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This paper investigates the high frequency quasi-periodic oscillations (HFQPOs) phenomenon around the black bounce-type (BBT) spacetime using the resonance models. We calculated the location of the innermost stable circular orbit (ISCO) for different types of celestial bodies, and derived the expression for the epicyclic frequencies of test particles. The results show that the BBT spacetime possesses unique observational characteristics, where the ordering of epicyclic frequencies varies with the regularization parameter a, enabling the excitation of low-order resonances and producing stronger observational signals. Using parametric and forced resonance models, we compared theoretical results with the observed 3:2 twin-peak HFQPOs in microquasars (GRO 1655-40, XTE 1550-564, GRS 1915+105), analyzed the formation mechanisms of HFQPOs, constrained the parameters of the BBT model, and explored the possible types of celestial objects corresponding to microquasars. The study indicates that, certain parametric resonance conditions (e.g., n=1,2) lead to traversable wormhole models in BBT that closely align with observations. And forced resonance corresponding to BH or wormhole models can be verified through observations. These results deviate from the data fits of the original black-bounce model. It is found that the oscillatory behavior of three types of microquasars can also be explained by particle oscillations generated in BBT theory, providing evidence for exploring the existence of wormholes, under the assumptions of parametric resonance and forced resonance.

In computed tomography (CT) imaging, optimizing the balance between radiation dose and image quality is crucial due to the potentially harmful effects of radiation on patients. Although subjective assessments by radiologists are considered the gold standard in medical imaging, these evaluations can be time-consuming and costly. Thus, objective methods, such as the peak signal-to-noise ratio and structural similarity index measure, are often employed as alternatives. However, these metrics, initially developed for natural images, may not fully encapsulate the radiologists' assessment process. Consequently, interest in developing deep learning-based image quality assessment (IQA) methods that more closely align with radiologists' perceptions is growing. A significant barrier to this development has been the absence of open-source datasets and benchmark models specific to CT IQA. Addressing these challenges, we organized the Low-dose Computed Tomography Perceptual Image Quality Assessment Challenge in conjunction with the Medical Image Computing and Computer Assisted Intervention 2023. This event introduced the first open-source CT IQA dataset, consisting of 1,000 CT images of various quality, annotated with radiologists' assessment scores. As a benchmark, this challenge offers a comprehensive analysis of six submitted methods, providing valuable insight into their performance. This paper presents a summary of these methods and insights. This challenge underscores the potential for developing no-reference IQA methods that could exceed the capabilities of full-reference IQA methods, making a significant contribution to the research community with this novel dataset. The dataset is accessible at https://zenodo.org/records/7833096., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jang-Hwan Choi reports financial support was provided by the National Research Foundation of Korea. Jang-Hwan Choi reports was provided by the Korea Medical Device Development Fund grant funded by the Korea government. Adrian Galdran reports financial support was provided by the Marie Sklodowska-Curie Fellowship. 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. Published by Elsevier B.V.)

Transient receptor potential vanilloid 1 (TRPV1) pathway can result in the disruption of intracellular calcium ion (Ca 2+ ) homeostasis, but how to effectively control the process of Ca 2+ overload needs to be addressed for tumor treatment. Herein, we developed a mild photothermal activation of TRPV1 pathway strategy for enhanced Ca 2+ overload therapy of hepatocellular carcinoma, in which the multifunctional nanoparticle (CNQ) loading with CaCO 3 , a novel polycyclic conjugated small molecule (2Br-NDIA) and quercetin (Qu) as the core for the efficient mild photothermal therapy (PTT). The photothermal property of CNQ can specifically activate the TRPV1 channel, which leads to mitochondrial Ca 2+ overloading and the disruption of intracellular Ca 2+ homeostasis. This CNQ-mediated activation of the TRPV1 channel by mild PTT provides an emerging paradigm for enhancing mitochondrial Ca 2+ overload therapy and dismantling tumor self-defense, safely expanding cancer therapies for highly refractory tumors., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Arteriosclerotic cerebral small vessel disease (aCSVD) is a major cause of stroke and dementia. Although its underlying pathogenesis remains poorly understood, both inflammaging and gut microbiota dysbiosis have been hypothesized to play significant roles. This study investigated the role of gut microbiota in the pathogenesis of aCSVD through a comparative analysis of the gut microbiome and metabolome between CSVD patients and healthy controls. The results showed that patients with aCSVD exhibited a marked reduction in potentially beneficial bacterial species, such as Faecalibacterium prausnitzli and Roseburia intestinalis, alongside an increase in taxa from Bacteroides and Proteobacteria. Integrated metagenomic and metabolomic analyses revealed that alterations in microbial metabolic pathways, including LPS biosynthesis and phenylalanine-tyrosine metabolism, were associated with the status of aCSVD. Our findings indicated that microbial LPS biosynthesis and phenylalanine-tyrosine metabolism potentially influenced the symptoms and progression of aCSVD via pro-inflammatory effect and modulation of systemic neurotransmitters, respectively. These results imply that gut microbiota characteristics may serve as indicators for early detection of aCSVD and as potential gut-directed therapeutic intervention target., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Mild photothermal therapy (MPTT) generates heat therapeutic effect at the temperature below 45 °C under near-infrared (NIR) irradiation, which has the advantages of controllable treatment efficacy, lower hyperthermia temperatures, reduced dosage, and minimized damage to surrounding tissues. Despite significant progress has been achieved in MPTT, it remains primarily in the stage of basic and clinical research and has not yet seen widespread clinical adoption. Herein, a comprehensive overview of the recent NIR MPTT development was provided, aiming to emphasize the mechanism and obstacles, summarize the used photothermal agents, and introduce various biomedical applications such as anti-tumor, wound healing, and vascular disease treatment. The challenges of MPTT were proposed with potential solutions, and the future development direction in MPTT was outlooked to enhance the prospects for clinical translation., Competing Interests: Declaration of competing interest The authors declare they have no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Endovascular stenting is a safer alternative to open surgery for use in treating cerebral arterial stenosis and significantly reduces the recurrence of ischemic stroke, but the widely used bare-metal stents (BMSs) often result in in-stent restenosis (ISR). Although evidence suggests that drug-eluting stents are superior to BMSs in the short term, their long-term performances remain unknown. Herein, we propose a potential vascular stent modified by immobilizing clickable chemerin 15 (C15) peptides on the stent surface to suppress coagulation and restenosis. Various characterization techniques and an animal model were used to evaluate the surface properties of the modified stents and their effects on endothelial injury, platelet adhesion, and inflammation. The C15-immobilized stent could prevent restenosis by minimizing endothelial injury, promoting physiological healing, restraining the platelet-leukocyte-related inflammatory response, and inhibiting vascular smooth muscle cell proliferation and migration. Furthermore, in vivo studies demonstrated that the C15-immobilized stent mitigated inflammation, suppressed neointimal hyperplasia, and accelerated endothelial restoration. The use of surface-modified, anti-inflammatory, endothelium-friendly stents may be of benefit to patients with arterial stenosis. STATEMENT OF SIGNIFICANCE: Endovascular stenting is increasingly used for cerebral arterial stenosis treatment, aiming to prevent and treat ischemic stroke. But an important accompanying complication is in-stent restenosis (ISR). Persistent inflammation has been established as a hallmark of ISR and anti-inflammation strategies in stent modification proved effective. Chemerin 15, an inflammatory resolution mediator with 15-aa peptide, was active at picomolar through cell surface receptor, no need to permeate cell membrane and involved in resolution of inflammation by inhibiting inflammatory cells adhesion, modulating macrophage polarization into protective phenotype, and reducing inflammatory factors release. The implications of this study are that C15 immobilized stent favors inflammation resolution and rapid re-endothelialization, and exhibits an inhibitory role of restenosis. As such, it helps the decreased incidence of ISR., 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.)

