Search

Naphthalimide derivatives have multiple biological activities, including antitumour and anti‐inflammatory activities. We previously synthesized several naphthalimide derivatives; of them, compound 5 was found to exert the strongest inhibitory effect on human DNA topoisomerase II activity. However, the effects of naphthalimide derivatives on platelet activation have not yet been investigated. Therefore, the mechanism underlying the antiplatelet activity of compound 5 was determined in this study. The data revealed that compound 5 (5–10 μM) inhibited collagen‐ and convulxin‐ but not thrombin‐ or U46619‐mediated platelet aggregation, suggesting that compound 5 is more sensitive to the inhibition of glycoprotein VI (GPVI) signalling. Indeed, compound 5 could inhibit the phosphorylation of signalling molecules downstream of GPVI, followed by the inhibition of calcium mobilization, granule release and GPIIb/IIIa activation. Moreover, compound 5 prevented pulmonary embolism and prolonged the occlusion time, but tended to prolong the bleeding time, indicating that it can prevent thrombus formation but may increase bleeding risk. This study is the first to demonstrate that the naphthalimide derivative compound 5 exerts antiplatelet and antithrombotic effects. Future studies should modify compound 5 to synthesize more potent and efficient antiplatelet agents while minimizing bleeding risk, which may offer a therapeutic potential for cardiovascular diseases.

In recurrent glioblastoma, Gliadel wafer implantation after surgery has been shown to result in incomplete chemical removal of residual tumor and development of brain edema. Furthermore, temozolomide (TMZ) resistance caused by O6-methylguanine-DNA-methyltransferase (MGMT) activation and programmed cell death-ligand 1 (PD-L1) expression leads to immune-cold lesions that result in poorer prognosis. Cerebraca wafer, a biodegradable polymer containing (Z)-n-butylidenephthalide (BP), is designed to eliminate residual tumor after glioma resection. An open-label, one-arm study with four dose cohorts, involving a traditional 3 + 3 dose escalation clinical trial, of the Cerebraca wafer combined with TMZ on patients with recurrent high-grade glioma, was conducted. Of the 12 patients who receive implantation of Cerebraca wafer, there were no drug-related adverse events (AEs) or serious AEs (SAEs). The median overall survival (OS) of patients receiving low-dose Cerebraca wafer was 12 months in the group with >25% wafer coverage of the resected tumor, which is longer than OS duration in previously published studies (Gliadel wafer, 6.4 months). Patients who received high-dose Cerebraca wafer treatment had not yet died at the data cut-off date; a 100% progression-free survival (PFS) rate at six month was achieved, indicating the median OS of cohort IV was more than 17.4 months. In vitro study of the primary cells collected from the patients revealed that the IC50 of BP against tumor stem cells was four times lower than that of bis-chloroethylnitrosourea (BCNU). A synergistic effect between BP and TMZ was demonstrated by a reduction in MGMT expression. Furthermore, BP inhibited PD-L1 expression, thereby activating T-cell cytotoxicity and increasing interferon-gamma (IFN-γ) secretion. The better therapeutic effect of Cerebraca wafer on recurrent high-grade glioma could occur through re-sensitization of TMZ and reduction of PD-L1.

Background: Hypnotics, such as benzodiazepines and nonbenzodiazepines, have been used to aid sleep and treat insomnia in older adults. However, there is limited information for the comparative efficacy and safety of different hypnotics for insomnia in older adults. Methods: EMBASE, PubMed, ClinicalTrials.gov, and ProQuest Dissertations and Theses A&I databases were searched. We included randomised controlled trials comparing hypnotics with either another hypnotic or placebo for insomnia treatment in elderly people. A multivariate random effect network meta-analysis in a frequentist framework was used for estimations of treatment effects and safety. Findings: Twenty-two articles with 5172 older adults were included. Eszopiclone was ranked as the best therapy for prolonging objective total sleep time (28·60 mins), and low-dose doxepin appeared to be the optimal treatment for increasing subjective total sleep time (28·19 mins) and objective sleep efficiency (6.8%) compared with control. Zaleplon was the most effective therapy in reducing objective and subjective sleep onset latency (-21·63 mins and -15·92 mins) compared with control. The risk of overall adverse events was highest with triazolam use (odd ratio, 1·89, 95% confidence interval 1·10 to 3·25) compared to placebo. Interpretation: Considering unclear risk of bias and the potential adverse effects of benzodiazepines and nonbenzodiazepines, we suggest that low-dose doxepin can be the optimal pharmacotherapy for the improvements of sleep duration and sleep efficiency. Future RCTs investigating the treatment effects of hypnotics, particularly low-dose doxepin, on insomnia in older adults are warranted. Funding Statement: HYC acknowledges the support of the Taiwan Ministry of Science and Technology (MOST 106-2314-B-038 -058 -MY3). YKT was supported by the Ministry of Science and Technology, Taiwan (MOST 106-2314-B-002 -098 -MY3). Declaration of Interests: All authors declared no conflicts of interest in this work. Ethics Approval Statement: The study is registered with PROSPERO, number CRD42016046301.

