A novel fusion protein consisting of anti-ANGPTL3 antibody and interleukin-22 ameliorates diabetic nephropathy in mice

IntroductionThe pathogenic mechanisms of diabetic nephropathy (DN) include podocyte injury, inflammatory responses and metabolic disorders. Although the antagonism of Angiopoietin-like protein 3 (ANGPTL3) can alleviate proteinuria symptoms by inhibiting the activation of integrin αvβ3 on the surface of podocytes, it can not impede other pathological processes, such as inflammatory responses and metabolic dysfunction of glucolipid. Interleukin-22 (IL-22) is considered to be a pivotal molecule involved in suppressing inflammatory responses, initiating regenerative repair, and regulating glucolipid metabolism.MethodsGenes encoding the mIL22IgG2aFc and two chains of anti-ANGPTL3 antibody and bifunctional protein were synthesized. Then, the DN mice were treated with intraperitoneal injection of normal saline, anti-ANGPTL3 (20 mg/kg), mIL22Fc (12 mg/kg) or anti-ANGPTL3 /IL22 (25.3 mg/kg) and irrigation of positive drug losartan (20mg/kg/d) twice a week for 8 weeks.ResultsIn this research, a novel bifunctional fusion protein (anti-ANGPTL3/IL22) formed by the fusion of IL-22 with the C-terminus of anti-ANGPTL3 antibody exhibited favorable stability and maintained the biological activity of anti-ANGPTL3 and IL-22, respectively. The fusion protein showed a more pronounced attenuation of proteinuria and improved dysfunction of glucolipid metabolism compared with mIL22Fc or anti-ANGPTL3. Our results also indicated that anti-ANGPTL3/IL22 intervention significantly alleviated renal fibrosis via inhibiting the expression of the inflammatory response-related protein nuclear factor kappa light-chain enhancer of activated B cells (NF-κB) p65 and NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome. Moreover, transcriptome analysis revealed the downregulation of signaling pathways associated with injury and dysfunction of the renal parenchymal cell indicating the possible protective mechanisms of anti-ANGPTL3/IL22 in DN.ConclusionCollectively, anti-ANGPTL3/IL22 bifunctional fusion protein can be a promising novel therapeutic strategy for DN by reducing podocyte injury, ameliorating inflammatory response, and enhancing renal tissue recovery

An analysis of farmers' perception of the new cooperative medical system in Liaoning Province, China

<p>Abstract</p> <p>Background</p> <p>Since 2003, the number of pilot areas of the New Rural Cooperative Medical System (NRCMS) has increased in rural China. And the major efforts have been concentrated on the enrollment of prospective members. In this study, we examined the satisfaction of the rural residents with the NRCMS as well as factors affecting their attitudes towards the NRCMS.</p> <p>Methods</p> <p>The data for this study were collected from a survey involving twenty counties in Liaoning Province. Interviews and focus groups were conducted between 10^thJanuary and 20^thAugust 2008. A total of 2,780 people aged 18-72 were randomly selected and interviewed. Data were evaluated by nonparametric tests and ordinal regression models.</p> <p>Results</p> <p>71.6% of the study subjects were satisfied with the NRCMS. Single factor analysis showed that attitudes towards the NRCMS were influenced by gender, age, marital status, and self-rated health status. In the ordinal regression analysis, gender, age, and self-rated health status affect satisfaction (P < 0.05).</p> <p>Conclusions</p> <p>We found that a considerable proportion of farmers were satisfied with the NRCMS. Gender, age, and self-rated health status had significant effects on farmers' attitudes towards the NRCMS. The Chinese Central Government attempted to adopt active measures in the future to continuously improve the NRCMS, including initiating educational programs, building new medical facilities and increasing financial investment.</p

LC-MS/MS spectrometry analysis of PLCE1.