A total of 19 resveratrol derivatives, including 12 imines and 7 amines, were synthesized, among which compounds 1, 5, 6, 7', 11', and 13 are new compounds. The anti-inflammatory and antitumor activities of these compounds were evaluated in vitro. The results revealed that compounds 1, 6, 8', 12, and 12' exhibited significant inhibitory effects (> 50%) on NO production at the concentration of 10 μM and their NO production inhibitory activities have a significant concentration-dependent ability. Additionally, compounds 8' and 12' showed promising COX-2 inhibitory activity, and the molecular docking analysis indicated their stable binding to multiple amino acid residues within the active pocket of COX-2 through hydrogen bonding. Moreover, compound 12' exhibited inhibitory effects on various tumor cell lines and induced apoptosis in MCF-7 breast cancer cells, which was not observed with resveratrol alone. Therefore, the N-substituted structural modification of resveratrol would have possibly enhanced the bioactivity of resveratrol and facilitated its application., Competing Interests: Declaration of competing interest The authors declare no conflict of interest, financial or otherwise., (Copyright © 2024. Published by Elsevier B.V.)

Introduction: Men are vulnerable to ambient heat-related kidney disease burden; however, limited evidence exists on how vulnerable women are when exposed to high ambient heat. We evaluated the sex-specific association between ambient temperature and urine electrolytes, and 24-hour urine total protein, and volume., Methods: We pooled a longitudinal 5624 person-visits data of 1175 participants' concentration and 24-hour excretion of urine electrolytes and other biomarkers (24-hour urine total protein and volume) from southwest coastal Bangladesh (Khulna, Satkhira, and Mongla districts) during November 2016 to April 2017. We then spatiotemporally linked ambient temperature data from local weather stations to participants' health outcomes. For evaluating the relationships between average ambient temperature and urine electrolytes and other biomarkers, we plotted confounder-adjusted restricted cubic spline (RCS) plots using participant-level, household-level, and community-level random intercepts. We then used piece-wise linear mixed-effects models for different ambient temperature segments determined by inflection points in RCS plots and reported the maximum likelihood estimates and cluster robust standard errors. By applying interaction terms for sex and ambient temperature, we determined the overall significance using the Wald test. Bonferroni correction was used for multiple comparisons., Results: The RCS plots demonstrated nonlinear associations between ambient heat and urine biomarkers for males and females. Piecewise linear mixed-effects models suggested that sex did not modify the relationship of ambient temperature with any of the urine parameters after Bonferroni correction ( P  < 0.004)., Conclusion: Our findings suggest that women are as susceptible to the effects of high ambient temperature exposure as men., (© 2024 International Society of Nephrology. Published by Elsevier Inc.)

Histone deacetylase 6 (HDAC6) contributes to cancer metastasis in several cancers, including triple-negative breast cancer (TNBC)-the most lethal form that lacks effective therapy. Although several efforts have been invested to develop selective HDAC6 inhibitors, none have been approved by the FDA. Toward this goal, existing computational studies used smaller compound libraries and shorter MD simulations. Here, we conducted a structure-based virtual screening of ZINC "Druglike" library containing 17,900,742 compounds using a Glide virtual screening protocol comprising various filters with increasing accuracy. The top 20 hits were subjected to molecular dynamics simulation, MM-GBSA binding energy calculations, and further ADMET prediction. Furthermore, enzyme inhibition assay and cell viability assay were performed on six available compounds from the identified hits. C4 (ZINC000077541942) with a good profile of predicted drug properties was found to inhibit HDAC6 (IC50: 4.7 ± 11.6 μM) with comparative affinity to that of the known HDAC6 selective inhibitor Tubacin (TA) in our experiments. C4 also demonstrated cytotoxic effects against triple-negative breast cancer (TNBC) cell line MDA-MB-231 with EC50 of 40.6 ± 12.7 μM comparable to that of TA (2-20 μM). Therefore, this compound, with pharmacophore features comprising a non-hydroxamic acid zinc-binding group, heteroaromatic linker, and cap group, is proposed as a novel HDAC6 inhibitor., Competing Interests: Declaration of competing interest None declared., (Copyright © 2023. Published by Elsevier Inc.)

Tumor microenvironment responsive photothermal ablation is a noninvasive and accurately targeted approach for cancer therapy. Herein, an intracellular directional assembly strategy for enhanced photothermal therapy (PTT) was realized by using ZIF-8 encapsulated Au nanorod (AuNR) heterostructure as the precursor of photothermal convertible material. The ZIF-8 shell selectively degraded in tumor cells upon the chelation between GSH and Zn 2+ , while the as-formed Zn(SG) connected the released AuNR in end-to-end fashion. The coating of ZIF-8 shell significantly improves the stability and targeting of AuNR, and the released Zn 2+ shielded the GSH binding site on the lateral side of AuNR, increased the plasmonic coupling efficiency of AuNR assembly geometer. This design enabled atomic-economical, efficient and low-side effect targeted photothermal therapy through the effective integration of heterostructures., 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.)

