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Background: Hypoxia-induced pulmonary hypertension (HPH) represents a severe pulmonary disorder with high morbidity and mortality, which necessitates identifying the critical molecular mechanisms underlying HPH pathogenesis. Method: The mRNA expression microarray GSE15197 (containing 8 pulmonary tissues from HPH and 13 normal controls) was downloaded from Gene Expression Omnibus (GEO). Gene ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) were executed by RStudio software. The Protein-Protein Interaction (PPI) network was visualized and established using Cytoscape, and the cytoHubba app from Cytoscape was used to pick out the hub modules. The infiltration of immune cells in HPH was analyzed using the CIBERSORTx. To confirm the potential hub genes, real-time quantitative reverse transcription PCR (qRT-PCR) was conducted using lung tissues of rat HPH models and controls. Results: A total of 852 upregulated and 547 downregulated genes were identified. The top terms in biological processes were apoptosis, proliferation, and regulation of the MAPK cascade, including ERK1/2. Cytoplasm, cytosol, and membrane were enriched in cellular component groups. Molecular functions mainly focus on protein binding, protein serine/threonine kinase activity and identical protein binding. KEGG analysis identified pathways in cancer, regulation of actin cytoskeleton and rap1 signaling pathway. There was significantly different immune cell infiltration between HPH and normal control samples. High proportions of the memory subsets of B cells and CD4 cells, Macrophages M2 subtype, and resting Dendritic cells were found in HPH samples, while high proportions of naive CD4 cells and resting mast cells were found in normal control samples. The qRTPCR results showed that among the ten identified hub modules, FBXL3, FBXL13 and XCL1 mRNA levels were upregulated, while NEDD4L, NPFFR2 and EDN3 were downregulated in HPH rats compared with control rats. Conclusion: Our study revealed the key genes and the involvement of immune cell infiltration in HPH, thus providing new insight into the pathogenesis of HPH and potential treatment targets for patients with HPH.

As a member of the Ephrin protein family that elicits short distance cell-cell signaling, EphrinA3 has been shown to promote or inhibit tumorigenesis depending on tumor types, but its roles and the underlying mechanisms in lung adenocarcinoma (LUAD) have not been reported.The TCGA database and Kaplan-Meier Plotter database were used to analyze the differential expression of EphrinA3 between LUAD and para-carcinoma tissues, and its effect on overall survival of LUAD patients. CCK-8 assay, Edu assay, and flow cytometry were used to probe the effect of EphrinA3 on the proliferation of LUAD cells, and transwell assay was employed to examine its effect on migration and invasion. In addition, the effect of EphrinA3 on the growth of LUAD was further evaluated using a xenograft tumor model.EphrinA3 was expressed highly in LUAD, and its expression level was negatively correlated with the prognosis of LUAD patients. In addition, EphrinA3 promoted proliferation, migration, and invasion of LUAD cells, and accelerated tumor growth in a xenograft LUAD model. The reported EphrinA3 receptors, EphA1 and EphA10, were expressed in clinical LUAD tissues and co-localized with EphrinA3 in LUAD cells. Mechanistically, EphrinA3/Eph signaling activated AKT, ERK, and p38MAPK, induced epithelial-mesenchymal transition (EMT), and upregulated matrix metalloproteases-2 and -9 (MMP-2/-9).EphrinA3 expression was negatively correlated with prognosis of patients with LUAD. EphrinA3 promoted proliferation, migration, and invasion of LUAD cells. EphrinA3 enhanced the phosphorylation of ERK and AKT, and potentiates EMT and MMP expression in LUAD cells.

