Structural insights into the role of the Smoothened cysteine-rich domain in Hedgehog signalling.

Smoothened (Smo) is a member of the Frizzled (FzD) class of G-protein-coupled receptors (GPCRs), and functions as the key transducer in the Hedgehog (Hh) signalling pathway. Smo has an extracellular cysteine-rich domain (CRD), indispensable for its function and downstream Hh signalling. Despite its essential role, the functional contribution of the CRD to Smo signalling has not been clearly elucidated. However, given that the FzD CRD binds to the endogenous Wnt ligand, it has been proposed that the Smo CRD may bind its own endogenous ligand. Here we present the NMR solution structure of the Drosophila Smo CRD, and describe interactions between the glucocorticoid budesonide (Bud) and the Smo CRDs from both Drosophila and human. Our results highlight a function of the Smo CRD, demonstrating its role in binding to small-molecule modulators

Targeted mutation of EphB1 receptor prevents development of neuropathic hyperalgesia and physical dependence on morphine in mice

EphB receptor tyrosine kinases, which play important roles in synaptic connection and plasticity during development and in matured nervous system, have recently been implicated in processing of pain after nerve injury and morphine dependence. Subtypes of the EphB receptors that may contribute to the neuropathic pain and morphine dependence have not been identified. Here we demonstrate that the subtype EphB1 receptor is necessary for development of neuropathic pain and physical dependence on morphine. The results showed that peripheral nerve injury produced thermal hyperalgesia in wild-type (EphB1+/+) control littermate mice, but not in EphB1 receptor homozygous knockout (EphB1-/-) and heterozygous knockdown (EphB1+/-) mice. Hyperalgesia in the wild-type mice was inhibited by intrathecal administration of an EphB receptor blocking reagent EphB2-Fc (2 μg). Intrathecal administration of an EphB receptor activator ephrinB1-Fc (1 μg) evoked thermal hyperalgesia in EphB1+/+, but not EphB1-/- and EphB1+/- mice. Cellularly, nerve injury-induced hyperexcitability of the medium-sized dorsal root ganglion neurons was prevented in EphB1-/- and EphB1+/- mice. In chronically morphine-treated mice, most of the behavioral signs and the overall score of naloxone-precipitated withdrawal were largely diminished in EphB1-/- mice compared to those in the wild-type. These findings indicate that the EphB1 receptor is necessary for development of neuropathic pain and physical dependence on morphine and suggest that the EphB1 receptor is a potential target for preventing, minimizing, or reversing the development of neuropathic pain and opiate dependence

The Impact of Proactive Environmental Strategy on Competitive and Sustainable Development of Organizations

The purpose of this research is to evaluate the impact of proactive environmental strategy, competitive differentiation advantage &amp; cost-leadership competitive advantage for the competitive, sustainable development of an organization in terms of its performances, for instance, product strategy, production, process &amp; financial performances. We incorporated technological eco-innovation as a mediating factor &amp; corporate image as a moderator between exogenous &amp; endogenous variables. We have collected 798 responses from China, India, Pakistan, Bangladesh, United Arab Emirates, and Vietnam. For the data analyses, we employed a structural equation modeling-based multivariate approach and conditional process modeling. The novelty and significance of the undertaken study rested in multifaceted outcomes; for instance, the proactive environmental strategy, the competitive advantage of differentiation &amp; competitive advantage of cost leadership have a significant &amp; positive impact on the sustainable development of an organization in terms of its performances, for example, product strategic, production &amp; financial performances. The findings further demonstrate that technological eco-innovation as a mediating factor &amp; corporate image as a moderating factor played vital and significant influencers between exogenous and endogenous variables. Finally, the Toda- Yamamoto causality showed the two-ways directionality between exogenous &amp; endogenous variables. The outcomes have provided critical practical and societal implications for the industry and society. The companies may incorporate the environment as a cornerstone in short &amp; longterm strategies for sustainable development. On the other hand, organizations may provide an eco-friendly environment to society.</jats:p

Effects of ferroelectric-poling-induced strain on the quantum correction to low-temperature resistivity of manganite thin films

Author name used in this publication: H. L. W. ChanAuthor name used in this publication: H. S. Luo2010-2011 > Academic research: refereed > Publication in refereed journalVersion of RecordPublishe