Acute kidney injury (AKI) is a prevalent condition in critically ill patients that is often associated with significant morbidity and mortality. As the lack of effective early diagnosis methods often delays AKI treatment, there is currently no definitive clinical intervention available. In this study, we aimed to address these challenges by developing a nano-system called Platelet membranes-ICG-SS31-PLGA (PISP), which was designed to selectively target to the kidney site, taking advantage of the natural tendency of platelets to accumulate at sites of vascular injury. This approach allowed for the accumulation of PISP within the kidney as the disease progresses. By incorporating ICG, the in vivo distribution of PISP can be observed for NIR diagnosis of AKI. This non-invasive imaging technique holds great promise for early detection and monitoring of AKI. Furthermore, Elamipretide (SS31) acts as a mitochondria-targeted antioxidant that protects against mitochondrial damage and reduces oxidative stress, inflammation, and apoptosis. The combination of diagnostic and therapeutic capabilities within a single nano-system makes the PISP approach a valuable tool for addressing AKI. This intervention helps to prevent the deterioration of AKI and promotes the recovery. STATEMENT OF SIGNIFICANCE., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interest., (Copyright © 2023 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Selective COX-2 inhibitors have been considered to be reliable alternatives to tNSAIDs, but most of them were withdrawn from the market due to their risk of heart attack and stroke. Therefore, it is urgent to develop a new type of selective COX-2 inhibitor with high efficiency and low toxicity. Inspired by the cardiovascular protection, and anti-inflammatory activity of resveratrol, we synthesized 38 resveratrol amide derivatives and evaluated their COX-1/COX-2 inhibitory activities. Compounds 8a, 6a, 8c and 13c showed important inhibitory activity against COX-2 (IC 50  = 0.42-2.54 μM) with definite selectivity (SI = 48-83). Molecular docking study demonstrated that these compounds partially entered the 2°-pocket of the COX-2 active site and interacted with the amino acid residues responsible for the COX-2 selectivity, which was in a similar orientation and binding interactions to rofecoxib. Further anti-inflammatory activity evaluation in vivo of these active compounds revealed that compound 8a showed no gastric ulcer toxicity, and displayed evident anti-inflammatory effect (45.95% inhibition of edema) with three oral doses of 50 mg/kg, which is worthy of further study. Moreover, compounds 6a and 8c also exhibited superior gastric safety profiles compared to the reference drugs celecoxib and indomethacin., 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 B.V. All rights reserved.)

The development of new diagnostic imaging and precise treatment methods for glioblastoma multiforme (GBM) is significant to improve patients' quality of life and prolong their survival time. Herein, we proposed a photoacoustic imaging (PAI)-guided GBM high-efficient photothermal therapy (PTT) based on a second near-infrared (NIR-II) absorptive polymer (PDTP-TBZ) conjugated with intense electron donor dithienopyrrole (DTP) and strong electron acceptor thiadiazolobenzotriazole (TBZ). By nanoprecipitation, PDTP-TBZ can form into nanoparticles (PT NPs), and c(RGDfK) cyclic peptide with integrin-specific targeting was then modified on the surface of PT NPs to obtain the ability of active targeting GBM multifunctional nano-reagent (cRGD@PT NPs). Both in vitro and in vivo experiments demonstrated that cRGD@PT NPs as NIR-II GBM phototheranostic reagents can greatly improve the enrichment rate at tumor sites under PAI monitoring, and carry out precise NIR-II PTT with high effective tumor cell phototoxicity and high biological safety. Thus, cRGD@PT NPs have great potential for the future GBM phototheranostic application in clinic. STATEMENT OF SIGNIFICANCE: In this work, we successfully constructed an intense electron donor dithienopyrrole (DTP) with a strong electron acceptor thiadiazolobenzotriazole (TBZ) into a novel NIR-II optical absorptive conjugated polymer (PDTP-TBZ). Then, the c(RGDfK) cyclic peptide was modified on the surface of PT NPs to obtain multifunctional nanodiagnostic reagents (cRGD@PT NPs) that can effectively target GBM neovascularization and tumor cells. Both in vitro and in vivo experiments demonstrate that cRGD@PT NPs possess high photothermal conversion efficiency and practical photoacoustic imaging capability under 1064 nm laser irradiation. The results of this work suggested that cRGD@PT NPs have great potential in efficient NIR-II PTT guided by accurate PAI, which provide a good perspective for the treatment and diagnosis of GBM., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interest., (Copyright © 2022 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Droplet dynamics and condensation phenomena are widespread in nature and industrial applications, and the fundamentals of various technological applications. Currently, with the rapid development of interfacial materials, microfluidics, micro/nano fabrication technology, as well as the intersection of fluid mechanics, interfacial mechanics, heat and mass transfer, thermodynamics and reaction kinetics and other disciplines, the preparation and design of various novel functional surfaces have contributed to the local modulation of droplets (including nucleation, jumping and directional migration) and the improvement of condensation heat transfer, further deepening the understanding of relevant mechanisms. The wetting and dynamic characteristics of droplets involve complex solid-liquid interfacial interactions, so that the local modulation of microdroplets and the extension of enhanced condensation heat transfer by means of complex micro/nano structures and hydrophilic/hydrophobic properties is one of the current hot topics in heat and mass transfer research. This work presents a detailed review of several scientific issues related to the droplet dynamics and dropwise condensation heat transfer under the influence of multiple factors (including fluid property, surface structure, wettability, temperature external field, etc.). Firstly, the basic theory of droplet wetting on the solid wall is introduced, and the mechanism of solid-liquid interfacial interaction involving droplet jumping and directional migration on the functional surfaces under the various influencing factors is discussed. Optimizing the surface structure for the local modulation of droplets is of guidance for condensation heat transfer. Secondly, we summarize the existing theoretical models of dropwise condensation applicable to various functional surfaces and briefly outline the current numerical models for simulating dropwise condensation at different scales, as well as the fabricating techniques of coatings and functional surfaces for enhancing heat transfer. Finally, the relevant problems and challenges are summarized and future research is discussed., (Copyright © 2022. Published by Elsevier B.V.)