Epithelial-mesenchymal transition (EMT) enables dissemination of neoplastic cells and onset of distal metastasis of primary tumors. However, the regulatory mechanisms of EMT by microenvironmental factors such as transforming growth factor-β (TGF-β) remain largely unresolved. Protein tyrosine phosphatase L1 (PTPL1) is a non-receptor protein tyrosine phosphatase that plays a suppressive role in tumorigenesis of diverse tissues. In this study we investigated the role of PTPL1/PTPN13 in metastasis of lung cancer and the signaling pathways regulated by PTPL1 in terms of EMT of non-small cell lung cancer (NSCLC) cells. We showed that the expression of PTPL1 was significantly downregulated in cancerous tissues of 23 patients with NSCLC compared with adjacent normal tissues. PTPL1 expression was positively correlated with overall survival of NSCLC patients. Then we treated A549 cells in vitro with TGF-β1 (10 ng/mL) and assessed EMT. We found that knockdown of PTPL1 enhanced the migration and invasion capabilities of A549 cells, through enhancing TGF-β1-induced EMT. In nude mice bearing A549 cell xenografts, knockdown of PTPL1 significantly promoted homing of cells and formation of tumor loci in the lungs. We further revealed that PTPL1 suppressed TGF-β-induced EMT by counteracting the activation of canonical Smad2/3 and non-canonical p38 MAPK signaling pathways. Using immunoprecipitation assay we demonstrated that PTPL1 could bind to p38 MAPK, suggesting that p38 MAPK might be a direct substrate of PTPL1. In conclusion, these results unravel novel mechanisms underlying the regulation of TGF-β signaling pathway, and have implications for prognostic assessment and targeted therapy of metastatic lung cancer.

This paper aims to examine the relationship between organisational learning and ESG (environmental, social, and governance) performance. The PRISMA protocol was followed by full-text reading 57 peer-reviewed academic journal articles published in different international journals from 2001 to 2021. After investigating and synthesising the empirical papers, the author found that organisational learning is instrumental to derive the fundamental factors and mechanisms to drive ESG performance. The findings of this research provide the first comprehensive assessment of the relationship between organisational learning and ESG, as well as highlight that organisational learning related to ESG is significantly important to ESG performance, which lies in the overlooked and hidden extant studies. The major contribution of this study is to connect organisational learning with ESG performance from a holistic perspective through different learning loops and put stress on the importance of two learning loops to better facilitate ESG strategy through ‘2P’ (people and process). Specifically, the conceptual framework of two learning loops was developed, which could lay the foundation for scholars’ future research on organisational learning related to ESG performance, such as single-loop learning about the process (i.e., control system, decision-making, ethics, gender balance, human resource management, knowledge management, risk management, and training), and double-loop learning about the roles of people (i.e., practitioners, professionals, managers, and the top management team). The ‘PPT’ (people, process, and technology) approach is also designed for future testing and validation to transform single-loop learning into double-loop learning.

Funding Information: This work made use of the Aalto University Nanomicroscopy Center (Aalto‐NMC) premises, The facilities of the ALD center Finland research infrastructure were exploited for SEM imaging. Financial support from the Academy of Finland (projects: 310481 & 311255) is gratefully acknowledged. We would also like to acknowledge our funding partner, CLIC Innovation as part of the ACel (Advanced Cellulose to Novel Products) program. Publisher Copyright: © 2022 The Authors. ChemPhysChem published by Wiley-VCH GmbH We have identified cellulose solvents, comprised of binary mixtures of molecular solvents and ionic liquids that rapidly dissolve cellulose to high concentration and show upper-critical solution temperature (UCST)-like thermodynamic behaviour - upon cooling and micro phase-separation to roughly spherical microparticle particle-gel mixtures. This is a result of an entropy-dominant process, controllable by changing temperature, with an overall exothermic regeneration step. However, the initial dissolution of cellulose in this system, from the majority cellulose I allomorph upon increasing temperature, is also exothermic. The mixtures essentially act as ‘thermo-switchable’ gels. Upon initial dissolution and cooling, micro-scaled spherical particles are formed, the formation onset and size of which are dependent on the presence of traces of water. Wide-angle X-ray scattering (WAXS) and 13C cross-polarisation magic-angle spinning (CP-MAS) NMR spectroscopy have identified that the cellulose micro phase-separates with no remaining cellulose I allomorph and eventually forms a proportion of the cellulose II allomorph after water washing and drying. The rheological properties of these solutions demonstrate the possibility of a new type of cellulose processing, whereby morphology can be influenced by changing temperature.

