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Doxorubicin (DOX) has been an emerging environmental pollutant due to its significant genotoxicity to mankind. Advanced oxidation processes are a potential strategy to remove DOX in water solution. To develop a highly efficient catalytic agent to remove DOX, bimetal MOFs were synthesized, with Cu 2+ and Co 2+ as the central ions and adenine as the organic ligand. This study investigated the degradation of DOX by Co/Cu-MOFs combined with peroxymonosulfate (PMS). It was found that the degradation of DOX by Co/Cu-MOFs can reach 80% in only 10 seconds. This can be explained by the charge transfer from Co(iii) to Co(ii) being accelerated by Cu 2+ , resulting in the rapid generation of free radicals, which was proved by the EIS Nyquist diagram. Co/Cu-MOFs can be reused by simply washing with water without inactivation. Therefore, Co/Cu-MOFs can be used as an efficient catalytic agent to degrade DOX in environmental water., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Freight train system is under constant pressure to optimize operational efficiency, a factor that has led the sector to spearhead many new technologies. To address this, the optimal guaranteed cost intermittent cruise control of freight train system with time-varying uncertain parameters is investigated. In particular, the guaranteed cost intermittent control approach is proposed, which can achieve both advantages of guaranteed cost control and intermittent control methods. In addition, the acceptable conditions for the guaranteed cost control laws are weakened to insure that the proposed strategy is suitable for the application in freight train systems. Moreover, to promote the optimal control design in the freight train system, the proposed optimal guaranteed cost intermittent control for the nonlinear system subjected to norm bounded parametric uncertainties is addressed. The results of numerical experiments are presented to ascertain the effectiveness of the proposed freight train control methodology and to compare it to prior methods., 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 © 2022 ISA. Published by Elsevier Ltd. All rights reserved.)

Chest X-ray is an important imaging method for the diagnosis of chest diseases. Chest radiograph diagnostic quality assessment is vital for the diagnosis of the disease because unqualified radiographs have negative impacts on doctors' diagnosis and thus increase the burden on patients due to the re-acquirement of the radiographs. So far no algorithms and public data sets have been developed for chest radiograph diagnostic quality assessment. Towards effective chest X-ray diagnostic quality assessment, we analyze the image characteristics of four main chest radiograph diagnostic quality issues, i.e. Scapula Overlapping Lung, Artifact, Lung Field Loss, and Clavicle Unflatness. Our experiments show that general image classification methods are not competent for the task because the detailed information used for quality assessment by radiologists cannot be fully exploited by deep CNNs and image-level annotations. Then we propose to leverage a multi-label semantic segmentation framework to find the problematic regions, and then classify the quality issues based on the results of segmentation. However, subsequent classification is often negatively affected by certain small segmentation errors. Therefore, we propose to estimate a distance map that measures the distance from a pixel to its nearest segment, and use it to force the prediction of semantic segmentation more holistic and suitable for classification. Extensive experiments validate the effectiveness of our semantic-segmentation-based solution for chest X-ray diagnostic quality assessment. However, general segmentation-based algorithms requires fine pixel-wise annotations in the era of deep learning. In order to reduce reliance on fine annotations and further validate how important pixel-wise annotations are, weak supervision for segmentation is applied, and demonstrates its ability close to that of full supervision. Finally, we present ChestX-rayQuality, a chest radiograph data set, which comprises 480 frontal-view chest radiographs with semantic segmentation annotations and four labels of quality issue. Also, other 1212 chest radiographs with limited annotations are imported to validate our algorithms and arguments on larger data set. These two data set will be made publicly available.

Beamforming and its applications in steered-response power (SRP) technology, such as steered-response power delay and sum (SRP-DAS) and steered-response power phase transform (SRP-PHAT), are widely used in sound source localization. However, their resolution and accuracy still need improvement. A novel beamforming method combining SRP and multi-channel cross-correlation coefficient (MCCC), SRP-MCCC, is proposed in this paper to improve the accuracy of direction of arrival (DOA). Directional weight (DW) is obtained by calculating the MCCC. Based on DW, suppressed the non-incoming wave direction and gained the incoming wave direction to improve the beamforming capabilities. Then, sound source localizations based on the dual linear array under different conditions were simulated. Compared with SRP-PHAT, SRP-MCCC has the advantages of high positioning accuracy, strong spatial directivity and robustness under the different signal-noise ratios (SNRs). When the SNR is -10 dB, the average positioning error of the single-frequency sound source at different coordinates decreases by 5.69%, and that of the mixed frequency sound sources at the same coordinate decreases by 5.77%. Finally, the experimental verification was carried out. The results show that the average error of SRP-MCCC has been reduced by 8.14% and the positioning accuracy has been significantly improved, which is consistent with the simulation results. This research provides a new idea for further engineering applications of sound source localization based on beamforming.