Background To evaluate the safety of using fluoroquinolones in pediatric population in Taiwan. Methods Patients aged 0~18 years old with fluoroquinolones prescriptions ≥5 consecutive days during year 2000 to 2013 were selected from the National Health Insurance Research Database, 4-time case number were selected as controls. We evaluated the patient’s outcome after the use of fluoroquinolones by reviewing a newly diagnosis of the following collagen-associated adverse events by International Classification of Diseases, Ninth Revision, Clinical Modification codes, covering tendons rupture, retinal detachments, gastrointestinal tract perforation, aortic aneurysm or dissection. Results Of the enrolled patients (n = 167,105), collagen-associated adverse effects developed in 85 cases (0.051%) in 6-month tracking, including 0.051% in the fluoroquinolones study cohort (17 in 33,421) and 0.051% (68 in 133,684) in the fluoroquinolones free comparison cohort. The crude hazard ratio for collagen-associated adverse events in the fluoroquinolones group was 0.997 (0.586–1.696; p = 0.990). After adjusting for age, sex, catastrophic illness, low-income household, seasons, levels of urbanization, and healthcare, the corrected hazard ratio in 6-month tracking with FQs was 1.330 (95% CI; 0.778–2.276; p = 0.255). Conclusions There is no significant difference of collagen-associated adverse effects between fluoroquinolones group and fluoroquinolones free group from our data. We propose that fluoroquinolones for pediatric population in clinical practice may be not so harmful as previous references reported.

Borneol is a plant terpene commonly used in traditional Chinese medicine. Optically pure (+)-borneol and (-)-borneol can be obtained by extraction from the plants Dipterocarpaceae and Blumea balsamifera, respectively. "Synthetic borneol" is obtained from the reduction of (±)-camphor to lead to four different stereoisomers: (+)-isoborneol, (-)-isoborneol, (+)-borneol, and (-)-borneol. In contrast, "semi-synthetic borneol" is produced from the reduction of natural camphor, (+)-camphor, to afford two isomers: (-)-isoborneol and (+)-borneol. We established a convenient method to identify them by treating the four stereoisomers with two chiral reagents, (R)-(+)-α-methoxy-α-trifluoromethylphenylacetyl chloride ((R)-(+)-MTPA-Cl) and (1S)-(-)- camphanic chloride. The resulting derivatives from the above mentioned method were analyzed by gas chromatography. The enantiomers of (+)- and (-)-isoborneol were successfully separated from (+)- and (-)-borneol isomers in this study to make this a useful method in the identification of "synthetic" and "semi-synthetic" borneols. Furthermore, we also examined five different commercial borneols. During this course, a novel and unprecedented partial epimerization from isoborneol-camphanic ester to borneol-camphanic ester was observed. However, this phenomenon did not occur in isoborneol-MTPA esters epimerization to borneol-MTPA case under the same conditions. The DFT calculation of activation energies for both reactions was in a good agreement with the results obtained from GC analysis.

Background Functional and biophysical constraints can cause different levels of sequence conservation in proteins. Previously, structural properties, e.g., relative solvent accessibility (RSA) and packing density of the weighted contact number (WCN), have been found to be related to protein sequence conservation (CS). The Voronoi volume has recently been recognized as a new structural property of the local protein structural environment reflecting CS. However, for surface residues, it is sensitive to water molecules surrounding the protein structure. Herein, we present a simple structural determinant termed the relative space of Voronoi volume (RSV); it uses the Voronoi volume and the van der Waals volume of particular residues to quantify the local structural environment. Methods RSV (range, 0–1) is defined as (Voronoi volume − van der Waals volume)/Voronoi volume of the target residue. The concept of RSV describes the extent of available space for every protein residue. Results RSV and Voronoi profiles with and without water molecules (RSVw, RSV, VOw, and VO) were compared for 554 non-homologous proteins. RSV (without water) showed better Pearson's correlations with CS than did RSVw, VO, or VOw values. The mean correlation coefficient between RSV and CS was 0.51, which is comparable to the correlation between RSA and CS (0.49) and that between WCN and CS (0.56). Conclusions RSV is a robust structural descriptor with and without water molecules and can quantitatively reflect evolutionary information in a single protein structure. Therefore, it may represent a practical structural determinant to study protein sequence, structure, and function relationships.