Endothelial–mesenchymal transition (EnMT) plays a pivotal role in various diseases, including pulmonary hypertension (PH), and transcription factors like Snail are key regulators of EnMT. In this study we investigated how these factors were regulated by PH risk factors (e.g. inflammation and hypoxia) in human umbilical vein endothelial cells (HUVECs). We showed that treatment with interleukin 1β (IL‐1β) induced EnMT of HUVECs via activation of NF-κB/Snail pathway, which was further exacerbated by knockdown of protein tyrosine phosphatase L1 (PTPL1). We demonstrated that PTPL1 inhibited NF-κB/Snail through dephosphorylating and stabilizing IκBα. IL‐1β or hypoxia could downregulate PTPL1 expression in HUVECs. The deregulation of PTPL1/NF-κB signaling was validated in a monocrotaline-induced rat PH (MCT-PH) model and clinical PH specimens. Our findings provide novel insights into the regulatory mechanisms of EnMT, and have implications for identifying new therapeutic targets for clinical PH.

Background: Myocardial infarction (MI) is a leading cause of disease with high morbidity and mortality worldwide. Recent studies have revealed that long non-coding RNAs (lncRNAs) are involved in heart disease pathogenesis. This study aimed to investigate the effect and the molecular basis of THRIL on hypoxia-injured H9C2 cells. Methods: THRIL, miR-99a and Brahma-related gene 1 (Brg1) expressions in H9C2 cells were altered by transient transfections. The cells were subjected to hypoxia for 4 h, and then the levels of THRIL, miR-99a and Brg1 were investigated. Cell viability, migration and invasion, and apoptotic cells were respectively measured by trypan blue exclusion assay, transwell migration assay and flow cytometry assay. Dual luciferase reporter assay was conducted to verify the interaction between miR-99a and THRIL. Furthermore, levels of apoptosis-, PI3K/AKT and mTOR pathways-related factors were measured by western blotting. Results: Hypoxia induced an increase of THRIL but a reduction of miR-99a and Brg1. THRIL inhibition significantly attenuated hypoxia-induced cell injuries, as increased cell viability, migration and invasion, and decreased cell apoptosis. THRIL negatively regulated miR-99a expression through sponging with miR-99a binding site, and miR-99a inhibition abolished the protective effects of THRIL knockdown against hypoxia-induced injury in H9C2 cells. Furthermore, miR-99a positively regulated the expression of Brg1. Brg1 inhibition promoted hypoxia-induced cell injuries, while Brg1 overexpression alleviated hypoxia-induced cell injuries. Moreover, Brg1 overexpression activated PI3K/AKT and mTOR pathways. Conclusions: This study demonstrated that THRIL inhibition represented a protective effect against hypoxia-induced injuries in H9C2 cells by up-regulating miR-99a expression.

Many blue and white porcelain are unearthed in Jingdezhen every year. The patterns on the sherds have important research significance. At present, the classification of porcelain shards is mainly b...

