Xiang Huang

Increased airway smooth muscle contractility and the development of airway hyperresponsiveness are cardinal features of asthma, but the signaling pathways that promote these changes are poorly understood. Tyrosine phosphorylation is tightly regulated by the opposing actions of protein tyrosine kinases and phosphatases, but little is known about whether tyrosine phosphatases influence AHR. Here, we demonstrate that genetic inactivation of receptor-like protein tyrosine phosphatase J, which encodes CD148, protected mice from the development of increased AHR in two different asthma models. Surprisingly, CD148 deficiency minimally affected the inflammatory response to allergen, but significantly altered baseline pulmonary resistance. Mice specifically lacking CD148 in smooth muscle had decreased AHR, and the frequency of calcium oscillations in CD148-deficient ASM was substantially attenuated, suggesting that signaling pathway alterations may underlie ASM contractility. Biochemical analysis of CD148-deficient ASM revealed hyper-phosphorylation of the C-terminal inhibitory tyrosine of SRC family kinases, implicating CD148 as a critical positive regulator of SFK signaling in ASM. The effect of CD148 deficiency on ASM contractility could be mimicked by treatment of both mouse trachea and human bronchi with specific SFK inhibitors. Our studies identify CD148 and the SFKs it regulates in ASM as potential targets for the treatment of AHR.

Exaggerated contraction of airway smooth muscle is the major cause of symptoms in asthma, but the mechanisms that prevent exaggerated contraction are incompletely understood. Here, we showed that integrin α 9β 1on airway smooth muscle localizes the polyamine catabolizing enzyme spermidine/spermine N 1-acetyltransferase in close proximity to the lipid kinase PIP5K1γ. As PIP5K1γ is the major source of PIP2 in airway smooth muscle and its activity is regulated by higher-order polyamines, this interaction inhibited IP3-dependent airway smooth muscle contraction. Mice lacking integrin α 9β 1 in smooth muscle had increased airway responsiveness in vivo, and loss or inhibition of integrin α 9β 1 increased in vitro airway narrowing and airway smooth muscle contraction in murine and human airways. Contraction was enhanced in control airways by the higher-order polyamine spermine or by cell-permeable PIP2, but these interventions had no effect on airways lacking integrin α 9β 1 or treated with integrin α 9β 1-blocking antibodies. Enhancement of SSAT activity or knockdown of PIP5K1γ inhibited airway contraction, but only in the presence of functional integrin α 9β 1. Therefore, integrin α 9β 1 appears to serve as a brake on airway smooth muscle contraction by recruiting SSAT, which facilitates local catabolism of polyamines and thereby inhibits PIP5K1γ. Targeting key components of this pathway could thus lead to new treatment strategies for asthma.

The intracellular scaffold protein IQGAP1 supports protein complexes in conjunction with numerous binding partners involved in multiple cellular processes. Here, we determined that IQGAP1 modulates airway smooth muscle contractility. Compared with WT controls, at baseline as well as after immune sensitization and challenge, Iqgap1-/- mice had higher airway responsiveness. Tracheal rings from Iqgap1-/- mice generated greater agonist-induced contractile force, even after removal of the epithelium. RhoA, a regulator of airway smooth muscle contractility, was activated in airway smooth muscle lysates from Iqgap1-/- mice. Likewise, knockdown of IQGAP1 in primary human airway smooth muscle cells increased RhoA activity. Immunoprecipitation studies indicated that IQGAP1 binds to both RhoA and p190A-RhoGAP, a GTPase-activating protein that normally inhibits RhoA activation. Proximity ligation assays in primary airway human smooth muscle cells and mouse tracheal sections revealed colocalization of p190A-RhoGAP and RhoA; however, these proteins did not colocalize in IQGAP1 knockdown cells or in Iqgap1-/- trachea. Compared with healthy controls, human subjects with asthma had decreased IQGAP1 expression in airway biopsies. Together, these data demonstrate that IQGAP1 acts as a scaffold that colocalizes p190ARhoGAP and RhoA, inactivating RhoA and suppressing airway smooth muscle contraction. Furthermore, our results suggest that IQGAP1 has the potential to modulate airway contraction severity in acute asthma.