Importance Antiviral treatment of influenza is recommended for patients with influenza-like illness during periods of community cocirculation of influenza viruses and SARS-CoV-2; however, questions remain about which treatment is associated with the best outcomes and fewest adverse events. Objective To compare the efficacy and safety of neuraminidase inhibitors and the endonuclease inhibitor for the treatment of seasonal influenza among healthy adults and children. Data sources Medline, Embase, and the Cochrane Register of Clinical Trials were searched from inception to January 2020 (the last search was updated in October 2020). Study selection Included studies were randomized clinical trials conducted among patients of all ages with influenza treated with neuraminidase inhibitors (ie, oseltamivir, peramivir, zanamivir, or laninamivir) or an endonuclease inhibitor (ie, baloxavir) compared with other active agents or placebo. Data extraction and synthesis Two investigators identified studies and independently abstracted data. Frequentist network meta-analyses were performed; relative ranking of agents was conducted using P-score probabilities. Quality of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluations criteria. Data were analyzed in October 2020. Main outcomes and measures The time to alleviation of influenza symptoms (TTAS), complications of influenza, and adverse events (total adverse events, nausea, and vomiting). Results A total of 26 trials were identified that investigated antiviral drugs at high or low doses; these trials included 11 897 participants, among whom 6294 (52.9%) were men and the mean (SD) age was 32.5 (16.9) years. Of all treatments comparing with placebo in efficacy outcomes, high-quality evidence indicated that zanamivir was associated with the shortest TTAS (hazard ratio, 0.67; 95% CI, 0.58-0.77), while baloxavir was associated with the lowest risk of influenza-related complications (risk ratio [RR], 0.51; 95% CI, 0.32-0.80) based on moderate-quality evidence. In safety outcomes, baloxavir was associated with the lowest risk of total adverse events (RR, 0.84; 95% CI, 0.74-0.96) compared with placebo based on moderate-quality evidence. There was no strong evidence of associations with risk of nausea or vomiting among all comparisons, except for 75 mg oseltamivir, which was associated with greater occurrence of nausea (RR, 1.82; 95% CI, 1.38-2.41) and vomiting (RR, 1.88; 95% CI, 1.47-2.41). Conclusions and relevance In this systematic review and network meta-analysis, all 4 antiviral agents assessed were associated with shortening TTAS; zanamivir was associated with the shortest TTAS, and baloxavir was associated with reduced rate of influenza-related complications.

Despite the improved overall survival rates in most cancers, pancreatic cancer remains one of the deadliest cancers in this decade. The rigid microenvironment, which majorly comprises cancer-associated fibroblasts (CAFs), plays an important role in the obstruction of pancreatic cancer therapy. To overcome this predicament, the signaling of receptor tyrosine kinases (RTKs) and TGF beta receptor (TGFβR) in both pancreatic cancer cell and supporting CAF should be considered as the therapeutic target. The activation of receptors has been reported to be aberrant to cell cycle regulation, and signal transduction pathways, such as growth-factor induced proliferation, and can also influence the apoptotic sensitivity of tumor cells. In this article, the regulation of RTKs/TGFβR between pancreatic ductal adenocarcinoma (PDAC) and CAFs, as well as the RTKs/TGFβR inhibitor-based clinical trials on pancreatic cancer are reviewed.

This study explored the potential of combining point cloud data (PCD) and data clustering algorithms for textural damage detection of commonly seen structural elements in Taiwan. Intensity and RGB (red, green, and blue color model) information acquired by ground LiDAR (light detection and ranging) were used for clustering analysis. Four data clustering algorithms, k-means (KM), fuzzy c-means (FCM), subtractive clustering (SC), and density-based spatial clustering of applications with noise (DBSCAN) were employed to detect the textural damages and to compare the corresponding efficiency and accuracy. The structural elements being studied were rusted rolling doors representing general metal materials with corrosion, walls with tile spall off representing structural elements with erosions and physical damages, and washing finish walls with water staining representing the aging and lichen covering of structural elements. Our study results suggested that both KM and FCM gave preferable clustering performance than SC and DBSCAN. They exhibited desired accuracy for the damage/anomaly identification as well as computational efficiency, suggesting that KM and FCM were more appropriate for these types of application when PCD was used. It was also concluded that intensity rather than RGB data was more appropriate for reflecting the damaged areas. Intensity data was less interfered by environmental effects such as sunlight and rainwater when used to detect the textural changes. The clustering results were also shown to be associated with the clustering number and with the nature of the textural damage type.