Protein pulldown was performed using a previously reported method (17). Briefly, HEK293 cells were transfected with a plasmid expressing PLCE1-Myc or TAK1. 24 h post-transfection, cells were harvested for preparing total cell lysates, which was then subjected to protein pulldown assay using the Myc-Tag beads (Sepharose® Bead Conjugate; #55464; CST, Beverley, MA, USA). After 4 h-incubation on a rotator, unbound proteins were removed using the ice-cold wash buffer. Finally, the resulting immunocomplex was subjected to LC-MS/MS spectrometry analysis (Shanghai Applied Protein Technology Co., Ltd.). MS/MS spectra were searched using MASCOT engine (Matrix Science, London, UK; version 2.4) against the UniProKB human (161584 total entries, downloaded 20180105).</p

Integrated Evaluation of Rivers Based upon the River Happiness Index (RHI): Happy Rivers in China

How to better harmonize the relationship between humans and rivers is a global issue of widespread concern at home and abroad, and science-based and integrated evaluation of rivers themselves is crucial to river management. Based on Maslow&rsquo;s hierarchy of needs and according to the World Happiness Report and the 2030 Agenda for Sustainable Development, this paper argues that a happy river is a river that can maintain its own health, support high-quality economic and social development in the river basin and the region, reflect harmony between humans and water, and give people in the river basin a high sense of security and the ability to gain and satisfaction. This paper also analyzes happy rivers at five levels, including water security, water resources, water environment, water ecology, and water culture, and develops the River Happiness Index (RHI) and its indicator system, as well as assesses the overall river happiness in China&rsquo;s 10 first-grade water resource zones. The results show that China&rsquo;s RHI is at a medium level, with flood control capacity at a near-good level. On the grounds of the RHI evaluation results, the paper puts forward targeted measures for river basin governance, and provides a systematic solution to national river protection and governance

An Approach for Measuring Complexity Degree of International Engineering Projects

With the increasing trend of globalization, countries actively join the international engineering market, increasing the complexity of projects. An appropriate method for assessing project complexity can help project managers recognize the current situation and solve problems. However, existing complexity studies ignored the contribution of human element. The impact of human activities on the complexity of socio-economic systems is concerned in the Harmony Management Theory (HMT), therefore, this study proposed a complexity measurement based on the Harmony Management Theory. Firstly, an evaluation indicator system including three dimensions of organizational, technological, and environmental complexity is proposed through a literature review, Back-Propagation Neural Network-Decision Making Trial and Evaluation Laboratory (BP-DEMATEL) method, and Interval-valued intuitionistic Fuzzy Sets (IIFS) are used to calculate complexity scores. Then, a case study of Yawan high-speed railway project is conducted to verify the effectiveness of the proposed method. The main conclusions are as follows: (1) The complexity measurement based on harmony theory can be carried out from three aspects: Organization, technology, and environment. (2) The overall complexity performance of case project is 0.52, showing a medium level. (3) Technical complexity is the most important factor of the case project. The method proposed in this study can identify the influencing factors of complexity and calculate the comprehensive evaluation value of complexity. Based on the final quantified results, managers can formulate appropriate measures and match the project with appropriate resources so as to improve the performance of International Engineering Projects (IEPs)

Optimization strategies to eliminate interface conflicts in complex supply chains of construction projects

The supply chains of complex construction projects are characterized by multi-disciplinary participants, adversarial short-term relationships and fragmentations in project delivery procedures. Multi-disciplinary participants tend to make deci­sions on project activities based on their own objectives and value systems independently with little regard of holistic project performance. The lack of common values results in a limited understanding of how behaviors of one discipline impact on the related disciplines. This has led to tons of interface conflicts which ultimately affect project effectiveness. This paper investi­gates this problem by discussing Interface Value for the core players to understand the value-driven behaviors on the boundaries among owner and multiple prime contractors in complex construction projects. Two types of interface conflicts are recognized and defined. Value Optimization Strategy is proposed under status quo delivery methods by adjusting and reallocating interface responsibilities between related contractors. Improvements of procurement procedures are the key solutions to interface con­flicts. Prospects of integrated project delivery (IPD) in eliminating interface conflicts are also discussed. The paper concludes that Value Optimization Strategy and IPD-based approach are expected to eliminate interface conflicts of complex construction projects, integrate the complex supply chain and lower the potential risks for project delivery delay and cost overrun. First published online:&nbsp;03 Apr 201

Health Status Stability of Patients in a Medical Rehabilitation Program: What Are the Roles of Time, Physical Fitness Level, and Self-efficacy?

