G-Quadruplex-Mediated Transcriptional Regulation of SYT7: Implications for Tumor Progression and Therapeutic Strategies.

Synaptotagmin 7 (SYT7), a member of the synaptotagmin family, exhibits high expression in various tumors and is closely associated with patient prognosis. The tight regulation of SYT7 expression assumes paramount significance in the progression of tumorigenesis. In this study, we detected a high GC content in the first 1000 bp of the promoter region of SYT7, suggesting a potential role of the G-quadruplex in its transcriptional regulation. Circular dichroism spectroscopy results showed that -187 to -172 bp sequence can form a typical parallel G-quadruplex structure, and site mutation revealed the critical role of the ninth guanine in its formation. Then, treatment of two ligands of G-quadruplex (TMPyP4 and Pyridostatin) reduced both the expression of SYT7 and subsequent tumor proliferation, demonstrating the potential of the G-quadruplex as a targeted therapy for tumors. By shedding light on the pivotal role of the G-quadruplex in regulating SYT7 transcription, our study not only advances our comprehension of this intricate regulatory mechanism but also emphasizes the significance of SYT7 in tumor proliferation. These findings collectively contribute to a more comprehensive understanding of the interplay between G-quadruplex regulation and SYT7 function in tumor development.

The 8-oxoguanine DNA glycosylase-synaptotagmin 7 pathway increases extracellular vesicle release and promotes tumour metastasis during oxidative stress.

Reactive oxygen species (ROS)-induced oxidative DNA damages have been considered the main cause of mutations in genes, which are highly related to carcinogenesis and tumour progression. Extracellular vesicles play an important role in cancer metastasis. However, the precise role of DNA oxidative damage in extracellular vesicles (EVs)-mediated cancer cell migration and invasion remains unclear. Here, we reveal that ROS-mediated DNA oxidative damage signalling promotes tumour metastasis through increasing EVs release. Mechanistically, 8-oxoguanine DNA glycosylase (OGG1) recognises and binds to its substrate 8-oxo-7,8-dihydroguanine (8-oxoG), recruiting NF-κB to the synaptotagmin 7 (SYT7) promoter and thereby triggering SYT7 transcription. The upregulation of SYT7 expression leads to increased release of E-cadherin-loaded EVs, which depletes intracellular E-cadherin, thereby inducing epithelial-mesenchymal transition (EMT). Notably, Th5487, the inhibitor of DNA binding activity of OGG1, blocks the recognition and transmission of oxidative signals, alleviates SYT7 expression and suppresses EVs release, thereby preventing tumour progression in vitro and in vivo. Collectively, our study illuminates the significance of 8-oxoG/OGG1/SYT7 axis-driven EVs release in oxidative stress-induced tumour metastasis. These findings provide a deeper understanding of the molecular basis of cancer progression and offer potential avenues for therapeutic intervention.

Ultralow-resistance and self-sterilization biodegradable nanofibrous membranes for efficient PM0.3 removal and machine learning-assisted health management.

The development of multifunctional nanofibrous membranes (NFMs) that enable anti-viral protection during air purification and respiratory disease diagnosis for health management is of increasing importance. Herein, we unraveled a heterostructure-enhanced electro-induced stereocomplexation (HEIS) strategy to fabrication of poly(lactic acid) (PLA) NFMs enabling a combination of efficient PM removal, respiratory monitoring and self-sterilization. The strategy involved an electro-induced stereocomplexation (EIS) approach to trigger the generation of hydrogen bonds between enantiomeric poly(L-lactic acid) (PLLA) and poly(D-lactic acid) (PDLA) chains, promoting CO dipole alignment and molecular polarization during electrospinning. This was further enhanced by incorporation of Ag-doped TiO2 (Ag-TIO) nanodielectrics to promote the electroactivity and surface activity, conferring profound refinement of PLA nanofibers (from 460 nm to an ultralow level of 168 nm) and high porosities of over 91 %. Arising from the sustainable generation of plentiful charges based on triboelectric nanogenerator (TENG) mechanisms, the electroactive PLA NFMs exhibited remarkable triboelectric properties even in high-humidity environments (80 %RH), excellent PM0.3 filtration efficiency with an ultralow pressure drop (93.1 %, 31.8 Pa, 32 L/min), and 100 % antimicrobial efficiency against both E. coli and S. aureus. Moreover, a deep-learning algorithm based on convolutional neural network (CNN) was proposed to recognize various respiratory patterns. The proposed strategy confers the biodegradable NFMs an unusual combination of ultralow-resistance air purification and machine learning-assisted health management, signifying promising prospects in environmental protection and personal healthcare.

Interfacial Polarization Strategy to Electroactive Poly(lactic acid) Nanofibers for Humidity-Resistant Respiratory Protection and Machine Learning-Assisted Monitoring.

