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Yun-Yun Yang,1 Wei Zhang,2 Hui Liu,2 Jun-Jie Jiang,2 Wen-Jie Wang,3 Zheng-Yan Jia4 1Outpatient Comprehensive Treatment, Cangzhou Central Hospital, Cangzhou, Hebei Province, People’s Republic of China; 2Department of Thyroid and Breast I, Cangzhou Central Hospital, Cangzhou, Hebei Province, People’s Republic of China; 3Department of General Surgery, Botou Hospital, Cangzhou, Hebei Province, People’s Republic of China; 4Department of General Surgery, Qingxian People’s Hospital, Cangzhou, Hebei Province, People’s Republic of ChinaCorrespondence: Wei ZhangDepartment of Thyroid and Breast I, Cangzhou Central Hospital, Cangzhou, Hebei Province, People’s Republic of ChinaEmail weiesiz685125@163.comIntroduction: Breast cancer is a malignant tumor that seriously threatens women’s life and health.Methods: In this study, we proposed to use graphene nanoparticles loaded with siRNA that can silence Rictor molecules essential for the mammalian target of rapamycin (mTOR) complex 2 (mTORC2) complex to enhance gene delivery to tumor cells through modification of cell-penetrating peptide (CPP) for the treatment of breast cancer.Results: Remarkably, we successfully synthesized graphene oxide (GO)/polyethyleneimine (PEI)/polyethylene glycol (PEG)/CPP/small interfering RNA (siRNA) system, and the results were observed by atomic force microscopy (AFM) and ultraviolet visible (UV-Vis) absorption spectra. The optimum mass ratio of siRNA to GO-PEI-PEG-CPP was 1:0.5. We screened out Rictor siRNA-2 from 9 candidates, which presented the highest inhibition rate, and this siRNA was selected for the subsequent experiments. We validated that Rictor siRNA-2 significantly reduced the Rictor expression in triple negative breast cancer (TNBC) cells. Confocal fluorescence microscope and flow cytometry analysis showed that GO-PEI-PEG-CPP/siRNA was able to be effectively uptake by TNBC cells. GO-PEI-PEG-CPP/siRNA improved the effect of siRNA on the inhibition of TNBC cell viability and the induction of TNBC cell apoptosis. The expression of Rictor and the phosphorylation of Akt and p70s6k were inhibited by GO-PEI-PEG-CPP/siRNA. Tumorigenicity analysis in nude mice showed that GO-PEI-PEG-CPP/siRNA significantly repressed the tumor growth of TNBC cells in vivo. The levels of ki-67 were repressed by GO-PEI-PEG-CPP/siRNA, and the apoptosis was induced by GO-PEI-PEG-CPP/siRNA in the system.Discussion: Therefore, we concluded that CPP-modified GO nanoparticles loaded with Rictor siRNA significantly repressed TNBC progression by the inhibition of PI3K/Akt/mTOR signaling. Our finding provides a promising therapeutic strategy for the treatment of TNBC.Keywords: triple-negative breast cancer, graphene oxide, cell-penetrating peptide, Rictor, PI3K/Akt/mTOR signaling

Danling Liu,1,* Tingting Qian,1,* Shan Sun,1 Jack J Jiang1,2 1Otorhinolaryngology Department, ENT Institute, Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology, NHC Key Laboratory of Hearing Medicine Research, Fudan University, Shanghai 200032, People’s Republic of China; 2Department of Surgery, Division of Otolaryngology Head and Neck Surgery, University of Wisconsin Medical School, Madison, WI 53792-7375, USA*These authors contributed equally to this workCorrespondence: Shan Sun Email Shansun@fudan.edu.cnJack J Jiang Email jjjiang@fudan.edu.cnAbstract: The upper aerodigestive tract (UAT) is the first line of defense against environmental stresses such as antigens, microbes, inhalants, foods, etc., and mucins, intracellular junctions, epithelial cells, and immune cells are the major constituents of this defensive mucosal barrier. Laryngopharyngeal reflux (LPR) is recognized as an independent risk factor for UAT mucosal disorders, and in this review, we describe the components and functions of the mucosal barrier and the results of LPR-induced mucosal inflammation in the UAT. We discuss the interactions between the refluxate and the mucosal components and the mechanisms through which these damaging events disrupt and alter the mucosal barriers. In addition, we discuss the dynamic alterations in the mucosal barrier that might be potential therapeutic targets for LPR-induced disorders.Keywords: laryngopharyngeal reflux, LPR, upper aerodigestive tract, UAT, inflammatory response, mucosal barrier dysfunction

Yili Zhang,1 Junjie Jiang,1 Hao Shen,1 Yan Chai,2 Xu Wei,3 Yanming Xie1 1Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China; 2Department of Epidemiology, University of California, Los Angeles, CA, USA; 3Department of Scientific Research, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing, China Abstract: This systematic review was performed to determine the clinical efficacy and safety of total flavonoids from Rhizoma Drynariae (TFRD) for osteoporotic fractures and to provide clear evidence for clinical practice. Eight databases were searched to identify relevant randomized controlled trials (RCTs) until December 2016. Six RCTs involving 846 patients were included. The primary outcomes included fracture recurrence and death. Meta-analysis showed that both the combination therapy and TFRD alone were better than conventional treatments in improving bone mineral density (BMD) value (weighted mean difference [WMD] =3.68, 95% confidence interval [CI]: 0.01 to 0.04, P=0.0002), (WMD =0.14; 95% CI: 0.11 to 0.16; P

