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Few of the interventions currently available for family caregivers (FCGs) of persons with dementia (PWDs) with long-term follow-ups have a grounding in theory and incorporate multicomponent case management formats.Based on Pearlin's Caregiving and Stress Process model, this study was developed to examine the effectiveness of a family-centered case management program for PWDs with early to moderate dementia in terms of reducing PWDs behavioral problems and improve FCG outcomes, including distress, self-efficacy, depression, caregiver burden, and health-promoting behaviors.This randomized, single-blind, parallel-controlled trial included 76 dyads of PWDs and their FCGs. The dyads were recruited from outpatient clinics at dementia centers in three district hospitals in northern Taiwan. The dyads were randomly assigned to the intervention group (IG, n = 39) and control group (CG, n = 37). The dyads in the IG received a four-month intervention with two home or clinic visits and two telephone interviews. The multi-component interventions provided assessment, education, consultations, support, and referrals to long-term care resources. The CG received routine care and two social phone calls. Data were collected upon enrollment (T0 = baseline) and at 4-,6-, and 12-months post-intervention (T1, T2, and T3, respectively). Generalized estimating equations were conducted to analyze the effects of the intervention.By controlling for the interaction between group and time, we made a comparison between IG and the CG. The results showed significant improvements from baseline measures in behavioral problems in the PWDs for mood, psychosis, and social engagement, and improvements in the FCGs for distress and self-efficacy for obtaining respite as well as for better control of distressing thoughts, feelings of depression, caregiver burden, and overall health promoting behaviors at T1 and T2 (p0.5). Significant improvements were also found in the IG for psychomotor regulation among PWDs and the self-efficacy of FCGs in managing the PWDs' disturbing behaviors and health promotion behaviors for nutrition at T1 (p0.5). There were no significant improvements in the outcome variables at T3.Significant interactions between group and time were found at the 6-month assessment (T2) for improvements in problem behaviors of PWDs and depression, caregiver burden, and distress in the FCGs. Positive effects on self-efficacy and health promotion behaviors among the FCGs were also achieved. The results suggest that a multicomponent case management intervention should be referenced in dementia care policymaking for FCGs and PWDs.多元個案管理對失智者問題行為及家庭照顧者困擾、自我效能、憂鬱、負荷和健康促進行為之成效.失智家庭照護較缺少理論基礎及長期追蹤的多元個案管理。.以Pearlin照護壓力過程模式為基礎，探討早至中期失智家庭的多元個案管理對失智者問題行為、照顧者困擾、自我效能、憂鬱、負荷和健康促進行為之成效。.採雙組單盲隨機對照試驗，於北台灣3家地區醫院失智症門診收集76對失智者及照顧者，隨機分配至實驗組39對、對照組37對。實驗組接受4個月介入，包含2次家訪（或門診訪）及2次電訪，內容包含評估、衛教、諮商、支持、轉介、使用長照2.0資源。對照組接受常規照護和2次社交電訪。資料收集為前測（T0），介入後第4（T1）、6（T2）、12（T3）個月後測，以廣義估計方程式驗證成效。.以對照組前測結果為基準，並控制組別與時間交互作用，實驗組於T1、T2，在失智者問題行為中的情緒與精神症狀、社會參與及照顧者困擾、獲得喘息與控制沮喪想法的自我效能、憂鬱、負荷、健康促進行為等成果達顯著差異（p.05）；失智者精神動作調節、照顧者處理干擾行為的自我效能及健康促進行為的營養部分，只在T1達顯著差異（p.05）。所有的結果變項在T3均無顯著差異。.本研究的個案管理介入成效可達6個月，能改善失智者的問題行為和照顧者憂鬱、負荷情形和對問題行為所產生的困擾並可提升照顧者的自我效能和健康促進行為，可作為失智症政策之參考。.

Purpose: Some patients with respiratory failure fail initial weaning attempts and need prolonged mechanical ventilation (MV). Prolonged MV is associated with many complications and consumption of heathcare resources. Objective weaning indices help staffs to identify high-potential patients for weaning from the MV. Traditional weaning indices are not reliable in clinical practice. Transitional percentage of minute volume (TMV%) is a new index of the work of breathing. This study aimed to investigate the utility of TMV% in the prediction of weaning potential. Methods: This study was prospectively performed including all patients with prolonged MV. Researchers recorded their demographics, TMV%, respiratory parameters, Acute Physiology and Chronic Health Evaluation II score, and laboratory data upon arrival at the respiratory care center. The factors associated with successful weaning were analyzed. Results: Out of the 120 patients included, 84 (70.0%) were successfully weaned from MV. Traditional weaning indices such as rapid shallow breathing index could not predict the weaning outcome. TMV% was a valuable parameter as patients with a lower TMV%, higher tidal volume, higher hemoglobin, lower blood urea nitrogen, and lower Acute Physiology and Chronic Health Evaluation II scores had a higher rate of successful weaning. TMV%, tidal volume, and HCO3- levels were independent predictors of successful weaning, and the area under the curve was .79 in the logistic regression model. Conclusion: TMV% is a novel and effective predictor of successful weaning. Patients with lower TMV% had a higher MV weaning outcome. Once patients with a high potential for successful weaning are identified, they should be aggressively weaned from MV as soon as possible. Clinical Trials Government Identifier: NCT033480. Keywords: respiratory insufficiency, ventilators, mechanical, work of breathing