Background: The mechanism underlying vascular remodeling of hypoxia-induced pulmonary hypertension (HPH) is not fully elucidated. We hypothesized that hypoxia promotes expression of N-myc downstream regulated gene-1 (NDRG1) in human pulmonary arterial endothelial cells (HPAECs), which in turn leads to endothelial dysfunction and contributing to HPH. Methods: Lung samples were obtained from qualified patients and HPH rat models. Quantitative polymerase chain reactions, western blotting and immunohistochemistry were used to measure the expression of NDRG1. EdU incorporation assays, cell counting kit-8 (CCK-8) assays, transwell migration assays, and matrigel assays were conducted to detect the role of NDRG1 in HPACE function in vitro. HPH models were established in SD rats and were treated with plasmids expressing short hairpin RNAs (shRNAs) to silence NDRG1. The candidate binding partner(s) of NDRG1 was screened and validated via co-immunoprecipitation and immunofluorescence staining. Results: NDRG1 is up-regulated by hypoxia in a time-dependent manner in HPAECs. Expression of NDRG1 was increased in lung tissues of HPH patient and rat model. In vitro, silencing NDRG1 attenuated proliferation, migration and tube formation of HPAECs under hypoxia, while NDRG1 over-expression promoted these behaviors of HPAECs in normoxia. NDRG1 knock-down alleviated vascular remodeling and right ventricular hypertrophy in rat models of HPH. NDRG1 can directly interact with TATA-box binding protein associated factor 15 (TAF15) and promote its nuclear localization. Bioinformatics study found that Notch1 signaling was downstream of TAF15 in endothelial cells. TAF15 can promote HPAECs dysfunction via binding to Notch1 promoter region and subsequently increasing Notch1 expression. Conclusions: Taken together, hypoxia-induced up-regulation of NDRG1 contributes to endothelial dysfunction and HPH development through TAF15 upregulation of Notch1, suggesting the applicability of targeting NDRG1 in clinical treatment of HPH.

Traffic load-balancing is important to data center performance. However, existing data center load-balancing solutions are either limited to simple topologies or cannot provide satisfactory performance. In this paper, we propose a multipath-aware TCP (MA-TCP) which can sense the path migration of TCP flows. With this new mechanism, the reduction in TCP congestion window due to packet reordering during the path migration can be avoided. This, in turn, makes the path migration more timely as soon as the original path is congested. Furthermore, if the new path is congested (again), the flow can securely continue to migrate without worrying about transmitting rate reduction. Through NS-3 simulations, we show that MA-TCP achieves better flow completion time (FCT) than existing data center load-balancing solutions.

Abstract Cellulose is an historical polymer, for which its processing possibilities have been limited by the absence of a melting point and insolubility in all non-derivatizing molecular solvents. More recently, ionic liquids (ILs) have been used for cellulose dissolution and regeneration, for example, in the development of textile fiber spinning processes. In some cases, organic electrolyte solutions (OESs), that are binary mixtures of an ionic liquid and a polar aprotic co-solvent, can show even better technical dissolution capacities for cellulose than the pure ILs. Herein we use OESs consisting of two tetraalkylphosphonium acetate ILs and dimethyl sulfoxide or γ-valerolactone, as co-solvents. Cellulose can be first dissolved in these OESs at 120 °C and then regenerated, upon cooling, leading to micro and macro phase-separation. This phenomenon much resembles the upper-critical solution temperature (UCST) type thermodynamic transition. This observed UCST-like behavior of these systems allows for the controlled regeneration of cellulose into colloidal dispersions of spherical microscale particles (spherulites), with highly ordered shape and size. While this phenomenon has been reported for other IL and NMMO-based systems, the mechanisms and phase-behavior have not been well defined. The particles are obtained below the phase-separation temperature as a result of controlled multi-molecular association. The regeneration process is a consequence of multi-parameter interdependence, where the polymer characteristics, OES composition, temperature, cooling rate and time all play their roles. The influence of the experimental conditions, cellulose concentration and the effect of time on regeneration of cellulose in the form of preferential gel or particles is discussed. Graphical abstract Regular micro-sized particles regenerated from a cellulose-OES mixture of tetrabutylphosphonium acetate:DMSO (70:30 w/w) upon cooling

Based on the panel data of Guangdong industrial enterprises from 2006 to 2013, this paper empirically studies the impact of public R & D subsidies on private R & D expenditure and the impact of the two on the innovation performance of enterprises by using random effects model and fixed effects model. The results show that public R & D subsidies can promote enterprises to carry out private R & D expenditure, and there is an obvious time lag. Using grouping studies, we found that low-level public R & D subsidies can encourage enterprises to increase their private R & D expenditure, but high-level public subsidies will crowd out part of private R & D expenditure. Finally, this paper divides the innovation performance of enterprises into the stage of knowledge output and the stage of marketization. In the knowledge output stage, public R & D subsidies and R & D staff input can significantly improve the innovation performance of enterprises; in the marketization stage, public R & D subsidies cannot promote the increase of new product income, while the private R & D expenditure of enterprises can significantly increase the income of new products.