The main steam temperature of boiler outlet has been deemed as a significant parameter of the safety and economic performances in the thermal power plant operation. The complex working status of the thermal generation endures highly uncertain factors and remarkable disturbance, which call for effective controlling approaches in the corresponding temperature management. The linear active disturbance rejection controller (LADRC) is a conducive and powerful controlling method, whereas strong correlation between LADRC parameters leads to difficulties in optimally determining the controller parameters. Aiming at eliminating the negative effects on main steam temperature control caused by uncertainties factors and disturbances, a high performance LADRC based on a novel parameters optimization strategy, the simultaneous heat transfer search (SHTS) algorithm, is designed to deliver a stability, rapidity, and precision of control process. In the presented SHTS algorithm, all the three phases of heat transfer are randomly and parallel operated, providing a significant improvement towards the optimization performance. The proposed algorithm is first verified on various benchmark functions contrasted to state-of-the-art counterparts in performance validating, and then adopted in the parameter selection of LADRC in the main steam temperature control system. The excellent control performance, strong robustness and disturbance rejection ability of the designed approach are illustrated through the simulation results on main steam temperature control system., 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 © 2021 ISA. Published by Elsevier Ltd. All rights reserved.)

Although local government staff are crucial in post-quake reconstruction, their long-term psychological and professional consequences remain unclear. This longitudinal study investigated changes of posttraumatic stress disorder (PTSD) and professional burnout over seven years, and their underlying relationship. The study assessed 250 staff at one year (T 1y ) after the earthquake, and 162 (64.8 %) were followed up at seven years (T 7y ). PTSD and professional burnout were assessed with the Short Screening Scale for DSM-IV PTSD and the burnout subscale of Professional Quality of Life Scale (ProQOL), respectively, at both time points. Longitudinal changes in PTSD and burnout were examined and cross-lagged panel analyses were conducted to test the relationship between PTSD and burnout. The rates of positive cases of PTSD screening were 23.2 % at T 1y and 11.1 % at T 7y . The percentages of moderate burnout were 61.7 % at T 1y and 23.5 % at T 7y . Scores of PTSD (z = -5.70, p < 0.001) and burnout (t = 10.07, p < 0.001) from T 1y to T 7y decreased. The cross-lagged analysis indicated that burnout at T 1y predicted PTSD at T 7y (β = 0.19, p = 0.025). In conclusion, the Wenchuan earthquake has long-lasting negative effects on local government staff, although they can recover over time. Interventions to reduce professional burnout after disaster may does be beneficial to decrease the risk of PTSD in the long run., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The monopolar spindle 1 ((hMps1/TTK) is a serine/threonine kinase that plays an important role in spindle assembly checkpoint signaling. To explore the possible relationship between TTK inhibition and radiosensitivity, we examined whether TTK inhibition influences cellular susceptibility of radiation. And we further revealed its mechanisms. We found that the expression of TTK was obviously higher in liver cancer tissues compared to the normal liver tissues. Kaplan-Meier Plotter demonstrated that patients with low TTK expression levels had a longer overall survival than patients with high TTK expression levels. TTK inhibitor AZ3146 could simulated liver cancer cells to accumulate in the G2/M phase, which ultimately enhances DNA damage with more γ-H2AX foci and more apoptosis and necrosis induced by radiation, which prompted that TTK inhibition sensitized liver cancer cells to radiation. In addition, TTK inhibition altered cell-cycle progression and exacerbated centrosome abnormalities, resulting in enhanced mitotic catastrophe (MC) induced by radiation in a p21-mediated manner. In this study, we present evidences that the TTK inhibitor promotes the radiosensitivity of liver cancer cells through regulating cell cycle in p21-mediated manner in vitro, indicating that TTK inhibitor may be an attractive radiosensitizer for the patients with liver cancer., (Copyright © 2021. Published by Elsevier Inc.)

