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Immunogenic cell death (ICD) can activate the anticancer immune response and is highly attractive to improve cancer treatment efficacy. ICD is closely related to endoplasmic reticulum (ER) stress, and a series of ICD inducers has recently been reported based on ER-targeted photodynamic/photothermal agents or metal complexes. However, these ER-targeted ICD inducers suffer from complicated synthesis and heavy-metal cytotoxicity. Inspired by the promising clinical potential of small organic molecules, herein, an ER-targeted fluorescent self-reporting ICD inducer, SA-Cbl, is developed by simple conjugation of the chemotherapeutic drug chlorambucil (Cbl) with salicylaldehyde (SA). SA-Cbl can selectively accumulate in the ER to induce rapid ROS generation and an unfolded protein response process, which leads to a fast release of damage-associated molecular patterns and efficient dendritic cells maturation. Meanwhile, the ER-targeted accumulation and ER-stress-inducing process can be in situ monitored based on the turn-on fluorescence of SA-Cbl, which is highly pH- and polarity-sensitive and can selectively interact with ER proteins. Compared with the traditional chemotherapy drug doxorubicin, the superior anticancer immunity effect of SA-Cbl is verified via an in vivo tumor model. This study thus provides a new strategy for developing fluorescent self-reporting ICD inducers by decoration of chemotherapeutic drugs with pH and polarity-sensitive organic fluorophores.

Photosensitizers with aggregation-induced emission properties (AIEgens) can produce reactive oxygen species (ROS) under irradiation, showing great potential in the antibacterial field. However, due to the limited molecular skeletons, the development of AIEgens with precisely adjustable antibacterial activity is still a daunting challenge. Herein, a series of AIE nanofibers (AIE-NFs) based on the AIEgen of DTPM as the inner core and rationally designed peptides as bacterial recognition ligands (e.g., antimicrobial peptide (AMP) HHC36, ditryptophan, polyarginine, and polylysine) is developed. These AIE-NFs show precisely adjustable antibacterial behaviors simply by changing the decorated peptides, which can regulate the aggregation and inhibition of different bacteria. By mechanistic analysis, it is demonstrated that this effect can be attributed to the synergistic antibacterial activities of the ROS and the peptides. It is noteworthy that the optimized AIE-NFs, NFs-K18, can efficiently aggregate bacteria to cluster and kill four types of clinical bacteria under irradiation in vitro, inhibit the infection of methicillin-resistant Staphylococcus aureus (MRSA) and promote wound healing in vivo. To the authors' knowledge, this is the first report of AIE-NFs with precisely adjustable antibacterial activity, providing new opportunities for photodynamic therapy (PDT) treatment of infection.

Background Induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs) share many common features, including similar morphology, gene expression and in vitro differentiation profiles. However, genomic stability is much lower in iPSCs than in ESCs. In the current study, we examined whether changes in DNA damage repair in iPSCs are responsible for their greater tendency towards mutagenesis. Methods Mouse iPSCs, ESCs and embryonic fibroblasts were exposed to ionizing radiation (4 Gy) to introduce double-strand DNA breaks. At 4 h later, fidelity of DNA damage repair was assessed using whole-genome re-sequencing. We also analyzed genomic stability in mice derived from iPSCs versus ESCs. Results In comparison to ESCs and embryonic fibroblasts, iPSCs had lower DNA damage repair capacity, more somatic mutations and short indels after irradiation. iPSCs showed greater non-homologous end joining DNA repair and less homologous recombination DNA repair. Mice derived from iPSCs had lower DNA damage repair capacity than ESC-derived mice as well as C57 control mice. Conclusions The relatively low genomic stability of iPSCs and their high rate of tumorigenesis in vivo appear to be due, at least in part, to low fidelity of DNA damage repair.

Certain missense mutations affecting LRP5 cause high bone mass (HBM) in humans. Based on in vitro evidence, HBM LRP5 receptors are thought to exert their effects by providing resistance to binding/inhibition of secreted LRP5 inhibitors such as sclerostin (SOST) and Dickkopf homolog-1 (DKK1). We previously reported the creation of two Lrp5 HBM knock-in mouse models, in which the human p.A214V or p.G171V missense mutations were knocked into the endogenous Lrp5 locus. To determine whether HBM knock-in mice are resistant to SOST- or DKK1-induced osteopenia, we bred Lrp5 HBM mice with transgenic mice that overexpress human SOST in osteocytes ((8kb) Dmp1-SOST) or mouse DKK1 in osteoblasts and osteocytes ((2.3kb) Col1a1-Dkk1). We observed that the (8kb) Dmp1-SOST transgene significantly lowered whole-body bone mineral density (BMD), bone mineral content (BMC), femoral and vertebral trabecular bone volume fraction (BV/TV), and periosteal bone-formation rate (BFR) in wild-type mice but not in mice with Lrp5 p.G171V and p.A214V alleles. The (2.3kb) Col1a1-Dkk1 transgene significantly lowered whole-body BMD, BMC, and vertebral BV/TV in wild-type mice and affected p.A214V mice more than p.G171V mice. These in vivo data support in vitro studies regarding the mechanism of HBM-causing mutations, and imply that HBM LRP5 receptors differ in their relative sensitivity to inhibition by SOST and DKK1.