Global aquaculture relies heavily on the farming of non-native aquatic species (hereafter, NAS). NAS escapes from aquaculture facilities can result in serious aquatic bio-invasions, which has been an important issue in the FAO Blue Growth Initiative. A regulatory quagmire regarding NAS farming and escapes, however, exists in most developing countries. We discuss aquaculture expansion and NAS escapes, illustrate emerging risks and propose recommendations for improved aquaculture management across developing countries and particularly for China. In China, 68 NAS are known to have successfully established feral populations in natural habitats due to recurrent leakages or escapes; among the 68 NAS, 52 represent risks to native aquatic ecosystems. In addition to affecting a country's own biodiversity and ecosystem functions, NAS escapees can also threaten the biosecurity of shared waters in neighbouring countries. Policy implications. Non-native aquatic species (NAS) escapes have already had adverse ecological effects in China and other developing countries. The importance of this problem, however, is not adequately recognized by current conservation policies in developing countries. To conserve biodiversity and to support the goal of FAO's sustainable aquaculture, developing countries should now take responsible actions to address NAS escapes through policy and management improvements. Specifically, these countries should pass comprehensive legislation, establish effective agencies and national standards and planning and enhance integrated research and education to deal with risk assessment, prevention, monitoring and control of NAS escapes. Given that China is the world's largest aquacultural producer, China can create a model for other developing countries that will increase the biosecurity and sustainability of global aquaculture.

Purpose: For spatiotemporal analysis to become a relevant clinical tool, it must be applied to human vocal fold vibration. Receiver operating characteristic (ROC) analysis will help assess the ability of spatiotemporal parameters to detect pathological vibration.Materials and Methods: Spatiotemporal parameters of correlation length and entropy were extracted from high-speed videos of 124 subjects, 67 without vocal fold pathology and 57 with either vocal fold polyps or nodules. Mann-Whitney rank sum tests were performed to compare normal vocal fold vibrations to pathological vibrations, and ROC analysis was used to assess the diagnostic value of spatiotemporal analysis.Results: A statistically significant difference was found between the normal and pathological groups in both correlation length (P < .001) and entropy (P < .001). The ROC analysis showed an area under the curve of 0.85 for correlation length, 0.87 for entropy, and 0.92 when the 2 parameters were combined. A statistically significant difference was not found between the nodules and polyps groups in either correlation length (P = .227) or entropy (P = .943). The ROC analysis showed an area under the curve of 0.63 for correlation length and 0.51 for entropy.Conclusions: Although they could not effectively distinguish vibration of vocal folds with nodules from those with polyps, the spatiotemporal parameters correlation length and entropy exhibit the ability to differentiate normal and pathological vocal fold vibration and may represent a diagnostic tool for objectively detecting abnormal vibration in the future, especially in neurological voice disorders and vocal folds without a visible lesion. [ABSTRACT FROM AUTHOR]

The human vocal fold is treated as a continuous, transversally isotropic, porous solid saturated with liquid. A set of mathematical equations, based on the theory of fluid-saturated porous solids, is developed to formulate the vibration of the vocal fold tissue. As the fluid-saturated porous tissue model degenerates to the continuous elastic tissue model when the relative movement of liquid in the porous tissue is ignored, it can be considered a more general description of vocal fold tissue than the continuous, elastic model. Using the fluid-saturated porous tissue model, the vibration of a bunch of one-dimensional fibers in the vocal fold is analytically solved based on the small-amplitude assumption. It is found that the vibration of the tissue will lead to the accumulation of excess liquid in the midmembranous vocal fold. The degree of liquid accumulation is positively proportional to the vibratory amplitude and frequency. The correspondence between the liquid distribution predicted by the porous tissue theory and the location of vocal nodules observed in clinical practice, provides theoretical evidence for the liquid accumulation hypothesis of vocal nodule formation (Jiang, Ph.D., dissertation, 1991, University of Iowa). [ABSTRACT FROM AUTHOR]

The purpose of this study was to evaluate the clinical utility of nonlinear dynamic analysis methods, including phase space portraits and measures of the correlation dimension (D(2)) to predict pre- versus post-treatment change in perceived dysphonia severity in a group of 88 patients with muscle tension dysphonia (MTD). Pre- and posttreatment vowel samples from 88 women with primary MTD (mean age=46.2 years; standard deviation=13.1) were selected for analysis (176 voice samples in total). Phase space reconstructions and correlation dimensions were computed to describe the nonlinear dynamic characteristics of all voice samples. Ten blinded listeners were asked to rate the vowel samples for severity of dysphonia using a 100-point visual analog scale (VAS). In the computation of D(2) results, 22 severely dysphonic pretreatment voice samples were not analyzed, as a finite value for the correlation dimension could not be computed. For the remaining pre-/post-treatment voice samples, a significant difference in the correlation dimension (D(2)) between the pre- versus post-treatment voice samples was observed; however, D(2) was poorly correlated with changes in perceived dysphonia severity ratings after treatment (r=0.244, P=0.056). Thus, the utility of the correlation dimension (D(2)) as a treatment-outcome measure and as a measure of dysphonia that may strongly relate to perceived dysphonia severity does not appear to be supported, particularly for pretreatment voices that may have increased levels of dysphonia severity. Instead, the strength of nonlinear dynamic methods may potentially reside in providing some insight into the theoretical rules or initial conditions that may result in different modes of normal or disordered phonation. [ABSTRACT FROM AUTHOR]