Background: The evaluation of tumor differentiation is an urgent clinical issue that would facilitate the establishment of individualized therapeutic strategies. Our aims were to develop a deep learning radiomics model based on computed tomography (CT) data for preoperative evaluation of hepatocellular carcinoma (HCC) differentiation (low vs high grade), and to preliminarily explore the biological basis of the radiomics model. Methods: A total of 1234 HCC patients with contrast-enhanced CT images were recruited from two institutions. Radiomics features were extracted from preoperative venous-phase CT data and selected in terms of reproducibility, relevance, and redundancy. The random forest (RF) algorithm was applied to establish a radiomics signature. Meanwhile, the deep learning model was constructed based on a VGG network. Additionally, clinical characteristics of the subjects were used to construct a clinical model. Finally, the fused model integrated a tripartite prediction based on a logistic regression algorithm. A correlation analysis was performed to explore the association between radiomics features and biological variables based on multiomics levels. Findings: The radiomics signature established with the RF algorithm comprised 25 radiomics features. The AUCs in the training, internal validation, and independent test cohorts were 0·82, 0·76, and 0·75, respectively, for the radiomics signature; 0·85, 0·81, and 0·75, respectively, for the deep learning model; and 0·89, 0·83, and 0·80, respectively, for the fused model. Multiomics analysis showed that the selected radiomics features contained abundant biological information that was related to tumor differentiation. Interpretation: Our deep learning radiomics model can serve as a noninvasive tool of preoperative HCC differentiation evaluation to guide clinical decision-making and prognostic stratification. Funding: National Key Research and Development Program of China, Natural Science Foundation of China, Zhejiang Provincial Education Department. Declaration of Interest: The authors declare that they have no competing interests. Ethical Approval: This study was approved by the institutional review boards of the First Affiliated Hospital, College of Medicine, Zhejiang University (Institution 1) and Ningbo Medical Center Lihuili Hospital (Institution 2), which waived the requirement for patients’ informed consent.

Objective: The folic acid analog pemetrexed (PMX) is recommended for the first-line chemotherapy for advanced non-squamous non-small cell lung cancer (NSCLC). However, the mechanisms underlying PMX cytotoxicity in NSCLC remain to be fully explored. Methods: PMX effect was evaluated in a urethane-induced lung adenocarcinoma mouse model. The interaction between PMX and intracellular proteins, particularly peroxisome proliferator-activated receptor γ (PPARγ), was investigated. The role of PPARγ in mediating pemetrexed cytotoxicity was investigated using NSCLC cell lines, mouse models and clinical specimens. Results: This study found that PPARγ expression was correlated with prolonged progression-free survival in NSCLC patients. PPARγ downregulated hypoxanthine-guanine phosphoribosyl transferase (HGPRT), a key enzyme for nucleotide salvage synthesis, thereby sensitizing cells to PMX inhibition on nucleotide de novo synthesis. PMX was also a candidate partial agonist of PPARγ, and PMX-activated PPARγ bound to NF-κB and transcriptionally suppressed the NF-κB target gene, c-Myc. PMX inhibited tumor growth by activating PPARγ in a urethane-induced lung cancer model characterized by elevated NF-κB activity. Conclusion: PPARγ improves pemetrexed therapeutic efficacy in non-squamous NSCLC. The cytotoxicity effect of PMX can be synergized by activating PPARγ and thereby inhibiting NF-κB pathway.

