Identification of a Signaling Pathway Involved in Calcium Regulation of BDNF Expression

AbstractA signaling pathway by which calcium influx regulates the expression of the major activity-dependent transcript of BDNF in cortical neurons has been elucidated. Deletion and mutational analysis of the promoter upstream of exon III reveals that transactivation of the BDNF gene involves two elements 5′ to the mRNA start site. The first element, located between 72 and 47 bp upstream of the mRNA start site, is a novel calcium response element and is required for calcium-dependent BDNF expression in both embryonic and postnatal cortical neurons. The second element, located between 40 and 30 bp upstream of the mRNA start site, matches the consensus sequence of a cAMP response element (CRE) and is required for transactivation of the promoter in postnatal but not embryonic neurons. The CRE-dependent component of the response appears to be mediated by CREB since it is part of the complex that binds to this CRE, and since dominant negative mutants of CRE B attenuate transactivation of the promoter. A constitutively active mutant of CaM kinase IV, but not of CaM kinase II, leads to activation of the promoter in the absence of extracellular stimuli, and partially occludes calcium-dependent transactivation. The effects of CaM kinase IV on the promoter require an intact CRE. These mechanisms, which implicate CaM kinase IV and CREB in the control of BDNF expression, are likely to be centrally involved in activity-dependent plasticity during development

New hybrid FMADM model for mobile commerce improvement

Internet of things (IoT) can provide an extensive scope of services via smart devices to promote the convenience of life. With advances being made in smart phones, enterprises are increasingly considering expanding their customer base through mobile commerce services. To promote m-commerce improvement, enterprises should organize an excellent m-commerce environment and attempt to realize user needs in the era of IoT. In a fuzzy environment of the real world, objective decision-making for m-commerce improvement is usually a FMADM problem involving feedback-effect and interdependence among the dimensions and criteria. But, many traditional decision models cannot conduct the complicated interrelationships among dimensions and criteria. This study proposes an improvement model that can promote m-commerce improvement towards achieving the aspiration level in fuzzy environment. The proposed hybrid model conducts the feedback-effect and dependence among attributes, and it combines the FDEMATEL technique, FDANP, and MFGRA methods. The empirical case study was conducted to prove the utility of the new hybrid FMADM model in evaluating an m-commerce environment. Comparative results exhibited that the proposed approach is superior to the traditional method and that it can obtain most real grey relational degree that can be used for establishing the best performance improvement strategy in reality

Arecoline induces HA22T/VGH hepatoma cells to undergo anoikis - involvement of STAT3 and RhoA activation

<p>Abstract</p> <p>Background</p> <p>Our previous study showed that, in basal cell carcinoma cells, arecoline reduces levels of the tumor cell survival factor interleukin-6 (IL-6), increases levels of tumor suppressor factor p53, and elicits cell cycle arrest, followed by apoptosis. In preliminarily studies, we observed that arecoline induces detachment of the human-derived hepatoma cell line HA22T/VGH from the extracellular matrix. In the present study, we explored the fate of the detached HA22T/VGH cells and investigated the underlying mechanism.</p> <p>Methods</p> <p>HA22T/VGH cells or primary cultured rat hepatocytes were treated with arecoline, then changes in morphology, viability, apoptosis, and the expression of surface β1-integrin, apoptosis-related proteins, and IL-6 were examined. Furthermore, activation of the signal transducer and activator of transcription 3 (STAT3) pathway and the RhoA/Rock signaling pathway, including p190RhoGAP and Src homology-2 domain-containing phosphatase SHP2, was examined.</p> <p>Results</p> <p>A low concentration of arecoline (≤ 100 μg/ml) caused cytoskeletal changes in HA22T/VGH cells, but not hepatocytes, and this was accompanied by decreased β1-integrin expression and followed by apoptosis, indicating that HA22T/VGH cells undergo anoikis after arecoline treatment. IL-6 expression and phosphorylation of STAT3, which provides protection against anoikis, were inhibited and levels of downstream signaling proteins, including Bcl-X_Land Bcl-2, were decreased, while Bax expression, mitochondrial cytochrome c release, and caspase-3 activity were increased. In addition, phosphorylation/activation of p190RhoGAP, a RhoA inhibitor, and of its upstream regulator, SHP2, was inhibited by arecoline treatment, while Rho/Rock activation was increased. Addition of the RhoA inhibitor attenuated the effects of arecoline.</p> <p>Conclusions</p> <p>This study demonstrated that arecoline induces anoikis of HA22T/VGH cells involving inhibition of STAT3 and increased RhoA/Rock activation and that the STAT3 and RhoA/Rock signaling pathways are connected.</p