Objectives/hypothesis: The present study proposed to estimate phonation threshold pressure (PTP) noninvasively using airflow redirection into a pneumatic capacitance system.Study Design: Prospective study.Methods: Subjects phonated into the device, which interrupts airflow mechanically and redirects the flow into a pneumatic capacitor. Five interruptions were effected per trial. PTP was estimated as the difference between subglottal pressure (SGP) and transglottal pressure at phonation offset. The novel method was tested for consistency in 20 normal human subjects at low (75 dB) and high (85 dB) sound pressure levels. The device was tested for validity on a tracheotomy patient.Results: Mean SGP was 9.02 +/- 3.27 cm H(2)O, and mean PTP was 3.68 +/- 1.41 cm H(2)O. Intrasubject coefficient of variation, a measure of intrasubject consistency, was 0.33 +/- 0.23. Statistically significant differences existed between the means of SGP but not PTP at 75 dB and 85 dB. The correlation coefficient between accepted and experimental SGP in a tracheotomy patient was 0.947 (P < .001).Conclusions: Measurements corresponded well to previously reported values, and intrasubject variability was low, indicating the device was consistent. Testing on a tracheotomy patient demonstrated validity. More research is needed to determine the sensitivity and specificity of the device in differentiating between normal and pathological voices. This device may have clinical application as a noninvasive and reliable method of estimating PTP and indicating that laryngeal health is likely abnormal. [ABSTRACT FROM AUTHOR]

Lasers are a relatively recent addition to laryngeal surgery. Since their invention, laser use and applications have expanded rapidly. In this article, we discuss the benefits and disadvantages of lasers for different procedures, as well as ways to overcome commonly faced clinical problems. The use of lasers in surgery has offered a time- and cost-efficient alternative to cold surgical techniques, and has been used in the treatment of numerous laryngeal pathologies, including stenoses, recurrent respiratory papillomatosis, leukoplakia, nodules, malignant laryngeal disease, and polypoid degeneration (Reinke's edema). However, lasers can incur adjacent tissue damage and vocal fold scarring. These problems can be minimized through understanding the mechanisms by which lasers function and correctly manipulating the parameters under a surgeon's control. By varying fluence, power density, and pulsation, tissue damage can be decreased and lasers can be used with greater confidence. The various types of lasers and their applications to the treatment of specific pathologies are reviewed with the intention of helping surgeons select the best tool for a given procedure. Recent applications of lasers to treat benign laryngeal lesions and severe laryngomalacia demonstrate that additional research must be conducted to realize the full potential of this surgical tool. [ABSTRACT FROM AUTHOR]

High-speed digital imaging can provide valuable information on disordered voice production in voice science. However, the large amounts of high-speed image data with limited image resolutions produce significant challenges for computer analysis, and thus effective and efficient image edge extraction methods allowing for the batch analysis of high-speed images of vocal folds is clinically important. In this paper, a novel algorithm for automatic image edge detection is proposed to effectively and efficiently process high-speed images of the vocal folds. The method integrates Lagrange interpolation, differentiation, and Canny edge detection, which allow objective extraction of aperiodic vocal fold vibratory patterns from large numbers of high-speed digital images. This method and two other popular algorithms, histogram and active contour, are performed on 10 sets of high-speed video data from excised larynx experiments to compare their performances in analyzing high-speed images. The accuracy in computing glottal area and the computation time of these methods are investigated. The results show that our proposed method provides the most accurate and efficient detection, and is applicable when processing low-resolution images. In this study, we focus on developing a method to effectively and efficiently process high-speed image data from excised larynges. However, in addition we show the clinical potential of this method by use of example high-speed image data obtained from a patient with vocal nodules.The proposed automatic image-processing algorithm may provide a valuable biomedical application for the clinical assessment of vocal disorders by use of high-speed digital imaging. [ABSTRACT FROM AUTHOR]

Objective: In recent years, a growing body of evidence has been reported that a tumor clone is organized as a hierarchy that originates from rare stem cells. CD133, a cell surface antigen, was identified as a stem cell maker for human leukemia, brain tumors, and prostate cancer. The purpose of this study was to detect the expression of CD133, a putative marker of cancer stem cells in the Hep-2 cell line, and isolate CD133 positive cells to observe their proliferation and differentiation ability in vitro. Method: Immunocytochemical staining technology and flow cytometry were used to detect the expression of the putative stem cell marker CD133 in a Hep-2 cell line. The immunomagnetic beads were applied to purify CD133 positive cells. CD133+ tumor cells were cultured in vitro to observe their ability to proliferate and differentiate. Results: Only a small proportion (<5%) of cells in the Hep-2 cell line expressed CD133. CD133+ cells possess a marked capacity for self renewal, extensive proliferation, and mutilineal differentiation potency in vitro. Conclusion: CD133 is one of the markers for cancer stem cells in human laryngeal tumors, the Hep-2 cell line. [ABSTRACT FROM AUTHOR]