Background: Arteriogenesis plays a critical role in maintaining adequate tissue blood supply and is related to a favorable prognosis in arterial occlusive diseases. Strategies aimed at promoting arteriogenesis have thus far not been successful because the factors involved in arteriogenesis remain incompletely understood. Previous studies suggest that evolutionarily conserved KANK4 (KN motif and ankyrin repeat domain-containing proteins 4) might involve in vertebrate vessel development. However, how the KANK4 regulates vessel function remains unknown. We aim to determine the role of endothelial cell-specifically expressed KANK4 in arteriogenesis., Methods: The role of KANK4 in regulating arteriogenesis was evaluated using Kank4 -/- and KANK4 iECOE mice. Molecular mechanisms underlying KANK4-potentiated arteriogenesis were investigated by employing RNA transcriptomic profiling and mass spectrometry analysis., Results: By analyzing Kank4-EGFP reporter mice, we showed that KANK4 was specifically expressed in endothelial cells. In particular, KANK4 displayed a dynamic expression pattern from being ubiquitously expressed in all endothelial cells of the developing vasculature to being explicitly expressed in the endothelial cells of arterioles and arteries in matured vessels. In vitro microfluidic chip-based vascular morphology analysis and in vivo hindlimb ischemia assays using Kank4 -/- and KANK4 iECOE mice demonstrated that deletion of KANK4 impaired collateral artery growth and the recovery of blood perfusion, whereas KANK4 overexpression leads to increased vessel caliber and blood perfusion. Bulk RNA sequencing and Co-immunoprecipitation/mass spectrometry (Co-IP/MS) analysis identified that KANK4 promoted EC proliferation and collateral artery remodeling through coupling VEGFR2 (vascular endothelial growth factor receptor 2) to TALIN-1, which augmented the activation of the VEGFR2 signaling cascade., Conclusions: This study reveals a novel role for KANK4 in arteriogenesis in response to ischemia. KANK4 links VEGFR2 to TALIN-1, resulting in enhanced VEGFR2 activation and increased EC proliferation, highlighting that KANK4 is a potential therapeutic target for promoting arteriogenesis for arterial occlusive diseases.

Time delays are unavoidable since they are ubiquitous and may have a great impact on the performance of neural networks. Resources efficiency is a common concern in many networked systems with limited resources. This article investigates quasisynchronization of the heterogeneous neural networks with time-varying delays via event-triggered impulsive controls which combine the impulsive control and the event-triggered technique. The centralized and distributed event-triggered impulsive controls are, respectively, presented. The suitable Lyapunov functions are constructed, and the triggering functions are derived, which guarantee that not only are the synchronization errors less than a non-negative bound but also the Zeno behaviors can be eliminated. It is suggested that the distributed one has great superiority in taking up fewer resources compared with the time-triggered impulsive control. Numerical examples are proposed to verify the validity of the centralized and distributed control methods.

In this study, batched hydrothermal experiments on corn stalk were conducted at 240-330 °C under CO 2 or inert (N 2 ) atmosphere. The distribution and characteristics of gaseous, solid, and liquid products were analyzed in detail to comprehensively investigate the effects of CO 2 on the hydrothermal conversion of biomass, especially on the cellulose and lignin in biomass. The results demonstrate that compared with N 2 , CO 2 slightly increased the liquid and gas yields and significantly improved the control effect of temperature on bio-oil components. Under CO 2 atmosphere, bio-oil achieved effective enrichment of ketones and phenols at 240 °C and 300 °C, respectively, and their highest relative contents reached 44.8% and 62.0%, respectively. In addition, the hydrochar obtained under CO 2 atmosphere showed higher crystallinity, which is conducive to its subsequent utilization. This study explored the feasibility of introducing CO 2 into the biomass hydrothermal process to realize the high-value utilization of biomass waste and the reuse of CO 2 ., 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 Elsevier B.V. All rights reserved.)

This article investigates a robust guaranteed cost finite-time control for coupled neural networks with parametric uncertainties. The parameter uncertainties are assumed to be time-varying norm bounded, which appears on the system state and input matrices. The robust guaranteed cost control laws presented in this article include both continuous feedback controllers and intermittent feedback controllers, which were rarely found in the literature. The proposed guaranteed cost finite-time control is designed in terms of a set of linear-matrix inequalities (LMIs) to steer the coupled neural networks to achieve finite-time synchronization with an upper bound of a guaranteed cost function. Furthermore, open-loop optimization problems are formulated to minimize the upper bound of the quadratic cost function and convergence time, it can obtain the optimal guaranteed cost periodically intermittent and continuous feedback control parameters. Finally, the proposed guaranteed cost periodically intermittent and continuous feedback control schemes are verified by simulations.