A data-driven MADM model for personnel selection and improvement

Personnel selection and human resource improvement are characteristically multiple-attribute decision-making (MADM) problems. Previously developed MADM models have principally depended on experts’ judgements as input for the derivation of solutions. However, the subjectivity of the experts’ experience can have a negative influence on this type of decision-making process. With the arrival of today’s data-based decision-making environment, we develop a data-driven MADM model, which integrates machine learning and MADM methods, to help managers select personnel more objectively and to support their competency improvement. First, RST, a machining learning tool, is applied to obtain the initial influential significance-relation matrix from real assessment data. Subsequently, the DANP method is used to derive an influential significance-network relation map and influential weights from the initial matrix. Finally, the PROMETHEE-AS method is applied to assess the gap between the aspiration and current levels for every candidate. An example was carried out using performance data with evaluation attributes obtained from the human resource department of a Chinese food company. The results revealed that the data-driven MADM model could enable human resource managers to resolve the issues of personnel selection and improvement simultaneously, and can actually be applied in the era of big data analytics in the future. First published online 15 May 202

A new era for studies on cross-Strait relations: introduction

After more than half a century’s separation, interaction between China and Taiwan has increased and has progressively changed from a politico-economic interaction to a more civic interaction. Scholars working on cross-Strait relations have recently begun to pay attention to the civic influence of Taiwanese businesses on the relationship. Some emphasize the importance of sub-governmental interactions in the process of cross-Strait integration. Others assert that Taiwanese businesses can exercise economic leverage to constrain the Chinese government in cross-Strait policymaking. These scholars stress bottom–up processes by observing current phenomena, then deducing the emerging pattern of cross-Strait relations that may be influenced by business activities. Taking account of changing trends in scholarly discussions of the cross-Strait relationship, this special issue of China Information presents current research in this field. Unlike studies on top–down processes that affect political and economic interactions between China and Taiwan, several contributions in the special issue highlight bottom–up mechanisms affecting such interactions by examining the identity of Taiwanese businesspeople and migrants, as well as the activities and implications of Taiwanese charitable organizations operating in China. This issue focuses not only on the impact of China on Taiwan, but also the impact of Taiwanese investments, migrants, and exports on Chinese society