Spinocerebellar ataxia (SCA) is a progressive neurodegenerative disease that affects the cerebellum and spinal cord. Among the 40 types of SCA, SCA type 3 (SCA3), also referred to as Machado–Joseph disease, is the most common. In the present study, we investigated the therapeutic effects of intracranial transplantation of human olfactory ensheathing cells (hOECs) in the ATXN3-84Q mouse model of SCA3. Motor function begins to decline in ATXN3-84Q transgenic mice at approximately 13 weeks of age. ATXN3-84Q mice that received intracranial hOEC transplantation into the dorsal raphe nucleus of the brain exhibited significant improvements in motor function, as measured by the rotarod performance test and footprint pattern analysis. In addition, intracranial hOEC transplantation alleviated cerebellar inflammation, prohibited Purkinje cells from dying, and enhanced the neuroplasticity of cerebellar Purkinje cells. The protein levels of tryptophan hydroxylase 2, the rate-limiting enzyme for serotonin synthesis in the cerebellum, and ryanodine receptor (RYR) increased in mice that received intracranial hOEC transplantation. Because both serotonin and RYR can enhance Purkinje cell maturation, these effects may account for the therapeutic benefits mediated by intracranial hOEC transplantation in SCA3 mice. These results indicate that intracranial hOEC transplantation has potential value as a novel strategy for treating SCA3.

Residues that are crucial to protein function or structure are usually evolutionarily conserved. In order to identify the important residues in protein, sequence conservation is estimated, and current methods rely upon the unbiased collection of homologous sequences. Surprisingly, our previous studies have shown that the sequence conservation is closely correlated with the weighted contact number (WCN), a measure of packing density for residue's structural environment, calculated only based on the Cα positions of a protein structure. Moreover, studies have shown that sequence conservation is correlated with environment-related structural properties calculated based on different protein substructures, such as a protein's all atoms, backbone atoms, side-chain atoms or side-chain centroid. To know whether the Cα atomic positions are adequate to show the relationship between residue environment and sequence conservation or not, here we compared Cα atoms with other substructures in their contributions to the sequence conservation. Our results show that Cα positions are substantially equivalent to the other substructures in calculations of various measures of residue environment. As a result, the overlapping contributions between Cα atoms and the other substructures are high, yielding similar structure-conservation relationship. Take the WCN as an example, the average overlapping contribution to sequence conservation is 87% between Cα and all-atom substructures. These results indicate that only Cα atoms of a protein structure could reflect sequence conservation at the residue level. This article is protected by copyright. All rights reserved.

Study objectives To systematically review and meta-analyze the associations between sleep disturbances and suicidal ideation, plans, and attempts in adolescents and explore potential moderators of these associations. Methods Embase, PubMed, ProQuest, and the China Knowledge Resource Integrated Database were searched from their inception dates to October 19, 2018. We selected cross-sectional, prospective, or retrospective studies without time or language restrictions. Results Nine cross-sectional studies, four prospective studies, and one retrospective report that, respectively, involved 37 536, 9295, and 80 adolescents were included in the meta-analysis. Cross-sectional analyses revealed that adolescents with sleep disturbances were at higher risks of suicidal ideation, plans, and attempts (pooled odds ratios [ORs] = 2.35, 1.58, and 1.92) than those without sleep disturbances. Prospective reports indicated that sleep disturbances in adolescents significantly predicted the risk of suicidal ideation but not suicide attempts (pooled ORs = 1.79 and 1.98, 95% confidence intervals = 1.36-2.36 and 0.62-6.29, respectively). The retrospective study did not support the association between sleep disturbances and suicide attempts. Depression did not moderate the associations between sleep disturbances and suicidal ideation or attempts in adolescents. Adolescents with insomnia complaints had a higher risk of suicidal ideation than those with other sleep complaints. Age, the female percentage, and reliable sleep measures were significant moderators (all p Conclusions Sleep disturbances, particularly insomnia, should be considered an influencing factor when developing preventive strategies against adolescent suicidal ideation. Additional prospective studies are warranted to establish causality of sleep disturbances in youth suicide plans and attempts.