Objective: Glucose-dependent insulinotropic polypeptide receptor (GIPR) has been identified as a contributor to obesity, and GIPR knockout mice are protected against diet-induced obesity (DIO). Therefore, we developed the anti-GIPR antagonistic monoclonal antibody (mAb) alone and in combination with DPP-4 inhibitor as potential therapeutic strategy for treating obesity and dyslipidemia based on this genetic evidence., Methods: Fully neutralized GIPR activity of GIPR-monoclonal antibody (mAb) was assessed by regulating the in vitro production of cAMP in the mouse GIPR stably expressing cells. Chronic efficacies of GIPR-mAb alone and in combination with DPP-4 inhibitor Sitagliptin in diabetic or DIO mice were both investigated. Multiple metabolic parameters including body weight, glucose level, fat mass, lipid metabolism-related indicators as well as H&E staining and immunohistochemical analysis were performed. Role of GIPR in pancreatic cells on regulating fat metabolism was explored in GIPR β-cell knockout mouse model., Results: Chronic treatment of GIPR-mAb improved body weight control, glucose metabolism, and was associated with reduced fat mass, enhanced pancreatic function and exchange ratio of the resting respiratory in diabetic mice. In addition, further study of anti-GIPR mAb combined with Sitagliptin in DIO mice demonstrated significantly improved weight loss compare to the both monomer treatment. Furthermore, we demonstrated important role of GIPR in β-cell in regulating the fat mass and response to antagonistic GIPR-mAb in a conditional GIPR-knockout mouse., Conclusion: Chronic treatment with anti-GIPR mAb alone and combined with DPP-4 inhibitor provide preclinical therapeutic approaches to treat obesity., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aims: To explore the protective efficacies and potent mechanism of amygdalin on high glucose-cultured renal cell HBZY-1 in vitro and streptozotocin (STZ)-induced diabetic nephropathy (DN) rat in vivo., Main Methods: The cellar proliferation and generation of ROS in high-glucose cultured HBZY-1 cell were assessed by MTT and DCFH-DA assay, respectively. The fasting blood glucose levels, renal function and inflammation indexes as well as oxidative stress markers in STZ-induced diabetic rats were all measured. The histologic renal section was stained with Mason and periodic acid-Schiff (PAS) method. Immunohistochemistry and western blotting methods were applied to assess expression levels of extracellular matrix (ECM), epithelial-mesenchymal transition (EMT)-related as well as TGF-β1/Smad signaling pathway-related proteins., Key Findings: Firstly, amygdalin significantly suppressed the excessive cell proliferation and ROS generation in HBZY-1 cells cultured with high glucose. The hyperglycemia, 24 h-UP excretion, BUN and Scr of DN rats were significantly attenuated after the chronic treatment of amygdalin. Moreover, MDA, SOD, IFN-γ and IL-12 levels in kidney tissues were all effectively reduced. Besides, amygdalin can suppress the ECM accumulation and EMT transformation by inhibiting Smad/TGF-β pathway to alleviate the renal fibrosis in renal tissues of DN model rats., Significance: Amygdalin ameliorates excessive oxidative stress, inflammation and renal tissue fibrosis of DN mainly by suppressing TGF-β1/Smad signaling pathway and regulating the key enzymes of ECM degradation., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Nanofiber materials are commonly used as delivery vehicles for dermatological drugs due to their high surface-area-to-volume ratio, porosity, flexibility, and reproducibility. In this study air-jet spinning was used as a novel and economic method to fabricate corn zein nanofiber meshes with model drugs of varying solubility, molecular weight and charge. The release profiles of these drugs were compared to their release from corn zein films to elucidate the effect of geometry and structure on drug delivery kinetics. In film samples, over 50% of drug was released after only 2 h. However, fiber samples exhibited more sustained release, releasing less than 50% after one day. FTIR, SEM, and DSC were performed on nanofibers and films before and after release of the drugs. Structural analysis revealed that the incorporation of model drugs into the fibers would transform the zein proteins from a random coil network to a more alpha helical structure. Upon release, the protein fiber reverted to its original random coil network. In addition, thermal analysis indicated that fibers can protect the drug molecules in high temperature above 160 °C, while drugs within films will degrade below 130 °C. These findings can likely be attributed to the mechanical infiltration of the drug molecules into the ordered structure of the zein fibers during their solution fabrication. The slow release from fiber samples can be attributed to this biophysical interaction, illustrating that release is dictated by more than diffusion in protein-based carriers. The controlled release of a wide variety of drugs from the air-jet spun corn zein nanofiber meshes demonstrates their success as drug delivery vehicles that can potentially be incorporated into different biological materials in the future., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Terrestrial organic carbon-lignin plays a crucial role in the global carbon balance. However, limited studies presented the functional and ecological traits of lignin decomposers population in natural aquatic ecosystem. In this study, we performed a multi-omics analysis by deploying amplicon, metagenomic, and metatranscriptomic approaches to identify the key potential degraders and pathways involved lignin-derived aromatic compounds in the later stage of lignin degradation. By establishing microcosms with model lignin-derived aromatic compound (vanillic acid, VAN), based on the estimated absolute abundance (EAA) and the metagenome-assembled genomes (MAGs), novel potential lignin-derived aromatic compounds degraders were identified in the aquatic ecosystem. Furthermore, members of the phyla Proteobacteria and Actinobacteria were the potential major lignin-derived aromatic compounds degraders in the studied ecosystem. Our study demonstrated that genomes of the class Betaproteobacteria (Proteobacteria) possess a complete enzymatic system for the degradation of diarylpropanes, vanillate and protocatechuate, besides having the capacity to degrade other lignin-derived aromatic compounds. This study provides strong evidence for the ability of aquatic bacteria to degrade lignin-derived aromatic compounds and suggest that different microbes might occupy different niches in the later stage of lignin degradation., 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 © 2020 Elsevier B.V. All rights reserved.)

RNA G-quadruplex (rG4) structure and its association with rG4-binding proteins/peptides are important for its function. However, there is very limited study that investigates what factors are involved in rG4 that drive the rG4-protein/peptide interaction. Here we study and uncover the effect of RNA sequence context and stereochemistry on G-quadruplex-peptide interaction. Using rG4-binding RHAU53 peptide as an example, we report that the number of G-quartet, thermostability, overhanging nucleotides, and RNA base chirality have an impact on rG4-RHAU53 binding. Notably, our data also demonstrate that RHAU53 preferentially binds to 5' G-quartet over 3' G-quartet, and showcase that RHAU53 interacts with unnatural L-rG4 for the first time. Our findings reported here offer unique insights to the potential development of targeting tools that recognize rG4 structure and rG4-binding peptide/protein., 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 © 2020 Elsevier Inc. All rights reserved.)

Microcystins (MCs) are among the predominant cyanotoxins that are primarily degraded by heterotrophic bacteria in various freshwater environments, including Lake Erie, a Laurentian Great Lake. However, despite the prevalence of MCs in Lake Erie basins, our knowledge about the taxonomic diversity of local MC-degrading bacteria is largely limited. The current study obtained thirty-four MC-degrading bacterial pure isolates from Lake Erie surface water and characterized their taxonomical and phenotypic identities as well as their MC-degradation rates under different pH, temperature, availability of organic substrates and with other MC-degrading isolates. Obtained MC-degrading isolates included both Gram-positive (18 isolates of Actinobacteria and Firmicutes) and Gram-negative bacteria (16 isolates of Gamma-proteobacteria); and 7 of these isolates were motile, and 13 had the capacity to form biofilms. In general, MC-degradation rates of the isolates were impacted by temperature and pH but insensitive to the presence of cyanobacterial exudates. At the optimal temperature (30-35°C) and pH (7-8), individual isolates degraded MC-LR, the most abundant MC isomer, at an average of 0.20 µg/mL/hr. With additions of cyanobacterial exudates, only Pseudomonas sp. LEw-2029, a non-motile biofilm maker, showed increased MC degradation (0.25 µg/mL/hr). Five out of nine tested dual culture mixtures showed rises in MC degradation rates than their corresponding monocultures; the highest rate reached 0.40 µg/mL/hr for the pair LEw-(1132 + 2029). PCR amplification of mlrA genes yielded negative results for all isolates; subsequent enzyme assay-Mass Spectrum analysis identified no product associated with the mlr gene-based MC degradation pathway. Collectively, our results demonstrated that a diversity of indigenous Lake Erie bacteria can degrade MCs via a novel mlr-independent pathway. Obtained MC degraders, especially Pseudomonas sp. LEw-2029, may serve as candidates for the development of biological filters to remove cyanotoxins in water treatment systems., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Chemical methods used to predict the bioaccessibility of hydrophobic organic compounds (HOCs) still need further development and improvement. In this work, magnetic solid-phase extraction (MSPE) based on poly(β-cyclodextrin)-coated magnetic polydopamine (Fe 3 O 4 @PDA@PCD) was first introduced to assess the bioaccessibility of polycyclic aromatic hydrocarbons (PAHs) in soils. Due to its good hydrophilicity and submicrometer scale, Fe 3 O 4 @PDA@PCD displayed a higher extraction rate for PAHs in an aqueous solution (equilibrium time < 5 min) than Tenax resin, which had an equilibrium time longer than 30 min. The merits of Fe 3 O 4 @PDA@PCD are beneficial to accelerate the desorption of PAHs from soil, especially for high molecular weight PAHs, in which the amounts extracted by Fe 3 O 4 @PDA@PCD were 1.2-2.8 times higher than those extracted by Tenax resin. The desorption kinetics data were well fitted with a two- or three-fraction model. The fitting results indicated that the MSPE method can be used to predict the bioaccessible fractions of PAHs. By comparing the prediction results obtained from the MSPE method with bioassays using earthworms, a significant linear correlation (R 2  = 0.98) with a slope statistically close to 1 was obtained. These results suggested that the MSPE method can act as a simple and efficient method to measure the bioaccessibility of PAHs in soil., 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 © 2020 Elsevier B.V. All rights reserved.)

