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Qiong Bai, Xuan Lai, Ai-Hua Zhang, Xin-Hong Lu, Shun-Li Tian, Min-Hua Fan, Yue Wang, Tao WangDivision of Nephrology, Peking University Third Hospital, Beijing, People's Republic of ChinaBackground: Cardiovascular disease is more common in patients with chronic kidney disease (CKD) than in the general population. Endothelial dysfunction is an early predictor of cardiovascular events.Objective: We conducted a cross-sectional study in CKD patients to explore the association of metabolic syndrome (MetS) components with endothelial cell function.Methods: We evaluated clinical and laboratory data in 161 CKD patients from stage 1 to stage 5. Endothelial function was estimated by flow-mediated dilatation (FMD) of the brachial artery and expressed as percentage change relative to baseline diameter. MetS was defined according to the National Cholesterol Education Program-Adult Treatment Panel III criteria.Results: Patients were grouped into two groups according to whether or not they had MetS. FMD was significantly lower in the MetS group than in the group without MetS (P = 0.012). In a Pearson's correlation analysis, FMD was significantly negatively correlated with waist circumference in women (r = –0.223, P = 0.03) and fasting blood glucose (r = –0.186, P = 0.001). Multiple linear regression analysis showed that fasting blood glucose was an independently associated factor for FMD.Conclusion: MetS and some components of MetS (waist circumference in women and fasting blood glucose) are closely associated with a decreased FMD in CKD patients.Keywords: metabolic syndrome, endothelial dysfunction, flow-mediated dilatation, chronic kidney disease

Vascular pathologies and injuries are important factors for the delayed wound healing in diabetes. Previous studies have demonstrated that hypoxic environments could induce formation of new blood vessels by regulating intercellular communication and cellular behaviors. In this study, we have enhanced the angiogenic potential of exosomes by subjecting urine-derived stem cells (USCs) to hypoxic preconditioning. To prolong the retention of exosomes at the wound site, we have also engineered a novel dECM hydrogel termed SISMA, which was modified from porcine small intestinal submucosa (SIS). For its rapid and controllable gelation kinetics, excellent biocompatibility, and exosome release capability, the SISMA hydrogel has proven to be a reliable delivery vehicle for exosomes. The hypoxia-induced exosomes-loaded hydrogel has promoted endothelial cell proliferation, migration, and tube formation. More importantly, as evidenced by significant in vivo vascular regeneration in the early stages post-injury, it has facilitated tissue repair. This may because miR-486-5p in H-exo inhibit SERPINE1 activity in endothelial cell. Additionally, miRNA sequencing analysis suggested that the underlying mechanism for enhanced angiogenesis may be associated with the activation of classical HIF-1α signaling pathway. In summary, our study has presented a novel non-invasive, cell-free therapeutic approach for accelerating diabetes wound healing and development of a practical and efficient exosomes delivery platform., 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. Published by Elsevier Ltd.)

The degradation of proteasomes or lysosomes is emerging as a principal determinant of programmed death ligand 1 (PDL1) expression, which affects the efficacy of immunotherapy in various malignancies. Intracellular cholesterol plays a central role in maintaining the expression of membrane receptors; however, the specific effect of cholesterol on PDL1 expression in cancer cells remains poorly understood. Cholesterol starvation and stimulation were used to modulate the cellular cholesterol levels. Immunohistochemistry and western blotting were used to analyze the protein levels in the samples and cells. Quantitative real-time PCR, co-immunoprecipitation, and confocal co-localization assays were used for mechanistic investigation. A xenograft tumor model was constructed to verify these results in vivo. Our results showed that cholesterol suppressed the ubiquitination and degradation of PDL1 in hepatocellular carcinoma (HCC) cells. Further mechanistic studies revealed that the autocrine motility factor receptor (AMFR) is an E3 ligase that mediated the ubiquitination and degradation of PDL1, which was regulated by the cholesterol/p38 mitogenic activated protein kinase axis. Moreover, lowering cholesterol levels using statins improved the efficacy of programmed death 1 (PD1) inhibition in vivo. Our findings indicate that cholesterol serves as a signal to inhibit AMFR-mediated ubiquitination and degradation of PDL1 and suggest that lowering cholesterol by statins may be a promising combination strategy to improve the efficiency of PD1 inhibition in HCC., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethical approval: This study was performed in line with the principles of the Declaration of Helsinki. This study was approved by the Ethics Committee of Ruian People’s Hospital (Grant No. YJ2024089). All animal experiments were approved by the Tab of Animal Experimental Ethical Inspection of Laboratory Animal Centre, Wenzhou Medical University (Grant No. wydw2020-0703). Consent to participate: Informed consent was obtained from all individual participants included in the study. Consent to publish: The authors affirm that human research participants provided informed consent for publication of the images in Fig. 1., (© 2024. The Author(s).)

Epilepsy, as a common brain disease, causes great pain and stress to patients around the world. At present, the main treatment methods are drug, surgical, and electrical stimulation therapies. Electrical stimulation has recently emerged as an alternative treatment for reducing symptomatic seizures. This study proposes a novel closed-loop epilepsy detection system and stimulation control chip. A time-domain detection algorithm based on amplitude, slope, line length, and signal energy characteristics is introduced. A new threshold calculation method is proposed; that is, the threshold is updated by means of the mean and standard deviation of four consecutive eigenvalues through parameter combination. Once a seizure is detected, the system begins to control the stimulation of a two-phase pulse current with an amplitude and frequency of 34 μA and 200 Hz, respectively. The system is physically designed on the basis of the UMC 55 nm process and verified by a field programmable gate array verification board. This research is conducted through innovative algorithms to reduce power consumption and the area of the circuit. It can maintain a high accuracy of more than 90% and perform seizure detection every 64 ms. It is expected to provide a new treatment for patients with epilepsy.

Three undescribed pregnane steroids, 12β-O-4-hydroxybenzoyl tenacigenin D (1), 12β-O-4-hydroxybenzoyl tenacigenin A (2), and 11α-nicotinoyl-17β-marsdenin (3), along with two known analogues (4 and 5), were isolated from the roots of Marsdenia tenacissima. Their structures were elucidated using one- and two-dimensional NMR, high-resolution electron ionization-mass spectrometry, single-crystal X-ray diffraction data, and experimental and density-functional-theory-calculated electronic circular dichroism measurements. All isolated compounds were evaluated for their cytotoxic activities against human lung cancer cells (A549), ovarian carcinoma cells (SKOV-3), gastric cancer cells (MGC 803) and breast cancer cells (MCF-7). Notably, 3 exhibited significant cytotoxic activity against both A549 (median inhibitory concentration (IC 50 )=16.79 μM) and SKOV-3 (IC 50 =12.30 μM) cells while exhibiting moderate cytotoxicity on MGC803 and MCF-7 cells., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

The atomic defect engineering could feasibly decorate the chemical behaviors of reaction intermediates to regulate catalytic performance. Herein, we created oxygen vacancies on the surface of In(OH) 3 nanobelts for efficient urea electrosynthesis. When the oxygen vacancies were constructed on the surface of the In(OH) 3 nanobelts, the faradaic efficiency for urea reached 80.1%, which is 2.9 times higher than that (20.7%) of the pristine In(OH) 3 nanobelts. At -0.8 V versus reversible hydrogen electrode, In(OH) 3 nanobelts with abundant oxygen vacancies exhibited partial current density for urea of -18.8 mA cm -2 . Such a value represents the highest activity for urea electrosynthesis among recent reports. Density functional theory calculations suggested that the unsaturated In sites adjacent to oxygen defects helped to optimize the adsorbed configurations of key intermediates, promoting both the C-N coupling and the activation of the adsorbed CO 2 NH 2 intermediate. In-situ spectroscopy measurements further validated the promotional effect of the oxygen vacancies on urea electrosynthesis.