Fibroblast growth factor 1 (FGF1) binds and activates FGF receptors, thereby regulating cell proliferation and neurogenesis. Human FGF1 gene 1B promoter (−540 to +31)-driven SV40 T antigen has been shown to result in tumorigenesis in the brains of transgenic mice. FGF1B promoter (−540 to +31)-driven green fluorescent protein (F1BGFP) has also been used in isolating neural stem cells (NSCs) with self-renewal and multipotency from developing and adult mouse brains. In this study, we provide six lines of evidence to demonstrate that FGF1/FGFR signaling is implicated in the expression of Aurora A (AurA) and the activation of its kinase domain (Thr288 phosphorylation) in the maintenance of glioblastoma (GBM) cells and NSCs. First, treatment of FGF1 increases AurA expression in human GBM cell lines. Second, using fluorescence-activated cell sorting, we observed that F1BGFP reporter facilitates the isolation of F1BGFP(+) GBM cells with higher expression levels of FGFR and AurA. Third, both FGFR inhibitor (SU5402) and AurA inhibitor (VX680) could down-regulate F1BGFP-dependent AurA activity. Fourth, inhibition of AurA activity by two different AurA inhibitors (VX680 and valproic acid) not only reduced neurosphere formation but also induced neuronal differentiation of F1BGFP(+) GBM cells. Fifth, flow cytometric analyses demonstrated that F1BGFP(+) GBM cells possessed different NSC cell surface markers. Finally, inhibition of AurA by VX680 reduced the neurosphere formation of different types of NSCs. Our results show that activation of AurA kinase through FGF1/FGFR signaling axis sustains the stem cell characteristics of GBM cells. Implications This study identified a novel mechanism for the malignancy of GBM, which could be a potential therapeutic target for GBM.

Patients with multiple system atrophy (MSA), a progressive neurodegenerative disorder of adult onset, were found less than 9 years of life expectancy after onset. The disorders include bradykinesia and rigidity commonly seen in Parkinsonism disease and additional signs such as autonomic dysfunction, ataxia, or dementia. In clinical treatments, MSA poorly responds to levodopa, the drug used to remedy Parkinsonism disease. The exact cause of MSA is still unknown, and exploring a therapeutic solution to MSA remains critical. A transgenic mouse model was established to study the feasibility of human adipose-derived stem cell (ADSC) therapy in vivo. The human ADSCs were transplanted into the striatum of transgenic mice via intracerebral injection. As compared with sham control, we reported significantly enhanced rotarod performance of transgenic mice treated with ADSC at an effective dose, 2 × 105 ADSCs/mouse. Our ex vivo feasibility study supported that intracerebral transplantation of ADSC might alleviate striatal degeneration in MSA transgenic mouse model by improving the nigrostriatal pathway for dopamine, activating autophagy for α-synuclein clearance, decreasing inflammatory signal, and further cell apoptosis, improving myelination and cell survival at caudate-putamen.

Induced pluripotent stem cells (iPSCs), which are generated through reprogramming adult somatic cells by expressing specific transcription factors, can differentiate into derivatives of the three embryonic germ layers and accelerate rapid advances in stem cell research. Neurological diseases such as amyotrophic lateral sclerosis (ALS) have benefited enormously from iPSC technology. This approach can be particularly important for creating iPSCs from patients with familial or sporadic forms of ALS. Motor neurons differentiated from the ALS-patient-derived iPSC can help to determine the relationship between cellular phenotype and genotype. Patient-derived iPSCs facilitate the development of new drugs and/or drug screening for ALS treatment and allow the exploration of the possible mechanism of ALS disease. In this article, we reviewed ALS-patient-specific iPSCs with various genetic mutations, progress in drug development for ALS disease, functional assays showing the differentiation of iPSCs into mature motor neurons, and promising biomarkers in ALS patients for the evaluation of drug candidates.

This study explored the potential of combining point cloud data (PCD) and 2D/3D PCD algorithms for deformation monitoring of common reinforced concrete (RC) structural elements. The RC specimens tested in the laboratory include three beam (30x50x400 cm) elements and three slab (150X15X350 cm) elements under uniaxial loading. PCDs of each specimen were acquired by 3D laser scanner over the loading processes and used to extract the deformation at each loading step. Deformation monitoring was also accompanied with traditional LVDT instrumentations for later comparison with the PCD ones. Each specimen was loaded with several steps till failure; within each interval the PCDs of RC specimens were scanned. 2D edge extractions and direct 3D surface fittings were used as the PCD algorithms for extracting the deformation information of the specimens at each loading step. By comparing the results with LVDT readings, it was shown that PCD algorithms can enhance the accuracy of laser scanner for deformation monitoring of RC structural elements and give comparable results with LVDTs. It is also shown that the enhanced measuring accuracy is subjected to the PCD algorithms. Nevertheless, this study successfully demonstrated the applicability of 2D/3D PCD algorithms for whole field deformation monitoring of RC structural elements.