Background!#!Individuals' physical and mental health, as well as their chances of returning to work after their ability to work is damaged, can be addressed by medical rehabilitation.!##!Aim!#!This study investigated the developmental trends of mental and physical health among patients in medical rehabilitation and the roles of self-efficacy and physical fitness in the development of mental and physical health.!##!Design!#!A longitudinal design that included four time-point measurements across 15 months.!##!Setting!#!A medical rehabilitation center in Germany.!##!Population!#!Participants included 201 patients who were recruited from a medical rehabilitation center.!##!Methods!#!To objectively measure physical fitness (lung functioning), oxygen reabsorption at anaerobic threshold (VO2AT) was used, along with several self-report scales.!##!Results!#!We found a nonlinear change in mental health among medical rehabilitation patients. The results underscored the importance of medical rehabilitation for patients' mental health over time. In addition, patients' physical health was stable over time. The initial level of physical fitness (VO2AT) positively predicted their mental health and kept the trend more stable. Self-efficacy appeared to have a positive relationship with mental health after rehabilitation treatment.!##!Conclusions!#!This study revealed a nonlinear change in mental health among medical rehabilitation patients. Self-efficacy was positively related to mental health, and the initial level of physical fitness positively predicted the level of mental health after rehabilitation treatment.!##!Clinical rehabilitation!#!More attention could be given to physical capacity and self-efficacy for improving and maintaining rehabilitants' mental health

Time-Resolved Analysis of Domain Growth and Alignment of Cylinder-Forming Block Copolymers Confined within Nanopatterned Substrates

In this Letter, we elucidate the microstructure evolution of asymmetric poly­(styrene-<i>b</i>-methyl methacrylate), PS-<i>b</i>-PMMA, block copolymer confined within nanoscale linear channels on silicon nitride substrates. We have directly observed the mechanism for cylinder alignment within the nanochannels using time-resolved AFM imaging and computerized image analysis. The overall alignment occurs via the coarsening of grains that have preferred cylinder orientation along the channel direction and is energetically driven by the interface energies of adjacent diblock domains of differing orientation. Grain coarsening is strongly affected by the annealing temperature and the geometry of the grain boundary itself. Grain coarsening promptly occurs when a domain is bordered by adjacent high-angle grain boundaries. The energetic term that drives this process arises from the fact that high-angle grain boundaries with larger excess energy migrate faster than other lower-angle grain boundaries. The velocity of grain boundary migration is proportional to the boundary tilt angle, while the activation energy depends weakly on this angle

Time-Resolved Analysis of Domain Growth and Alignment of Cylinder-Forming Block Copolymers Confined within Nanopatterned Substrates

In this Letter, we elucidate the microstructure evolution of asymmetric poly­(styrene-<i>b</i>-methyl methacrylate), PS-<i>b</i>-PMMA, block copolymer confined within nanoscale linear channels on silicon nitride substrates. We have directly observed the mechanism for cylinder alignment within the nanochannels using time-resolved AFM imaging and computerized image analysis. The overall alignment occurs via the coarsening of grains that have preferred cylinder orientation along the channel direction and is energetically driven by the interface energies of adjacent diblock domains of differing orientation. Grain coarsening is strongly affected by the annealing temperature and the geometry of the grain boundary itself. Grain coarsening promptly occurs when a domain is bordered by adjacent high-angle grain boundaries. The energetic term that drives this process arises from the fact that high-angle grain boundaries with larger excess energy migrate faster than other lower-angle grain boundaries. The velocity of grain boundary migration is proportional to the boundary tilt angle, while the activation energy depends weakly on this angle

Time-Resolved Analysis of Domain Growth and Alignment of Cylinder-Forming Block Copolymers Confined within Nanopatterned Substrates

In this Letter, we elucidate the microstructure evolution of asymmetric poly­(styrene-<i>b</i>-methyl methacrylate), PS-<i>b</i>-PMMA, block copolymer confined within nanoscale linear channels on silicon nitride substrates. We have directly observed the mechanism for cylinder alignment within the nanochannels using time-resolved AFM imaging and computerized image analysis. The overall alignment occurs via the coarsening of grains that have preferred cylinder orientation along the channel direction and is energetically driven by the interface energies of adjacent diblock domains of differing orientation. Grain coarsening is strongly affected by the annealing temperature and the geometry of the grain boundary itself. Grain coarsening promptly occurs when a domain is bordered by adjacent high-angle grain boundaries. The energetic term that drives this process arises from the fact that high-angle grain boundaries with larger excess energy migrate faster than other lower-angle grain boundaries. The velocity of grain boundary migration is proportional to the boundary tilt angle, while the activation energy depends weakly on this angle