CyanoHABs have substantial impacts on the functioning and sustainability of freshwater ecosystems by restricting light penetration, depleting dissolved oxygen, and producing various toxins. This study combined physicochemical variable measurements, 16S rRNA gene sequencing and microscopy observations to examine mechanisms that govern the assembly of bacterioplankton communities following the progress of cyanobacterial blooms in a freshwater reservoir. Throughout the sampling season, bacterioplankton distribution patterns were well predicted by a neutral model, which assumes passive dispersal and ecological drift as the predominate mechanisms for community assembly. The neutral model consistently explained the distribution of over 67% of bacterioplankton OTUs and its fit was weaker during the cyanobacterial blooms (R 2  = 0.322) than the before- (R 2  = 0.549) and after-bloom stages (R 2  = 0.535). Variations of environmental factors, acting as selective pressures, explained shifts of non-neutral OTUs (above/under neutral prediction) (63.9%) better than neutral OTUs (34.5%). Co-occurrence network analysis organized microbial communities into modules and revealed strong positive correlations between bacterioplankton and cyanobacteria than with planktonic algae and zooplankton. Overall, our results suggest that neutral processes play significant roles in assembling bacterioplankton communities over a cyanobacterial bloom succession and its relative importance may be weakened by biotic pressures (interspecific interactions) during the bloom period. Our results also indicate that among biotic factors, cyanobacteria had greater impacts on bacterioplankton community assembly than planktonic algae and zooplankton., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Polyurethane is a good matrix material with wide application prospects in tissue engineering because of its adjustable and mechanical properties. A novel biodegradable crosslinked poly(ester urethane) (CPU) with flexible poly(caprolactone) (PCL) and hydrophilic poly(ethylene glycol) (PEG) components has been synthesized using a ferric iron catalyst in our laboratory. In the present study, to promote the interaction between the CPU material and cells, the material was superficially modified by silk fibroin (SF) grafting using an aminolysis and glutaraldehyde crosslinking method to achieve a biocompatible material, CPU-SF. Considering the esophageal-specific architecture, three types of scaffolds were fabricated. S1 was a CPU-SF channel (200 μm in diameter and 30 μm in depth with 30 μm of wall thickness) to support muscle regeneration; S2 was the decellularized matrix of the esophageal mucosa/submucosa obtained by enzyme treatment; and S3 was a combination of S1 and S2, aiming to promote esophageal regeneration with histological structure and function. The biological properties and functions of the materials and scaffolds were investigated by qualitative and quantitative analyses using scanning electron microscopy, immunofluorescence staining, cell adhesion and proliferation measurements, and western blotting technology. The results showed that esophageal smooth muscle cells (SMCs) and epithelial cells (ECs) were very well supported by the scaffolds. In particular, SMCs exhibited guided directional growth and ECs infiltrated the acellular mucosa with retained biological functions when co-cultured on the composite scaffold S3. These findings suggest that the composite bionic scaffold will be a good alternative for esophageal replacement., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: To investigate the association between myasthenia gravis (MG) and human parvovirus B19 (B19V) infection in the thymus., Methods: The presence of human B19V DNA and protein was assessed in 138 samples-including 68 thymic hyperplasias (39 with MG), 58 thymomas (23 with MG), and 12 normal thymus tissues-using a nested polymerase chain reaction, immunohistochemistry, laser capture microdissection, and sequencing in a double-blinded manner., Results: B19V DNA was detected mainly in thymic hyperplasia, and the positivity rate (41.18%, 28/68) was significantly higher than that in thymoma (3.45%, 2/58) (p <0.001) but not that in normal thymic tissues. Correspondingly, the positivity rate in thymic hyperplasia with MG (30.77%, 12/39) was significantly higher than that in thymoma with MG (4.35%, 1/23) (p=0.021). However, it was higher in thymic hyperplasia without MG (55.17%, 16/29) than in thymic hyperplasia with MG (30.77%, 12/39) (p=0.043). Cells in thymic hyperplasia positive for B19V VP1/VP2 protein (63.24%, 43/68) were identified mainly in ectopic germinal centres and thymic corpuscle epithelial cells, but were rare in thymomas (1.72%, 1/58) (p <0.001). Moreover, the positivity rate was significantly higher in thymic hyperplasia with MG (74.36%, 29/39) than in thymic hyperplasia without MG (48.28%, 14/29) (p=0.027)., Conclusions: To our knowledge, the present study is the first to show that human B19V infection is closely associated with thymic hyperplasia and thymic-hyperplasia-associated MG, but is not related to thymoma or thymoma-associated MG. The findings reveal a previously unrecognized aetiopathogenic mechanism of thymic-hyperplasia-associated MG, evoking numerous questions that require further investigation., (Copyright © 2018 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