Background & Aims: The liver has complex interconnecting blood vessel and biliary networks; however, how the vascular and biliary network form and regulate each other and liver function are not well-understood. We aimed to examine the role of Heg in mammalian liver development and functional maintenance., Methods: Global (Heg -/- ) or liver endothelial cell (EC)-specific deletion of Heg (Lyve1-Cre;Heg fl/fl ) mice were used to study the in vivo function of Heg in the liver. Carbon-ink anterograde and retrograde injection were used to visualize the 3-dimensional patterning of liver portal and biliary networks, respectively. RNA sequencing, histology, and molecular and biochemical assays were used to assess liver gene expression, protein distribution, liver injury response, and function., Results: Heg deficiency in liver ECs led to a sparse liver vascular and biliary network. This network paucity does not compromise liver function under baseline conditions but did alter liver zonation. Molecular analysis revealed that endothelial Heg deficiency decreased expression of Wnt ligands/agonists including Wnt2, Wnt9b, and Rspo3 in ECs, which limits Axin2 mediated canonical Wnt signaling and the expression of cytochrome P450 enzymes in hepatocytes. Under chemical-induced stressed conditions, Heg-deficiency in liver ECs protected mice from drug-induced liver injuries., Conclusion: Our study found that endothelial Heg is essential for the 3-D patterning of the liver vascular and indirectly regulates biliary networks and proper liver zonation via its regulation of Wnt ligand production in liver endothelial cells. The endothelial Heg-initiated changes of the liver metabolic zonation and metabolic enzyme expression in hepatocytes was functionally relevant to xenobiotic metabolism and drug induced liver toxicity., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The aging process and declining estradiol levels are two important factors that cause structural brain alterations. Many prior studies have investigated these two elements and revealed controversial results in menopausal women. Here, a cross-sectional study was designed to individually evaluate estradiol-related structural changes in the brain. Methods: A total of 45 early menopausal women and 54 age-matched premenopausal controls were enrolled and subjected to magnetic resonance imaging (MRI) scans, blood biochemistry tests, and neuropsychological tests. MRI structural images were analyzed using FreeSurfer to detect changes in subcortical and cortical volumes as well as cortical thickness. Finally, structural brain data as well as clinical and neuropsychological data were used for Pearson's correlation analyses to individually determine estradiol-related structural and functional changes in the brains of early menopausal women. Results: Compared with the premenopausal controls, the early menopausal women showed significant subcortical volumetric loss in the left amygdala and right amygdala, higher serum follicle-stimulating hormone (FSH) levels, more recognizable climacteric and depressive symptoms, decreased quality of sleep, and decreased working memory and executive functions. Simultaneously, FSH levels were related to lower working memory accuracy and longer working memory reaction time. Decreased subcortical volume in the bilateral amygdala was also related to lower working memory accuracy and longer executive reaction time in early menopausal women. Conclusion: The data suggest that estradiol deficiency in early menopausal women can lead to subcortical volume and functional brain changes, which may contribute to further understanding the neurobiological role of declined estradiol levels in early menopausal women., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhang, Fan, Hu, Wen, Gong, Liu, Hu, Li and Zhang.)

Background and Aims: HSCs and portal fibroblasts (PFs) are the major sources of collagen-producing myofibroblasts during liver fibrosis, depending on different etiologies. However, the mechanisms by which their dynamic gene expression directs the transition from the quiescent to the activated state-as well as their contributions to fibrotic myofibroblasts-remain unclear. Here, we analyze the activation of HSCs and PFs in CCL 4 -induced and bile duct ligation-induced fibrosis mouse models, using single-cell RNA sequencing and lineage tracing., Approach and Results: We demonstrate that HSCs, rather than PFs, undergo dramatic transcriptomic changes, with the sequential activation of inflammatory, migrative, and extracellular matrix-producing programs. The data also reveal that HSCs are the exclusive source of myofibroblasts in CCL 4 -treated liver, while PFs are the major source of myofibroblasts in early cholestatic liver fibrosis. Single-cell and lineage-tracing analysis also uncovers differential gene-expression features between HSCs and PFs; for example, nitric oxide receptor soluble guanylate cyclase is exclusively expressed in HSCs, but not in PFs. The soluble guanylate cyclase stimulator Riociguat potently reduced liver fibrosis in CCL 4 -treated livers but showed no therapeutic efficacy in bile duct ligation livers., Conclusions: This study provides a transcriptional roadmap for the activation of HSCs during liver fibrosis and yields comprehensive evidence that the differential transcriptomic features of HSCs and PFs, along with their relative contributions to liver fibrosis of different etiologies, should be considered in developing effective antifibrotic therapeutic strategies., (© 2021 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Background: Heart failure is a global health problem, and elevated left atrial pressure (LAP) is a precursor to identifying decompensated heart failure. At present, out-of-hospital monitoring of patients with heart failure is mostly based on the patient's symptoms and signs, and the use of non-invasive technology is scarce. In this study, a non-invasive ballistocardiography (BCG) device was used to collect thoracic vibration signals generated by heartbeat. We collected these signals from more than 1,000 adults, including those with different heart diseases, and used a sensor system and a composite index related to LAP recognition named the LAP-index, to analyze them. This study aimed to verify the reliability and accuracy of the LAP-index in identifying elevated LAP within heart failure patients., Methods: We prospectively included 158 patients with various extent of diastolic function, some of whom had various underlying diseases, and collected BCG and echocardiographic data using a cross-section methodology. The BCG signal was recorded from multiple optical fiber vibration sensors placed on the back of each patient. We adopted the 2016 ASE/EACVI echocardiography guideline as the standard for determining LAP level from echocardiography parameters. To evaluate the diagnostic efficacy of the LAP-index, we drew a receiver operating characteristic (ROC) curve and calculated the area under the ROC curve (AUC)., Results: The LAP-index of the 158 patients ranged from 6 to 32. Of them, 39 were diagnosed as high LAP by echocardiography, and 119 cases had normal or slightly elevated LAP. Comparison of the LAP-index results and echocardiographic results revealed the ROC c-statistic of the LAP-index for identifying high LAP was 0.86 (95% CI: 0.79-0.93; P<0.0001). When the LAP-index was at the best cut-off value of 15.5, the positive agreement rate between it and echocardiography LAP was 0.85, the negative agreement rate was 0.80, and the overall agreement rate was 0.81., Conclusions: The sensor system and the LAP-index, a composite index derived from BCG, have high reliability and accuracy in identifying elevated LAP, which provides a novel possibility for the non-invasive detection of hemodynamic congestion in heart failure patients., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/atm-21-5161). All authors reported this study was funded by the 2019 Shantou Medical Science Talent Cultivation and Clinical Technology Promotion Project (190917105269872). The payments were made to the First Affiliated Hospital of Shantou University Medical College. Dr. ZC, Dr. QS, Dr. FY, Dr. JH, and Dr. CY reported that they employed by DARMA technology Co., Ltd. (DARMA Lab), China; Dr. SZ reported that he employed by Cardiostory Inc., the United States. The authors have no other conflicts of interest to declare., (2021 Annals of Translational Medicine. All rights reserved.)