The adaptability of insects to hosts has long been a focal point in the study of insect-plant interactions. The pea aphid (Acythosiphon pisum), a significant pest of numerous leguminous crops, not only inflicts direct economic losses but also disseminates various plant viruses. To understand how pea aphids adapt to diverse alfalfa varieties. We analyzed the differentially expressed genes (DEGs) of pea aphids in distinct alfalfa varieties using transcriptome sequencing, and subsequently conducted functional validation of these genes. Comparative analysis between pea aphids feeding on susceptible and resistant strains revealed that DEGs in aphids feeding on resistant strains were primarily associated with transcriptional enrichment in the sugar, amino acid, protein, and lipid metabolism pathways. Fourteen DEGs related to adaptation of the pea aphid to alfalfa were chosen, including five carboxylesterases (CarE), four cytochrome P450s, three glutathione S-transferases, and two peroxidases (POD). RT-qPCR results indicated significant up-regulation of two carboxylesterase genes and two peroxidase genes after 24 h of feeding resistant alfalfa (Gannong 5, GN5) compared to the susceptible varieties (Hunter River, LRH), particularly highlighting the high expression levels of ApCarE4 and ApPOD3. Simultaneously, RNAi-induced knockdown of ApCarE4 and ApPOD3 led to a higher mortality of pea aphids in the alfalfa Hunter River. These results indicate that ApPOD3 and ApCarE4 are involved in the detoxification of metabolic functions in the adaptation of pea aphids to host switching. These findings contribute to the understanding of pea aphid adaptation to host plants and lay a foundation for further exploration of the physiological roles of carboxylesterase and peroxidase genes in pea aphids., (© 2024. The Author(s).)

Due to a lack of understanding of the disease epidemiology and comprehensive control measures, tea leaf spot caused by Didymella segeticola has a significant negative impact on tea yield and quality in the tea plantations of Southwest China. Phenazine-1-carboxamide (PCN) is a phenazine compound derived from Pseudomonas species, which exhibits antimicrobial activity against various pathogens. However, its inhibitory mechanism is not yet clear. The current study evaluated the inhibitory activity of PCN against various phytopathogenic fungi and found that PCN has inhibitory activity against multiple pathogens, with a half-maximal effective concentration (EC 50 ) value for D. segeticola of 16.11 μg/mL in vitro and a maximum in-vivo curative activity of 72.28% toward tea leaf spot. Morphological changes in the hyphae after exposure to PCN were observed through microstructure and ultrastructure analysis, and indicated that PCN causes abnormalities in the hyphae, such as cytoplasmic coagulation, shortened hyphal inter-septum distances, and unclear boundaries of organelles. Transcriptomic analysis revealed that PCN upregulated the expression of genes related with energy metabolism. PCN significantly reduced the ATP concentration in the hyphae and decreased mitochondrial membrane potential. Molecular docking analysis indicated that PCN binds to one of the candidate target proteins, pyruvate dehydrogenase, with lower free energy of -10.7 kcal/mol. This study indicated that PCN can interfere with energy metabolism, reducing ATP generation, ultimately affecting hyphal growth. Overall, PCN shows potential for future application in the control of tea leaf spot due to its excellent antifungal activity and unique mode of action.

Tea leaf spot caused by Didymella segeticola is a disease that has recently been discovered in the tea plantations of Southwest China, and which has a significant negative impact on the yield and quality of tea leaves. Wuyiencin is a nucleotide antimicrobial that is effective against a range of fungal diseases. However, its mode of action is still unclear. The current study found that wuyiencin inhibited the mycelial growth of D. segeticola in vitro. Meanwhile, in vivo experiments confirmed that wuyiencin had a significant curative effect on tea leaf spot. Microscopic observation represented it damaged the organelles and nucleus in fungal cells. Reverse transcription quantitative PCR assays revealed that mycelium treated with wuyiencin at the half-maximal effective concentration (EC 50 ) dosage for 1 hour exhibited 3.23 times lower expression of Threonine dehydratase ( Td ) gene, which is responsible for producing pyruvate. The wild type (WT) strain had a 1.77-fold higher pyruvate concentration than that in the td mutant ( P < 0.05). The td mutant was more sensitive than the WT to wuyiencin treatment, with the EC 50 value in the td mutant being 30.01 μg/ml, compared with 82.34 μg/ml in the WT. Molecular docking demonstrated that wuyiencin bound to Td, with a binding energy of -10.47 kcal/mol. Compared with the WT strain, wuyiencin significantly reduced ATP concentration of the td mutant strain at dosages of 80.0 and 160.0 µg/ml. In total, wuyiencin reduced Td activity, inhibited pyruvate production, and decreased ATP content in the phytopathogenic fungus, ultimately disturbing the growth of the mycelium.