© 2015.We describe a near infrared light-activated gene silencing method in undifferentiated human embryonic stem cell using a plasmonic hollow gold nanoshell as the siRNA carrier. Our modular biotin-streptavidin coupling strategy enables positively charged TAT-peptide to coat oligonucleotides-saturated nanoparticles as a stable colloid formation. TAT-peptide coated nanoparticles with dense siRNA loading show efficient penetration into a wide variety of hESC cell lines. The siRNA is freed from the nanoparticles and delivered to the cytosol by femtosecond pulses of NIR light with potentially exquisite spatial and temporal control. The effectiveness of this approach is shown by targeting GFP and Oct4 genes in undifferentiated hESC. The accelerated expression of differentiation markers for all three germ layers resulting from Oct4 knockdown confirms that this method has no detectable adverse effects that limit the range of differentiation. This biocompatible and NIR laser-activated patterning method makes possible single cell resolution of siRNA delivery for diverse studies in stem cell biology, tissue engineering and regenerative medicine.

Dynamic modulation of cell adhesion is integral to a wide range of biological processes. The small guanosine triphosphatase Rap1 is an important regulator of cell - cell and cell - matrix adhesions. We show here that induced expression of activated Abl tyrosine kinase reduces Rap1-GTP levels through phosphorylation of Tyr221 of CrkII, which disrupts interaction of CrkII with C3G, a guanine nucleotide exchange factor for Rap1. Abl-dependent down-regulation of Rap1-GTP causes cell rounding and detachment only when the Rho - ROCK1 pathway is also activated, for example, by lysophosphatidic acid. During ephrin-A1 - induced retraction of PC3 prostate cancer cells, we show that endogenous Abl is activated and disrupts the CrkII - C3G complex to reduce Rap1-GTP. Interestingly, ephrin-A1 - induced PC3 cell retraction also requires LPA, which stimulates Rho to a much higher level than that is activated by ephrin-A1. Our results establish Rap1 as another downstream target of the Abl - CrkII signaling module and show that Abl - CrkII collaborates with Rho - ROCK1 to stimulate cell retraction. © 2008 Huang et al.

Background: High throughput screens with RNA interference technology enable loss-of-function analyses of gene activities in mammalian cells. While the construction of genome-scale shRNA libraries has been successful, results of large-scale screening of those libraries can be difficult to analyze because of the relatively high noise levels and the fact that not all shRNAs in a library are equally effective in silencing gene expression. Results: We have screened a library consisting of 43,828 shRNAs directed against 8,500 human genes for functions that are necessary in cell detachment induced by a constitutively activated c-Abl tyrosine kinase. To deal with the issues of noise and uncertainty of knockdown efficiencies, we employed an analytical strategy that combines quantitative data analysis with biological knowledge, i.e. Gene Ontology and pathway information, to increase the power of the RNAi screening technique. Using this strategy we found 16 candidate genes to be involved in Abl-induced disruption of cell adhesion, and verified that the knockdown of IL6ST is associated with enhanced cell attachment. Conclusion: Our results suggest that the power of genome-wide quantitative shRNA screens can be significantly increased when analyzed using a systems biology-based approach to identify functional gene networks. © 2008 Huang et al; licensee BioMed Central Ltd.

© 2015 The Authors.Here, we examine the mechanism by which plasmacytoid dendritic cells and type I interferons promote humoral autoimmunity. In an amyloid-induced experimental autoimmune model, neutrophil depletion enhanced anti-nuclear antibody development, which correlated with heightened IFN-γ production by natural killer cells. IFN-α/β produced by pDCs activated NK cells via IL-15 induction. Neutrophils released reactive oxygen species, which negatively modulated the levels of IL-15, thereby inhibiting IFN-γ production. Mice deficient in NADPH oxidase 2 produced increased amounts of IFN-γ and developed augmented titers of autoantibodies. Both the pDC-IFN-α/β pathway and IFN-γ were indispensable in stimulating humoral autoimmunity. Male NZB/W F1 mice expressed higher levels of superoxide than their female lupus-prone siblings, and depletion of neutrophils resulted in spontaneous NK cell and autoimmune B cell activation. Our findings suggest a regulatory role for neutrophils in vivo and highlight the importance of an NK-IFN-γ axis downstream of the pDC-IFN-α/β pathway in systemic autoimmunity.