Metastasis is the primary cause of cancer-related mortality. Tumor cell interactions with cells of the vessel wall are decisive and potentially rate-limiting for metastasis. The molecular nature of this cross-talk is, beyond candidate gene approaches, hitherto poorly understood. Using endothelial cell (EC) bulk and single-cell transcriptomics in combination with serum proteomics, we traced the evolution of the metastatic vascular niche in surgical models of lung metastasis. Temporal multiomics revealed that primary tumors systemically reprogram the body’s vascular endothelium to perturb homeostasis and to precondition the vascular niche for metastatic growth. The vasculature with its enormous surface thereby serves as amplifier of tumor-induced instructive signals. Comparative analysis of lung EC gene expression and secretome identified the transforming growth factor–β (TGFβ) pathway specifier LRG1, leucine-rich alpha-2-glycoprotein 1, as an early instructor of metastasis. In the presence of a primary tumor, ECs systemically up-regulated LRG1 in a signal transducer and activator of transcription 3 (STAT3)–dependent manner. A meta-analysis of retrospective clinical studies revealed a corresponding up-regulation of LRG1 concentrations in the serum of patients with cancer. Functionally, systemic up-regulation of LRG1 promoted metastasis in mice by increasing the number of prometastatic neural/glial antigen 2 (NG2) + perivascular cells. In turn, genetic deletion of Lrg1 hampered growth of lung metastasis. Postsurgical adjuvant administration of an LRG1-neutralizing antibody delayed metastatic growth and increased overall survival. This study has established a systems map of early primary tumor-induced vascular changes and identified LRG1 as a therapeutic target for metastasis.

Background: Cardiomyocyte metabolism changes before cardiac remodeling, but its role in early cardiac hypertrophy detection remains unclear. This study investigated early changes in plasma metabolomics in a pressure-overload cardiac hypertrophy model induced by transverse aortic constriction (TAC)., Methods: The TAC model was constructed by partly ligating the aortic arch. Twelve Sprague-Dawley rats were randomly divided into the TAC group (n = 6) and sham group (n = 6). Three weeks after surgery, cardiac echocardiography was performed to assess cardiac remodeling and function. Hematoxylin/eosin (HE), Masson, and wheat germ agglutinin (WGA) stains were used to observe pathological changes. Plasma metabolites were detected by UPLC-QTOFMS and Q-TOFMS. Specific metabolites were screened by orthogonal partial least squares discriminant analysis (OPLS-DA). Metabolic pathways were characterized by Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and the predictive value of the screened metabolites was analyzed by receiver operating characteristic (ROC) curve analysis., Results: Three weeks after surgery, the TAC and sham groups had similar left heart function and interventricular septum and diastolic left ventricular posterior wall thicknesses. However, on pathological examination, the cross-sectional area of cardiomyocytes and myocardial fibrosis severity were significantly elevated in TAC rats. OPLS-DA showed different metabolic patterns between the TAC and sham groups. Based on the criteria VIP > 1 and P < 0.05, 13 metabolites were screened out. KEGG analysis identified disrupted lysine degradation through the related metabolites 5-aminopentanoic acid, N6-acetyl-L-lysine, and L-lysine, with areas under the ROC curve (AUCs) of 0.917, 0.889, and 0.806, respectively, for predicting compensated cardiomyocyte hypertrophy., Conclusion: Disruption of lysine degradation might be involved in early cardiac hypertrophy development, and related metabolites might be potential predictive and interventional targets for subclinical cardiomyocyte hypertrophy., (© 2021. The Author(s).)

Background: Due to a high prevalence and morbidity rate, heart failure (HF) constitutes an immense economic burden on the global health care system. An increase in left atrial pressure (LAP) precedes the occurrence of any HF symptoms. In this study, we applied a novel non-invasive method of ballistocardiography (BCG) to extract early diastolic ventricular vibration waves [the BCG-B3 index, which corresponds to the third heart sound (S3) at the end of the rapid filling phase of diastole]. This study evaluated the predictive value of the BCG-B3 index for LAP in HF patients., Methods: A total of 83 HF patients and 20 patients with underlying diseases were prospectively enrolled, and their cross-sectional BCG and echocardiography (ECHO) data were collected. BCG obtains a signal through a high-precision fiber-optic sensor placed on the patient's back. LAP or pulmonary capillary wedge pressure (PCWP) was estimated by the ratio of mitral inflow peak early diastolic velocity to the early diastolic velocity of the mitral annulus (E/e') or the Nagueh equation (LAP = 1.24 × E/e' + 1.9). To evaluate the diagnostic efficacy of the BCG-B3 index, a receiver operating characteristic (ROC) curve was plotted, and the area under the ROC curve (AUC) was calculated. The best cutoff value for the BCG-B3 index was determined by the maximum Youden index., Results: The correlation coefficient between the BCG-B3 index and E/e' ratio was 0.51 (P<0.01). Under an optimal cutoff value of 55.13, the BCG-B3 index showed a positive consistency value of 0.93, a negative consistency value of 0.53, and an overall consistency value of 0.82 for identification of significantly elevated LAP., Conclusions: The BCG-B3 index derived by noninvasive BCG using a built-in fiber-optic sensor has important diagnostic value for identifying significantly elevated LAP in HF patients with high accuracy. BCG examination is not limited by place or the doctor's experience. Therefore, BCG can provide timely assessments for HF patients, enabling early diagnosis and treatment.