Radioiodine-refractory advanced or metastatic thyroid cancer has poor prognosis. We conducted a meta-analysis of randomized controlled trials to evaluate the effectiveness and safety of tyrosine kinase inhibitors (TKIs) for advanced or metastatic thyroid cancer treatment.Studies published up to April 2017 were selected. The pooled effect size was calculated through meta-analysis by using random effects models. Outcomes were overall survival (OS), progression-free survival (PFS), objective response rate (RR), and adverse events (AEs).Six studies examining 1615 patients were included. TKI treatment significantly improved PFS in patients with differentiated thyroid cancer (DTC; hazard ratio [HR] = 0.43; 95% confidence interval [CI], 0.23-0.82) and those with medullary thyroid cancer (MTC; HR = 0.36; 95% CI, 0.22-0.58). TKI treatment significantly prolonged OS in patients with DTC (HR = 0.74; 95% CI, 0.58-0.95). The TKI treatment group exhibited a significantly improved partial response rate (risk ratio = 15.8; 95% CI, 1.77-140.69) but a significantly higher number of AEs compared with the control group.TKIs significantly improved PFS and RR in patients with advanced or metastatic DTC or MTC. We recommend thoroughly evaluating patients' health status and cautiously using TKIs to maximize their benefits and minimize their toxicity.

Background Despite the impact of medication literacy (ML) on patients’ safe use of medications, existing instruments are mostly for general health literacy measurement or designed for specific disease populations, with few specifically designed for ML. Objective To develop and validate the first Chinese medication literacy measure (ChMLM). Methods The ChMLM was developed by a multidisciplinary and bilingual expert panel and subsequently pilot-tested. The final version had 17 questions in four sections: vocabulary, non-prescription drug, prescription drug and drug advertisement. Face-to-face interviews were administered in a convenience sample of adults with diverse sociodemographic characteristics. Internal consistency was assessed by Cronbach's alpha. Content validity was confirmed by the expert panel, and hypothesis testing was performed to assess construct validity. Results A total of 634 adults were interviewed. The mean (SD) total ChMLM score was 13.0 (2.8). The internal validity was acceptable (Cronbach's alpha=0.72). Nine of the ten a priori hypotheses were fulfilled. Younger age, higher income and higher education levels were significantly associated with a higher ChMLM score. Furthermore, higher scores on the ChMLM were associated with higher confidence or less difficulty in writing, reading, speaking and listening abilities in a health-care encounter. No association was found between ChMLM total scores and frequency of doctor's visits. Conclusion The ChMLM is a valid and reliable ML measure. It may help pharmacists and other health-care providers to target patients and problem areas that need interventions with the ultimate goal of preventing medication errors and harm.

This paper presents the numerical analysis and synthesis of metallic reflectarray antennas to radiate multi-beams for the multi-sector coverage in wireless communications. The synthesis procedure is developed based on the concept of steepest descent method to optimize the phase variation of reflecting elements. In particular, closed-form formulations are obtained to update the phases in each iteration and completely avoid the cumbersome numerical summations of scattering fields. Numerical examples will be presented to demonstrate the concepts and validate the feasibility.

Functional and biophysical constraints result in site-dependent patterns of protein sequence variability. It is commonly assumed that the key structural determinant of site-specific rates of evolution is the Relative Solvent Accessibility (RSA). However, a recent study found that amino acid substitution rates correlate better with two Local Packing Density (LPD) measures, the Weighted Contact Number (WCN) and the Contact Number (CN), than with RSA. This work aims at a more thorough assessment. To this end, in addition to substitution rates, we considered four other sequence variability scores, four measures of solvent accessibility (SA), and other CN measures. We compared all properties for each protein of a structurally and functionally diverse representative dataset of monomeric enzymes. We show that the best sequence variability measures take into account phylogenetic tree topology. More importantly, we show that both LPD measures (WCN and CN) correlate better than all of the SA measures, regardless of the sequence variability score used. Moreover, the independent contribution of the best LPD measure is approximately four times larger than that of the best SA measure. This study strongly supports the conclusion that a site’s packing density rather than its solvent accessibility is the main structural determinant of its rate of evolution.