Objective We generated knock-in mice that express a tamoxifen-inducible Cre recombinase from the Prg4 locus (Prg4GFPCreERt2), and used these animals to fate-map the progeny of Prg4-positive articular cartilage cells at various ages.

This paper addresses the task allocation problem in an open, dynamic grid environments and service-oriented environments. In such environments, both grid/service providers and consumers can be modelled as intelligent agents. These agents can leave and enter the environment freely at any time. Task allocation under time constraints becomes a challenging issue in such environments because it is difficult to apply a central controller during the allocation process due to the openness and dynamism of the environments. This paper proposes a negotiation-based method for task allocation under time constraints in an open, dynamic grid environment, where both consumer and provider agents can freely enter or leave the environment. In this method, there is no central controller available, and agents negotiate with each other for task allocation based only on local views. The experimental results show that the proposed method can outperform the current methods in terms of the success rate of task allocation and the total profit obtained from the allocated tasks by agents under different time constraints. Copyright ©2014 John Wiley & Sons, Ltd.

Manuscript Type Empirical Research Question/Issue What is the impact of entrepreneurship on GDP/capita, unemployment, exports/GDP, and patents per population across countries? Is the impact of entrepreneurship mitigated by legal and cultural differences across countries? Do different international datasets provide different answers to these questions? We empirically compare the impact of entrepreneurship on GDP/capita, unemployment, exports/GDP, and patents per population across countries by examining three datasets from the World Bank, the OECD, and Compendia. Research Findings/Insights Based on a comprehensive sample of all available countries and years, with the World Bank data being the most comprehensive, we find entrepreneurship has a significantly positive impact on GDP/capita, exports/GDP, and patents per population, and a negative impact on unemployment. Inferences from the Compendia data are very consistent. By contrast, inferences from the OECD data are not supportive of any of these propositions. Theoretical/Academic Implications Our findings point to institutional and cultural impediments to the effectiveness of entrepreneurship. Most notably, the impact of entrepreneurship is significantly mitigated by excessively strong creditor rights that limit entrepreneurial risk-taking. Furthermore, the data indicate that cultural attitudes associated with low risk-taking limit the effectiveness of entrepreneurship. By contrast, the impact of entrepreneurship on exports/GDP does not appear to be directly tied to costs of exporting, which is perhaps best explained by the new economy goods and services created by entrepreneurs that depend less on such costs. For some subsets of the data we find evidence consistent with the view that top tier venture capital funds enhance the impact of entrepreneurship on GDP/capita. Finally, our results show how different definitions of new business entry matter for empirical analysis of entrepreneurship across countries. Practitioner/Policy Implications The data highlight the importance of access to finance without downside costs so that entrepreneurs are encouraged to take risk. Further, the data highlight institutional differences in risk attitudes that more generally inhibit risk-taking and thereby limit the effectiveness of entrepreneurship. Moreover, the data highlight a central role for careful measurement of entrepreneurial activities and for inclusion of as many countries and years as possible in order to effectively analyze the impact of entrepreneurship.

SUMMARY Multiagent learning provides a promising paradigm to study how autonomous agents learn to achieve coordinated behavior in multiagent systems. In multiagent learning, the concurrency of multiple distributed learning processes makes the environment nonstationary for each individual learner. Developing an efficient learning approach to coordinate agents’ behavior in this dynamic environment is a difficult problem especially when agents do not know the domain structure and at the same time have only local observability of the environment. In this paper, a coordinated learning approach is proposed to enable agents to learn where and how to coordinate their behavior in loosely coupled multiagent systems where the sparse interactions of agents constrain coordination to some specific parts of the environment. In the proposed approach, an agent first collects statistical information to detect those states where coordination is most necessary by considering not only the potential contributions from all the domain states but also the direct causes of the miscoordination in a conflicting state. The agent then learns to coordinate its behavior with others through its local observability of the environment according to different scenarios of state transitions. To handle the uncertainties caused by agents’ local observability, an optimistic estimation mechanism is introduced to guide the learning process of the agents. Empirical studies show that the proposed approach can achieve a better performance by improving the average agent reward compared with an uncoordinated learning approach and by reducing the computational complexity significantly compared with a centralized learning approach. Copyright © 2012 John Wiley & Sons, Ltd.