The averaging principle for Caputo fractional stochastic differential equations has recently attracted much attention. In this paper, we investigate the averaging principle for a type of Caputo fractional stochastic differential equation. Comparing with the existing literature, we shall use different estimate methods to investigate the averaging principle, which will enrich the development of theory for Caputo fractional stochastic differential equations.

Uric acid (UA) is the end metabolic product of purine metabolism. Early on, UA was considered to be a metabolite with a certain antioxidant capacity. As research has progressed, other properties of UA have been explored, and its association with many diseases has been found. The association between UA and kidney disease and cardiovascular disease is well established; however, there is still a paucity of reviews on the association between UA and the female reproductive system. An increasing number of epidemiological studies have shown elevated serum UA levels in patients with polycystic ovary syndrome (PCOS), endometriosis, etc. Additionally, serum UA can be used as a predictor of pregnancy complications and adverse foetal outcomes. An increasing number of animal experiments and clinical studies have revealed possible mechanisms related to the involvement of UA in certain female reproductive disorders: oxidative stress, chronic inflammation, mitochondrial dysfunction, etc. This article reviews the current mainstream mechanisms regarding the pathogenesis of UA and the role of UA in certain specific female reproductive disorders (direct involvement in the development of certain diseases or enhancement of other risk factors) in the hope of contributing to clinical prevention, diagnosis, treatment and improvement in prognosis.

Recent clinical and preclinical advances have highlighted the existence of a previously hypothesized lymphogenous route of metastasis. However, due to a lack of suitable preclinical modeling tools, its contribution to long-term disease outcome and relevance for therapy remain controversial. Here, we established a genetically engineered mouse model (GEMM) fragment-based tumor model uniquely sustaining a functional network of intratumoral lymphatics that facilitates seeding of fatal peripheral metastases. Multiregimen survival studies and correlative patient data identified primary tumor-derived Angiopoietin-2 (Ang2) as a potent therapeutic target to restrict lymphogenous tumor cell dissemination. Mechanistically, tumor-associated lymphatic endothelial cells (EC), in contrast to blood vascular EC, were found to be critically addicted to the Angiopoietin-Tie pathway. Genetic manipulation experiments in combination with single-cell mapping revealed agonistically acting Ang2-Tie2 signaling as key regulator of lymphatic maintenance. Correspondingly, acute presurgical Ang2 neutralization was sufficient to prolong survival by regressing established intratumoral lymphatics, hence identifying a therapeutic regimen that warrants further clinical evaluation. SIGNIFICANCE: Exploiting multiple mouse tumor models including a unique GEMM-derived allograft system in combination with preclinical therapy designs closely matching the human situation, this study provides fundamental insight into the biology of tumor-associated lymphatic EC and defines an innovative presurgical therapeutic window of migrastatic Ang2 neutralization to restrict lymphogenous metastasis. This article is highlighted in the In This Issue feature, p. 211 ., (©2020 American Association for Cancer Research.)

We study a class of super-linear stochastic differential delay equations with Poisson jumps (SDDEwPJs). The convergence and rate of the convergence of the truncated Euler-Maruyama numerical solutions to SDDEwPJs are investigated under the generalized Khasminskii-type condition., (© Higher Education Press 2021.)

Online shopping for customized garments has become the fastest-growing field of the Chinese eBusiness market. Most consumers not only limit themselves to buying standardized garments but also want to buy garments customized to their preferences. This phenomenon has pushed the fashion textile and apparel industry to change its supply chain operations to meet the customization demand. Besides, the fashion textile and apparel industry also want to study how different channel factors will affect consumers' perceived value and further influence consumers' purchasing decisions. We initiated this study and empirically tested more than 200 experienced consumers. This study collaborated with a fashion textile and apparel company that aims to implement customized product lines soon. Based on the perceived value theory and risk management theory, we investigated whether product involvement and channel identification on supply chain design will affects potential customized product consumers' purchasing decisions. The findings reveal that channel recognition affects consumer decisions by having a positive impact on their perceived value. The perceived risk and shopping channel involvement of consumers have a negative impact on their perceived values and channel selections. In addition, product involvement has a moderating effect on the relationship between channel's perceived risk, perceived values, and channel selections as well., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Li, Yuan, Du, Hu, Yuan, Palladini, Yu and Zhou.)

Background: Previous studies have found that women with polycystic ovary syndrome (PCOS) have some degree of brain function change as well as cognitive function and emotions, such as poor executive functioning and memory, anxiety and depressive symptoms. However, the neurobiological mechanisms underlying these alterations have not yet been clarified., Method: Fasting serum hormone testing, neuropsychological testing and resting-state magnetic resonance imaging (rs-fMRI) were performed in 41 women with newly diagnosed PCOS and 41 healthy controls matched by age and education during their 2-5 days of menstrual period. Analysis of the amplitude of low-frequency fluctuation (ALFF) was used to calculate the seed points. Then, the functional connectivity (FC) values between these abnormal seed points and other voxels in the whole brain were calculated. Finally, the correlations among clinical indexes, neuropsychological evaluation scores, and neuroimaging data were analyzed., Results: Compared with the control group, the PCOS group showed higher luteinizing hormone (LH) and serum insulin levels, worse sleep quality, increased depressive and anxiety state scores, and memory and executive function impairments. Pearson's correlation analysis showed that the decreased ALFF value in the left middle frontal gyrus (MFG.L), which is related to poor executive performance and depressive disorders, was negatively correlated with the plasma insulin level in subjects with insulin resistance. Furthermore, the increased FC strength between the MFG.L and left inferior frontal gyrus (IFG.L) was positively correlated with the serum testosterone level. The enhanced FC strength between the left posterior cingulate gyrus (PCG.L) and triangular part of the left inferior frontal gyrus (IFGtriang.L) was negatively correlated with the plasma LH level. When use the right middle occipital gyrus (MOG.R) as the seed point, the FC strength with the right inferior occipital gyrus (IOG.R), which is associated with impaired memory, was decreased., Conclusion: The ALFF and FC results elucidated brain functional abnormalities at the regional and network levels in women with PCOS, while correlation analyses simultaneously demonstrated that these alterations were associated with serum hormones and cognitive function. These results may provide useful information regarding the potential mechanisms of cognitive impairment and emotional changes in this population., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Li, Hu, Zhang, Fan, Wen, Wang and Zhang.)

