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ABSTRACTPublic-private-partnership (PPP) model has been widely used in public services and infrastructure projects, and many relevant studies on PPP have emerged. Based on CiteSpace and VOS viewer, this study aims to comprehensively analyze the research status and development trend of the PPP model in China and US. Firstly, the essential statistical characteristics of authors, institutions, and publications are given based on the relevant data collection in Web of Science core collection database. Secondly, the research hotspots and evolution trends of PPP by scholars in China and US are discussed by carrying out keywords co-occurrence analysis and cluster analysis. Finally, from the literature analysis and keyword co-occurrence network over time, the research directions, such as payment risks for the government during the operation period, early termination mechanism and system compensation mechanism, government supervision, and related information, are summarized and forecast, to provide theoretical guidance for the future research on PPP.

Vasopressin V2receptors (V2R) are a promising drug target for autosomal dominant polycystic kidney disease (ADPKD). As previous research demonstrated that the residence time of V2R antagonists is critical to their efficacy in both ex vivo and in vivo models of ADPKD, we performed extensive structure–kinetic relationship (SKR) analyses on a series of benzodiazepine derivatives. We found that subtle structural modifications of the benzodiazepine derivatives dramatically changed their binding kinetics but not their affinity. Compound 18exhibited a residence time of 77 min, which was 7.7-fold longer than that of the reference compound tolvaptan (TVP). Accordingly, compound 18exhibited higher efficacy compared to TVP in an in vivo model of ADPKD. Overall, our study exemplifies a kinetics-directed medicinal chemistry effort for the development of efficacious V2R antagonists. We envision that this strategy may also have general applicability in other therapeutic areas.

Cyst formation and enlargement in autosomal dominant kidney disease (ADPKD) is mainly driven by aberrantly increased cytosolic cAMP in renal tubule epithelial cells. Because the vasopressin V2receptor (V2R) regulates intracellular cAMP levels in kidneys, a series of benzodiazepine derivatives were developed targeting the V2R. Among these derivatives, compound 25exhibited potent binding affinity to the V2R (Ki= 9.0 ± 1.5 nM) and efficacious cAMP inhibition (IC50= 9.2 ± 3.0 nM). This led to the suppression of cyst formation and growth in both an MDCK cell model and an embryonic kidney cyst model. Further advancing compound 25in a murine model of ADPKD demonstrated a significantly improved in vivoefficacy compared with the reference compound tolvaptan. Overall, compound 25holds therapeutic potential for the treatment of ADPKD.

Appropriate risk sharing is crucial for the successful implementation of Public-Private Partnership projects. However, under different social systems, the international community lacks a clear risk-sharing framework in Public-Private Partnership research. This study employs a multi-case study method to examine the practice of risk sharing in infrastructure Public-Private Partnership projects within China and the US, aiming to provide a clear risk management framework for Public-Private Partnership projects. The research findings reveal common elements and similar characteristics in risk-sharing practices. Contrary to the goal of transferring all risks to the private sector, both countries actually allocate risks to the party with stronger risk control capabilities or share risks between the government and the private sector. The US benefits from more mature policies and has a comprehensive Public-Private Partnership model implementation framework; in contrast, as an emerging market for Public-Private Partnership models, China's current laws and regulations need further improvement. The results of this study not only contribute to optimizing risk-sharing arrangements and improving investment efficiency of the project, but also promote the development of cross-border infrastructure projects, and provide valuable experience and insights for the sustainable development of global infrastructure.

A project procurement method (PPM) defines the roles and responsibilities of the participates involved in the construction project. Selecting a suitable PPM is one of the critical issues to achieve the success of a construction project. The selection of PPM is a typical multi-criteria decision-making problem under uncertainty. Moreover, interval-valued intuitionistic fuzzy set (IVIFS) is a useful tool for depicting uncertainty of the multi-criteria decision-making (MCDM) problems. In this paper, the authors consider the PPM selection under IVIFS circumstance. Firstly, they introduce the concept of Spearman rank correlation coefficient (SRCC) between two IVIFSs and then calculate the SRCC between the ideal alternative and each alternative. The ideal option of PPM is determined according to the computed value of SRCC. Overall, the proposed method can avoid the calculation of the criteria weights, and the selection process is simple and straightforward. Finally, a real-world infrastructure project PPM selection has been illustrated the applicability and effectiveness of this methodology.