Gold nanoclusters (AuNCs) are a type of rising-star fluorescence nanomaterials, but their properties and applications are hindered by the multi-step synthesis and purification routes, as well as the lack of desired supporting substrates. To enhance optical performance and working efficiency, the synthesis and applications of AuNCs are suggested to be merged with emerging substrates. Herein, glutathione-modified hydrophilic rice papers are incubated in chloroauric acid aqueous solutions, and the oxidation-reduction reaction between glutathione and Au ions enables the in situ formation of fluorescent AuNCs on the solid fibres of rice papers. The in situ growth of fluorescent AuNCs on rice papers resulted in eye-catching fluorescence tracks, similar to traditional Chinese conventional calligraphy; thus, this fluoresence calligraphy is defined in this work. The entire process, including synthesis and signal responses, is extremely simple, rapid, and repeatable. Moreover, the diversity of additive chemical reagents in the studied rice papers resulted in responsive fluorescence calligraphy, and the as-synthesized AuNC materials exhibited high reliability and optical stability. Significantly, with the integration of synchronous formation and application of Au nanoclusters on hydrophilic paper substrates, high-performance logical gates and information encryption systems were constructed, remarkably facilitating the progress of molecular sensing and important information transmission.

The emergence of multidrug resistance (MDR) in malignant tumors is one of the major threats encountered currently by many chemotherapeutic agents. Among the various mechanisms involved in drug resistance, P-glycoprotein (P-gp, ABCB1), a member of the ABC transporter family that significantly increases the efflux of various anticancer drugs from tumor cells, and the metabolic enzyme CYP1B1 are widely considered to be two critical targets for overcoming MDR. Unfortunately, no MDR modulator has been approved by the FDA to date. In this study, based on pharmacophore hybridization, bioisosteric and fragment-growing strategies, we designed and synthesized 11 novel tetrahydroisoquinoline-benzo[h]chromen-4-one conjugates as dual ABCB1/CYP1B1 inhibitors. Among them, the preferred compound A10 exhibited the best MDR reversal activity (IC 50  = 0.25 μM, RF = 44.4) in SW620/AD300 cells, being comparable to one of the most potent third-generation P-gp inhibitors WK-X-34. In parallel, this dual ABCB1/CYP1B1 inhibitory effect drives compound A10 exhibiting prominent drug resistance reversal activity to doxorubicin (IC 50  = 4.7 μM, RF = 13.7) in ABCB1/CYP1B1-overexpressing DOX-SW620/AD300-1B1 resistant cells, which is more potent than that of the CYP1B1 inhibitor ANF. Furthermore, although compound A2 possessed moderate ABCB1/CYP1B1 inhibitory activity, it showed considerable antiproliferative activity towards drug-resistant SW620/AD300 and MKN45-DDP-R cells, which may be partly related to the increase of PUMA expression to promote the apoptosis of the drug-resistant MKN45-DDP-R cells as confirmed by proteomics and western blot assay. These results indicated that the tetrahydroisoquinoline-benzo[h]chromen-4-one conjugates may provide a fundamental scaffold reference for further discovery of MDR reversal agents., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jinyun Dong reports financial support was provided by the National Natural Science Foundation of China. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

A Cu(I)-catalyzed highly regioselective synthesis of 2-acetamidequinoline N -oxides using dioxazolones with quinoline N -oxides has been reported. The reaction possesses mild reaction conditions and excellent functional group compatibility. Furthermore, the addition of hydrochloric acid promotes the decomposition of copper complexes, which is beneficial for postprocessing.

Exploring the different spin states of central metals in the complex to regulate the anti-tumor activity of cancer cells is of great significance in drug design and clinical use. However, it is a challenge to build a strong coupling between spin states and anti-tumor activities in one system. Herein, we present two complexes {Fe II 2 L 2 [Pd II (CN) 4 ] 2 }·2H 2 O (L = Bztpen (1), Bztppn (2); Bztpen = N -benzyl- N , N ', N '-tris(2-pyridylmethyl)ethylenediamine, Bztppn = N -benzyl- N , N ', N '-tris(2-pyridylmethyl)propylenediamine) showing different cytotoxic activities actuated by fine-tuning the structure with different spin states of Fe(II). Magnetic susceptibility measurements and X-ray diffraction revealed that the Fe(II) ion in complexes 1 and 2 remains in the LS and HS state, respectively, at room temperature. Cytotoxicity tests indicate that complex 1 is more biologically effective than complex 2. In complex 2, however, the high-spin Fe(II) played a key role in regulating its in vitro antitumor effects and seems to be associated with ROS-mediated apoptosis. These findings offer a new avenue for developing anti-cancer drugs by designing complexes with different spin states.