The advancement of intelligent and biodegradable respiratory protection equipment is pivotal in the realm of human health engineering. Despite significant progress, achieving a balance between efficient filtration and intelligent monitoring remains a great challenge, especially under conditions of high relative humidity (RH) and high airflow rate (AR). Herein, we proposed an interfacial stereocomplexation (ISC) strategy to facilitate intensive interfacial polarization for poly(lactic acid) (PLA) nanofibrous membranes, which were customized for machine learning-assisted respiratory diagnosis. Theoretical principles underlying the facilitated formation of the electroactive phase and aligned PLA chains were quantitatively depicted in the ISC-PLA nanofibers, contributing to the increased dielectric constant and surface potential (as high as 2.2 and 5.1 kV, respectively). Benefiting from the respiration-driven triboelectric mechanisms, the ISC-PLA demonstrated a high PM0.3 filtration efficiency of over 99% with an ultralow pressure drop (75 Pa), even in challenging circumstances (95 ± 5% RH, AR of 85 L/min). Furthermore, we implemented the ISC-PLA with multifunction respiratory monitoring (response time of 0.56 s and recovery time of 0.25 s) and wireless transmission technology, yielding a high recognition rate of 83% for personal breath states. This innovation has practical implications for health management and theoretical advancements in respiratory protection equipment.

Orthogonal bioconjugation targeting cysteine-containing peptides and proteins using alkyl thianthrenium salts.

Late-stage specific and selective diversifications of peptides and proteins performed at target residues under ambient conditions are recognized to be the most facile route to various and abundant conjugates. Herein, we report an orthogonal modification of cysteine residues using alkyl thianthreium salts, which proceeds with excellent chemoselectivity and compatibility under mild conditions, introducing a diverse array of functional structures. Crucially, multifaceted bioconjugation is achieved through clickable handles to incorporate structurally diverse functional molecules. This "two steps, one pot" bioconjugation method is successfully applied to label bovine serum albumin. Therefore, our technique is a versatile and powerful tool for late-stage orthogonal bioconjugation.

Improving the efficacy of cancer immunotherapy by host-defence caerin 1.1 and 1.9 peptides.

Cancer remains a major global health challenge. Immunotherapy has revolutionized the management of cancer, yet only a limited number of patients respond to such treatments. This is largely attributed to the immunosuppressive tumor microenvironment, which diminishes the effectiveness of immunotherapy. Recent studies have underscored the potential of naturally derived caerin 1 peptides, particularly caerin 1.1 and caerin 1.9, which exhibit strong antitumor effects and enhance the efficacy of immunotherapies in animal models. This review encapsulates the current research aimed at augmenting the effectiveness of immunotherapy, focusing on the role of caerin 1.1 and caerin 1.9 in boosting immunotherapeutic outcomes, elucidating possible mechanisms, and discussing their limitations and challenges.

The genetic diversity and evolution analysis of the Hainan melioidosis outbreak strains.

Melioidosis is a zoonotic disease, with its outbreaks being rare and indicative of an unusual concurrence of extreme climate and natural environmental factors. An outbreak of melioidosis cases emerged in Hainan following Typhoon "Dianmu" from October to December 2021, presenting an opportunity to identify the environmental sources of infection for these cases due to its nature as a well-defined point-source cluster. To investigate the relationship between the occurrence of these melioidosis cases and the environment, we extracted the entire genome of 25 clinical strains and conducted MLST typing, followed by whole genome sequencing and analysis of molecular genetic information for four ST46 genotypes from these strains. Phylogenetic and evolutionary relationships between Hainan sequence types (STs) and those found in other endemic regions were analyzed using IslandPath-DIMO, PHASTER, e-BURST, PHYLOViZ, and the maximum likelihood method. Notably, a total of 25 clinical strains were identified, encompassing 12 STs (ST46, ST1105, ST1991, ST30, ST1992, ST50, ST164, ST55, ST70, ST1993, ST1545, and ST58), with ST1991, ST1992, and ST1993 being newly discovered subtypes. PHYLOViZ clustering analysis divided the strains into two groups (A and B), both closely related to the Asian region. Phylogenetic tree analysis further revealed that most of the strains in this study were closely related to those found in Australia and Thailand. Analysis of patient information and visits to their residences suggested that contaminated water sources might be the primary source of infection during this outbreak. Our findings underscore that extreme weather events, such as typhoons, significantly increase the infection rate of B. pseudomallei, along with its genetic diversity, necessitating additional prevention strategies to control these B. pseudomallei infections.

Celastrol alleviates atopic dermatitis by regulating Ezrin-mediated mitochondrial fission and fusion.