This study analyzed the effects of low-carbon tourism awareness, attitudes, and behaviors on the development of villages in the catchment area of Erhai Lake in China. We quantitatively analyzed data from 828 valid questionnaires in IBM SPSS 26.0 using Pearson correlation analysis. Thereafter, we interviewed nine respondents, including scholars, seniors, tour guides, and local businessmen, about the results. Finally, we summarized the data and subjected them to multivariate analysis. The results revealed that low-carbon tourism education and promotion increased public recognition of the need to protect the environment by using low-pollution transportation, staying close to home, and buying minimally packaged goods to create a safe leisure environment. However, many tourists are not willing to accept having to increase their budgets for accommodations, food, and living to engage in low-carbon tourism. Therefore, we suggest that increasing incentives to encourage the public to engage in low-carbon tourism and other consumption behaviors may help reduce the damage to the ecological environments of catchment areas, improve the village’s economic development, and promote the sustainable development of the catchment area.

Neuroblastoma is the most common malignant disease of infancy, and amplification of the MYCN oncogene is closely associated with poor prognosis. Recently, expression of MYCN was shown to be inversely correlated with aryl hydrocarbon receptor (AHR) expression in neuroblastoma, and overexpression of AHR downregulated MYCN expression, promoting cell differentiation. Therefore, we further investigated the potential of AHR to serve as a prognostic indicator or a therapeutic target in neuroblastoma. First, the clinical significance of AHR in neuroblastoma was examined. Positive AHR immunostaining strongly correlated with differentiated histology of neuroblastoma and predicted better survival for patients. The mouse xenograft model showed that overexpression of AHR significantly suppressed neuroblastoma tumor growth. In addition, activation of AHR by the endogenous ligand kynurenine inhibited cell proliferation and promoted cell differentiation in vitro and in vivo. kynurenine treatment also upregulated the expression of KISS1, a tumor metastasis suppressor, and attenuated metastasis in the xenograft model. Finally, analysis of KISS1 levels in neuroblastoma patient tumors using the R2: Genomics Analysis and Visualization Platform revealed that KISS1 expression positively correlated with AHR, and high KISS1 expression predicted better survival for patients. In conclusion, our results indicate that AHR is a novel prognostic biomarker for neuroblastoma, and that overexpression or activation of AHR offers a new therapeutic possibility for patients with neuroblastoma. Significance: These findings show that AHR may function as a tumor suppressor in childhood neuroblastoma, potentially influencing the aetiologic and therapeutic targeting of the disease.

Aryl hydrocarbon receptor (AHR) signaling has been suggested to play roles in various physiological functions independent of its xenobiotic activity, including cell cycle regulation, immune response, and embryonic development. Several endogenous ligands were also identified by high-throughput screening techniques. However, the mechanism by which these molecules mediate AHR signaling in certain functions is still elusive. In this study, we investigated the possible pathway through which AHR and its endogenous ligands regulate neural development. We first identified two neuroactive steroids, 3α,5α-tetrahydrocorticosterone and 3α,5β-tetrahydrocorticosterone (5α- and 5β-THB), as novel AHR endogenous ligands through the use of an ultrasensitive dioxin-like compound bioassay and liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS). We then treated zebrafish embryos with 5α- and 5β-THB, which enhance the expression of neurogenesis marker HuC. Furthermore, 5α- and 5β-THB both enhanced the expression of myelinating glial cell markers, sex determining region Y-box 10 (Sox10), and myelin-associated proteins myelin basic protein (Mbp) and improved the mobility of zebrafish larvae via the Ahr2 pathway. These results indicated that AHR mediates zebrafish neurogenesis and gliogenesis, especially the differentiation of oligodendrocyte or Schwann cells. Additionally, we showed that these molecules may induce neuroblastoma (NB) cell differentiation suggesting therapeutic potential of 5α- and 5β-THB in NB treatment. In summary, our results reveal that 5α- and 5β-THB are endogenous ligands of AHR and have therapeutic potential for NB treatment. By the interaction with THB, AHR signaling regulates various aspects of neural development.

Selenocystine (SeC) has been identified as a novel compound with broad-spectrum anticancer activity. However, the effects of SeC on modifying DNA repair mechanism were less addressed. In this study, we demonstrated that SeC selectively induced cytotoxicity and genotoxicity against HepG2 hepatoma cell line. Comet assay revealed SeC-induced DNA damage in HepG2 cells, particularly in the form of DNA double strand breaks (DSBs), corroborated by the increase expression of the DSB marker, gamma-H2AX. We further demonstrated that SeC suppressed DNA homologous recombination repair, exacerbating DNA damage accumulation. Such effects on DNA damage and cell viability inhibition were alleviated by antioxidants, glutathione and Trolox, suggesting the involvement of reactive oxygen species (ROS). High levels of intracellular and mitochondrial ROS were detected in SeC-treated HepG2. In addition, SeC impaired the expression of antioxidant enzymes (superoxidase mutases and catalase), prompting the imbalance between antioxidant protection and excessive ROS formation and eliciting DSBs and cellular death. Decreased procaspase-3, 7, and 9 and Bcl-2 proteins and an increased Bax/Bcl-2 ratio, were observed after SeC treatment, but could be reversed by Torlox, confirming the action of SeC on ROS-induced apoptosis. In vivo, the xenograft tumor model of HepG2 cells validated the inhibition of SeC on tumor growth, and the induction of DSBs and apoptosis. In summary, SeC has the capability to induce ROS-dependent DNA damage and impeded DBS repair in HepG2 cells. Thus, SeC holds great promise as a therapeutic or adjuvant agent targeting DNA repair for cancer treatment.