TUG1 has been reported to play an important role in various cancer types. However, the study about the function of lncRNA TUG1 in myocardial infarction is limited. This study was aimed to investigate the role of TUG1 in H9c2 cell injury induced by hypoxia and explore its possible molecular mechanism. The proliferation assay, migration assay, invasion assay, and apoptosis assay were performed. RT-PCR was used to determine the relative RNA expression of TUG1, miR-124 and Hic-5. Western blotting was used to detect the expression levels of apoptotic proteins, Hic-5, Sp1, and Survivin. Hypoxia could significantly decrease cell proliferation, migration and invasion and increase H9c2 cell apoptosis. Knock-down of TUG1 promoted the cell damage induced by hypoxia. miR-124 was the direct target of TUG1 and down-regulated by TUG1. TUG1 silence aggravated hypoxia injury by up-regulating miR-124. In addition, Hic-5 was the target of miR-124 and negatively regulated by miR-124. Our findings showed that Hic-5 over-expression could significantly induce increases in cell viability, migration and invasion, and induce decrease in cell apoptosis after hypoxia damage. Over-expression of Hic-5 could increase the expression of Sp1 and Survivin, which inhibited the cell apoptosis, thereby reducing the cell damage induced by hypoxia.

Background The functional role of corin in H2O2-induced apoptosis is largely unexplored. The present study investigated the protective role of corin against cell injury by possible involvement of PI3K/AKT and NF-kB signaling pathways in cardiomyocytes. Method Cardiomyocytes H9c2 and HL-1 cells were used in the study. Cell viability was measured using CCK-8 assay; cell apoptosis was analyzed by flow cytometry, TUNEL assay, and western blot; and cell migration was measured using wound healing assay. The fluorescent intensities of reactive oxygen species (ROS) were measured using a flow cytometer. Quantitative RT-PCR was used to measure the mRNA expression of corin. Western blot was used to measure the protein expression of corin, apoptosis-related proteins (Bax, cleaved-Caspase-3 and -9), and PI3K/AKT and NF-κB signaling pathway proteins. Results Treatment with H2O2 (150 μM, 6 h) significantly decreased cell viability and relative migration, increased apoptosis, and decreased the expression of corin in H9c2 and HL-1 cells. Overexpression of corin alleviated the H2O2-induced cell injury by increasing cell viability and migration and decreasing apoptosis in the cardiomyocytes. Overexpression of corin also decreased the ROS level in the cardiomyocytes likely through upregulating HIF-1α. These effects of corin on the cell injury might be mediated via the corin-induced activations of PI3K/AKT and NF-κB signaling pathways. Conclusion Overexpression of corin protected cardiomyocytes from H2O2-induced injury by decreasing apoptosis and ROS level via activations of the PI3K/AKT and NF-κB signaling pathways and upregulating HIF-1α.

First-generation epithelial growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have markedly improved the treatment of non-small cell lung cancer (non-SCLC) with EGFR-sensitive mutations. However, acquired resistance to these drugs was inevitable. The transformation of lung adenocarcinoma to SCLC following treatment with EGFR-TKIs is a rare phenomenon that contributes to resistance to EGFR-TKIs. The present case concerns a 74-year-old man previously diagnosed with and treated for pneumonia; however, this was later pathologically confirmed as lung adenocarcinoma by transbronchial lung biopsy. Deletion of exon 19 of EGFR was identified by next-generation sequencing technology. The patient improved markedly when treated with gefitinib, but relapsed after 1 year, with markedly increased serum levels of neuron-specific enolase (NSE). Transformation to SCLC was detected by endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA) re-biopsy, which was negative for the deletion of exon 19 of EGFR. The patient was positive for vimentin expression and refractory to etoposide and cisplatin chemotherapy, and succumbed to the disease 18 months after diagnosis. Transformation of the disease from adenocarcinoma to SCLC may have been due to cancer heterogeneity. Re-biopsy is therefore important in EGFR-TKI-resistant patients for genetic and histological re-evaluation. NSE serum levels may also be useful for detecting early SCLC transformation.