A novel process and temperature compensation design for 2 VDD output buffers is proposed, where the threshold voltages (Vth) of PMOSs and NMOSs varying with process and temperature deviation could be detected, respectively. A prototype 2 × VDD output buffer using the proposed compensation design is fabricated using a typical 0.18 μm CMOS process. By adjusting output currents, the slew rate of output signals could be compensated over 117%. The maximum data rate with compensation is 120 MHz in contrast with 95 MHz without compensation, which is measured on silicon with an equivalent probe capacitive load of 10 pF.

Valproic acid (VPA) is the primary mood-stabilizing drug to exert neuroprotective effects and to treat bipolar disorder in clinic. Fibroblast growth factor 1 (FGF1) has been shown to regulate cell proliferation, cell division, and neurogenesis. Human FGF1 gene 1B promoter (-540 to +31)-driven green fluorescence (F1BGFP) has been shown to recapitulate endogenous FGF1 gene expression and facilitates the isolation of neural stem/progenitor cells (NSPCs) from developing and adult mouse brains. In this study, we provide several lines of evidence to demonstrate the underlying mechanisms of VPA in activating FGF-1B promoter activity: (i) VPA significantly increased the FGF-1B mRNA expression and the percentage of F1BGFP(+) cells; (ii) the increase of F1BGFP expression by VPA involves changes of regulatory factor X (RFX) 1-3 transcriptional complexes and the increase of histone H3 acetylation on the 18-bp cis-element of FGF-1B promoter; (iii) treatments of other histone deacetylases (HDAC) inhibitors, sodium butyrate and trichostatin A, significantly increased the expression levels of FGF-1B, RFX2, and RFX3 transcripts; (iv) treatments of glycogen synthase kinase 3 (GSK-3) inhibitor, lithium, or GSK-3 siRNAs also significantly activated FGF-1B promoter; (v) VPA specifically enhanced neuronal differentiation in F1BGFP(+) embryonic stem cells and NSPCs rather than GFP(-) cells. This study suggested, for the first time, that VPA activates human FGF1 gene promoter through inhibiting HDAC and GSK-3 activities.

In regular culture conditions with leukemia inhibitory factor (LIF), the majority of mouse embryonic stem cells (mESCs) are maintained in a self-renewal stage; very few mESCs have differentiated morphology. When LIF is withdrawn, mESCs tend to differentiate; this differentiation process can be enhanced by the introduction of exogenous fibroblast growth factor (FGF). Here, we show that even in the presence of exogenous FGF1, mESCs can maintain self-renewal and expression of pluripotency markers in the presence of LIF. To elucidate the mechanism in which LIF dominates over the FGF1, extracellular signal-regulated kinase 1/2 (Erk1/2) signaling of mESCs cultured in a medium containing FGF1 or LIF/FGF1 was examined. The results demonstrate that Erk1/2 was activated by FGF1 in the absence of LIF; however, the FGF1-induced Erk1/2 phosphorylation was suppressed when LIF was introduced. Moreover, FGF1-Erk1/2 downregulation was inhibited by a signal transducer and activator of the transcription 3 (Stat3) inhibitor WP1066, suggesting that LIF-induced Stat3 activation plays an important role in the FGF1-Erk1/2 inhibition in mESCs. We further demonstrate that the binding affinity of phospho-Erk1/2 and Sprouty2 was increased via Stat3 activation. Binding of phospho-Erk1/2 and Sprouty2 blocks the activation of Erk1/2 signaling, thus inhibiting the downstream differentiation process in mESCs. Our findings demonstrate, for the first time, that LIF-induced Stat3 phosphorylation plays an important role in promoting the binding of phospho-Erk1/2 and Sprouty2, and thus inhibiting FGF-induced differentiation.

Novel C4-benzazole naphthalimide derivatives were synthesized and tested in vitro and in vivo as anti-cancer drugs. Among these synthetic molecules, compounds 9 and 10 exhibited cytotoxicity against murine B16F10 melanoma cells. In addition, the above-mentioned compounds significantly suppressed lung tumor metastasis with no visible sign of toxicity.