In electrocardiograms (ECGs), multiple forms of encryption and preservation formats create difficulties for data sharing and retrospective disease analysis. Additionally, photography and storage using mobile devices are convenient, but the images acquired contain different noise interferences. To address this problem, a suite of novel methodologies was proposed for converting paper-recorded ECGs into digital data. Firstly, this study ingeniously removed gridlines by utilizing the Hue Saturation Value (HSV) spatial properties of ECGs. Moreover, this study introduced an innovative adaptive local thresholding method with high robustness for foreground-background separation. Subsequently, an algorithm for the automatic recognition of calibration square waves was proposed to ensure consistency in amplitude, rather than solely in shape, for digital signals. The original signal reconstruction algorithm was validated with the MIT-BIH and PTB databases by comparing the difference between the reconstructed and the original signals. Moreover, the mean of the Pearson correlation coefficient was 0.97 and 0.98, respectively, while the mean absolute errors were 0.324 and 0.241, respectively. The method proposed in this study converts paper-recorded ECGs into a digital format, enabling direct analysis using software. Automated techniques for acquiring and restoring ECG reference voltages enhance the reconstruction accuracy. This innovative approach facilitates data storage, medical communication, and remote ECG analysis, and minimizes errors in remote diagnosis.

Scarce and expensive iridium oxide is still the cornerstone catalyst of polymer-electrolyte membrane electrolyzers for green hydrogen production because of its exceptional stability under industrially relevant oxygen evolution reaction (OER) conditions. Earth-abundant transition metal oxides used for this task, however, show poor long-term stability. We demonstrate here the use of nitrogen-doped cobalt oxide as an effective iridium substitute. The catalyst exhibits a low overpotential of 240 mV at 10 mA cm -2 and negligible activity decay after 1000 h of operation in an alkaline electrolyte. Incorporation of nitrogen dopants not only triggers the OER mechanism switched from the traditional adsorbate evolution route to the lattice oxygen oxidation route but also achieves oxygen nonbonding (O NB ) states as electron donors, thereby preventing structural destabilization. In a practical anion-exchange membrane water electrolyzer, this catalyst at anode delivers a current density of 1000 mA cm -2 at 1.78 V and an electrical efficiency of 47.8 kW-hours per kilogram hydrogen.

The rational design of hydrogel materials to modulate the immune microenvironment has emerged as a pivotal approach in expediting tissue repair and regeneration. Within the immune microenvironment, an array of immune cells exists, with macrophages gaining prominence in the field of tissue repair and regeneration due to their roles in cytokine regulation to promote regeneration, maintain tissue homeostasis, and facilitate repair. Macrophages can be categorized into two types: classically activated M1 (pro-inflammatory) and alternatively activated M2 (anti-inflammatory and pro-repair). By regulating the physical and chemical properties of hydrogels, the phenotypic transformation and cell behavior of macrophages can be effectively controlled, thereby promoting tissue regeneration and repair. A full understanding of the interaction between hydrogels and macrophages can provide new ideas and methods for future tissue engineering and clinical treatment. Therefore, this paper reviews the effects of hydrogel components, hardness, pore size, and surface morphology on cell behaviors such as macrophage proliferation, migration, and phenotypic polarization, and explores the application of hydrogels based on macrophage immune regulation in skin, bone, cartilage, and nerve tissue repair. Finally, the challenges and future prospects of macrophage-based immunomodulatory hydrogels are discussed., 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.)

Characterized by their pivotal roles in cell-to-cell communication, cell proliferation, and immune regulation during tissue repair, exosomes have emerged as a promising avenue for "cell-free therapy" in clinical applications. Hydrogels, possessing commendable biocompatibility, degradability, adjustability, and physical properties akin to biological tissues, have also found extensive utility in tissue engineering and regenerative repair. The synergistic combination of exosomes and hydrogels holds the potential not only to enhance the efficiency of exosomes but also to collaboratively advance the tissue repair process. This review has summarized the advancements made over the past decade in the research of hydrogel-exosome systems for regenerating various tissues including skin, bone, cartilage, nerves and tendons, with a focus on the methods for encapsulating and releasing exosomes within the hydrogels. It has also critically examined the gaps and limitations in current research, whilst proposed future directions and potential applications of this innovative approach., Competing Interests: 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., (© 2024 The Authors.)

The three-dimensional (3D) cell culture technique has been applied comprehensively as a variable platform for medical research, biochemical signal pathway analysis, and evaluation of anti-tumor treatment response due to an excellent recapitulation of a tumor microenvironment (TME) in the in vitro cultured cancer cells. Pancreatic cancer (PaC) is one of the toughest malignancies with a complex TME and refractory treatment response. To comprehensively study the TME of PaC, there is an eager need to develop a 3D culture model to decompose the cellular components and their cross interactions. Herein, we establish a 3D PaC culture system with cancer stem cell (CSC) and scalability properties. To validate our model, we tested the individual PaC cell and the combined effects with cancer-associated fibroblasts (CAFs) on cancer tumorigenicity, the cellular interaction through the CXCR3/CXCL10 axis, and cellular responses reflection of anti-cancer treatments. With the help of our 3D technology, a simulated malignant spheroid with important stromal populations and TME physiochemical properties may be successfully recreated. It can be used in a wide range of preclinical research and helpful in advancing basic and translational cancer biology., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Reservoir computing is an effective model for learning and predicting nonlinear and chaotic dynamical systems; however, there remains a challenge in achieving a more dependable evolution for such systems. Based on the foundation of Koopman operator theory, considering the effectiveness of the sparse identification of nonlinear dynamics algorithm to construct candidate nonlinear libraries in the application of nonlinear data, an alternative reservoir computing method is proposed, which creates the linear Hilbert space of the nonlinear system by including nonlinear terms in the optimization process of reservoir computing, allowing for the application of linear optimization. We introduce an implementation that incorporates a polynomial transformation of arbitrary order when fitting the readout matrix. Constructing polynomial libraries with reservoir-state vectors as elements enhances the nonlinear representation of reservoir states and more easily captures the complexity of nonlinear systems. The Lorenz-63 system, the Lorenz-96 system, and the Kuramoto-Sivashinsky equation are used to validate the effectiveness of constructing polynomial libraries for reservoir states in the field of state-evolution prediction of nonlinear and chaotic dynamical systems. This study not only promotes the theoretical study of reservoir computing, but also provides a theoretical and practical method for the prediction of nonlinear and chaotic dynamical system evolution.

Rapid and effective control of non-compressible massive hemorrhage poses a great challenge in first-aid and clinical settings. Herein, a biopolymer-based powder is developed for the control of non-compressible hemorrhage. The powder is designed to facilitate rapid hemostasis by its excellent hydrophilicity, great specific surface area, and adaptability to the shape of wound, enabling it to rapidly absorb fluid from the wound. Specifically, the powder can undergo sequential cross-linking based on "click" chemistry and Schiff base reaction upon contact with the blood, leading to rapid self-gelling. It also exhibits robust tissue adhesion through covalent/non-covalent interactions with the tissues (adhesive strength: 89.57 ± 6.62 KPa, which is 3.75 times that of fibrin glue). Collectively, this material leverages the fortes of powder and hydrogel. Experiments with animal models for severe bleeding have shown that it can reduce the blood loss by 48.9%. Studies on the hemostatic mechanism also revealed that, apart from its physical sealing effect, the powder can enhance blood cell adhesion, capture fibrinogen, and synergistically induce the formation of fibrin networks. Taken together, this hemostatic powder has the advantages for convenient preparation, sprayable use, and reliable hemostatic effect, conferring it with a great potential for the control of non-compressible hemorrhage., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Electrochemical synthesis of valuable chemicals and feedstocks through carbon dioxide (CO 2 ) reduction in acidic electrolytes can surmount the considerable CO 2 loss in alkaline and neutral conditions. However, achieving high productivity, while operating steadily in acidic electrolytes, remains a big challenge owing to the severe competing hydrogen evolution reaction. Here, we show that vertically grown bismuth nanosheets on a gas-diffusion layer can create numerous cavities as electrolyte reservoirs, which confine in situ-generated hydroxide and potassium ions and limit inward proton diffusion, producing locally alkaline environments. Based on this design, we achieve formic acid Faradaic efficiency of 96.3% and partial current density of 471 mA cm -2 at pH 2. When operated in a slim continuous-flow electrolyzer, the system exhibits a full-cell formic acid energy efficiency of 40% and a single pass carbon efficiency of 79% and performs steadily over 50 h. We further demonstrate the production of pure formic acid aqueous solution with a concentration of 4.2 weight %., Competing Interests: Competing interests statement:The authors declare no competing interest.