It has not been well studied which cells and related mechanisms contribute to endochondral ossification. Here, we fate mapped the leptin receptor-expressing (LepR+) mesenchymal stem cells (MSCs) in different embryonic and adult extremities using Lepr-cre; tdTomato mice and investigated the underling mechanism using Lepr-cre; Ppp2r1afl/fl mice. Tomato+ cells appear in the primary and secondary ossification centers and express the hypertrophic markers. Ppp2r1a deletion in LepR+ MSCs reduces the expression of Runx2, Osterix, alkaline phosphatase, collagen X, and MMP13, but increases that of the mature adipocyte marker perilipin, thereby reducing trabecular bone density and enhancing fat content. Mechanistically, PP2A dephosphorylates Runx2 and BRD4, thereby playing a major role in positively and negatively regulating osteogenesis and adipogenesis, respectively. Our data identify LepR+ MSC as the cell origin of endochondral ossification during embryonic and postnatal bone growth and suggest that PP2A is a therapeutic target in the treatment of dysregulated bone formation., Yen et al use tissue-specific PP2A knockout mice to show that PP2A in LepR positive mesenchymal stem cells positively regulates endochondral ossification. They find that PP2A dephosphorylates Runx2 and BRD4, thereby playing a major role in positively and negatively regulating osteogenesis and adipogenesis, respectively.

Alzheimer's disease (AD) is characterized by a chronic decline in cognitive function and is pathologically typified by cerebral deposition of amyloid-β peptide (Aβ). The production of Aβ is mediated by sequential proteolysis of amyloid precursor protein (APP) by β- and γ-secretases, and has been implicated as the essential determinant of AD pathology. Previous studies have demonstrated that the level of phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] in the membrane may potentially modulate Aβ production. Given that PI(4,5)P2 is produced by type 1 phosphatidylinositol-4-phosphate 5-kinases (PIP5Ks), we sought to determine whether the level of PIP5K type Iα (PIP5K1A) can affect production of Aβ by modulating the lipid composition of the membrane. Using a HEK-derived cell line that constitutively expresses yellow fluorescent protein-tagged APP (APP-YFP), we demonstrated that overexpression of PIP5K1A results in significant enhancement of non-amyloidogenic APP processing and a concomitant suppression of the amyloidogenic pathway, leading to a marked decrease in secreted Aβ. Consistently, cells overexpressing PIP5K1A exhibited a significant redistribution of APP-YFP from endosomal compartments to the cell surface. Our findings suggest that PIP5K1A may play a critical role in governing Aβ production by modulating membrane distribution of APP, and as such, the pathway may be a valuable therapeutic target for AD.

background: Mechanical ventilation(MV) in patient with respiratory failure that can provide patient to keep adequate oxygenation and ventilation. After acute ilness, the number of patients requiring prolong MV has increased because they cannot be weaned from MV. It is poorly outcome that patients undergoing prolonged MV, and that is associated with various complications. Therefore, how to wean from MV as soon as possible is important issue. Transition MinVol% (TMV%) is an index of work breathing, and it means the transition of spontaneous breathing to mandatory breathing. Aim: We try to established a utility and accuracy weaning parameter to predicate weaning successful. Methods: This was a prospective study and included 120 adult patients between January,2017 and December,2017. All patients, using mechanical ventilator for at least 21 days and in stable hemodynamics condition, admitted to our 12-bed respiratory care center (RCC) in Taiwan. We recorded and analyzed their demographics, TMV%, respiratory parameters, APACHE II score, and laboratory data upon arrived at RCC. Results: Successful weaned from MV in 70% (84/120) of patients. Lower TMV% had higher successful weaning rate. Multivariate logistic regression analysis identified TMV%(OR=0.983, p=0.006); VT (OR=1.011, p Conclusions: TMV%, a novel respiratory parameter, is a useful predictor of weaning outcome in patients with prolonged MV.

Watermelon (Citrullus lanatus) is an important crop of the Cucurbitaceae family in fruit production worldwide. During its production, bacterial fruit blotch (BFB) caused by Acidovorax citrulli (Acidovorax avenae subsp. citrulli) is an important limiting factor on the volume and value of crops. This pathogen is known as a seed-borne pathogen, and the infested seeds can be a primary source of inoculum. Hence, a rapid and sensitive method for detecting A. citrulli on seeds would be an important tool in the management of BFB. In this study, we sought to develop a method to detect A. citrulli bacterial cells based on a TaqMan probe-based insulated isothermal PCR (TiiPCR) assay. Firstly, the specific primers and probe were designed based on a specific DNA fragment from the genome of A. citrulli. Then, PCR amplification was performed with the plasmid DNA to adjust the components of the PCR reagents, such as the concentrations of primers, magnesium chloride, and Taq DNA polymerase. Results revealed that 10 copies of plasmid DNA were detectable within the modified reagents by TiiPCR. Moreover, 10 bacterial cells in each reaction tube were detectable at a 100 % detection rate in this condition with a fluorescent signal intensification over 1.8. Based on these results, we concluded that a specific, rapid, and sensitive method based on TiiPCR had been successfully developed to detect bacterial cells of A. citrulli.