Sensorimotor Inhibition and Mobility in Genetic Subgroups of Parkinson's Disease

Background: Mobility and sensorimotor inhibition impairments are heterogeneous in Parkinson's disease (PD). Genetics may contribute to this heterogeneity since the apolipoprotein (APOE) ε4 allele and glucocerebrosidase (GBA) gene variants have been related to mobility impairments in otherwise healthy older adult (OA) and PD cohorts. The purpose of this study is to determine if APOE or GBA genetic status affects sensorimotor inhibition and whether the relationship between sensorimotor inhibition and mobility differs in genetic sub-groups of PD. Methods: Ninety-three participants with idiopathic PD (53 non-carriers; 23 ε4 carriers; 17 GBA variants) and 72 OA (45 non-carriers; 27 ε4 carriers) had sensorimotor inhibition characterized by short-latency afferent inhibition. Mobility was assessed in four gait domains (pace/turning, rhythm, trunk, variability) and two postural sway domains (area/jerkiness and velocity) using inertial sensors. Results: Sensorimotor inhibition was worse in the PD than OA group, with no effect of genetic status. Gait pace/turning was slower and variability was higher (p &lt; 0.01) in PD compared to OA. Postural sway area/jerkiness (p &lt; 0.01) and velocity (p &lt; 0.01) were also worse in the PD than OA group. Genetic status was not significantly related to any gait or postural sway domain. Sensorimotor inhibition was significantly correlated with gait variability (r = 0.27; p = 0.02) and trunk movement (r = 0.23; p = 0.045) in the PD group. In PD non-carriers, sensorimotor inhibition related to variability (r = 0.35; p = 0.010) and trunk movement (r = 0.31; p = 0.025). In the PD ε4 group, sensorimotor inhibition only related to rhythm (r = 0.47; p = 0.024), while sensorimotor inhibition related to pace/turning (r = -0.49; p = 0.046) and rhythm (r = 0.59; p = 0.013) in the PD GBA group. Sensorimotor inhibition was significantly correlated with gait pace/turning (r = -0.27; p = 0.04) in the OA group. There was no relationship between sensorimotor inhibition and postural sway. Conclusion: ε4 and GBA genetic status did not affect sensorimotor inhibition or mobility impairments in this PD cohort. However, worse sensorimotor inhibition was associated with gait variability in PD non-carriers, but with gait rhythm in PD ε4 carriers and with gait rhythm and pace in PD with GBA variants. Impaired sensorimotor inhibition had a larger effect on mobility in people with PD than OA and affected different domains of mobility depending on genetic status

DJ-1 isoforms in whole blood as potential biomarkers of Parkinson disease

DJ-1 is a multifunctional protein that plays an important role in oxidative stress, cell death, and synucleinopathies, including Parkinson disease. Previous studies have demonstrated that total DJ-1 levels decrease in the cerebrospinal fluid, but do not change significantly in human plasma from patients with Parkinson disease when compared with controls. In this study, we measured total DJ-1 and its isoforms in whole blood of patients with Parkinson disease at various stages, Alzheimer disease, and healthy controls to identify potential peripheral biomarkers of PD. In an initial discovery study of 119 subjects, 7 DJ-1 isoforms were reliably detected, and blood levels of those with 4-hydroxy-2-nonenal modifications were discovered to be altered in late-stage Parkinson disease. This result was further confirmed in a validation study of another 114 participants, suggesting that, unlike total DJ-1 levels, post-translationally modified isoforms of DJ-1 from whole blood are candidate biomarkers of late-stage Parkinson disease

Activation of p53/miR-34a Tumor Suppressor Axis by Chinese Herbal Formula JP-1 in A549 Lung Adenocarcinoma Cells

Lung cancer is the leading cause of cancer death worldwide; the most common pathologic type is lung adenocarcinoma (LADC). In spite of the recent progress in targeted therapy, most LADC patients eventually expired due to the inevitable recurrence and drug resistance. New complementary agent with evidence-based molecular mechanism is urgently needed. MiR-34a is an important p53 downstream tumor suppressor, which regulates apoptosis, cell-cycle, EMT (epithelial mesenchymal transition), and so forth. Its expression is deficient in many types of cancers including LADC. Here, we show that a Chinese herbal formula JP-1 activates p53/miR-34a axis in A549 human LADC cells (p53 wild-type). Treatment with JP-1 induces p53 and its downstream p21 and BAX proteins as well as the miR-34a, resulting in growth inhibition, colony formation reduction, migration repression, and apoptosis induction. Accordingly, the decreases of miR-34a downstream targets such as CDK6, SIRT1, c-Myc, survivin, Snail, and AXL were observed. Moreover, JP-1 activates AMPKα and reduces mTOR activity, implying its inhibitory effect on the energy-sensitive protein synthesis and cell proliferation signaling. Our results show that JP-1 activates p53/miR-34a tumor suppressor axis and decreases proteins related to proliferation, apoptosis resistance, and metastasis, suggesting its potential as a complementary medicine for LADC treatment