Mobile agents often travel in a hostile environment where their security and privacy could be compromised by any party including remote hosts in which agents visit and get services. It is believed that the host visited by an agent should jointly sign a service agreement with the agent's owner; hence a proxy-signing model was proposed in the literature, allowing every host in the agent system to sign a service agreement. We observe that this actually poses a serious problem whereby a host that should be excluded from an underlying agent network could also send a signed service agreement. In order to solve this problem, we propose two schemes achieving host authentication with controlled resources, where only selected hosts can be included in the agent network. We provide two schemes in this paper. The second scheme offers a smaller data size. We also define security models and provide rigorous security proofs to our schemes. Copyright © 2010 John Wiley & Sons, Ltd.

Osteoporosis is defined as reduced bone mineral density with a high risk of fragile fracture. Current available treatment regimens include antiresorptive drugs such as estrogen receptor analogues and bisphosphates and anabolic agents such as parathyroid hormone (PTH). However, neither option is completely satisfactory because of adverse effects. It is thus highly desirable to identify novel anabolic agents to improve future osteoporosis treatment. Osthole, a coumarin-like derivative extracted from Chinese herbs, has been shown to stimulate osteoblast proliferation and differentiation, but its effect on bone formation in vivo and underlying mechanism remain unknown. In this study, we found that local injection of Osthole significantly increased new bone formation on the surface of mouse calvaria. Ovariectomy caused evident bone loss in rats, whereas Osthole largely prevented such loss, as shown by improved bone microarchitecture, histomorphometric parameters, and biomechanical properties. In vitro studies demonstrated that Osthole activated Wnt/β-catenin signaling, increased Bmp2 expression, and stimulated osteoblast differentiation. Targeted deletion of the β-catenin and Bmp2 genes abolished the stimulatory effect of Osthole on osteoblast differentiation. Since deletion of the Bmp2 gene did not affect Osthole-induced β-catenin expression and the deletion of the β-catenin gene inhibited Osthole-regulated Bmp2 expression in osteoblasts, we propose that Osthole acts through β-catenin–BMP signaling to promote osteoblast differentiation. Our findings demonstrate that Osthole could be a potential anabolic agent to stimulate bone formation and prevent estrogen deficiency–induced bone loss. © 2010 American Society for Bone and Mineral Research.

1 Creatine (CR) supplementation augments muscle strength in skeletal muscle cells by increasing intracellular energy pools. However, the effect of CR supplementation on endothelial cells remains to be clarified. 2 In this study, we investigated whether CR supplementation had any anti-inflammatory activity against human pulmonary endothelial cells in culture. 3 We confirmed that supplementation with 0.5 mM CR significantly increased both intracellular CR and phosphocreatine (PC) through a CR transporter while keeping intracellular ATP levels constant independent of CR supplementation and a CR transporter antagonist. 4 In the assay system of endothelial permeability, supplementation with 5 mM CR significantly suppressed the endothelial permeability induced by serotonin and H(2)O(2). 5 In cell adhesion experiments, supplementation with 5 mM CR significantly suppressed neutrophil adhesion to endothelial cells. 6 In the measurement of adhesion molecules, CR supplementation with more than 0.5 mM CR significantly inhibited the expressions of ICAM-1 and E-selectin on endothelial cells, and the inhibition was significantly suppressed by an adenosine A(2A) receptor antagonist. 7 The present study suggests that CR supplementation has anti-inflammatory activities against endothelial cells.

Summary In market-based cloud environments, both resource consumers and providers are self-interested; additionally, they can come and leave the environment freely. Therefore, the environment is competitive and uncertain. Because of the competition, participants may cheat in making deals, and this represents that the environment is insecure to resource providers who intend to earn profits through renting their resources to the tasks of resource consumers. Against this, in this paper, intelligent agents are designed to strategically quote for the tasks that they are interested in, on behalf of resource providers. Agents could quote according to the messages it obtained and the information learnt and predicted from the messages, to minimize the influence of insecure factors, such as cheating, competition, and dynamism. The experimental evaluation shows that the proposed method outperforms both a well-known multiresource negotiation-based task allocation method and a max-sum belief propagation–based method.