WPMP-2 is an acid polysaccharide isolated from Polygonum multiflorum, which demonstrated excellent immunomodulatory activity. In order to reduce immunosuppression of 5-fluorouracil (5-Fu), WPMP-2 was utilized as a macromolecular carrier to conjugate the 5-Fu derivatives 5-fluorouracil-1-acetic acid (5-FUAC) through ester bond. The conjugate showed controlled drug release behaviour in vitro at 37°C in phosphate buffer (pH7.4), and only 5-FUAC was detected in the media. The cytotoxicity test in vitro showed that the conjugate exhibited different cytotoxicity to HepG-2 and HT-29 cells. In addition, immunization study in vivo illustrated that the conjugate displayed immunoprotective effect by mitigating inhibition and damage effects of 5-Fu on secretion of cytokines, proliferation of splenocytes, and phagocytosis of peritoneal macrophages. It was indicated that the conjugation of 5-Fu and WPMP-2 could be a potential double effective drug delivery system., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Marginal sea sediments receive organic substrates of different origins, but whether and to what extent sediment microbial communities are reflective of the different sources of organic substrates remain unclear. To address these questions, sediment samples were collected in two connected China marginal seas, i.e., Bohai Sea and Yellow Sea, and their two major tributaries (Yellow River and Liao River). Sediment bacterial community composition (BCC) was examined using 16S rRNA gene pyrosequencing. In addition, physicochemical variables that describe environmental conditions and sediment features were measured. Our results revealed that BCCs changed with salinity and organic carbon (OC) content. Members of Gaiellaceae and Comamonadaceae showed a rapid decrease as salinity and phytoplankton-derived OC increased, while Piscirickettsiaceae and Desulfobulbaceae exhibited an opposite distribution pattern. Differences of riverine vs. marginal sea sediment BCCs could be mostly explained by salinity. However, within the marginal seas, sediment BCC variations were mainly explained by OC-related variables, including terrestrial-derived fatty acids (Terr&#95;FA), phytoplankton-derived polyunsaturated fatty acids (Phyto&#95;PUFA), stable carbon isotopes (δ 13 C), and carbon to nitrogen ratio (C/N). In addition to environmental variables, network analysis suggested that interactions among individual bacterial taxa might be important in shaping sediment BCCs in the studied areas., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Two purified polysaccharides named WPMP-1 and WPMP-2 were obtained from Polygonum multiflorum with an average molecular weight of 2.04kDa and 92.13kDa, respectively. Structural characterization revealed that WPMP-1was supposed to be a glucan composed of 1,4-linked α-d-Glcp, 1,4,6-linked α-d-Glcp, and terminal α-d-Glcp. WPMP-2 contained a complex branched structre formed by 1,2-linked α-d-Rhap, 1,2,4-linked α-d-Rhap, 1,3,5-linked α-l-Ara, 1,5- linked α-l-Araf, terminal α-l-Araf, 1,4-linked β-d-Galp, 1,4-linked α-d-GalpA, and 4-linked α-d-GalpA. In vitro, WPMPs were of activation effect on splenocyte and macrophages, and could also protect immunocyte against 5-Fu induced immunosupression by restoring the proliferation rate, phagocytic index and cytokines secretion level. Moreover, the acid polysaccharide WPMP-2 exhibited better immunomodulatory activity than neutral polysaccharide WPMP-1, which indicated that the immunomodulatory activity of WPMPs were positively associated with higher content of uronic acid, percentage of rhamnose, arabinose and galactose, and branching degree. These findings could promote the polysaccharides from Polygonum multiflorum to be attractive functional food supplement and immunomodulatory adjuvant., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Dysregulation of mammalian target of rapamycin (mTOR) in hepatocellular carcinoma (HCC) represents a valuable treatment target. Recent studies have developed a highly-selective and potent mTOR kinase inhibitor, CZ415. Here, we showed that nM concentrations of CZ415 efficiently inhibited survival and induced apoptosis in HCC cell lines (HepG2 and Huh-7) and primary-cultured human HCC cells. Meanwhile, CZ415 inhibited proliferation of HCC cells, more potently than mTORC1 inhibitors (rapamycin and RAD001). CZ415 was yet non-cytotoxic to the L02 human hepatocytes. Mechanistic studies showed that CZ415 disrupted assembly of mTOR complex 1 (mTORC1) and mTORC2 in HepG2 cells. Meanwhile, activation of mTORC1 (p-S6K1) and mTORC2 (p-AKT, Ser-473) was almost blocked by CZ415. In vivo studies revealed that oral administration of CZ415 significantly suppressed HepG2 xenograft tumor growth in severe combined immuno-deficient (SCID) mice. Activation of mTORC1/2 was also largely inhibited in CZ415-treated HepG2 tumor tissue. Together, these results show that CZ415 blocks mTORC1/2 activation and efficiently inhibits HCC cell growth in vitro and in vivo., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Three one-off burial treatments were designed in intertidal zone of the Yellow River estuary to determine the effects of sediment burial on decomposition and heavy metal levels of Suaeda salsa. Sediment burial showed significant effect on decomposition rate of S. salsa. With increasing burial depth, Cu, Zn, Cd and Co levels generally increased, while Cr and Mn levels decreased. Except for Zn, Mn, Cd and Co, stocks of Pb, Cr, Cu, Ni and V in S. salsa among burials were greatly different. The S. salsa in three burials was particular efficient in binding V and Co and releasing Pb, Zn and Cd, and, with increasing burial depth, stocks of Cr, Cu, Ni and Mn shifted from accumulation to release. In future, the eco-toxic risk of Pb, Cr, Cu, Zn, Ni, Mn and Cd exposure might be serious as the strong burial episodes occurred in S. salsa marsh., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Water-sediment regulation (WSR) of the Xiaolangdi Reservoir in the Yellow River is different from other water conservancy projects, with sediment resuspending along the river downstream of the reservoir during water regulation while some suspended sediment depositing during sediment regulation. In this study, samples were collected before, during, and after WSR to investigate the effect of WSR on the suspended sediment and organic carbon downstream of the reservoir. The suspended sediment concentration ([SPS]) increased with the river flow velocity (V) as a power function ([SPS]=1.348V(2.519)) during the three periods. The suspended sediment grain size decreased along the river during water and sediment regulations and after WSR; they were generally below 200μm with the fine particles (<50μm) of 68.0%-93.7% and positively correlated with the flow velocity. The black carbon content in suspended sediment elevated along the river during both water and sediment regulations, and it increased with 2-50μm fraction during water regulation and with <2μm fraction during sediment regulation, suggesting that black carbon mainly exists in fine particles and is influenced by both suspended sediment source and characteristics. There was no significant difference in dissolved organic carbon (DOC) concentration during water regulation, sediment regulation, and after WSR, inferring that the effect of sediment resuspension/deposition on DOC concentration was insignificant. The contribution of DOC flux (27.3%) during WSR period to the annual flux was comparable to that (22.6%) of water, but lower than the sediment (32.5%) and particulate organic carbon (POC) (49.5%). This study suggests that WSR will exert significant influence on the concentrations, characteristics and fluxes of POC (p<0.05) and sediment (p<0.05) but have no significant influence on DOC (p>0.1) of the Yellow River., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Lung adenocarcinoma, as a common form of non-small cell lung cancer, poses a significant threat to public health worldwide. Previous studies have reported that flotillin-2 (Flot2) is often overexpressed in various tumors and is h correlated with tumor progression and patient survival. Dysregulated microRNA (miRNA) is associated with various cancers, including lung adenocarcinoma. However, little is known about the miRNAs targeting Flot2 in lung adenocarcinoma. In this study, we found that the expression level of miR-485 was downregulated in four lung adenocarcinoma cell lines and tissues and that the reduced miR-485 expression was associated with tumor metastasis. Luciferase assay revealed that Flot2 is direct target of miR-485, while the expression levels of Flot2 were inversely correlated with the expression levels of miR-485 in lung adenocarcinoma tissues. Ectopic Flot2 could significantly reverse miR-485-mediated inhibition of metastasis and EMT, demonstrating Flot2 downregulation is involved in function of miR-485. Subsequently, we found that miR-485 suppressed the activity of PI3K/AKT/mTOR signaling in lung adenocarcinoma cells. In conclusion, the present study provided novel insight into the molecular mechanism of lung adenocarcinoma progression and demonstrating miR-485 as a potential therapeutic target in human lung adenocarcinoma., (Copyright © 2016. Published by Elsevier Inc.)