A microfluidic colorimetric system comprising of a colorimetric paper-chip device and a microanalysis cassette is presented for detecting the nitrite concentration in foods. In the proposed system, 1 μl of nitrite sample is dropped into the reaction region of the colorimetric paper-chip device, where its reacts with embedded Griess reagent to produce a pink complex. A color image of the reaction complex is caught using an embedded camera and transmitted to a cell phone within the microanalysis cassette via a WiFi connection. Finally, the images were analyzed by self-written RGB (Red, Green, and Blue) software to evaluate the nitrite concentration. The results acquired for 11 known nitrite solutions ranging from 1 to 100 ppm show that the measured R + G + B intensity is related to the nitrite concentration, and the determination coefficient (R2) are 0.9908 and 0.9948 in the two concentration ranges of 1–50 ppm and 50–100 ppm, respectively. The practical feasibility of the current microfluidic system is indicated by analysis the nitrite concentrations of 24 actual samples. Therefore, the difference between the concentration analysis obtained with the current system differ from those obtained using a conventional TFDA (Taiwan Food and Drug Administration) standard method by no more than 7.3%. Furthermore, the detection limit is just 1 ppm.

We have developed a pair of cell-based reporter gene assays to quantitatively measure γ-secretase cleavage of distinct substrates. This manuscript describes procedures that may be used to monitor γ-secretase-mediated cleavage of either APP-C99 or Notch, using a Gal4 promoter-driven firefly luciferase reporter system. These assays were established by stably co-transfecting HEK293 cells with the Gal4-driven luciferase reporter gene and either the Gal4/VP16-tagged C-terminal fragment of APP (APP-C99; CG cells), or the Gal4/VP16-tagged Notch-ΔE (NΔE; NG cells). Using these reporter assays in parallel, we have demonstrated that an ErbB2 inhibitor, CL-387,785, can preferentially suppress γ-secretase cleavage of APP-C99 in CG cells, but not NΔE in NG cells. The differential responses exhibited by the CG and NG cells, when treated with CL-387,785, represent a preferred characteristic for γ-secretase modulators, and these responses are in stark contrast to the pan-inhibition of γ-secretase induced by DAPT. Our studies provide direct evidence that γ-secretase activities toward different substrates can be differentiated in a cellular context. These new assays may therefore be useful tools in drug discovery for improved AD therapies.

We have developed a pair of cell-based reporter gene assays to quantitatively measure γ-secretase cleavage of distinct substrates. This manuscript describes procedures that may be used to monitor γ-secretase-mediated cleavage of either APP-C99 or Notch, using a Gal4 promoter-driven firefly luciferase reporter system. These assays were established by stably co-transfecting HEK293 cells with the Gal4-driven luciferase reporter gene and either the Gal4/VP16-tagged C-terminal fragment of APP (APP-C99; CG cells), or the Gal4/VP16-tagged Notch-ΔE (NΔE; NG cells). Using these reporter assays in parallel, we have demonstrated that an ErbB2 inhibitor, CL-387,785, can preferentially suppress γ-secretase cleavage of APP-C99 in CG cells, but not NΔE in NG cells. The differential responses exhibited by the CG and NG cells, when treated with CL-387,785, represent a preferred characteristic for γ-secretase modulators, and these responses are in stark contrast to the pan-inhibition of γ-secretase induced by DAPT. Our studies provide direct evidence that γ-secretase activities toward different substrates can be differentiated in a cellular context. These new assays may therefore be useful tools in drug discovery for improved AD therapies.

This study aimed to establish the professional competency indicators for rhythmic gymnastics coaches. A literature review was performed to explore the current developments of rhythmic gymnastics and the professional competency of athletic coaches. The Delphi technique was used to identify the professional competency indicators for rhythmic gymnastics coaches from 10 experts. The weighted scores of all indicators were determined by analytic hierarchy process. The results are as follows: (1) The professional competency indicator system for rhythmic gymnastics coaches consists of seven indicators for the dimension of professional knowledge, eight indicators for the dimension of professional skill and four indicators for the dimension of professional attitude. (2) The most important dimension in the professional competency indicator system for rhythmic gymnastics coaches is professional skill, followed by professional attitude and professional knowledge. (3) The key indicators of the dimensions of professional knowledge, professional skill and professional attitude are apparatus manipulation knowledge, choreographic ability and professional dedication respectively. It is hoped that the professional competency indicators for rhythmic gymnastics coaches proposed by this research could be a reference for the government and related agencies in cultivating the rhythmic gymnastics coaches.

Neuroblastoma (NB) is a childhood cancer with a low survival rate and great metastatic potential. Vascular endothelial growth factor (VEGF), an angiogenesis factor, has been found to be involved in CRT-related neuronal differentiation of NB cells. In this study, we further confirmed the role VEGF in NB through mouse xenograft model and clinical analysis from NB patients. In xenograft experiments, CRT overexpression effectively inhibited the tumor growth. In addition, the mRNA and protein levels of VEGF and differentiation marker GAP-43 were upregulated by induced CRT expression. However, no significant correlation between the expression level of VEGF and microvessel density was observed in human NB tumors, suggesting a novel mechanism of VEGF participating in NB tumorigenesis through an angiogenesis-independent pathway. In NB patients’ samples, mRNA expression levels of CRT and VEGF were positively correlated. Furthermore, positive VEGF expression by immunostaining of NB tumors was found to correlate well with histological grade of differentiation and predicted a favorable prognosis. In conclusion, our findings suggest that VEGF is a favorable prognostic factor of NB and might affect NB tumor behavior through CRT-driven neuronal differentiation rather than angiogenesis that might shed light on a novel therapeutic strategy to improve the outcome of NB.