Visual domain adaptation aims to seek an effective transferable model for unlabeled target images by benefiting from the well-labeled source images following different distributions. Many recent efforts focus on extracting domain-invariant image representations via exploring target pseudo labels, predicted by the source classifier, to further mitigate the conditional distribution shift across domains. However, two essential factors are overlooked by most existing methods: 1) the learned transferable features should be not only domain invariant but also category discriminative; and 2) the target pseudo label is a two-edged sword to cross-domain alignment. In other words, the wrongly predicted target labels may hinder the class-wise domain matching. In this article, to address these two issues simultaneously, we propose a discriminative transfer feature and label consistency (DTLC) approach for visual domain adaptation problems, which can naturally unify cross-domain alignment with discriminative information preserved and label consistency of source and target data into one framework. To be specific, DTLC first incorporates class discriminative information by penalizing the maximum distance of data pair in the same class and the minimum distance of data pair sharing the different labels for each data into the distribution alignment of both domains. The target pseudo labels are then refined based on the label consistency within the domains. Thus, the transfer feature learning and coarse-to-fine target labels would be coupled to benefit each other in an iterative way. Comprehensive experiments on several visual cross-domain benchmarks verify that DTLC can gain remarkable margins over state-of-the-art (SOTA) nondeep visual domain adaptation methods and even be comparable to competitive deep domain adaptation ones.

Aquaporin-2 (AQP2) is a water channel protein expressed in principal cells (PCs) of the kidney collecting ducts (CDs) and plays a critical role in mediating water reabsorption and urine concentration. AQP2 undergoes both regulated trafficking mediated by vasopressin (VP) and constitutive recycling, which is independent of VP. For both pathways, actin cytoskeletal dynamics is a key determinant of AQP2 trafficking. We report here that manganese chloride (MnCl2) is a novel and potent regulator of AQP2 trafficking in cultured cells and in the kidney. MnCl2treatment promoted internalization and intracellular accumulation of AQP2. The effect of MnCl2on the intracellular accumulation of AQP2 was associated with activation of RhoA and actin polymerization without modification of AQP2 phosphorylation. Although the level of total and phosphorylated AQP2 did not change, MnCl2treatment impeded VP-induced phosphorylation of AQP2 at its serine-256, -264, and -269 residues and dephosphorylation at serine 261. In addition, MnCl2significantly promoted F-actin polymerization along with downregulation of RhoA activity and prevented VP-induced membrane accumulation of AQP2. Finally, MnCl2treatment in mice resulted in significant polyuria and reduced urinary concentration, likely due to intracellular relocation of AQP2 in the PCs of kidney CDs. More importantly, the reduced urinary concentration caused by MnCl2treatment in animals was not corrected by VP. In summary, our study identified a novel effect of MnCl2on AQP2 trafficking through modifying RhoA activity and actin polymerization and uncovered its potent impact on water diuresis in vivo.

Autosomal dominant polycystic kidney disease (ADPKD) is a common monogenetic disease characterized by the progressive development of renal cysts with further need for effective therapy. Here our aim was to investigate the effect of Ganoderma triterpenes(GT) on the development of kidney cysts. Importantly, GT attenuated cyst development in two mouse models of ADPKD with phenotypes of severe cystic kidney disease. Assays for tubulogenesis showed that GT promoted epithelial tubule formation in MDCK cells, suggesting a possible effect on epithelial cell differentiation. The role of GT in regulating key signaling pathways involved in the pathogenesis of PKD was further investigated by immune blotting. This showed that GT specifically downregulated the activation of the Ras/MAPK signaling pathway both in vitroand in vivowithout detectable effect on the mTOR pathway. This mechanism may be involved in GT downregulating intracellular cAMP levels. Screening of 15 monomers purified from GT for their effects on cyst development indicated that CBLZ-7 (ethyl ganoderate C2) had a potent inhibitory effect on cyst development in vitro. Additionally, like GT, CBLZ-7 was able to downregulate forskolin-induced activation of the Ras/MAPK pathway. Thus, GT and its purified monomer CBLZ-7 may be potential therapeutic regents for treating ADPKD.

Prevailing strategies directing early-phase drug discovery heavily rely on equilibrium-based metrics such as affinity, which overlooks the kinetic process of a drug molecule interacting with its target. Herein, we developed a number of vasopressin V2receptor (V2R) antagonists with divergent binding affinities and kinetics for autosomal dominant polycystic kidney disease (ADPKD). Surprisingly, the residence time of the V2R antagonists, but not their affinity, was correlated with the efficacy in both ex vivoand in vivomodels of ADPKD. We envision that the kinetics-directed drug candidate selection and development may have general applicability for ADPKD and other therapeutic areas as well.