MRSA MIC = 0.5-2 µg/mL). Among these derivatives, 7g demonstrated strong antibacterial activity without resistance development over two months. Mechanistic studies suggest that 7g asserted its activity by targeting bacterial cell membranes. In addition, 7g exhibited significant synergistic antibacterial effects with oxacillin both in vitro and in vivo, with a tendency to eradicate MRSA biofilms. 7g is a promising lead for the treatment of MRSA.

Design, Synthesis, and Biological Activity Determination of Novel Phenylpyrazole Protoporphyrinogen Oxidase Inhibitor Herbicides Containing Five-Membered Heterocycles.

Protoporphyrinogen oxidase (PPO, EC 1.3.3.4) inhibitor herbicides have attracted widespread attention in recent years as ideal herbicides due to their high efficiency, low toxicity, and low pollution. In this article, 30 phenylpyrazole derivatives containing five-membered heterocycles were designed and synthesized according to the principle of bioelectronic isoarrangement and active substructure splicing. A series of structural characterizations were performed on the synthesized compounds. The herbicide activity in greenhouse was evaluated to determine their growth inhibition effect on weeds, their IC50 value through in vitro PPO enzyme activity measurement was calculated, and target compounds 2i and 3j that have herbicide effects comparable to pyraflufen-ethyl were selected. Crop safety experiments have shown that when the spraying concentration is 300 g of ai/ha, gramineous crops such as wheat, corn, and rice are more tolerant to compound 2i, with wheat exhibiting high tolerance, which is equivalent to the crop safety of pyraflufen-ethyl. Compound 2i can be used as a candidate herbicide for wheat, corn, and paddy fields, and the results are consistent with the cumulative concentration experiment. Molecular docking results showed that compound 2i interacted with the amino acid residue ARG-98 by forming two hydrogen bonds and interacted with the amino acid residue PHE-392 by forming two π-π stacking interactions, indicating that compound 2i has more excellent herbicidal activity than pyraflufen-ethyl and is expected to become a potential lead compound of phenylpyrazole PPO inhibitor herbicides.

Protective effects and regulatory mechanisms of Shen-shuai-yi recipe on renal fibrosis in unilateral ureteral obstruction-induced mice.

Renal fibrosis (RF) is a common pathological feature of chronic kidney disease (CKD), which remains a major public health problem. As now, there is still lack of chemical or biological drugs to reverse RF. Shen-shuai-yi Recipe (SSYR) is a classical Chinese herbal formula for the treatment of CKD. However, the effects and mechanisms of SSYR in treating RF are still not clear. In this study, the active constituents SSYR for treating RF were explored by UHPLC-Q-Orbitrap HRMS. Bioinformatics analyses were employed to analyze the key pharmacological targets and the core active constituents of SSYR in the treatment of RF. In experimental validation, vehicle or SSYR at doses of 2.12 g/kg/d and 4.25 g/kg/d were given by orally to unilateral ureteric obstruction (UUO) mice. 13 days after treatment, we detected the severity of renal fibrosis, extracellular collagen deposition and pre-fibrotic signaling pathways. Bioinformatics analysis suggested that signal transducer and activator of transcription 3 (STAT3) was the core target and lenticin, luteolin-7-O-rutinoside, hesperidin, kaempferol-3-O-rutinoside, and 3,5,6,7,8,3',4'-heptamethoxyflavone were the key constituents in SSYR for treating RF. SSYR significantly reduced the expressions of fibronectin (FN), α-smooth muscle actin (α-SMA), collagen-I and alleviated renal interstitial collagen deposition in UUO kidneys. In mechanism, SSYR potently blocked the phosphorylation of STAT3 and Smad3 and suppressed the expression of connective tissue growth factor (CTGF). Collectively, SSYR can ameliorate RF via inhibiting the phosphorylation of STAT3 and its downstream and reducing the collagen deposition, suggesting that SSYR can be developed as a novel medicine for treating RF.

Pharmacological interventions targeting α-synuclein aggregation triggered REM sleep behavior disorder and early development of Parkinson's disease.

Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by elevated motor behaviors and dream enactments in REM sleep, often preceding the diagnosis of Parkinson's disease (PD). As RBD could serve as a biomarker for early PD developments, pharmacological interventions targeting α-synuclein aggregation triggered RBD could be applied toward early PD progression. However, robust therapeutic guidelines toward PD-induced RBD are lacking, owing in part to a historical paucity of effective treatments and trials. We reviewed the bidirectional links between α-synuclein neurodegeneration, progressive sleep disorders, and RBD. We highlighted the correlation between RBD development, α-synuclein aggregation, and neuronal apoptosis in key brainstem regions involved in REM sleep atonia maintenance. The current pharmacological intervention strategies targeting RBD and their effects on progressive PD are discussed, as well as current treatments for progressive neurodegeneration and their effects on RBD. We also evaluated emerging and potential pharmacological solutions to sleep disorders and developing synucleinopathies. This review provides insights into the mechanisms and therapeutic targets underlying RBD and PD, and explores bidirectional treatment effects for both diseases, underscoring the need for further research in this area.