The health of the aquatic ecosystem has recently been severely affected by cyanobacterial blooms brought on by eutrophication. Therefore, it is critical to develop efficient and secure methods to control dangerous cyanobacteria, such as Microcystis aeruginosa. In this research, we tested the inhibition of M. aeruginosa growth by a Scenedesmus sp. strain isolated from a culture pond. Scenedesmus sp. culture filtrate that had been lyophilized was added to M. aeruginosa, and cultivation for seven days, the cell density, chlorophyll a (Chl-a) concentration, maximum quantum yield of photosystem II (Fv/Fm), the activities of superoxide dismutase (SOD), catalase (CAT), and the concentration of malondialdehyde (MDA) and glutathione (GSH) were measured. Moreover, non-targeted metabolomics was carried out to provide light on the inhibitory mechanism in order to better understand the metabolic response. According to the results, M. aeruginosa is effectively inhibited by the lyophilized Scenedesmus sp. culture filtrate at a rate of 51.2%. Additionally, the lyophilized Scenedesmus sp. clearly inhibit the photosystem and damages the antioxidant defense system of M. aeruginosa cells, resulting in oxidative damage, which worsens membrane lipid peroxidation, according to changes in Chl-a, Fv/Fm, SOD, CAT enzyme activities and MDA, GSH. Metabolomics analysis revealed that the secondary metabolites of Scenedesmus sp. significantly interfere with the metabolism of M. aeruginosa involved in amino acid synthesis, membrane creation and oxidative stress, which is coherent with the morphology and physiology outcomes. These results demonstrate that the secondary metabolites of Scenedesmus sp. exert algal inhibition effect by breaked the membrane structure, destroyed the photosynthetic system of microalgae, inhibited amino acid synthesis, reduced antioxidant capacity, and eventually caused algal cell lysis and death. Our research provides a reliable basis for the biological control of cyanobacterial blooms on the one hand, and on other hand supply application of non-targeted metabolome on the study of microalgae allelochemicals., 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 © 2023 Elsevier Ltd. All rights reserved.)

Background: Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy with a 5-year survival rate of 6% following a diagnosis, and novel therapeutic modalities are needed. Protease-activated receptor 1 (PAR1) is abundantly overexpressed by both tumor cells and multiple stroma cell subsets in the tumor microenvironment (TME), thereby offering a suitable immunotherapy target., Methods: A chimeric antigen receptor (CAR) strategy was applied to target PAR1 using a human anti-PAR1 scFv antibody fused to the transmembrane region with two co-stimulatory intracellular signaling domains of cluster of differentiation 28 (CD28) and CD137 (4-1BB), added to CD3ζ in tandem., Results: The engineered PAR1CAR-T cells eliminated PAR1 overexpression and transforming growth factor (TGF)-β-mediated PAR1-upregulated cancer cells by approximately 80% in vitro. The adoptive transfer of PAR1CAR-T cells was persistently enhanced and induced the specific regression of established MIA PaCa-2 cancer cells by > 80% in xenograft models. Accordingly, proinflammatory cytokines/chemokines increased in CAR-T-cell-treated mouse sera, whereas Ki67 expression in tumors decreased. Furthermore, the targeted elimination of PAR1-expressing tumors reduced matrix metalloproteinase 1 (MMP1) levels, suggesting that the blocking of the PAR1/MMP1 pathway constitutes a new therapeutic option for PDAC treatment., Conclusions: Third-generation PAR1CAR-T cells have antitumor activity in the TME, providing innovative CAR-T-cell immunotherapy against PDAC., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Twenty-one previously undescribed compounds, including nineteen 3,4-seco-labdanes (nudiflopenes P-W, Y, A I -J I ), one 3,4-seco-pimarane (nudiflopene X), and one labdane (nudiflopene Z), along with nine known compounds (one 3,4-seco-pimarane and eight 3,4-seco-labdanes) were isolated from the leaves of Callicarpa nudiflora Hook. Et Arn. The structures of these compounds were elucidated by high-resolution electrospray ionization mass spectrometry and one- and two-dimensional nuclear magnetic resonance spectroscopy. In addition, configurations of the isolated compounds were determined by electronic circular dichroism, DP4+ probability analysis, and single-crystal X-ray diffraction experiments. All undescribed compounds were evaluated for their cytotoxicity against HepG2 cells in vitro, among which compound 12 exhibited a moderate activity with an IC 50 value of 27.8 μM., 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 © 2023 Elsevier Ltd. All rights reserved.)

Electrocatalytic carbon dioxide reduction (CO 2 R) in neutral electrolytes can mitigate the energy and carbon losses caused by carbonate formation but often experiences unsatisfied multicarbon selectivity and reaction rates because of the kinetic limitation to the critical carbon monoxide (CO)-CO coupling step. Here, we describe that a dual-phase copper-based catalyst with abundant Cu(I) sites at the amorphous-nanocrystalline interfaces, which is electrochemically robust in reducing environments, can enhance chloride-specific adsorption and consequently mediate local *CO coverage for improved CO-CO coupling kinetics. Using this catalyst design strategy, we demonstrate efficient multicarbon production from CO 2 R in a neutral potassium chloride electrolyte (pH ∼6.6) with a high Faradaic efficiency of 81% and a partial current density of 322 milliamperes per square centimeter. This catalyst is stable after 45 h of operation at current densities relevant to commercial CO 2 electrolysis (300 mA per square centimeter).

Artemisia annua L. is a Chinese medicinal herb, but the origin of its pharmacological properties, including its anti-inflammatory activity, remain unknown. In this study, five new monoterpene glycosides (1-5) and two new sesquiterpene glycosides (6 and 7) were isolated from the aqueous extract of the aerial parts of A. annua. The structures of these glycosides were determined using high-resolution electrospray ionization mass spectrometry, nuclear magnetic resonance spectroscopy, electronic circular dichroism calculations, and chemical hydrolysis methods. The anti-inflammatory activities of the isolated compounds were evaluated by down-regulating interleukin-6 (IL-6) in lipopolysaccharide-stimulated RAW 264.7 macrophages. Notably, all the new compounds significantly inhibited the expression of IL-6 in a dose-dependent manner., (© 2023 Wiley-VHCA AG, Zurich, Switzerland.)