The INK4b-ARF-INK4a gene cluster encodes three tumor suppressors: p15(INK4b), p14(ARF), and p16(INK4a). Antisense non-coding RNA in the INK4 locus (ANRIL) is transcribed in the opposite direction from this gene cluster. Recent studies suggest that ANRIL represses the expression of p15(INK4b), p14(ARF), and p16(INK4a); however, the underlying mechanism is unclear. In this study, the expressions of ANRIL in human esophageal squamous cell carcinoma (ESCC) tissues and matched adjacent non-tumor tissues were examined by quantitative real-time polymerase chain reaction. Compared with matched adjacent non-tumor tissues, the expression levels of ANRIL in ESCC tissues were significantly increased. Furthermore, inhibition of ANRIL was found to increase the expression of p15(INK4b) and transforming growth factor β1 (TGFβ1) and depletion of ANRIL in ESCC cell lines may inhibit cellular proliferation. Thus, our findings suggest a significant role of ANRIL in the occurrence and development of ESCC through TGFβ1 signaling pathways., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The intestinal epithelium functions as a physical barrier against the harmful environment of the lumen, which usually becomes impaired in the presence of intestinal diseases. In this work, we introduce an electronic impedance-based analysis using a real-time xCELLigence system to record the dynamic processes of ethanol-induced intestinal barrier dysfunction. In terms of analyzing morphological alterations in the paracellular junction complex and the organization of pericellular F-actin, this novel, real-time, cell-based technology shows considerable correlations with the standard transepithelial electrical resistance endpoint assay. In addition, monitoring barrier functions in real time allows unbiased screening and characterization of biochemical agents in the lumen that affect epithelial integrity. This functional assay further identifies the in vitro roles of the inducible nitric oxide synthase inhibitor, epithelial growth factor, tyrosine kinases, and phosphatases in regulating epithelial barrier function in response to ethanol administration. Taken together, our findings suggest that this novel, real-time, high-throughput method offers a promising tool for monitoring epithelial barrier functions in situations with more physiological relevance., (Copyright © 2012 Elsevier Inc. All rights reserved.)

We describe the performance of fibrin glue (FG) as modulated by heparin, aprotinin, or factor XIII levels. In vitro tests and a rat kidney excision model demonstrated that the hemostatic efficacy of fibrin was not modulated by aprotinin. Overlapping rat skin sections demonstrated that adhesion strength (AS) was proportional to the area of overlap as well as to fibrinogen levels. AS was not modulated by exogenous heparin or aprotinin and was independent of the endogenous factor XIII in fibrinogen. SDS-PAGE developed by Coomassie or Western blots with anti-gamma chain antibody confirmed that normal skin sections contain adequate trans-glutaminase to maximally cross-link normal, as well as XIII-depleted, fibrin. Fibrin glue (FG) sprayed onto rat skin incision wounds with a dual channel spray applicator acted in 2 phases: initially (day 1), compared to wounds stapled without or treated with only thrombin, FG significantly increased breaking strength. In the second phase of wound healing (after day 3), all groups achieved increased but equivalent breaking strength. FG containing aprotinin (to 3000 U/m; Immuno, Behringwerke, Germany) exhibited initial tissue bonding strength equivalent to fibrin without aprotinin, but histological examination showed delayed fibrinolysis and a concomitant slower regeneration of granulation tissue. Thus, our data indicated that aprotinin was not particularly beneficial to wound healing and that the endogenous factor XIII level in the fibrinogen did not contribute significantly to skin bonding. Rather, the tissue supplied adequate trans-glutaminase activity required to crosslink fibrin to itself and to the tissue.

We tested the ability of purified, ultraviolet C virally inactivated components of human fibrin sealant (FS) to modulate the chemotaxis, adherence, and proliferation of cultured cells. A fibrin clot formed on a near-confluent layer of human fibroblasts (HFs) recruited cells from the surrounding area. Thrombin (Thr) enhanced HF proliferation by a factor of 1.5 to 1.8, whereas fibrinogen (Fib) exerted only a minimal proliferative effect. We developed a new cell haptotactic/attachment assay by using Thr and Fib covalently bound to Sepharose beads (SBs). The kinetics of cell binding were approximately equivalent for beads coated with either protein. Uncoated SBs or fibrinogen-bound SBs (Fib-SB) pretreated with plasmin did not attract HFs. AlphaThr-SB induced a positive migratory response that was not affected by blocking its proteolytic site, whereas gammaThr-SB elicited no response. X irradiation of HFs at a dose of 6 Gy showed that the migratory response of HF is independent of proliferation, as confirmed by a bromodeoxyuridine uptake assay. Several types of cultured cells (murine fibroblasts, smooth muscle cells, aortic endothelial cells, and murine mammary carcinoma cells) also attached to Fib-SB. By contrast, human keratinocytes, human ovarian carcinoma cells, murine macrophage-like cells, leukemic cells, and murine mast cells did not attach. Our results provide some mechanistic insights into the haptotactic and proliferative effects of Fib and Thr on different cells.