Screening for biomarkers in age-related macular degeneration.

Objective: Age-related macular degeneration (AMD) is a significant cause of blindness, initially characterized by the accumulation of sub-Retinal pigment epithelium (RPE) deposits, leading to progressive retinal degeneration and, eventually, irreversible vision loss. This study aimed to elucidate the differential expression of transcriptomic information in AMD and normal human RPE choroidal donor eyes and to investigate whether it could be used as a biomarker for AMD. Methods: RPE choroidal tissue samples (46 Normal samples, 38 AMD samples) were obtained from the GEO (GSE29801) database and screened for differentially expressed genes in normal and AMD patients using GEO2R and R to compare the degree of enrichment of differentially expressed genes in the GO, KEGG pathway. Firstly, we used machine learning models (LASSO, SVM algorithm) to screen disease signature genes and compare the differences between these signature genes in GSVA and immune cell infiltration. Secondly, we also performed a cluster analysis to classify AMD patients. We selected the best classification by weighted gene co-expression network analysis (WGCNA) to screen the key modules and modular genes with the strongest association with AMD. Based on the module genes, four machine models, RF, SVM, XGB, and GLM, were constructed to screen the predictive genes and further construct the AMD clinical prediction model. The accuracy of the column line graphs was evaluated using decision and calibration curves. Results: Firstly, we identified 15 disease signature genes by lasso and SVM algorithms, which were associated with abnormal glucose metabolism and immune cell infiltration. Secondly, we identified 52 modular signature genes by WGCNA analysis. We found that SVM was the optimal machine learning model for AMD and constructed a clinical prediction model for AMD consisting of 5 predictive genes. Conclusion: We constructed a disease signature genome model and an AMD clinical prediction model by LASSO, WGCNA, and four machine models. The disease signature genes are of great reference significance for AMD etiology research. At the same time, the AMD clinical prediction model provides a reference for early clinical detection of AMD and even becomes a future census tool. In conclusion, our discovery of disease signature genes and AMD clinical prediction models may become promising new targets for the targeted treatment of AMD.

Impact of a staggered scaffold structure on the mechanical properties and cell response in bone tissue engineering.

The primary goal of bone tissue engineering is to fabricate scaffolds that can provide a microenvironment similar to that of natural bone. Therefore, various scaffolds have been designed to replicate the bone structure. Although most tissues exhibit complicated structures, their basic structural unit includes stiff platelets arranged in a staggered micro-array. Therefore, many researchers have designed scaffolds with staggered patterns. However, relatively few studies have comprehensively analyzed this type of scaffold. In this review, we have analyzed scientific research pertaining to staggered scaffold designs and summarized their effects on the physical and biological properties of scaffolds. Compression tests or finite element analysis are typically used to evaluate the mechanical properties of scaffolds, and most studies have performed experiments in cell cultures. Staggered scaffolds improve mechanical strength and are beneficial for cell attachment, proliferation, and differentiation in comparison with conventional designs. However, very few have been studied in vivo experiments. Additionally, studies on the effect of staggered structures on angiogenesis or bone regeneration in vivo, particularly in large animals, are required. Currently, with the prevalence of artificial intelligence (AI)-based technologies, highly optimized models can be developed, resulting in better discoveries. In the future, AI can be used to deepen our understanding on the staggered structure, promoting its use in clinical applications.

Utilization of PAX1 methylation test for cervical cancer screening of non-HPV16/18 high-risk HPV infection in women.

Aim: To evaluate the clinical performance of PAX1 methylation (PAX1m) and cytology for patients with non-HPV16/18 high-risk HPV (hrHPV) infection. Methods: Cervical exfoliated cells from 387 outpatients with non-HPV16/18 hrHPV - positive were collected for cytology and PAX1m assays. Results: The PAX1m level increased with the severity of cytology and histopathology. For cervical intraepithelial neoplasia (CIN)CIN2+/CIN3+, the areas under the curve were both 0.87. The specificity and positive predictive value (PPV) of PAX1m were greater than abnormal cytology (CIN2+ specificity: 75.5 vs 24.8%; PPV: 38.8 vs 18.7%; CIN3+ specificity: 69.3 vs 22.7%; PPV: 14.0 vs 6.7%). Conclusion: PAX1m increased specificity and PPV for CIN2+/CIN3+ compared with cytology for women with non-HPV16/18 hrHPV (+).

Epstein-Barr virus downregulates the α7 nicotinic acetylcholine receptor of CD8+ T lymphocytes might associate with coronary artery lesions in Kawasaki disease patients.