Ethoxysanguinarine (ESG) is a benzophenanthridine alkaloid extracted from plants of Papaveraceae family, such as Macleaya cordata (Willd) R. Br. The anti-cancer activity of ESG has been rarely reported. In this study, we investigated the anti-breast cancer effect of ESG and its underlying mechanism. MTT assay and flow cytometry analysis showed that ESG inhibited the viability and induced apoptosis in MCF7 and MDA-MB-231 human breast cancer cells. Western blot revealed that ESG triggered intrinsic and extrinsic apoptotic pathways, as evidenced by the activation of caspase-8, caspase-9 and caspase-3. ESG attenuated breast cancer cell migration and invasion through Hakai/E-cadherin/N-cadherin. Moreover, Hakai knockdown sensitized ESG-triggered viability and motility inhibition, suggesting that Hakai mediated the anti-breast cancer effect of ESG. In addition, ESG potentiated the anti-cancer activity of docetaxel (DTX) in breast cancer cells. Overall, our findings demonstrate that ESG exhibits outstanding pro-apoptosis and anti-metastasis effects on breast cancer via a mechanism related to Hakai-related signaling pathway., (© 2023 Wiley-VHCA AG, Zurich, Switzerland.)

Urinary stone is conceptualized as a chronic metabolic disorder punctuated by symptomatic stone events. It has been shown that the occurrence of calcium oxalate monohydrate (COM) during stone formation is regulated by crystal growth modifiers. Although crystallization inhibitors have been recognized as a therapeutic modality for decades, limited progress has been made in the discovery of effective modifiers to intervene with stone disease. In this study, we have used metabolomics technologies, a powerful approach to identify biomarkers by screening the urine components of the dynamic progression in a bladder stone model. By in-depth mining and analysis of metabolomics data, we have screened five differential metabolites. Through density functional theory studies and bulk crystallization, we found that three of them (salicyluric, gentisic acid and succinate) could effectively inhibit nucleation in vitro. We thereby assessed the impact of the inhibitors with an EG-induced rat model for kidney stones. Notably, succinate, a key player in the tricarboxylic acid cycle, could decrease kidney calcium deposition and injury in the model. Transcriptomic analysis further showed that the protective effect of succinate was mainly through anti-inflammation, inhibition of cell adhesion and osteogenic differentiation. These findings indicated that succinate may provide a new therapeutic option for urinary stones., (© 2023. The Author(s).)

Aberrant activation of receptor tyrosine kinases (RTKs) and the subsequent metabolic reprogramming play critical roles in cancer progression. Our previous study has shown that Golgi membrane protein 1 (GOLM1) promotes hepatocellular carcinoma (HCC) metastasis by enhancing the recycling of RTKs. However, how this RTK recycling process is regulated and coupled with RTK degradation remains poorly defined. Here, we demonstrate that cholesterol suppresses the autophagic degradation of RTKs in a GOLM1-dependent manner. Further mechanistic studies reveal that GOLM1 mediates the selective autophagy of RTKs by interacting with LC3 through an LC3-interacting region (LIR), which is regulated by a cholesterol-mTORC1 axis. Lowering cholesterol by statins improves the efficacy of multiple tyrosine kinase inhibitors (TKIs) in vivo. Our findings indicate that cholesterol serves as a signal to switch GOLM1-RTK degradation to GOLM1-RTK recycling and suggest that lowering cholesterol by statin may be a promising combination strategy to improve the TKI efficiency in HCC., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022. Published by Elsevier Inc.)

Upregulation of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1, also known as nuclear-enriched abundant transcript 2 (NEAT2) or LINC00047) was found in various solid tumors, including epithelial ovarian cancer (EOC). MALAT1 is a long noncoding (lnc)RNA that regulates many functional signaling pathways, including tumorigenesis. Herein, we observed the consistent upregulation of MALAT1 in MYST4-overexpressing cell lines, while MALAT1 was frequently found to be upregulated in various types of clinical carcinoma tissues, especially EOC. To further investigate the lncRNA MALAT1 in EOC progression, the transduced overexpression of MALAT1 in EOC cell lines and cancer-associated fibroblasts (CAFs) was employed. We found that MALAT1 overexpression in EOC cell lines significantly increased drug resistance, cell migration, and invasion. Furthermore, the concomitant overexpression of MALAT1 in EOC cells and CAFs dramatically increased EOC cell invasion. Accordingly, a mechanistic investigation of MALAT1 overexpression in EOC cells showed that expressions of the cytokines interleukin (IL)-1β and p-P38/p-NFκB/Cox2/prostaglandin E2 (PGE2) signaling were significantly increased, which stimulated inflammatory responses, whereas cell apoptosis was inhibited due to increased Bcl-2 levels and reduced Caspase3 levels. After MALAT1 was overexpressed in EOC cells, and the cyclin D1, p-PI3K, and p-Akt expressions increased, suggesting the promotion of tumor cell proliferation, while increased zinc finger E-box-binding homeobox-2 (ZEB2), yes-associated protein (YAP), and vimentin expression with E-cadherin downregulation indicated the enhancement of the epithelial-to-mesenchymal transition (EMT) in terms of metastasis, thereby triggering EOC progression. Together, our findings demonstrate how MALAT1 overexpression facilitates an oncogenic function through inhibiting tumor cell apoptosis, combined with increasing tumor cell inflammation, proliferation, and invasion in the EOC tumor microenvironment. MALAT1 is thus a potential diagnostic marker and therapeutic for this malignancy.

In this work, a novel multichromic cationic coordination polymer, named [Zn4(BTC)3(bcbpy)2]·5H2O (1), based on a new flexible viologen ligand 1,1'-bis(3-cyanobenzyl)-[4,4'-bipyridine]-1,1'-diium (H2bcbpy·2Cl), Zn(NO3)2·6H2O and pyromellitic acid (H4BTC) was synthesized. Compound 1 has good photosensitive activity and can respond to sunlight at room temperature. The colour of compound 1 changes rapidly in response to UV light and blue ray irradiation within 5 s. We rarely obtained the crystal structures after irradiation under UV light and blue ray. At the same time, compound 1 shows the hydrochromism phenomenon when heated at 120 °C, and it also shows the ability of detecting aniline and NO2- under low-concentration conditions (10-4 M).

Cancer stem cells (CSCs) are considered to be the origin of ovarian cancer (OC) development, recurrence, and chemoresistance. We investigated changes in expression levels of the CSC biomarker, cluster of differentiation 133 (CD133), from primary OC cell lines to induction of CSC-spheres in an attempt to explore the mechanisms related to modulation of stemness, drug resistance, and tumorigenesis in CSCs, thus facilitating the search for new therapeutics for OC. The effect of CD133 overexpression on the induction of CSC properties was evaluated by sphere-forming assays, RT-qPCR, flow cytometry, cell viability assays, and in vivo xenograft experiments. Moreover, the potential signaling molecules that participate in CD133 maintenance of stemness were screened by RNA-sequencing. CD133 expression was upregulated during OCSC induction and chemotherapeutic drug treatment over time, which increased the expressions of stemness-related markers (SOX2, OCT4, and Nanog). CD133 overexpression also promoted tumorigenesis in NOD/SCID mice. Several signalings were controlled by CD133 spheres, including extracellular matrix receptor interactions, chemokine signaling, and Wnt signaling, all of which promote cell survival and cell cycle progression. Our findings suggest that CD133 possesses the ability to maintain functional stemness and tumorigenesis of OCSCs by promoting cell survival signaling and may serve as a potential target for stem cell-targeted therapy of OC.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a 5-year survival rate of 9%. Major obstacles to successful treatment of pancreatic cancer are the immunosuppressive tumor microenvironment (TME) and antigenic complexity or heterogeneity. Programmed death-ligand 1 (PD-L1) is expressed on PDAC and immunosuppressed cells within the TME, providing suitable immunotherapy targets. We applied a chimeric antigen receptor (CAR) strategy to target immune checkpoint programmed death-1 (PD-1)/PD-L1 interactions. Lentiviral vectors were used to express the extracellular domain of human PD-1 (PD-1-CD28-4-1BB activating chimeric receptor [PD1ACR]) or the single-chain variable fragment (scFv) region of anti-PD-L1 (PDL1CAR) that binds to PD-L1, and each was fused to intracellular signaling domains containing CD3 zeta, CD28, and 4-1BB (CD137). Both engineered CAR T cells recognized and eliminated PD-L1-overexpressing CFPAC1 cells efficiently at approximately 80% in vitro . Adoptive transfer of both CAR T cells enhanced T cell persistence and induced specific regression of established CFPAC1 cancer by >80% in both xenograft and orthotopic models. Ki67 expression in tumors decreased, whereas proinflammatory cytokines/chemokines increased in CAR T cell-treated mouse sera. PD1ACR and PDL1CAR obtained a similar therapeutic efficacy. Thus, these armed third-generation PD-L1-targeted CAR T cells confer antitumor activity and the ability to combat T cell exhaustion, providing a potentially new and innovative CAR T cell immunotherapy against pancreatic cancers., (© 2020 The Author(s).)