Tea leaf spot caused by Lasiodiplodia theobromae is a newly discovered fungal disease in southwest China. Due to a lack of knowledge of its epidemiology and control strategies, the disease has a marked impact on tea yield and quality. Pyriofenone is a new fungicide belonging to the aryl phenyl ketone fungicide group, which has shown marked efficacy in controlling various fungal diseases. However, its mechanism of action is not yet understood. This study found that pyriofenone exhibits strong in vitro inhibitory activity against various phytopathogenic fungi. Specifically, it showed strong inhibitory activity against L. theobromae , with a half-maximal effective concentration (EC 50 ) value of 0.428 μg/ml determined by measuring mycelial growth rate. Morphological observations, using optical, scanning electron, and transmission electron microscopy, revealed that pyriofenone induces morphological abnormalities in L. theobromae hyphae. At lower doses, the hyphae became swollen, the distance between septa decreased, and the hyphal growth rate slowed. At higher doses and longer exposures, the hyphae collapsed. Transcriptomic and bioinformatic analyses indicated that pyriofenone can affect the expression of genes related to membrane transporters. Homology modeling suggested that pyriofenone may bind to a candidate target protein of the major facilitator superfamily (MFS) transporter, with a free binding energy of -7.1 kcal/mol. This study suggests that pyriofenone may potentially regulate the transport of metabolites in L. theobromae , thus affecting hyphal metabolism and interfering with hyphal growth. Pyriofenone exhibits in vitro inhibitory activity against various tea foliar pathogens and holds promise for future applications to the control of tea foliar diseases.

Membrane-free biphasic self-stratified batteries (MBSBs) utilizing aqueous/nonaqueous electrolyte systems have garnered significant attention owing to their flexible manufacturing and cost-effectiveness. In this study, we present an ultrastable high-voltage Mg MBSB based on an aqueous/nonaqueous electrolyte system. The engineered aqueous electrolyte had a wide electrochemical stability window of 3.24 V. The Mg metal anode features a Mg 2+ -conductive protective coating. Two metal-free redox compounds, 2,2,6,6-tetramethylpiperdinyl oxy ( TEMPO ) and N -propyl phenothiazine ( C3-PTZ ), were used as catholytes. The Mg|| TEMPO and Mg|| C3-PTZ MBSBs exhibited high cell voltages of 2.07 and 2.12 V, respectively, and were studied under static, stirred, and flow conditions. The Mg MBSBs were initially evaluated at different catholyte concentrations (0.1, 0.3, and 0.5 M) under static conditions. Notably, the Mg|| TEMPO (0.5 M) and Mg|| C3-PTZ (0.5 M) static batteries maintained exceptional performances over 500 cycles at 8 mA/cm 2 , with capacity retention rates of 97.84% and 98.87%, Coulombic efficiencies of 99.17% and 99.12%, and capacity utilization of 70.2% and 71.3%, respectively. Under stirred and flow conditions, the Mg|| TEMPO (0.5 M) and Mg|| C3-PTZ (0.5 M) batteries cycled 500 times at 12 mA/cm 2 demonstrated capacity retention rates of 99.82% and 99.88% (stirred), 93.58% and 92.16% (flow), respectively. Under flow conditions, the Mg|| TEMPO (0.5 M) and Mg|| C3-PTZ (0.5 M) batteries demonstrated power densities of 195 and 191 mW/cm 2 , respectively, surpassing those of 139 and 144 mW/cm 2 under static conditions. These cost-effective Mg MBSBs exhibit remarkable performance and advance the application of Mg chemistry in organic flow batteries.

Numerous studies have established a strong association between Malassezia and various skin disorders, including atopic dermatitis. Finding appropriate methods or medications to alleviate Malassezia-induced skin damage is of notable public interest. This study aimed to evaluate the therapeutic effect of the exopolysaccharide EPS1, produced by Paenibacillus polymyxa, on Malassezia restricta-induced skin damage. In vitro assays indicated that EPS1 reduced the expression of pro-inflammatory cytokine genes in TNF-α-induced HaCaT cells. In a murine model, EPS1 was found to mitigate clinical symptoms, reduce epidermal thickness and mast cell infiltration, improve skin barrier function, decrease pro-inflammatory cytokine levels associated with type 17 inflammation, enhance Tregs in the spleen, upregulate the transcription of Treg-related genes in skin lesions, and modulate the skin microbiota. This study is the first to report the alleviating effect of Paenibacillus exopolysaccharide on Malassezia-induced skin inflammation and its impact on the skin microbiota. These findings support the potential of Paenibacillus exopolysaccharides as consumer products and therapeutic agents for managing Malassezia-induced skin damage by improving skin barrier function, modulating immune responses, and influencing skin microbiota., Competing Interests: Declaration of competing interest The authors declare that they do not possess any financial or commercial conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The liver is a frequent site of metastasis in advanced gastric cancer (GC). Despite significant advancements in diagnostic and therapeutic techniques, the overall survival rate for patients afflicted with gastric cancer liver metastasis (GCLM) remains dismally low. Precision oncology has made significant progress in identifying therapeutic targets and enhancing our understanding of metastasis mechanisms through genome sequencing and molecular characterization. Therefore, it is crucial to have a comprehensive understanding of the various molecular processes involved in GCLM and the fundamental principles of systemic therapy to develop new treatment approaches. This paper aims to review recent findings on the diagnosis, potential biomarkers, and therapies targeting the multiple molecular processes of GCLM, with the goal of improving treatment strategies for patients with GCLM., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