Research shows that entrepreneurial activities significantly promote economic development, which enhances the importance of the innovative entrepreneurial potential of college students. This study analyzes the effect of entrepreneurship education on entrepreneurial intention from the perspective of planned behavior theory. By examining the significant role of entrepreneurship education at colleges and universities on economic and social development, we established a conceptual model. To understand the relationship between entrepreneurship education and entrepreneurial intention, the hypotheses propose the intermediary role of entrepreneurial ability, and the study provides evidence from China the relationship between entrepreneurship education and entrepreneurial intention. Improving entrepreneurial intention and encouraging college students to establish businesses through entrepreneurship education in universities is crucial. This study proposes a hypothetical model of the relationship between entrepreneurial competence and entrepreneurial intention in entrepreneurship education at universities. Using a questionnaire survey of college students with practical experience in the Yangtze River Delta of China, the bootstrap method in the SPSS macro program process software verifies the hypotheses. The results show that entrepreneurial teaching, business plan competition, and entrepreneurial practice support positively affect entrepreneurial competence. In addition, entrepreneurial competence plays an intermediary role in the relationship between entrepreneurial teaching, business plan competition, entrepreneurship practice support, and entrepreneurial intention. Entrepreneurship education improves the ability to establish a business in the present and in entrepreneurial activities in the future. Entrepreneurial competence obtained through entrepreneurship education continuously affects entrepreneurial intention.

This study investigated the differences between past and future temporal discounting in terms of neural activity in relation to temporal distance. Results show that brain regions are engaged differently in past and future temporal discounting. This is likely because past temporal discounting requires memory reconstruction, whereas future temporal discounting requires the processing of uncertainty about the future. In past temporal discounting, neural activity differed only when preferences were made between rewards received one hour prior and rewards received further in the past. The peak amplitudes of P2 and P3 varied as the temporal distance increased from 2 weeks to 50 years. In future temporal discounting, neural activity differed only when preferences were evaluated between two delayed rewards. The delay conditions and had a significant influence on P2 and N2. Findings indicate the existence of different decision-making systems operating in past and future temporal discounting

Las críticas de la epistemología social y la teoría de prácticas científicas dePhilip Kitcher se han concentrado en los problemas entorno a su adopciónde la metodología individualista. Señalo en este artículo que, por un lado, elmotivo de Kitcher de adoptar la metodología individualista es para encontraruna epistemología social adecuada, y que, por otro lado, el problema de suadopción de la metodología individualista reside en dos presupuestos: a)existe una distinción tajante entre lo interno, identificado por propiedadesindividuales, y lo externo, identificado por propiedades no individuales,incluyendo las propiedades sociales entendidas como interacciones entreindividuos; b) las normas epistémicas que sirven como razones para establecerel conocimiento tienen que ser internas. Argumento que, si bien el motivo deKitcher es correcto, ambos presupuestos son problemáticos y que la reflexiónsobre ellos exige una nueva perspectiva para analizar los problemas acercade la epistemología social.

Up till now, China has not enacted any legal mechanisms governing certification or supervision for ethics committees. This article analyses deficiencies in the protection of subjects in clinical drug trials under China’s current laws and regulations; it emphasizes that investigators, as practitioners who have direct contact with subjects, play significant roles in protecting and safeguarding subjects’ rights and interests. The paper compares the status quo in China in this area to that of other countries and discusses ways China might enhance the protection of rights and interests of trial subjects, such as enhancing the ethical awareness of investigators through training, improving laws and regulations, and strengthening the communication between investigators and ethics committees.

When fcc single crystals with high-symmetry crystal orientations are deformed to moderate strains by rolling, tension or channel die compression, long dislocation boundaries inclined to the extension axis form. Similarly, long dislocation boundaries are often found in grains embedded in polycrystals deformed in the same manner. These extended planar boundaries are characteristically - 30-40° from the extension direction and contain the transverse specimen axis. The objective of the present article is to demonstrate that EPBs formed during plane strain deformation are parallel to equivalent slip planes, a pair of hypothetical slip systems used for analyses of the strain and crystal rotation components in place of the larger number of physical slip systems. The coincidence of EPBs and equivalent slip plane inclinations is shown to account for persistent observations of EPBs in the angle range - 30-40° from the rolling direction, in rolled single crystals of various initial orientations. The tendency of EPBs towards tilt or twist boundary character can also be rationalized on the basis of the equivalent slip system concept and consideration of the dislocation types available to be incorporated into EPBs

In the philosophy of science, abstraction has usually been analyzed in terms of the interface between our experience and the design of our concepts. The often implicit assumption here is that such interface has a definite identifiable and universalizable structure, determining the epistemic correctness of any abstraction. Our claim is that, on the contrary, the epistemic grounding of abstraction should not be reduced to the structural norms of such interface but is also related to the constraints on the cognitive processes of specific abstractions. This suggests that we should understand abstraction as embodied in different kinds of abstraction practices.