Purpose: Patients with Type 2 diabetes (T2D) have increased risk of depression and anxiety. Evidence suggests that a heightened inflammatory state may contribute to this association. Females experience more depression and higher inflammation levels than males. This study compared associations of serum high-sensitivity C-reactive protein (hs-CRP) levels with symptoms of depression and anxiety between men and women with Type 2 diabetes mellitus (T2DM)., Method: Cross-sectional data including demographic and disease characteristics, symptoms of depression and anxiety, clinical data, and laboratory values were collected from 392 patients with T2DM recruited from a general hospital in Shandong Province, China. We evaluated associations between serum hs-CRP level and symptoms of depression and anxiety in males and females separately using multiple linear regressions and χ 2 tests for trend., Results: Sex moderated the association between serum hs-CRP level and symptoms of depression ( B = .112 [ SE = 0.049]; p = .022) and anxiety ( B = .137 [ SE = 0.053]; p = .011). Among females, hs-CRP level was positively associated with depression ( B = .034, 95% confidence interval [CI] = [.006, .061]; p = .016, false discovery rate [FDR]-adjusted p = .020) and anxiety ( B = .041, 95% CI [.011, .071], p = .007, FDR-adjusted p = .007). Positive trends indicated a higher prevalence of clinically significant symptoms of depression and anxiety in higher serum hs-CRP categories in females. No associations were found in males., Conclusion: Findings demonstrate that associations between serum hs-CRP level and symptoms of depression and anxiety in patients with T2D are sex-specific, with only females demonstrating a significant positive association.

Cancer‑associated fibroblasts (CAFs) are known to be essential in cancer initiation and development. However, the role of CAFs in promoting ovarian cancer (OC) invasion remains to be fully elucidated. To address this in the present study, 49 clinical OC specimens were used to evaluate the roles of CAFs in promoting ovarian tumor migration and invasion and disease progression. It was found that the sushi repeat‑containing protein, X‑linked (SRPX) and hemicentin 1 (HMCN1) genes were significantly upregulated in CAFs from high‑grade serous carcinoma (HGSC) and clear cell carcinoma (CCC) samples, the two major histological types of OC with frequently poor patient survival rates. The short hairpin (sh)RNA‑mediated silencing of SRPX and HMCN1 in fibroblasts significantly suppressed the Transwell invasive activities of OC cells. Further experiments showed that SRPX and HMCN1 regulated the invasiveness of OC via the Ras homology family member A (RhoA) signaling pathway in fibroblasts. Therefore, the findings of the present study suggest that targeting the CAF genes, SRPX and HMCN1, can inhibit OC migration and invasion. These data highlight the importance of CAF‑OC crosstalk signaling in cancer invasion and demonstrate the potential for improved efficacy of OC treatment by targeting CAF‑SRPX/HMCN1.

This study presents a low-power multi-lead wearable electrocardiogram (ECG) signal sensor system design that can simultaneously acquire the electrocardiograms from three leads, I, II, and V1. The sensor system includes two parts, an ECG test clothing with five electrode patches and an acquisition device. Compared with the traditional 12-lead wired ECG detection instrument, which limits patient mobility and needs medical staff assistance to acquire the ECG signal, the proposed vest-type ECG acquisition system is very comfortable and easy to use by patients themselves anytime and anywhere, especially for the elderly. The proposed study incorporates three methods to reduce the power consumption of the system by optimizing the micro control unit (MCU) working mode, adjusting the radio frequency (RF) parameters, and compressing the transmitted data. In addition, Huffman lossless coding is used to compress the transmitted data in order to increase the sampling rate of the acquisition system. It makes the whole system operate continuously for a long period of time and acquire abundant ECG information, which is helpful for clinical diagnosis. Finally, a series of tests were performed on the designed wearable ECG device. The results have demonstrated that the multi-lead wearable ECG device can collect, process, and transmit ECG data through Bluetooth technology. The ECG waveforms collected by the device are clear, complete, and can be displayed in real-time on a mobile phone. The sampling rate of the proposed wearable sensor system is 250 Hz per lead, which is dependent on the lossless compression scheme. The device achieves a compression ratio of 2.31. By implementing a low power design on the device, the resulting overall operational current of the device is reduced by 37.6% to 9.87 mA under a supply voltage of 2.1 V. The proposed vest-type multi-lead ECG acquisition device can be easily employed by medical staff for clinical diagnosis and is a suitable wearable device in monitoring and nursing the off-ward patients.

Objective: Mental disorders of the elderly population in China deserve attention. Social health is significantly associated with depression. This study aimed to evaluate the rate of depressive symptoms and to test the relationships between social health and depressive symptoms among a large sample of community-dwelling elderly adults., Methods: We conducted a cross-sectional study among community-dwelling adults aged 60 years or above in Zhejiang Province, China. Face-to-face interviews were used to complete a structured questionnaire for all participants. We used the Social Health Scale for the Elderly (SHSE) to evaluate social health status and used the short form of the Geriatric Depression Scale to evaluate depressive symptoms. Multivariate logistic regression was used to evaluate the association between social health status and depressive symptoms., Results: Of the total of 3757 participants included, 1887 (50.23%) were female, and the mean±standard deviation (SD) age was (70.0±8.3) years. The rate of depressive symptoms was 25.92%. The social health score was higher in non-depressed participants than in depressed participants (raw score 50.7 vs. 48.3, P<0.001). Participants with "moderate" or "good" social health had a significantly lower risk of depressive symptoms than those with "poor" social health (odds ratio (OR)=0.55, 95% confidence interval (CI): 0.46-0.66 for moderate social health; OR=0.45, 95% CI: 0.35-0.60 for good social health). The association between social health and depressive symptoms was consistent across several subgroups., Conclusions: Social health is significantly inversely associated with depressive symptoms. The SHSE may serve as an efficient screener to identify those elderly adults with social health deficits, but systematic assessment to guide intervention merits further investigation.

For understanding the structural characteristics and the proteome of Perna shell, the microstructure, polymorph, and protein composition of the adult Perna viridis shell were investigated. The P. viridis shell have two distinct mineral layers, myostracum and nacre, with the same calcium carbonate polymorph of aragonite, determined by scanning electron microscope, Fourier transform infrared spectroscopy, and x-ray crystalline diffraction. Using Illumina sequencing, the mantle transcriptome of P. viridis was investigated and a total of 69,859 unigenes was generated. Using a combined proteomic/transcriptomic approach, a total of 378 shell proteins from P. viridis shell were identified, in which, 132 shell proteins identified with more than two matched unique peptides. Of the 132 shell proteins, 69 are exclusive to the nacre, 12 to the myostracum, and 51 are shared by both. The Myosin-tail domain containing proteins, Filament-like proteins, and Chitin-binding domain containing proteins represent the most abundant molecules. In addition, the shell matrix proteins (SMPs) containing biomineralization-related domains, such as Kunitz, A2M, WAP, EF-hand, PDZ, VWA, Collagen domain, and low complexity regions with abundant certain amino acids, were also identified from P. viridis shell. Collagenase and chitinase degradation can significantly change the morphology of the shell, indicating the important roles of collagen and chitin in the shell formation and the muscle-shell attachment. Our results present for the first time the proteome of P. viridis shell and increase the knowledge of SMPs in this genus., Competing Interests: The authors have declared that no competing interests exist.