To investigate the impact of chlorantraniliprole on Procambarus clarkii, acute toxicity tests were performed. Results indicated that 96 h post-exposure to chlorantraniliprole (60 mg/L) led to the separation of the hepatopancreas basement membrane, causing cell swelling, rupture, and vacuolation. Moreover, acid phosphatase (ACP) and alkaline phosphatase (AKP) activities exhibited divergent trends across four concentrations of chlorantraniliprole (0, 30, 60, and 90 mg/L). Hydrogen peroxide (H 2 O 2 ) and catalase (CAT) levels significantly increased, while total superoxide dismutase (T-SOD) and malonaldehyde (MDA) activities decreased, indicating oxidative stress in the hepatopancreas. A total of 276 differentially expressed genes (DEGs) were identified, with 204 up-regulated and 72 down-regulated. Out of these, 114 DEGs were successfully annotated and classified into 99 pathways, with a primary focus on the cytochrome P450-mediated xenobiotic metabolism pathway. The DEGs enriched in this pathway, along with transcriptome data, were validated using quantitative-polymerase chain reaction. This study enhances the transcriptome database of P. clarkii and provides fundamental insights into its immune defense and antioxidant mechanisms. Additionally, it lays a theoretical foundation for future research on disease prevention in P. clarkii within rice-shrimp culture systems., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Lysine (Lys) and arginine (Arg) play a crucial role in the human diets, medical diagnostics, and functional biomaterial synthesis. The imbalance of intake for these two amino acids causes various diseases. Although many analytical techniques have been reported for the detection of amino acids, there are still some issues such as the need for bulky instruments, professional operators, sensitivity to be improved, and real-time detection. Here, a novel colorimetric-fluorimetric probe based on a terphenyl derivative (TPT) has been synthesized for the precise detection of Lys and Arg. In the EtOH-H 2 O solution of TPT, the NH 2 group at the chain end of Lys/Arg undergoes a nucleophilic addition reaction with CN groups of benzothiazole groups of the probe TPT, which breaks the initial long-conjugated system of the probe molecule. As a result, blue shifts can be observed for both UV-vis absorption spectra and fluorescence spectra, accompanying with color changes of the TPT solution. The UV-vis absorption peak of TPT solution shifts from ∼410 nm to ∼325 nm, and the solution color changes from light-yellow to colorless. The fluorescence emission shifts from ∼580 nm to ∼470 nm and the bright-yellow TPT solution changes to blue under the irradiation of 365 nm UV light. For colorimetric method, the limits of detection (LoD) are 0.82 μM and 0.90 μM for Lys and Arg, respectively. For fluorimetric method, they are 2.02 nM and 1.62 nM for Lys and Arg, respectively. In addition, TPT has good selectivity and anti-interference for Lys and Arg. The synthesized probe TPT has been successfully used for the precise detection of Lys and Arg in drugs and for fluorescence imaging of living cells. This work demonstrates that terphenyl-based derivatives are promising organic probes for the detection of Lys and Arg, providing a new way for designing other amino acids probes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The emergence of large language models (LLMs) has provided robust support for application tasks across various domains, such as name entity recognition (NER) in the general domain. However, due to the particularity of the medical domain, the research on understanding and improving the effectiveness of LLMs on biomedical named entity recognition (BNER) tasks remains relatively limited, especially in the context of Chinese text. In this study, we extensively evaluate several typical LLMs, including ChatGLM2-6B, GLM-130B, GPT-3.5, and GPT-4, on the Chinese BNER task by leveraging a real-world Chinese electronic medical record (EMR) dataset and a public dataset. The experimental results demonstrate the promising yet limited performance of LLMs with zero-shot and few-shot prompt designs for Chinese BNER tasks. More importantly, instruction fine-tuning significantly enhances the performance of LLMs. The fine-tuned offline ChatGLM2-6B surpassed the performance of the task-specific model BiLSTM+CRF (BC) on the real-world dataset. The best fine-tuned model, GPT-3.5, outperforms all other LLMs on the publicly available CCKS2017 dataset, even surpassing half of the baselines; however, it still remains challenging for it to surpass the state-of-the-art task-specific models, i.e., Dictionary-guided Attention Network (DGAN). To our knowledge, this study is the first attempt to evaluate the performance of LLMs on Chinese BNER tasks, which emphasizes the prospective and transformative implications of utilizing LLMs on Chinese BNER tasks. Furthermore, we summarize our findings into a set of actionable guidelines for future researchers on how to effectively leverage LLMs to become experts in specific tasks.

Targeted protein degradation (TPD) is an emerging therapeutic paradigm aimed at eliminating the disease-causing protein with aberrant expression. Herein, we report a new approach to inducing intracellular glutathione peroxidase 4 (GPX4) protein degradation to trigger ferroptosis by bridging the target protein to heat shock protein 90 (HSP90), termed HSP90 interactome-mediated proteolysis targeting chimera (HIM-PROTAC). Different series of HIM-PROTACs were synthesized and evaluated, and two of them, GDCNF-2/GDCNF-11 potently induced ferroptosis via HSP90-mediated ubiquitin-proteasomal degradation of GPX4 in HT-1080 cells with DC 50 values of 0.18 and 0.08 μM, respectively. In particular, GDCNF-11 showed 15-fold more ferroptosis selectivity over GPX4 inhibitor ML162. Moreover, these two degraders effectively suppress tumor growth in the mice model with relatively low toxicity as compared to the combination therapy of GPX4 and HSP90 inhibitors. In general, this study demonstrated the feasibility of degrading GPX4 via HSP90 interactome, and thus provided a significant complement to existing TPD strategies.