Since their introduction in the early 2000s, the use of social networking websites has exploded. Many businesses are seeing increased revenue due to their social commerce strategy. Despite the popularity of social commerce websites, some consumers are still hesitate to use them. This study aims to evaluate the factors that influence the adoption of social commerce. A sample of 721 Chinese We Chat users took part in the research. The findings reveal that social capital mediates the positive effect of social commerce adoption and perceived ease of use on techno-stress and online impulse purchasing. Likewise, information overloading mediates the positive effect of social commerce adoption and PERU on techno-stress and online impulse purchasing. The findings have implications for both practice and research in understanding social commerce adoption in emerging economies.

The notion of “agent bookkeeping” was proposed when the “Accounting Law of the People’s Republic of China” was updated in 1993. Since their business is specialized in serving small and micro-enterprises, this has created the industry characteristic of generally small in the size of company and low in the salary of employees in Chinese agent bookkeeping companies. Such characteristic results in a series of problems including negative work attitude of employees in the development process, which seriously limit the development of Chinese agent bookkeeping companies. However, issues occurred in the development of agent bookkeeping, such as negative employee attitudes, which severely hampered the growth of Chinese agent bookkeeping companies. Therefore, a model of three dimensions of work attitude has been set up in this paper to demonstrate the working attitude of the staff of the agent bookkeeping companies in China’s Guangdong-Hong Kong-Macao Greater Bay Area, including emotional dimension, behavioral dimension, and cognitive dimension which consists of eight factors: work environment, career satisfaction, interpersonal relationship, role engagement, work vitality, responsibility attitude, emotional identity, and retention attitude. The result indicates that female employees outnumber male ones in agent bookkeeping companies, most employees have a low sense of belonging to the company, limited career development affects employees’ enthusiasm for work, work attitudes are influenced by mediocre work performance among employees with a graduate degree or higher.

Employability is a vital aspect for human development in career fields. In order to explore the factors affecting the employability of finance and trade graduates in higher vocational colleges, the researchers focused on human development in educational settings and conducted a piece of quantitative research within nine higher vocational colleges. The study uses descriptive statistical analysis to demonstrate the sample structure, using t-test, rank sum test, and chi-square test to assess the variables. It also adopts exploratory factor analysis to identify the classification of both educational practice and employability. Then, a multivariable linear regression model was adopted to examine the relationships between three main factors as well as the employability and career development of finance and trade graduates. The findings imply that the soft skills and basic skills of finance and trade college graduates have immensely improved through educational practice; graduates with high motivation for learning could enhance their soft skills and more internships or club engagement brings stronger professional skills. Based on these results, higher vocational colleges, enterprises, policymakers, teachers, and finance and trade graduates will benefit from the findings related to the reform of educational practice for strengthening graduate employability and human development. The originality of this paper is the conceptual evolution of finance and trade college graduate employability, as well as the empirical analysis on educational practice, student engagement, and family background affecting their human development.

The linguistic relativist thesis maintains that there is no neutral ground for different scientific traditions with different theoretic frameworks to communicate rationally, due to the fact that linguistic structure crucially decides the way people think about reality. For quite a long time, historical studies of scientific exchange between East and West have been guided by this thesis. The challenge to this thesis comes from recent studies by Peter Galison, who argues that scientists from different research traditions can communicate rationally in a way similar to the trading exchanges between two countries, in which a local coordination can be reached even if there is a global disagreement about the corresponding word usage in two natural languages. In this paper, I try to show that the concept of trading zone communication provides an interesting and useful theoretical tool to examine how, in the sixteenth, seventeenth, and eighteenth centuries, Chinese scientists communicated with and learned Western knowledge from Jesuit scientists by building local coordination among them. In the first section I introduce the basic ideas of Galison's trading zone theory. In the second section I study the metaphysical, ontological, and epistemological differences between Chinese science and Western science. If the linguistic relativist thesis is taken for granted, these differences are likely to lead many historical studies on Jesuit science in China to reach the relativist conclusion. The third section deals with some of the basic concepts of the trading zone theory to explain how local rational communication among Chinese and Jesuit scientists was built and developed. In the last section I argue that Galison's trading zone theory can help us understand how Chinese scientists learned new knowledge from the Jesuits, especially astronomical and mathematical knowledge, despite the global differences between these two research traditions.