Fish skin mucus serves as the first line of defence against pathogens and external stressors. The mudskipper Boleophthalmus pectinirostris inhabits intertidal mudflats containing abundant and diverse microbial populations; thus, the skin and mucus of B. pectinirostris are very important for immune defence. However, the molecules involved in the immune response and mucus secretion in the skin of this fish are poorly understood. To explore the proteomic profile of the skin mucus and understand the molecular mechanisms underlying B. pectinirostris adaption to amphibious environments, the microstructure of B. pectinirostris skin was analysed, and a series of histochemical procedures were employed for mucous glycoprotein localization and characterization. In addition, the antibacterial activity of B. pectinirostris skin mucus was studied, and the transcriptome of the skin and in-depth proteome of the mucus were determined. These studies revealed the hierarchical structure of B. pectinirostris skin and different types of glycoproteins (GPs) in the dermal bulge (DB) of the B. pectinirostris skin epidermis. The mucus has a broad antimicrobial spectrum and significant effects on the bacterial morphology. Furthermore, 93,914 unigenes were sequenced from B. pectinirostris skin tissue, and a total of 559 proteins were identified from B. pectinirostris skin mucus. SIGNIFICANCE., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Acute respiratory distress syndrome is an often fatal disease that develops after acute lung injury and trauma. How released tissue damage signals, or alarmins, orchestrate early inflammatory events is poorly understood. Herein we reveal that IL-33, an alarmin sequestered in the lung epithelium, is required to limit inflammation after injury due to an unappreciated capacity to mediate Foxp3+ Treg control of local cytokines and myeloid populations. Specifically, Il33-/- mice are more susceptible to lung damage-associated morbidity and mortality that is typified by augmented levels of the proinflammatory cytokines and Ly6Chi monocytes in the bronchoalveolar lavage fluid. Local delivery of IL-33 at the time of injury is protective but requires the presence of Treg cells. IL-33 stimulates both mouse and human Tregs to secrete IL-13. Using Foxp3Cre × Il4/Il13fl/fl mice, we show that Treg expression of IL-13 is required to prevent mortality after acute lung injury by controlling local levels of G-CSF, IL-6, and MCP-1 and inhibiting accumulation of Ly6Chi monocytes. Our study identifies a regulatory mechanism involving IL-33 and Treg secretion of IL-13 in response to tissue damage that is instrumental in limiting local inflammatory responses and may shape the myeloid compartment after lung injury.

Chitinase is an important enzyme for many physiological processes. Mytichitin-1 is a chitinase-like protein in Mytilus coruscus, and its C-terminal 55-AA fragment (mytichitin-CB) is a novel antimicrobial peptide, suggesting a new immune process in which chitinase is involved; mytichtin-1 may have various forms in the different biological processes of M. coruscus. Thus, the study of mytichitin-1 will be helpful for understanding the mechanism of mussel immune biology and the functional diversity of chitinase. In this study, mytichitin-1 was recombinantly expressed with different lengths, full-length mytichtin-1 (rMchi-F) and the N-terminal region (rMchi-N) in Escherichia coli BL21 with codon optimization. The results of SDS-PAGE, Western blotting, and mass spectrometry confirmed that the two forms of mytichitin-1 had been successfully recombinant expressed with a yield of 40 mg purified enzyme per L culture. In addition, the 55-AA fragment of mytichitin-CB was chemically synthesized (sMchi-CB). After purification and oxidation, the functions of the three protein products were analysed, including chitin degradation, chitin binding, and antimicrobial activities. Both rMchi-F and rMchi-N displayed enzymatic activity with the optimum pH of 4.0 and optimum temperature of 40 °C, and rMchi-N showed a stronger activity than rMchi-F. Enzymatic activities of rMchi-F and rMchi-N were stimulated by the metal ions Fe 2+ , Ba 2+ , and Na + and partially inhibited by Cu 2+ , Ni 2+ and Zn 2+ . rMchi-F, rMchi-N, and sMchi-CB had the ability to combine with colloid chitin. The antimicrobial activities of these proteins were tested against bacteria and fungi, and the results indicated the strongest activity for sMchi-CB and the weakest activity for rMchi-N. Using a prepared anti-rMchi-F polyclonal antibody, immunohistochemistry and immunoprecipitation were performed and the results revealed the location of mytichitin-1 in mantle, digestive gland and blood cells. In addition, two forms of mytichitin-1, mytichitin-CB (6 kD) and full-length mytichitin-1 (48 kD), were detected, and a 35 kD protein was identified as the third form of mytichitin-1, existing in various tissues of M. coruscus. These findings suggest that mytichitin-1 may play different roles, with at least three forms, in different M. coruscus tissues., (Copyright © 2018. Published by Elsevier Ltd.)

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Background: A wealth of research has reported on the anti-obesity effects of green tea extract (GTE). Although browning of white adipose tissue (WAT) has been reported to attenuate obesity, no study has disclosed the effects of GTE on browning in Sprague Dawley rats. Objectives: The aims of the study were to investigate the effects of GTE on anti-obesity and browning, and their underlying mechanisms. Methods: Four groups of rats (n=10/group) were used including a normal diet with vehicle treatment, and a high-energy diet (HED) with vehicle or GTE by oral gavage at 77.5 or 155 mg/kg/day for 8 weeks. Body weight, fat accumulation, and serum biochemical parameters were used to evaluate obesity. The gene expressions were analyzed using RT-qPCR and western blotting. Results: GTE modulated HED-induced body weight, fat accumulation, and serum levels of triacylglycerol, total cholesterol, low-density lipoprotein, free fatty acids, aspartate aminotransferase, and alanine aminotransferase. Moreover, GTE enhanced the serum high-density lipoprotein. Most importantly, the biomarkers of beige adipose tissue were up-regulated in WAT in GTE-given groups. GTE induced genes involved in different pathways of browning, and reduced transducin-like enhancer protein-3 in WAT. Conclusion: Our results suggest that GTE may improve obesity through inducing browning in HED-fed rats. Abbreviations : ALT: Alanine transaminase; AST: Aspartate transaminase; BAT: Brown adipose tissue; BMP-7: Bone morphogenetic protein-7; BW: Body weight; CIDEA: Cell death activator; CPT-1: Carnitine palmitoyltransferase-1; EFP: Epididymal fat pad; FFA: Free fatty acid; FGF-21: Fibroblast growth factor-21; GTE: Green tea extract; HDL: High-density lipoprotein; HED: high-energy diet; LDL: Low-density lipoprotein; MFP: Mesenteric fat pad; PGC-1α: Activates PPAR-γ coactivator-1; PPAR-γ: Peroxisome proliferator-activated receptor-γ; PRDM-16: PR domain containing 16; RFP: Renal fat pad; SD: Sprague Dawley; TC: Total cholesterol; TG: Triacylglycerol; TLE-3: Transducin-like enhancer protein-3: UCP-1: Uncoupling protein-1; WAT: White adipose tissue.