Transforming growth factor β-activated kinase1 (TAK1) encoded by the gene MAP3K7 regulates multiple important downstream effectors involved in immune response, cell death, and carcinogenesis. Hepatocyte-specific deletion of TAK1 in Tak1 ΔHEP mice promotes liver fibrosis and hepatocellular carcinoma (HCC) formation. Here, we report that genetic inactivation of RIPK1 kinase using a kinase dead knockin D138N mutation in Tak1 ΔHEP mice inhibits the expression of liver tumor biomarkers, liver fibrosis, and HCC formation. Inhibition of RIPK1, however, has no or minimum effect on hepatocyte loss and compensatory proliferation, which are the recognized factors important for liver fibrosis and HCC development. Using single-cell RNA sequencing, we discovered that inhibition of RIPK1 strongly suppresses inflammation induced by hepatocyte-specific loss of TAK1. Activation of RIPK1 promotes the transcription of key proinflammatory cytokines, such as CCL2, and CCR2 + macrophage infiltration. Our study demonstrates the role and mechanism of RIPK1 kinase in promoting inflammation, both cell-autonomously and cell-nonautonomously, in the development of liver fibrosis and HCC, independent of cell death, and compensatory proliferation. We suggest the possibility of inhibiting RIPK1 kinase as a therapeutic strategy for reducing liver fibrosis and HCC development by inhibiting inflammation., Competing Interests: Competing interest statement: J.Y. is a consultant for Denali Therapeutics.

In this paper, we are concerned with global stabilization for a kind of delayed memristive neural network with an inertial term. By building a new Lyapunov functional and designing a feedback controller, we obtain some new results on global stabilization of the addressed delayed memristive inertial neural networks (MINNs). An adaptive control strategy is also designed to realize the global stabilization. Compared with the reduced-order method used in the existing literature, we consider the stabilization directly from the MINNs themselves without a reduced-order method. In addition, the new results proposed here are shown as algebraic criteria, which are easy to test. At last, some simulations are given to show the validity of the derived criteria.

Mixed-lineage kinase domain-like protein (MLKL) is known as the terminal executor of necroptosis. However, its function outside of necroptosis is still not clear. Herein, we demonstrate that MLKL promotes vascular inflammation by regulating the expression of adhesion molecules ICAM1, VCAM1, and E-selectin in endothelial cells (EC). MLKL deficiency suppresses the expression of these adhesion molecules, thereby reducing EC-leukocyte interaction in vitro and in vivo. Mechanistically, we show that MLKL interacts with RBM6 to promote the mRNA stability of adhesion molecules. In conclusion, this study identified a novel role of MLKL in regulating endothelial adhesion molecule expression and local EC-leukocyte interaction during acute inflammation.

Objective: Angiocrine factors, mediating the endothelial-mural cell interaction in vascular wall construction as well as maintenance, are incompletely characterized. This study aims to investigate the role of endothelial cell-derived FSTL1 (follistatin-like protein 1) in vascular homeostasis. Approach and Results: Using conditional knockout mouse models, we show that loss of FSTL1 in endothelial cells ( Fstl1 ECKO ) led to an increase of pulmonary vascular resistance, resulting in the heart regurgitation especially with tricuspid valves. However, this abnormality was not detected in mutant mice with Fstl1 knockout in smooth muscle cells or hematopoietic cells. We further showed that there was excessive αSMA (α-smooth muscle actin) associated with atrial endocardia, heart valves, veins, and microvessels after the endothelial FSTL1 deletion. There was also an increase in collagen deposition, as demonstrated in livers of Fstl1 ECKO mutants. The SMAD3 (mothers against decapentaplegic homolog 3) phosphorylation (pSMAD3) was significantly enhanced, and pSMAD3 staining was colocalized with αSMA in vein walls, suggesting the activation of TGFβ (transforming growth factor β) signaling in vascular mural cells of Fstl1 ECKO mice. Consistently, treatment with a TGFβ pathway inhibitor reduced the abnormal association of αSMA with the atria and blood vessels in Fstl1 ECKO mutant mice., Conclusions: The findings imply that endothelial FSTL1 is critical for the homeostasis of vascular walls, and its insufficiency may favor cardiovascular fibrosis leading to heart failure.