OBJECTIVES: Kawasaki disease (KD) is a systemic vasculitis that is caused by immunological dysregulation in children exposed to pathogens like Epstein-Barr virus (EBV). Myocardial ischemia or infarction due to coronary artery lesions (CALs) might be lethal. However, it is unclear how pathogens, immunomodulation, and CALs interact, particularly in KD patients co-infected with the most widespread virus, EBV. METHODS: We investigated pathogen carriage and fundamental clinical data in 281 KD patients. Immunological differences between CALs and non-CALs in KD patients under different conditions were analyzed. Then, the effect of infection by different pathogens on the immune response was excluded, and most EBV co-infected KD patients were included to assess the incidence of CALs, the level of immune modulation, and regulatory mechanisms in different EBV infection states. RESULTS: Our results showed multiple pathogenic infections occur in KD patients, with EBV being the most prevalent. The incidence of CALs in the EBV-DNA (+) acute infection group, EBV-DNA (-) acute infection group, and EBV latent infection group was 0 (0/6), 27.27% (3/11) and 41.67% (10/24), respectively. The two groups were younger and had increased IL-6 levels and B cells, decreasing CD8+ T cells than the EBV-DNA (+) acute infection group. Interestingly, the increased B cells were not associated with immunoglobulin release. Additionally, these patients down-regulated α7 nicotinic acetylcholine receptor (α7nAChR) and downstream molecule PI3K/AKT/mTOR while activating the NF-κB. CONCLUSION: Patients with different EBV infection statuses exhibit different incidences of CALs. In acute EBV-DNA (-) infected and latent EBV-infected patients, the number of CD8+ T cells decreased and downregulated CD8+ T cells' α7nAChR and PI3K/AKT/mTOR, which may associate with CALs, while the expression of NF-κB and the pro-inflammatory factor IL-6 was upregulated by inhibiting the anti-inflammatory molecule α7nAChR.

Visible Light-Driven Micromotors in Fuel-Free Environment with Promoted Ion Tolerance.

Light-driven electrophoretic micromotors have gained significant attention recently for applications in drug delivery, targeted therapy, biosensing, and environmental remediation. Micromotors that possess good biocompatibility and the ability to adapt to complex external environments are particularly attractive. In this study, we have fabricated visible light-driven micromotors that could swim in an environment with relatively high salinity. To achieve this, we first tuned the energy bandgap of rutile TiO2 that was hydrothermally synthesized, enabling it to generate photogenerated electron-hole pairs under visible light rather than solely under UV. Next, platinum nanoparticles and polyaniline were decorated onto the surface of TiO2 microspheres to facilitate the micromotors swimming in ion-rich environments. Our micromotors exhibited electrophoretic swimming in NaCl solutions with concentrations as high as 0.1 M, achieving a velocity of 0.47 µm/s without the need for additional chemical fuels. The micromotors' propulsion was generated solely by splitting water under visible light illumination, therefore offering several advantages over traditional micromotors, such as biocompatibility and the ability to operate in environments with high ionic strength. These results demonstrated high biocompatibility of photophoretic micromotors and high potential for practical applications in various fields.

Natural carrier-free self-assembled diterpene nanoparticles with its efficient anti-inflammation through the inhibition of NF-κB pathway for accelerated wound healing.

Nanoscience has set off a wave in biomedicine to improve the performance of drugs in recent years, but additional materials are usually required for supramolecular nanoconstruction, undoubtedly increasing the health risks. Herein, we discovered a novel diterpene supramolecular self-assembly system without additional chemicals, Nepebracteatalic Acid nanoparticles (NA NPs), mediated through hydrogen bond, hydrophobic and electrostatic interaction. NA NPs performed sustained release behavior, lower expression levels for IL-6 and TNF-α than clinical anti-inflammatory drug Indometacin. Furthermore, the effect of NA NPs on the related protein p65 expression levels of nuclear factor-κB (NFκB) signaling pathway is quantified to confirm the enhanced anti-inflammatory property based on the self-assembly strategy. Meanwhile, the prepared nanoparticles have good biocompatibility which ensures outstanding inflammation inhibition, collagen deposition, angiogenesis during wound healing. This work opens up new prospects that carrier-free nanoparticles from NPMs have great potential to exert clinical application value, meanwhile providing reference for developing green nanoscience.

Synthesis of 2-Fluorobenzofuran by Photocatalytic Defluorinative Coupling and 5-endo-trig Cyclization.

An alkyl radical-triggered dual C-F bond cleavage of α-CF3-ortho-hydroxystyrenes for the synthesis of 2-fluorobenzofurans was developed. The visible-light-induced defluorinative cross-coupling reactions of α-CF3-ortho-hydroxystyrenes with a variety of carboxylic acids produced gem-difluoroalkenes, which underwent SNV-type 5-endo-trig cyclization to give 2-fluorobenzofurans. Mechanistic studies indicated that the electron transfer between phenoxyl radicals and carboxylates was the major pathway for the generation of alkyl radicals.