Kupffer cells (KCs) influence liver allografts by interacting with other non‑parenchymal cells. However, the exact mechanism remains unclear. Upregulation of heme oxygenase-1 (HO-1) in KCs upon interaction with mast cells (MCs), and the effects on dendritic cell (DC) function, were investigated in the present study. KCs, MCs and DCs were prepared from 8‑10‑week‑old C57BL/6 mice. KCs were pretreated with PBS, dimethyl sulfoxide, hemin (50 µM; HO‑1 inducer), and zinc protoporphyrin (50 µM; HO‑1 inhibitor) for 8 h. Reverse transcription‑polymerase chain reaction and western blotting was performed to determine HO‑1 mRNA and protein levels in KCs, respectively. C‑C motif chemokine receptor 7 (CCR7) surface molecules were measured using flow cytometry, and prostaglandin E2 (PGE2), C‑C motif chemokine ligand (CCL) 19 and CCL21 were measured by ELISA. The Transwell model was used to investigate the migration of DCs. Pretreatment of KCs with hemin induced HO‑1 transcription and protein expression, and interacted with and stabilized MC membranes. When co‑cultured with MCs, the expression of CCR7 on DCs was reduced, and PGE2, CCL19 and CCL21 were similarly decreased. DC migration was also impaired. Upregulation of HO‑1 in KCs blocked MC degranulation and reduced DC migration.

Background: To evaluate the effect of individualized education for patients with type 2 diabetes mellitus (T2DM)., Methods: A total of 280 patients (158 males, mean age 63 ± 10 years) with T2DM were randomly divided into study and control group. Eysenck Personality questionnaire was used to assess the personality of the patients in the study group, which was provided us one-on-one counseling and individualized management plan. Group education was provided to the control group., Results: At the end of the study, the body mass index (21.5±2.5 vs 23.6±1.6 kg/m 2 , P =0.002), waist circumference (83.7±6.4 vs 85.7±7.7 cm, P =0.03), fasting blood glucose (6.0±0.8 vs 6.9±2.1 mmol/L, P =0.004), HbA1c (6.2±0.6% vs 6.9±3.1%, P =0.03), systolic blood pressure (130.1±8.8 vs 135.1±8.4 mmHg, P =0.003),triglyceride (1.21±0.66 vs 1.46±0.58 mmol/L) and low-density lipoprotein (2.36±0.44 vs 2.84±0.64 mmol/L, P =0.03) in the study group was lower than in the control group., Conclusion: Individualized diabetes education is more effective than group education in facilitating the control of type 2 diabetes.

Unlabelled: Mussels attach to various submerged surfaces by using the byssus, which contains different proteins and is a promising source of water-resistant bio-adhesives for potential use in biotechnological and medical applications. The protein composition of the byssus has not yet been fully understood although at least eleven byssal proteins were characterized previously. In order to increase genomic resources and identify new byssal proteins from mussel Mytilus coruscus, high-throughput Illumina sequencing was undertaken on the foot, and 79,997,776 paired-ends reads were generated, yielding a library containing 88,825ft unigenes. The M. coruscus byssus was divided into three parts, the proximal thread, the distal thread, and the plaque. Byssal proteins from each part of the byssus were analyzed by shotgun-LTQ analysis. The MS/MS spectra were searched against the foot unigenes dataset and 48 byssal proteins were identified from the M. coruscus byssus. From the whole set, 17, 5, and 11 proteins were exclusive to the proximal thread, the distal thread, and the plaque, respectively. These data can be used as a resource for further studies on the roles of byssal proteins in the deposition of different byssus parts (thread vs. plaque) or in the different mechanical properties (tenacity vs. adhesion)., Biological Significance: Byssal proteins are the major component that controls different aspects of the byssal formation process and thus a source of bioactive molecules that would offer interesting perspectives in biomaterials and bio-adhesive fields. In this paper, we characterized the protein set from different partsof Mytilus coruscus byssus by a combination of transcriptome/proteome technical. A whole set of 48 byssal proteins were described here, including proteins of collagen-like, C1q domain-containing, protease inhibitor-like, tyrosinase-like, SOD, and others. Thread (the distal portion and the proximal portion) and plaque showed distinct protein composition. Of the whole byssal protein set, 11 are exclusive to the plaque, 17 are exclusive to the proximal thread, and 5 are exclusive to the distal thread. Only four proteins are shared by all the three parts of the byssus. The new byssal proteins reported here represent a significant expansion of the knowledge base of Mytilus byssal proteins, and are important for further exploring the mechanism of adhesion in mussel., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Idiopathic pulmonary fibrosis is a disease characterized by progressive, unrelenting lung scarring, with death from respiratory failure within 2-4 years unless lung transplantation is performed. New effective therapies are clearly needed. Fibroblast activation protein (FAP) is a cell surface-associated serine protease up-regulated in the lungs of patients with idiopathic pulmonary fibrosis as well as in wound healing and cancer. We postulate that FAP is not only a marker of disease but influences the development of pulmonary fibrosis after lung injury. In two different models of pulmonary fibrosis, intratracheal bleomycin instillation and thoracic irradiation, we find increased mortality and increased lung fibrosis in FAP-deficient mice compared with wild-type mice. Lung extracellular matrix analysis reveals accumulation of intermediate-sized collagen fragments in FAP-deficient mouse lungs, consistent within vitrostudies showing that FAP mediates ordered proteolytic processing of matrix metalloproteinase (MMP)-derived collagen cleavage products. FAP-mediated collagen processing leads to increased collagen internalization without altering expression of the endocytic collagen receptor, Endo180. Pharmacologic FAP inhibition decreases collagen internalization as expected. Conversely, restoration of FAP expression in the lungs of FAP-deficient mice decreases lung hydroxyproline content after intratracheal bleomycin to levels comparable with that of wild-type controls. Our findings indicate that FAP participates directly, in concert with MMPs, in collagen catabolism and clearance and is an important factor in resolving scar after injury and restoring lung homeostasis. Our study identifies FAP as a novel endogenous regulator of fibrosis and is the first to show FAP's protective effects in the lung., (© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.)

Doxorubicin is a widely used chemotherapeutic agent, but its utility is limited by cellular resistance and off-target effects. To understand the molecular mechanisms regulating chemotherapeutic responses to doxorubicin, we previously carried out a genomewide search of doxorubicin-resistance genes in Schizosaccharomyces pombe fission yeast and showed that these genes are organized into networks that counteract doxorubicin cytotoxicity. Here, we describe the identification of a subgroup of doxorubicin-resistance genes that, when disrupted, leads to reduced tolerance to exogenous calcium. Unexpectedly, we observed a suppressive effect of calcium on doxorubicin cytotoxicity, where concurrent calcium and doxorubicin treatment resulted in significantly higher cell survival compared with cells treated with doxorubicin alone. Conversely, inhibitors of voltage-gated calcium channels enhanced doxorubicin cytotoxicity in the mutants. Consistent with these observations in fission yeast, calcium also suppressed doxorubicin cytotoxicity in human breast cancer cells. Further epistasis analyses in yeast showed that this suppression of doxorubicin toxicity by calcium was synergistically dependent on Rav1 and Vph2, two regulators of vacuolar-ATPase assembly; this suggests potential modulation of the calcium-doxorubicin interaction by fluctuating proton concentrations within the cellular environment. Thus, the modulatory effects of drugs or diet on calcium concentrations should be considered in doxorubicin treatment regimes., (© 2016 The Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.)