Acute myocardial infarction (AMI) results from long-term diminished blood supply diminishment (ischemia) to the heart, and the main reason for ischemia is hypoxia. BCL2 interaction protein 3 (BNIP3) can be upregulated by hypoxia and participates in the mediation of hypoxia-activated apoptosis in cardiac myocyte death. The purpose of this study was to interrogate the mechanism of BNIP3 in hypoxia-activated cardiac myocyte injury. Cell viability and apoptosis were evaluated by Cell counting kit 8 (CCK-8), 5-ethynyl-2’-deoxyuridine (EdU), TdT-mediated dUTP Nick-End Labeling (TUNEL), and caspase-3 activity assays. Molecular interactions were assessed by RNA immunoprecipitation (RIP) and pull-down assays. Gene levels were assessed via quantitative real-time PCR and western blot. BNIP3 expression was upregulated by hypoxia in H9c2 cells. We found that circ-BNIP3 (hsa_circ_0005972), whose annotated gene was BNIP3, was induced by hypoxia and positively regulated BNIP3 expression. Knockdown of BNIP3 or circ-BNIP3 reversed the effect of hypoxia in attenuating H9c2 cell viability and inducing apoptosis. circ-BNIP3 sponged miRNA-27a-3p (miR-27a-3p) to upregulate BNIP3 expression. Moreover, eukaryotic translation initiation factor 4A3 (EIF4A3) bound with the upstream region of the circ-BNIP3 mRNA transcript and induced circ-BNIP3 expression in H9c2 cells. EIF4A3-induced circ-BNIP3 aggravated hypoxia-caused injury of H9c2 cells through targeting miR-27a-3p/BNIP3 pathway, indicating circ-BNIP3 as a new target for relieving hypoxia-induced injury of cardiac myocytes., Graphical Abstract

Abnormal wound healing by pulmonary artery smooth muscle cells (PASMCs) promotes vascular remodeling in hypoxia-induced pulmonary hypertension (HPH). Increasing evidence shows that both the mammalian target of rapamycin complex 1 (mTORC1) and nuclear factor-kappa B (NF-κB) are involved in the development of HPH. In this study, we explored the crosstalk between mTORC1 and NF-κB in PASMCs cultured under hypoxic condition and in a rat model of hypoxia-induced pulmonary hypertension (HPH). We showed that hypoxia promoted wound healing of PASMCs, which was dose-dependently blocked by the mTORC1 inhibitor rapamycin (5−20 nM). In PASMCs, hypoxia activated mTORC1, which in turn promoted the phosphorylation of NF-κB. Molecular docking revealed that mTOR interacted with IκB kinases (IKKs) and that was validated by immunoprecipitation. In vitro kinase assays and mass spectrometry demonstrated that mTOR phosphorylated IKKα and IKKβ separately. Inhibition of mTORC1 decreased the level of phosphorylated IKKα/β, thus reducing the phosphorylation and transcriptional activity of NF-κB. Bioinformatics study revealed that dipeptidyl peptidase-4 (DPP4) was a target gene of NF-κB; DPP4 inhibitor, sitagliptin (10−500 μM) effectively inhibited the abnormal wound healing of PASMCs under hypoxic condition. In the rat model of HPH, we showed that NF-κB activation (at 3 weeks) was preceded by mTOR signaling activation (after 1 or 2 weeks) in lungs, and administration of sitagliptin (1−5 mg/kg every day, ig) produced preventive effects against the development of HPH. In conclusion, hypoxia activates the crosstalk between mTORC1 and NF-κB, and increased DPP4 expression in PASMCs that leads to vascular remodeling. Sitagliptin, a DPP4 inhibitor, exerts preventive effect against HPH.

This paper uses P.R. China’s provincial data from 2003 to 2012 to empirically measure the impact of marketization on the reverse technology spillover effects of outward foreign direct investment (OFDI) using a panel threshold regression model. Results show a positive reverse technology spillover effect of OFDI when the degree of marketization exceeds certain threshold levels. P.R. China can increase total factor productivity by accelerating the implementation of reforms in market policy toward outward FDI that take into account the differential regional marketization levels. JEL Classification: C32, C51, F21, O3