Celastrol, a bioactive molecule extracted from the plant Tripterygium wilfordii Hook F., possesses anti-inflammatory, anti-obesity and anti-tumour properties. Despite its efficacy in improving erythema and scaling in psoriatic mice, the specific therapeutic mechanism of celastrol in atopic dermatitis (AD) remains unknown. This study aims to examine the role and mechanism of celastrol in AD using TNF-α-stimulated HaCaT cells and DNCB-induced Balb/c mice as in vitro and in vivo AD models, respectively. Celastrol was found to inhibit the increased epidermal thickness, reduce spleen and lymph node weights, attenuate inflammatory cell infiltration and mast cell degranulation and decrease thymic stromal lymphopoietin (TSLP) as well as various inflammatory factors (IL-4, IL-13, TNF-α, IL-5, IL-31, IL-33, IgE, TSLP, IL-17, IL-23, IL-1ß, CCL11 and CCL17) in AD mice. Additionally, celastrol inhibited Ezrin phosphorylation at Thr567, restored mitochondrial network structure, promoted translocation of Drp1 to the cytoplasm and reduced TNF-α-induced cellular reactive oxygen species (ROS), mitochondrial ROS (mtROS) and mitochondrial membrane potential (MMP) production. Interestingly, Mdivi-1 (a mitochondrial fission inhibitor) and Ezrin-specific siRNAs lowered inflammatory factor levels and restored mitochondrial reticular formation, as well as ROS, mtROS and MMP production. Co-immunoprecipitation revealed that Ezrin interacted with Drp1. Knocking down Ezrin reduced mitochondrial fission protein Drp1 phosphorylation and Fis1 expression while increasing the expression of fusion proteins Mfn1 and Mfn2. The regulation of mitochondrial fission and fusion by Ezrin was confirmed. Overall, celastrol may alleviate AD by regulating Ezrin-mediated mitochondrial fission and fusion, which may become a novel therapeutic reagent for alleviating AD.

Caerin 1.9-Titanium Plates Aid Implant Healing and Inhibit Bacterial Growth in New Zealand Rabbit Mandibles.

OBJECTIVES: With rising rates of maxillofacial fracture, postoperative infection following rigid internal fixation is an important issue that requires immediate resolution. It is important to explore an alternative antibacterial method apart from conventional antibiotics. A controlled experiment was conducted to evaluate the effectiveness of a caerin 1.9 peptide-coated titanium plate in reducing mandibular infection in New Zealand (NZ) rabbits, aiming to minimise the risk of post-metallic implantation infection. METHODS: Twenty-two NZ rabbits were randomly divided into 3 groups. The experiment group received caerin 1.9 peptide-coated titanium plates and mixed oral bacteria exposure. The control group received normal titanium plates with mixed oral bacteria exposure. The untreated group served as a control to prove that bacteria in the mouth can cause infection. Weight, temperature, hepatic function, and C-reactive protein levels were measured. Wound and bone conditions were evaluated. Further analysis included local infection, anatomic conditions, histology, and bacterial load. RESULTS: No significant differences were found in temperature, weight, blood alanine aminotransferase, and C-reactive protein levels amongst the 3 groups. The experiment group showed the lowest amount of bacterial RNA in wounds. Additionally, the experiment group had higher peripheral lymphocyte counts compared to the control group and lower neutrophil counts on the third and seventh day postoperatively. Histologic analysis revealed lower levels of inflammatory cell infiltration, bleeding, and areas of necrosis in the experimental group compared with the controls. CONCLUSIONS: A caerin 1.9-coated titanium plate is able to inhibit bacterial growth in a NZ rabbit mandibular mixed bacteria infection model and is worth further investigation.

High output flexible polyvinylidene fluoride based piezoelectric device incorporating cellulose nanofibers/BaTiO3@TiO2 piezoelectric core-shell structure.

Flexible composite film has gained increasing attention in the fields of wearable devices and portable electronic products. In this work, a novel core-shell structure of cellulose nanofibers/BaTiO3@TiO2 (CNF/BTO@TiO2) was synthesized with the assistant of the biological macromolecule material of cellulose nanofiber (CNF), in which the CNF can improve the stability and dispersibility of BaTiO3 (BTO) in the aqueous phase and elevate the integrity of the core-shell structure. The core-shell structure can reduce the agglomeration of fillers in polyvinylidene fluoride (PVDF) and improve the structural defects of the composite film. Meanwhile, the core-shell structure can promote the polarization of the electric dipole and the formation of ß phase in PVDF due to the generated interface spatial polarization between the shell of TiO2 and the core of BTO. When the content of the core-shell structure was 5 wt%, the ß phase content reaches 61.89 %, and the piezoelectric coefficient of composite film reaches 84.29 pm/V. Thus the maximum output open-circuit voltage (VOC) and short-circuit current (ISC) of the piezoelectric composite film is as high as 13.10 V and 464.3 nA. In addition, its excellent pressure sensing capability allows for its application in various flexible electronic devices.