Proteolytic processing of amyloid precursor protein (APP) C-terminal fragments (CTFs) by γ-secretase underlies the pathogenesis of Alzheimer's disease (AD). An RNA interference screen using APP-CTF [99-residue CTF (C99)]- and Notch-specific γ-secretase interaction assays identified a unique ErbB2-centered signaling network that was predicted to preferentially govern the proteostasis of APP-C99. Consistently, significantly elevated levels of ErbB2 were confirmed in the hippocampus of human AD brains. We then found that ErbB2 effectively suppressed autophagic flux by physically dissociating Beclin-1 from the Vps34-Vps15 complex independent of its kinase activity. Down-regulation of ErbB2 by CL-387,785 decreased the levels of C99 and secreted amyloid-β in cellular, zebrafish, and mouse models of AD, through the activation of autophagy. Oral administration of an ErbB2-targeted CL-387,785 for 3 wk significantly improves the cognitive functions of APP/presenilin-1 (PS1) transgenic mice. This work unveils a noncanonical function of ErbB2 in modulating autophagy and establishes ErbB2 as a therapeutic target for AD.

Calreticulin (CRT) has been previously correlated with the differentiation of neuroblastoma (NB), implying a favorable prognostic factor. Vascular endothelial growth factor (VEGF) has been reported to participate in the behavior of NB. This study investigated the association of CRT and VEGF-A in NB cells. The expressions of VEGF-A and HIF-1α, with overexpression or knockdown of CRT, were measured in three NB cells (SH-SY5Y, SK-N-DZ, and stNB-V1). An inducible CRT NB cell line and knockdown CRT stable cell lines were also established. The impacts of CRT overexpression on NB cell apoptosis, proliferation, and differentiation were also evaluated. We further examined the role of VEGF-A in the NB cell differentiation via VEGF receptor blockade. Constitutive overexpression of CRT led to NB cell differentiation without proliferation. Thus, an inducible CRT stNB-V1 cell line was generated by a tetracycline-regulated gene system. CRT overexpression increased VEGF-A and HIF-1α messenger RNA (mRNA) expressions in SH-SY5Y, SK-N-DZ, and stNB-V1 cells. CRT overexpression also enhanced VEGF-A protein expression and secretion level in conditioned media in different NB cell lines. Knockdown of CRT decreased VEGF-A and HIF-1α mRNA expressions and lowered VEGF-A protein expression and secretion level in conditioned media in different NB cell lines. We further demonstrated that NB cell apoptosis was not affected by CRT overexpression in stNB-V1 cells. Nevertheless, overexpression of CRT suppressed cell proliferation and enhanced cell differentiation in stNB-V1 cells, whereas blockage of VEGFR-1 markedly suppressed the expression of neuron-specific markers including GAP43, NSE2, and NFH, as well as TrkA, a molecular marker indicative of NB cell differentiation. Our findings suggest that VEGF-A is involved in CRT-related neuronal differentiation in NB. Our work may provide important information for developing a new therapeutic strategy to improve the outcome of NB patients.

Fucosylation regulates various pathological events in cells. We reported that different levels of CRT (calreticulin) affect the cell adhesion and metastasis of bladder cancer. However, the precise mechanism of tumour metastasis regulated by CRT remains unclear. Using a DNA array, we identified FUT1 (fucosyltransferase 1) as a gene regulated by CRT expression levels. CRT regulated cell adhesion through α1,2-linked fucosylation of β1 integrin and this modification was catalysed by FUT1. To clarify the roles for FUT1 in bladder cancer, we transfected the human FUT1 gene into CRT-RNAi stable cell lines. FUT1 overexpression in CRT-RNAi cells resulted in increased levels of β1 integrin fucosylation and rescued cell adhesion to type-I collagen. Treatment with UEA-1 ( Ulex europaeus agglutinin-1), a lectin that recognizes FUT1-modified glycosylation structures, did not affect cell adhesion. In contrast, a FUT1-specific fucosidase diminished the activation of β1 integrin. These results indicated that α1,2-fucosylation of β1 integrin was not involved in integrin–collagen interaction, but promoted β1 integrin activation. Moreover, we demonstrated that CRT regulated FUT1 mRNA degradation at the 3′-UTR. In conclusion, the results of the present study suggest that CRT stabilized FUT1 mRNA, thereby leading to an increase in fucosylation of β1 integrin. Furthermore, increased fucosylation levels activate β1 integrin, rather than directly modifying the integrin-binding sites. Abbreviations: Act-D, actinomycin D; ARE, AU-rich element; ARE-BP, ARE-binding protein; CDS, coding sequence; CMV, cytomegalovirus; CRT, calreticulin; EF1α, elongation factor 1α; FBP1/FUBP1, far-upstream-binding protein 1; FUT, fucosyltransferase; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GnT, N-acetylglucosaminyltransferase; HRP, horseradish peroxidase; LTL, Lotus tetragonolobus lectin; mARE, mutant ARE; NP40, Nonidet P40; PE, phycoerythrin; REMSA, RNA EMSA; UEA-1, Ulex europaeus agglutinin-1