The synergy effect between coal and biomass in their co-gasification was studied in a vertical fixed bed reactor, and the physic-chemical structural characteristics and gasification reactivity of the residual char obtained from co-gasification were also investigated. The results shows that, conversion of the residual char and tar into gas is enhanced due to the synergy effect between coal and biomass. The physical structure of residual char shows more pore on coal char when more biomass is added in the co-gasification. The migration of inorganic elements between coal and biomass was found, the formation and competitive role of K 2 SiO 3 , KAlSiO 4 , and Ca 3 Al 2 (SiO 4 ) 3 is a mechanism behind the synergy. The graphization degree is enhanced but size of graphite crystallite in the residual char decreases with biomass blending ratio increasing. TGA results strongly suggest the big difference in the reactivity of chars derived from coal and biomass in spite of influence from co-gasification., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Endothelial cells (ECs) not only are important for oxygen delivery but also act as a paracrine source for signals that determine the balance between tissue regeneration and fibrosis. Here we show that genetic inactivation of flow-induced transcription factor Krüppel-like factor 2 (KLF2) in ECs results in reduced liver damage and augmentation of hepatocyte proliferation after chronic liver injury by treatment with carbon tetrachloride (CCl 4 ). Serum levels of GLDH3 and ALT were significantly reduced in CCl 4 -treated EC-specific KLF2-deficient mice. In contrast, transgenic overexpression of KLF2 in liver sinusoidal ECs reduced hepatocyte proliferation. KLF2 induced activin A expression and secretion from endothelial cells in vitro and in vivo, which inhibited hepatocyte proliferation. However, loss or gain of KLF2 expression did not change capillary density and liver fibrosis, but significantly affected hepatocyte proliferation. Taken together, the data demonstrate that KLF2 induces an antiproliferative secretome, including activin A, which attenuates liver regeneration.

Disrupting Notch signaling ameliorates experimental liver fibrosis. However, the role of individual Notch ligands in liver damage is unknown. We investigated the effects of Delta-like ligand 4 (Dll4) in liver disease. DLL4 expression was measured in 31 human liver tissues by immunohistochemistry. Dll4 function was examined in carbon tetrachloride- and bile duct ligation-challenged mouse models in vivo and evaluated in hepatic stellate cells, hepatocytes, and Kupffer cells in vitro. DLL4 was expressed in patients' Kupffer and liver sinusoidal endothelial cells. Recombinant Dll4 protein (rDll4) ameliorated hepatocyte apoptosis, inflammation, and fibrosis in mice after carbon tetrachloride challenge. In vitro, rDll4 significantly decreased lipopolysaccharide-dependent chemokine expression in both Kupffer and hepatic stellate cells. In bile duct ligation mice, rDll4 induced massive hepatic necrosis, resulting in the death of all animals within 1 week. Inflammatory cell infiltration and chemokine ligand 2 (Ccl2) expression were significantly reduced in rDll4-receiving bile duct ligation mice. Recombinant Ccl2 rescued bile duct ligation mice from rDll4-mediated death. In patients with acute-on-chronic liver failure, DLL4 expression was inversely associated with CCL2 abundance. Mechanistically, Dll4 regulated Ccl2 expression via NF-κB. Taken together, Dll4 modulates liver inflammatory response by down-regulating chemokine expression. rDll4 application results in opposing outcomes in two models of liver damage. Loss of DLL4 may be associated with CCL2-mediated cytokine storm in patients with acute-on-chronic liver failure., (Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Retinopathy of prematurity causes visual impairment due to destructive neoangiogenesis after degeneration of the retinal microvasculature. This study was aimed at analyzing whether local delivery of Semaphorin-3C (Sema3C) suppresses pathological retinal angiogenesis. Sema3C exerted potent inhibiting effects in cellular models of angiogenesis. In an endothelial cell xenotransplantation assay, Sema3C acted primarily on immature microvessels by inducing endothelial cell apoptosis. Intravitreal administration of recombinant Sema3C disrupted endothelial tip cell formation and cell-cell contacts, which led to decreased vascular bed expansion and vessel branching in the growing retinal vasculature of newborn mice, while not affecting mature vessels in the adult retina. Sema3C administration strongly inhibited the formation of pathological pre-retinal vascular tufts during oxygen-induced retinopathy. Mechanistically, Sema3C signaled through the receptors Neuropilin-1 and PlexinD1, which were strongly expressed on vascular tufts, induced VE-cadherin internalization, and abrogated vascular endothelial growth factor (VEGF)-induced activation of the kinases AKT, FAK, and p38MAPK. This disrupted endothelial cell junctions, focal adhesions, and cytoskeleton assembly resulted in decreased cell migration and survival. Thus, this study identified Sema3C as a potent and selective inhibitor of pathological retinal angiogenesis., (© 2015 The Authors. Published under the terms of the CC BY 4.0 license.)