Although extracorporeal membrane oxygenation (ECMO) has been used frequently as a bridge to primary lung transplantation, active centers are conservative with this approach in patients requiring redo lung transplantation. We report the use of extracorporeal carbon dioxide removal, using the Hemolung respiratory assist system, as a prolonged bridge to lung transplantation, and the first use of the Hemolung as a bridge to redo lung transplantation. Hemolung support improved the patient's clinical status and allowed redo lung transplantation., (Copyright © 2015 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Bivalve shell is a biomineralized tissue with various layers/microstructures and excellent mechanical properties. Shell matrix proteins (SMPs) pervade and envelop the mineral crystals and play essential roles in biomineralization. Despite that Mytilus is an economically important bivalve, only few proteomic studies have been performed for the shell, and current knowledge of the SMP set responsible for different shell layers of Mytilus remains largely patchy. In this study, we observed that Mytilus galloprovincialis shell contained three layers, including nacre, fibrous prism, and myostracum that is involved in shell-muscle attachment. A parallel proteomic analysis was performed for these three layers. By combining LC-MS/MS analysis with Mytilus EST database interrogations, a whole set of 113 proteins was identified, and the distribution of these proteins in different shell layers followed a mosaic pattern. For each layer, about a half of identified proteins are unique and the others are shared by two or all of three layers. This is the first description of the protein set exclusive to nacre, myostracum, and fibrous prism in Mytilus shell. Moreover, most of identified proteins in the present study are novel SMPs, which greatly extended biomineralization-related protein data of Mytilus. These results are useful, on one hand, for understanding the roles of SMPs in the deposition of different shell layers. On the other hand, the identified protein set of myostracum provides candidates for further exploring the mechanism of adductor muscle-shell attachment.

Mytilus is an economically important bivalve and its shell is a biomineralized tissue with various microstructures/layers. In the present study, the shell of marine mussel, Mytilus coruscus, was analyzed and three shell layers with different morphologies and polymorphs were observed, which includes nacre, fibrous prism, and myostracum strongly attached by adductor muscles to the interior of the shell surface. In order to understand whether these different shell layers contain different shell matrix proteins (SMPs), the transcriptome sequencing of M. coruscus mantle and a parallel proteomic analysis of SMPs in the three shell layers were performed. A combination of LC-MS/MS analysis with the mantle transcriptome dataset search resulted in the identification of a total of 63 proteins from M. coruscus shell. From this protein set, fifteen, fourteen, and eight proteins were found to be unique to nacre, fibrous prism, and myostracum layers, respectively. In addition, many novel shell proteins were also identified. The data in this study could be used as a background to explore the roles of SMPs in the deposition of different shell layers (nacre vs. fibrous prism vs. myostracum), the different polymorphisms of calcium carbonate (aragonite vs. calcite); and further, the identified proteins from the myostracum could provide candidates for studying the mechanism of adductor muscle-shell attachment., Biological Significance: In this paper, we characterized for the first time the protein set from different shell layers in Mytilus. Shell matrix proteins are the major component that controls different aspects of the shell formation process and thus a source of bioactive molecules that would offer interesting perspectives in biomaterials and biomedical fields. Our data can be used as a resource for further exploring the roles of shell matrix proteins in the deposition of different shell layers (nacre vs. fibrous prism vs. myostracum) or different polymorphisms of calcium carbonate (aragonite vs. calcite), and the identified protein set of myostracum provided candidates for studying the mechanism of adductor muscle-shell attachment., (Copyright © 2015 Elsevier B.V. All rights reserved.)

IL-33, a relatively new member of the IL-1 cytokine family, plays a crucial role in allergic inflammation and acute lung injury. Long form ST2 (ST2L), the receptor for IL-33, is expressed on immune effector cells and lung epithelia and plays a critical role in triggering inflammation. We have previously shown that ST2L stability is regulated by the ubiquitin-proteasome system; however, its upstream internalization has not been studied. In this study, we demonstrate that glycogen synthase kinase 3β (GSK3β) regulates ST2L internalization and IL-33 signaling. IL-33 treatment induced ST2L internalization, and an effect was attenuated by inhibition or downregulation of GSK3β. GSK3β was found to interact with ST2L on serine residue 446 in response to IL-33 treatment. GSK3β binding site mutant (ST2L(S446A)) and phosphorylation site mutant (ST2L(S442A)) are resistant to IL-33-induced ST2L internalization. We also found that IL-33 activated focal adhesion kinase (FAK). Inhibition of FAK impaired IL-33-induced GSK3β activation and ST2L internalization. Furthermore, inhibition of ST2L internalization enhanced IL-33-induced cytokine release in lung epithelial cells. These results suggest that modulation of the ST2L internalization by FAK/GSK3β might serve as a unique strategy to lessen pulmonary inflammation., (Copyright © 2015 by The American Association of Immunologists, Inc.)

Using reverse phase high performance liquid chromatography (RP-HPLC), a novel antimicrobial peptide with 55 amino acid residues was isolated from the hemolymph of Mytilus coruscus. This new antimicrobial peptide displays predominant antimicrobial activity against fungi and Gram-positive bacteria. The molecular mass and the N-terminal sequence of this peptide were analyzed by Mass Spectrometry and Edman degradation, respectively. This antimicrobial peptide, with molecular mass of 6621.55 Da, is characterized by a chitin-biding domain and by 6 Cysteine residues engaged in three intra-molecular disulfide bridges. The full-length of cDNA sequence of this new peptide was obtained by rapid amplification of cDNA ends (RACE) and the encoded precursor was turn out to be a chitotriosidase-like protein. Therefore, we named the precursor with mytichitin-1 and the new antimicrobial peptide (designated as mytichitin-CB) is the carboxyl-terminal part of mytichitin-1. The mRNA transcripts of mytichitin-1 are mainly detected in gonad and the expression level of mytichitin-1 in gonad was up-regulated and reached the highest level at 12 h after bacterial challenge, which was 9-fold increase compared to that of the control group. These results indicated that mytichitin-1 was involved in the host immune response against bacterial infection and might contribute to the clearance of invading bacteria., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Purpose of Review: Systemic sclerosis (SSc), or scleroderma, is a heterogeneous and complex autoimmune disease characterized by varying degrees of skin and organ fibrosis and obliterative vasculopathy. The disease results in significant morbidity and mortality, and to date, available treatments are limited. Lung involvement is the leading cause of death of patients with SSc. Over the past year, significant advances have been made in our understanding of SSc-associated lung disease, and this review attempts to encapsulate these most recent findings and place them in context., Recent Findings: We divide our discussion of the most recent literature into the following: first, clinical aspects of SSc lung management, including classification, imaging, biomarkers, and treatment; second, promising new animal models that may improve our ability to accurately study this disease; and third, studies that advance or change our understanding of SSc lung disease pathogenesis, thereby raising the potential for new targets for therapeutic intervention., Summary: Recent advances have resulted in a better understanding of SSc-associated lung disease, the development of new in-vivo models for exploring disease pathogenesis, and the identification of potential novel targets for the development of therapies.

A strain of the microalga Chlorella pyrenoidosa F-9 in our laboratory showed special characteristics when transferred from autotrophic to heterotrophic culture. In order to elucidate the possible metabolic mechanism, the gene expression profiles of the autonomous organelles in the green alga C. pyrenoidosa under autotrophic and heterotrophic cultivation were compared by suppression subtractive hybridization technology. Two subtracted libraries of autotrophic and heterotrophic C. pyrenoidosa F-9 were constructed, and 160 clones from the heterotrophic library were randomly selected for DNA sequencing. Dot blot hybridization showed that the ratio of positivity was 70.31% from the 768 clones. Five chloroplast genes (ftsH, psbB, rbcL, atpB, and infA) and two mitochondrial genes (cox2 and nad6) were selected to verify their expression levels by real-time quantitative polymerase chain reaction. Results showed that the seven genes were abundantly expressed in the heterotrophic culture. Among the seven genes, the least increment of gene expression was ftsH, which was expressed 1.31-1.85-fold higher under heterotrophy culture than under autotrophy culture, and the highest increment was psbB, which increased 28.07-39.36 times compared with that under autotrophy conditions. The expression levels of the other five genes were about 10 times higher in heterotrophic algae than in autotrophic algae. In inclusion, the chloroplast and mitochondrial genes in C. pyrenoidosa F-9 might be actively involved in heterotrophic metabolism.