Lysophosphatidic acid (LPA) is a lipid growth factor with multiple biological functions and has been shown to stimulate cancer cell secretion of vascular endothelial growth factor-A (VEGF-A) and trigger angiogenesis. Hypoxia-inducible factor-1 (HIF-1), a heterodimer consisting of HIF-1α and HIF-1β (also known as aromatic hydrocarbon receptor nuclear translocator (ARNT)) subunits, is an important regulator of angiogenesis in prostate cancer (PC) through the enhancement of VEGF-A expression. In this study, we first confirmed the ability of LPA to induce VEGF-A expression in PC-3 cells and then validated that LPA-induced VEGF-A expression was regulated by HIF-1α and ARNT through phosphatidylinositol 3-kinase activation. Aromatic hydrocarbon receptor (AHR), a receptor for dioxin-like compounds, functions as a transcription factor through dimerization with ARNT and was found to inhibit prostate carcinogenesis and vanadate-induced VEGF-A production. Since ARNT is a common dimerization partner of AHR and HIF-1α, we hypothesized that AHR might suppress LPA-induced VEGF-A expression in PC-3 cells by competing with HIF-1α for ARNT. Here we demonstrated that overexpression and ligand activation of AHR inhibited HIF-1-mediated VEGF-A induction by LPA treatment of PC-3 cells. In conclusion, our results suggested that AHR activation may inhibit LPA-induced VEGF-A expression in PC-3 cells by attenuating HIF-1α signaling, and subsequently, suppressing angiogenesis and metastasis of PC. These results suggested that AHR presents a potential therapeutic target for the prevention of PC metastasis.

Dioxins are byproducts from incomplete combustion processes and belong to a group of mostly toxic chemicals known as persistent organic pollutants, and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is considered to be the most toxic species of all dioxin-like compounds. Analytical chemical processes are employed to determine the specific dioxin content in environmental samples. However, cost-ineffectiveness and excess time consumption limit their routine utilization. The aryl hydrocarbon receptor (AhR) is the major TCDD receptor. Upon binding to dioxin, the AhR dissociates from Hsp90 and other cofactors. TCDD-bound AhR subsequently translocates to the nucleus and interacts with the AhR nuclear translocator (Arnt) to induce signal transduction. Here, we describe a highly sensitive and cost-effective alternative assay based on detecting stability of bioluminescence signals. We generated cells that stably co-express Renilla luciferase tagged-AhR (AhR-RL), Ah receptor-interacting protein (AIP), p23 and yellow fluorescent protein-tagged Arnt (Arnt-YFP) (AAPA cells) for detection of dioxin-like compounds. Treatment with 3-methylcholanthrene (3MC), AhR agonist, enhanced the interaction between AhR and Arnt and avoided proteosomal degradation. In addition, treatment with 3MC or TCDD stabilized Renilla luminescence from AhR-RL of AAPA cell-free extracts in a concentration-dependent manner. The TCDD detection limit in this cell-free system was as low as 10(-18 )M. These results highlight the potential of AAPAA cell-free extracts to detect dioxin-like pollutants.

A key issue in cancer therapy is how to enhance the tumor-targeting efficacy of chemotherapeutic agents. In this study, we developed a cooperative dual-targeted delivery platform for paclitaxel (PTX) that has potential application as a powerful prostate cancer treatment. The nanomedicine was prepared by first conjugating PTX to nontoxic high-magnetization nanocarriers which can be actively guided and targeted by an external magnet. Next, the surface was functionalized with carboxylated o-(2-aminoethyl)polyethyleneglycol (NH(2)-EPEG-COOH) to enable uptake by the reticuloendothelial system. Antiprostate-specific membrane antigen antibodies (APSMAs) were then conjugated onto the carrier to recognize the extracellular domain of the prostate-cancer specific membrane antigen (PSMA), thus binding to cancer cells as a secondary active targeting mechanism. We found a significant enhancement of PTX concentration at the tumor site by nearly 20-fold. In addition, the drug half-life was prolonged more than 4.1-fold (from 24 to 99 h) at 37 °C. Low-dose (4.5 mg/kg) injection of the dual-targeted therapeutic nanomedicine in the presence of magnetic targeting significantly prolonged the median survival of nude mice from 35 to 58 days compared to mice that received a high dose (6 mg/kg) of free PTX. This report demonstrates the potential utility of targeted nanomedicine in the clinical treatment of cancer.