Tie1 is a mechanistically poorly characterized endothelial cell (EC)-specific orphan receptor. Yet, Tie1 deletion is embryonic lethal and Tie1 has been implicated in critical vascular pathologies, including atherosclerosis and tumor angiogenesis. Here, we show that Tie1 does not function independently but exerts context-dependent effects on the related receptor Tie2. Tie1 was identified as an EC activation marker that is expressed during angiogenesis by a subset of angiogenic tip and remodeling stalk cells and downregulated in the adult quiescent vasculature. Functionally, Tie1 expression by angiogenic EC contributes to shaping the tip cell phenotype by negatively regulating Tie2 surface presentation. In contrast, Tie1 acts in remodeling stalk cells cooperatively to sustain Tie2 signaling. Collectively, our data support an interactive model of Tie1 and Tie2 function, in which dynamically regulated Tie1 versus Tie2 expression determines the net positive or negative effect of Tie1 on Tie2 signaling., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Liver fibrosis is a reversible wound-healing response to injury reflecting the critical balance between liver repair and scar formation. Chronic damage leads to progressive substitution of liver parenchyma by scar tissue and ultimately results in liver cirrhosis. Stromal cells (hepatic stellate cells [HSC] and endothelial cells) have been proposed to control the balance between liver fibrosis and regeneration. Here, we show that endosialin, a C-type lectin, expressed in the liver exclusively by HSC and portal fibroblasts, is upregulated in liver fibrosis in mouse and man. Chronic chemically induced liver damage resulted in reduced fibrosis and enhanced hepatocyte proliferation in endosialin-deficient (EN(KO)) mice. Correspondingly, acute-liver-damage-induced hepatocyte proliferation (partial hepatectomy) was increased in EN(KO) mice. A candidate-based screen of known regulators of hepatocyte proliferation identified insulin-like growth factor 2 (IGF2) as selectively endosialin-dependent hepatocyte mitogen. Collectively, the study establishes a critical role of HSC in the reciprocal regulation of fibrogenesis vs. hepatocyte proliferation and identifies endosialin as a therapeutic target in non-neoplastic settings., (© 2015 The Authors. Published under the terms of the CC BY 4.0 license.)

Antiangiogenic tumor therapy has failed in the adjuvant setting. Here we show that inhibition of the Tie2 ligand angiopoietin-2 (Ang2) effectively blocks metastatic growth in preclinical mouse models of postsurgical adjuvant therapy. Ang2 antibody treatment combines well with low-dose metronomic chemotherapy (LDMC) in settings in which maximum-dose chemotherapy does not prove effective. Mechanistically, Ang2 blockade could be linked to quenching the inflammatory and angiogenic response of endothelial cells (ECs) in the metastatic niche. Reduced EC adhesion molecule and chemokine expression inhibits the recruitment of tumor-promoting CCR2(+)Tie2(-) metastasis-associated macrophages. Moreover, LDMC contributes to therapeutic efficacy by inhibiting the recruitment of protumorigenic bone marrow-derived myeloid cells. Collectively, these data provide a rationale for mechanism-guided adjuvant tumor therapies., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Liver regeneration requires spatially and temporally precisely coordinated proliferation of the two major hepatic cell populations, hepatocytes and liver sinusoidal endothelial cells (LSECs), to reconstitute liver structure and function. The underlying mechanisms of this complex molecular cross-talk remain elusive. Here, we show that the expression of Angiopoietin-2 (Ang2) in LSECs is dynamically regulated after partial hepatectomy. During the early inductive phase of liver regeneration, Ang2 down-regulation leads to reduced LSEC transforming growth factor-β1 production, enabling hepatocyte proliferation by releasing an angiocrine proliferative brake. During the later angiogenic phase of liver regeneration, recovery of endothelial Ang2 expression enables regenerative angiogenesis by controlling LSEC vascular endothelial growth factor receptor 2 expression. The data establish LSECs as a dynamic rheostat of liver regeneration, spatiotemporally orchestrating hepatocyte and LSEC proliferation through angiocrine- and autocrine-acting Ang2, respectively.

Septic shock is characterized by increased vascular permeability and hypotension despite increased cardiac output. Numerous vasoactive cytokines are upregulated during sepsis, including angiopoietin 2 (ANG2), which increases vascular permeability. Here we report that mice engineered to inducibly overexpress ANG2 in the endothelium developed sepsis-like hemodynamic alterations, including systemic hypotension, increased cardiac output, and dilatory cardiomyopathy. Conversely, mice with cardiomyocyte-restricted ANG2 overexpression failed to develop hemodynamic alterations. Interestingly, the hemodynamic alterations associated with endothelial-specific overexpression of ANG2 and the loss of capillary-associated pericytes were reversed by intravenous injections of adeno-associated viruses (AAVs) transducing cDNA for angiopoietin 1, a TIE2 ligand that antagonizes ANG2, or AAVs encoding PDGFB, a chemoattractant for pericytes. To confirm the role of ANG2 in sepsis, we i.p. injected LPS into C57BL/6J mice, which rapidly developed hypotension, acute pericyte loss, and increased vascular permeability. Importantly, ANG2 antibody treatment attenuated LPS-induced hemodynamic alterations and reduced the mortality rate at 36 hours from 95% to 61%. These data indicate that ANG2-mediated microvascular disintegration contributes to septic shock and that inhibition of the ANG2/TIE2 interaction during sepsis is a potential therapeutic target.

The mechanisms of blood vessel maturation into distinct parts of the blood vasculature such as arteries, veins, and capillaries have been the subject of intense investigation over recent years. In contrast, our knowledge of lymphatic vessel maturation is still fragmentary. In this study, we provide a molecular and morphological characterization of the major steps in the maturation of the primary lymphatic capillary plexus into collecting lymphatic vessels during development and show that forkhead transcription factor Foxc2 controls this process. We further identify transcription factor NFATc1 as a novel regulator of lymphatic development and describe a previously unsuspected link between NFATc1 and Foxc2 in the regulation of lymphatic maturation. We also provide a genome-wide map of FOXC2-binding sites in lymphatic endothelial cells, identify a novel consensus FOXC2 sequence, and show that NFATc1 physically interacts with FOXC2-binding enhancers. As damage to collecting vessels is a major cause of lymphatic dysfunction in humans, our results suggest that FOXC2 and NFATc1 are potential targets for therapeutic intervention.