One-dimensional (1D) van der Waals (vdW) heterotubes, where different kinds of 1D nanotubes coaxially nest inside each other, offer a flexible platform for promising applications. The various properties of these 1D heterotubes depend on their diameter. Here, we present a systematic theoretical investigation into the structural and electronic properties of two kinds of 1D transition-metal dichalcogenide (TMD) heterotubes. We demonstrate that the thermodynamic stability of 1D heterotubes is determined by their interlayer distance. Additionally, we establish that the band alignment transition changes from type I to type II in 1D TMD heterotubes. We identify two distinct transition mechanisms, originating from the exchange of either the valence band maximum or the conduction band minimum. According to an electrostatic model, the band alignment transition is attributed to the interlayer electric field effect, which depends on the heterotube diameter. The findings in this work provide valuable physical insights into the band alignment transition in 1D heterotubes and are instrumental for their potential applications in nanotechnology.

Chronic kidney disease (CKD) is a clinical syndrome characterized by persistent renal function decline. Renal fibrosis is the main pathological process in CKD, but an effective treatment does not exist. Stratifin (SFN) is a highly-conserved, multi-function soluble acidic protein. Therefore, this study explored the effects of SFN on renal fibrosis. First, we found that SFN was highly expressed in patients with CKD, as well as in renal fibrosis animal and cell models. Next, transforming growth factor-beta 1 (TGF-β 1 ) induced injury and fibrosis in human renal tubule epithelial cells, and SFN knockdown reversed these effects. Furthermore, SFN knockdown mitigated unilateral ureteral obstruction (UUO)-induced renal tubular dilatation and renal interstitial fibrosis in mice. Liquid chromatography-tandem mass spectrometry/mass spectrometry (LC-MS/MS), co-immunoprecipitation (Co-IP), and immunofluorescence co-localization assays demonstrated that SFN bound the non-muscle myosin-encoding gene, myosin heavy chain 9 (MYH9), in the cytoplasm of renal tubular epithelial cells. MYH9 knockdown also reduced Col-1 and α-SMA expression, which are fibrosis markers. Finally, silencing SFN decreased MYH9 expression, alleviating renal fibrosis. These results suggest that SFN promotes renal fibrosis in CKD by interacting with MYH9. This study may provide potential strategies for the treatment of CKD., Competing Interests: Declaration of competing interest We declare that we do not have any commercial or associative interest that represents., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Precision graphene nanoribbons (GNRs) offer distinctive physicochemical properties that are highly dependent on their geometric topologies, thereby holding great potential for applications in carbon-based optoelectronics and spintronics. While the edge structure and width control has been a popular strategy for engineering the optoelectronic properties of GNRs, non-hexagonal-ring-containing GNRs remain underexplored due to synthetic challenges, despite offering an equally high potential for tailored properties. Herein, we report the synthesis of a wavy GNR (wGNR) embedding periodic eight-membered rings into its carbon skeleton, which is achieved by the A2B2-type Diels-Alder polymerization between dibenzocyclooctadiyne (6) and dicyclopenta[e,l]pyrene-5,11-dione derivative (8), followed by a selective Scholl reaction of the obtained ladder-type polymer (LTP) precursor. The obtained wGNR, with a length of up to 30 nm, is thoroughly characterized by solid-state NMR, FT-IR, Raman, and UV-Vis spectroscopy with the support of DFT calculations. The non-planar geometry of wGNR efficiently prevents the inter-ribbon π-π aggregation, leading to photoluminescence in solution. Consequently, the wGNR can function as an emissive layer for organic light-emitting electrochemical cells (OLECs), offering a proof-of-concept exploration in implementing luminescent GNRs into optoelectronic devices. The fast-responding OLECs employing wGNR will pave the way for advancements in OLEC technology and other optoelectronic devices., (© 2024 Wiley‐VCH GmbH.)

A novel approach for efficient synthesis of chiral C,O-chelated BINOL/gold(iii) complexes by diastereomeric resolution using enantiopure BINOL as a chiral resolving agent was demonstrated. The BINOL/gold(iii) diastereomers with different solubility were separated by simple filtration, providing optically pure BINOL/gold(iii) complexes with up to >99 : 1 dr. By combining this with an efficient BINOL ligand dissociation process, a simple and column-free method for chiral resolution of racemic gold(iii) dichloride complexes on a gram scale was established, affording their enantiopure forms in good yields. Conversely, the resolved enantiopure gold(iii) dichloride complexes could serve as chiral resolving agents to resolve disubstituted BINOL derivatives, achieving both BINOLs and gold(iii) complexes in good to excellent yields (overall 77-96% and 76-95%, respectively) with a high optical purity of up to 99% ee. Through a consecutive chirality transfer process, the chiral information from an inexpensive chiral source was transferred to highly valuable gold(iii) complexes, followed by sterically bulky BINOL derivatives. This work would open a new synthetic strategy facilitating the development of structurally diverse chiral gold(iii) complexes and gold(iii)-mediated chiral resolution of BINOL derivatives. In addition, this new class of C,O-chelated BINOL/gold(iii) complexes achieved asymmetric carboalkoxylation of ortho -alkynylbenzaldehydes with an excellent enantioselectivity of up to 99% ee., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)