Many biological functions of heme oxygenase (HO) have been attributed to its enzymatic byproduct carbon monoxide (CO). CO has been demonstrated to play an important role in down-regulation of pro-inflammatory cytokines, but few studies have investigated the effects of CO on the cyclooxygenase-2 (COX-2) expression in macrophage. Here, we assessed the induction of COX-2 by CO in macrophage with or without lipopolysaccharide (LPS) stimulation. Tricarbonyldichloro ruthenium (II) dimmer (CORM-2) is a well known CO-releasing molecule, and exhibits anti-inflammatory activity in several cell types. In this study, both CORM-2 and CO gas were used to investigate the induction of COX-2 and the underlying molecular mechanisms in macrophage. Western blot and RT-PCR analysis demonstrated that CORM-2 and CO gas (500 ppm) significantly inhibited the protein and mRNA expression of iNOS in LPS-activated macrophages. In contrast, CORM-2 and CO gas up-regulated COX-2 expression and prostaglandin E2 (PGE2) production in the macrophage with or without LPS. CORM-2 time-dependently induced the phosphorylation of Akt and MAPKs, and the induction of COX-2 could be blocked by Akt, PKG, and MAPKs inhibitors. Indomethacin was used to decrease CORM-2-induced PGE2 production by inhibiting COX-2 enzyme activity. Indomethacin was unable to reverse the decrease of iNOS, but it could restore the IL-1β expression and decrease the IL-10 expression in CORM-2-treated cells. The results suggest that CO induced COX-2 expression and PGE2 production through activating the Akt, PKG, and MAPK pathways, and CO-induced PGE2 may modulate inflammation during macrophage activation by suppressing IL-1β expression and inducing IL-10 production.

Prostate cancer (PCa) is the most common noncutaneous cancer in men worldwide. One of its major treatments is androgen deprivation therapy, but PCa frequently relapses as aggressive castration resistant local tumors and distal metastases. Hence, the development of novel agents or treatment modalities for advanced PCa is crucial. Many tumors, including PCa, first metastasize to regional lymph nodes via lymphatic vessels. Recent findings demonstrate that the bioactive lipid lysophosphatidic acid (LPA) promotes PCa progression by regulating vascular endothelial growth factor-C (VEGF-C), a critical mediator of tumor lymphangiogenesis and lymphatic metastasis. Many of the underlying molecular mechanisms of the LPA–VEGF-C axis have been described, revealing potential biomarkers and therapeutic targets that may aid in the diagnosis and treatment of advanced PCa. Herein, we review the literature that illustrates a functional role for LPA signaling in PCa progression. These discoveries may be especially applicable to anti-lymphangiogenic strategies for the prevention and therapy of metastatic PCa.

The social cognitive perspective of self-regulated learning suggests that effective learning is determined by the interactions among personal, behavioral, and environmental influences; particularly, high self-regulated learners hold higher motivation (personal), apply better learning strategies (behavioral) and respond to environmental demand more appropriately (environmental). The study thus uses the social cognitive perspective to explore the role of self-efficacy (personal), student feedback behavior, use of learning strategies (behavioral), performance and receiving feedback (environmental) in Web-based learning. There were 76 university students participated in this study. Both quantitative and qualitative methods were applied for data analysis. The results supported that self-efficacy predicted student use of learning strategies and related to elaborated feedback behavior (personal->behavioral). High self-efficacy students applied more high-level learning strategies, such as elaborative strategy and critical thinking. Students who provided elaborated feedback also had higher self-efficacy than those who did not. Moreover, receiving elaborative feedback significantly promoted student self-efficacy (environmental->personal), while receiving knowledge of correct response improved student performance. However, the results indicated that feedback behaviors did not predict academic performance, which may be interfered by modeling effects.

This article aims to explore how the thermoplastic polyurethane (TPU) affects the various conditions of chitosan. Several processes were used and two of them are the TPU film and chitosan lamination process intended to complete a membrane, and the TPU and chitosan blending process designed to manufacture a film. This research shall also probe into the acetylation degree of chitosan so as to understand how an increase in content may affect the antibacterial qualities, manufacturing process, mechanism, and thermal properties.

// Wen-Ming Hsu 1 , Chao-Cheng Huang 2 , Hsin-Yu Lee 3 , Pei-Yi Wu 3 , Min-Tsui Wu 4 , Hui-Ching Chuang 5 , Li-Ling Lin 4, 6 , Jiin-Haur Chuang 4 1 Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan 2 Department of Pathology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan 3 Department of Life Science and Institute of Zoology, National Taiwan University, Taipei, Taiwan 4 Department of Pediatric Surgery, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan 5 Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan 6 Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan Correspondence to: Jiin-Haur Chuang, e-mail: jhchuang@adm.cgmh.org.tw Keywords: MDA5, neuroblastoma, poly(I:C), RIG-I, TLR3 Received: February 05, 2015 Accepted: June 26, 2015 Published: July 09, 2015 ABSTRACT Toll-like receptor3 (TLR3) has been confirmed to be differentially expressed in neuroblastoma (NB), and predicts a favorable prognosis with a high expression in tumor tissues. Treatment with TLR3 agonist - polyinosinic-polycytidylic acid [poly(I:C)] could induce significant but limited apoptosis in TLR3-expressing NB cells, suggesting that other viral RNA sensors, including melanoma differentiation-associated gene 5 (MDA5) and retinoic acid-inducible gene-I (RIG-I) in the cytosolic compartment might also be implicated in poly(I:C)-induced NB cell death. MDA5 and RIG-I were induced by poly(I:C) to express in two of six NB cell lines, SK-N-AS (AS) and SK-N-FI, which were associated with up-regulation of caspase9 and active caspase3. While knockdown of either MDA5 or RIG-I alone is ineffective to decrease caspase9 and active caspase3, simultaneously targeting MDA5 and TLR3 showed the best effect to rescue poly(I:C) induced up-regulation of mitochondrial antiviral signaling protein (MAVS), caspase9, active caspase3, and apoptosis in AS cells. Over-expression of MDA5 in FaDu cells resulted in significantly less colony formation and more poly(I:C)-induced cell death. Further studies in human NB tissue samples revealed that MDA5 expression in NB tissues predicted a favorable prognosis synergistically with TLR3. Our findings indicate that MDA5 may serve as a complementary role in the TLR3 activated suppression of NB.

Hidden just below the surface in the Songshi is the story of a woman who contradicts every stereotypical view of her gender. Yang Miaozhen was a warrior, peerless both in single combat and in strategic planning. Before she was twenty, she commanded an armed band of ten thousand. She met her future husband when he and his soldiers flocked to her banner. The apparently uxorilocal marriage lasted as a partnership of equality. The couple went on to carve out a large area between Shandong and the Yangzi River and ruled it as their private domain. Although they ostensibly pledged allegiance to the Southern Song, any overseer sent from the court, whatever his station or achievement, could enjoy his tenure only at Yang Miaozhen's pleasure. After her husband's death, she led her troops to join the Mongols, who appointed her governor of Shandong. Thus her story stands on its head the complex patrilineal, patriarchal, and patrilocal system generally believed to have prevailed throughout Chinese history.

This theoretical paper presents the influence of learning styles and culture values on facilitating undergraduate students’ learning. Learning styles describe the way people process information. Many learning style inventories have been developed and applied widely, for example, Kolb’s Learning Style Inventory (LSI) and Honey and Mumford’s Learning Styles Questionnaire (LSQ). However, limited research has been conducted in the field of hospitality and tourism higher education, particularly in eastern culture. Past research in the hospitality and tourism higher education did not reveal if certain learning styles can contribute to better learning outcomes, however, there is a significant difference in preferred learning styles of students in terms of different cultural values. Therefore, it makes it pivotal to consider the influence of culture difference when examining how learning styles contribute to better learning outcomes in future research. Therefore, hospitality and tourism educators can properly plan useful strategies to accommodate different learning styles and enhance students’ learning.

Neuroblastoma (NB) is the most common malignant disease of infancy. MYCN amplification is a prognostic factor for NB and is a sign of highly malignant disease and poor patient prognosis. In this study, we aimed to investigate novel MYCN-related genes and assess how they affect NB cell behavior. The different gene expression found in 10 MYCN amplification NB tumors and 10 tumors with normal MYCN copy number were analyzed using tissue oligonucleotide microarrays. Ingenuity Pathway Analysis was subsequently performed to identify the potential genes involved in MYCN regulation pathways. Aryl hydrocarbon receptor (AHR), a receptor for dioxin-like compounds, was found to be inversely correlated with MYCN expression in NB tissues. This correlation was confirmed in a further 14 human NB samples. Moreover, AHR expression in NB tumors was found to correlate highly with histological grade of differentiation. In vitro studies revealed that AHR overexpression in NB cells induced spontaneous cell differentiation. In addition, it was found that ectopic expression of AHR suppressed MYCN promoter activity resulting in downregulation of MYCN expression. The suppression effect of AHR on the transcription of MYCN was compensated for by E2F1 overexpression, indicating that E2F1 is involved in the AHR-regulating MYCN pathway. Furthermore, AHR shRNA promotes the expression of E2F1 and MYCN in NB cells. These findings suggest that AHR is one of the upstream regulators of MYCN. Through the modulation of E2F1, AHR regulates MYCN gene expression, which may in turn affect NB differentiation.

To evaluate the clinical significance of TLR3 expression on neuroblastomas, we performed immunohistochemical study on archival tissues and in vitro studies on neuroblastoma cell lines. The results showed that positive TLR3 expression was associated with favorable histology and prognosis. Activation of TLR3 by polyinosinic:polycytidylic acid [poly(I:C)] treatment is effective to suppress cell migration and invasion and to decrease organized assembly of F-actin and filopodia formation, in TLR3-expressing SK-N-AS cells, which could be reversed by TLR3-targeting siRNA treatment. TLR3 agonist poly(I:C) promotes GAP-43 expression also in SK-N-AS cells only. Taken together, TLR3 could serve to predict favorable behavior in neuroblastomas.

Communication between cells and extracellular environments is of interest because of its critical roles in cell development and differentiation. Particularly, this signal transduction is commonly believed to rely on the contact and binding of the participating molecules/proteins, suggesting that the binding distance needed is less than a few nanometers. However, it is difficult to precisely match the rapidly binding interaction which depends on the probability of molecular collision in living systems, raising a hypothesis that another mechanism exists, could promote this signal communication, and remains unknown. Here we report that a long-range signal delivery over 10-μm and 20-μm polydimethylsiloxane(PDMS) barriers can be observed in microfluidically tetracycline (Tet) inducible expression systems. Results show that a significant increment of the long-range induced green fluorescent protein in human embryonic kidney 293T (HEK 293T) cells by the stimulation of Tet is demonstrated, and that such a signal induction is not dominated by Tet diffusion and displays a specific bindingless property. In addition, our experimental results, combined with theoretical modeling, suggest that this communication exhibits a bump-shaped characteristic depending on barrier thickness, materially structural property, surface roughness, and agonist concentration. It strongly relies on the PDMS barrier to delivery signal; therefore, we call such a mechanism as “wired” cell communication instead of wireless. These results could ignite interests in the novel and “wired” cell communication, which we call it X-signal, and in the use of such systems for the study of cellular biology and development of new drug.