This paper describes how the development of the microelectronics industry in Taiwan has followed an evolutionary path that eventually led to the formation of the ‘ Triple - alliance ’. The ‘ Triple - alliance ’ model postulates that a nation's industrialization is fundamentally underpinned by the arrangement of three distinct institutions: state bureaucracy, domestic business groups and multinational corporations. The paper delineates the role of each participating institution in the context of Taiwan's microelectronics industry, and discusses the interaction between domestic and foreign institutions to demonstrate how the alliance facilitates the transfer and absorption of technology. Using the creation of the flat panel display industry in Taiwan as an example, the paper shows that understanding the interactions among these three institutions is essential for uncovering how technology-intensive industries are created in late-industrializing countries. The paper adopts an evolutionary approach in tracing how the web of linkages and alliances among these three institutions has led to the successful creation of Taiwan's technology-intensive flat panel display industry.

In this paper, a single-chip 60-V battery charger prototype is presented. The newly proposed charge mode transition can ensure smooth transitions between incremental current (IC), constant current (CC), and constant voltage (CV) modes. The charger sources a current of 136 mA in CC mode and has an efficiency up to 92% during the charging sequence. Intentional saturation of both the IC and CV regulation loops ensure the stability of the charger throughout the charging sequence. Bonding PAD designed to remove the constraints on the aspect ratio of input transistors as a prevention of antenna effect is also disclosed. The proposed design has been implemented on silicon using the TSMC 0.25 μm 1-poly 3-metal bipolar-CMOS-DMOS (BCD) 60-V process.

A 0.9 V to 5 V (0.9/1.2/1.8/2.5/3.3/5 V) mixed-voltage I/O buffer with NMOS clamping technique is proposed. By using a dynamic gate bias generator to provide appropriate gate drive voltages for the output stage, the I/O buffer can transmit a sub-3 t VDD voltage-level signal without gate-oxide overstress hazard. Besides, the leakage current is eliminated by adopting a floating N-well circuit. The maximum data rate is measured at 66 MHz for 5/3.3/2.5/1.8/1.2/0.9 V with an equivalent probe capacitive load of 10 pF.

Hemorrhoidectomy is associated with postoperative pain and prolonged wound healing. Glyceryl trinitrate has been shown to decrease muscle spasm and increase anodermal blood flow. A meta-analysis of randomized controlled trials was conducted to evaluate the efficacy of topical glyceryl trinitrate application in pain relief after hemorrhoidectomy. PubMed, EMBASE, Cochrane Library, Scopus, and ClinicalTrials.gov registries were searched for studies published before August 2015. Individual effect sizes were standardized, and a meta-analysis was conducted to calculate a pooled effect size using random effects models. Pain was assessed using a visual analog scale on days 1, 3, 7, and 14 after operation. Secondary outcomes included time taken to resume routine activities, wound healing at 3 weeks after operation, complication, and headache incidence. A total of 12 trials with 1095 patients were reviewed. Significant pain reduction was observed on days 1, 3, 7, and 14 after hemorrhoidectomy in the glyceryl trinitrate groups. Glyceryl trinitrate-treated patients appeared to resume routine activities earlier than those in the control group (weight mean difference −7.52; 95 % confidence interval: 16.13–1.08). The wound healing rates 3 weeks after operation were significant higher in the glyceryl trinitrate-treated groups than in the control group (risk ratio 1.79; 95 % confidence interval: 1.38–2.33). However, the incidence of headache significantly increased in the glyceryl trinitrate group (risk ratio 3.68; 95 % confidence interval: 1.62–8.34). Topical application of glyceryl trinitrate effectively relieves pain and promotes wound healing after hemorrhoidectomy; however, the substantial headache incidence may limit extensive application.

As assuring cell quality is an essential parameter for the success of stem cell therapy, the impact of various senescence-inducing stress signals, and strategies to circumvent them, has been an important area of focus in stem cell research. The aim of this study was to demonstrate the capacity of trans-cinnamaldehyde (TC) in reversing stress-induced senescence and maintaining the quality of stem cells in a chemically (H2O2)-induced cell senescence model. Because of the availability and the promising application potential in regenerative medicine, adipose-derived stem cells (ADSCs) were chosen for the study. We found that H2O2 treatment resulted in the expression of senescence characteristics in the ADSCs, including decreased proliferation rate, increased senescence-associated β-galactosidase (SA-β-gal) activity, decreased silent mating type information regulation 2 homolog ( SIRT1) expression, and decreased telomerase activity. However, TC treatment was sufficient to rescue or reduce the effects of H2O2 induction, ultimately leading to an increased proliferation rate, a decrease in the percentage of SA-β-gal-positive cells, upregulation of SIRT1 expression, and increased telomerase activity of the senescent ADSCs at the cellular level. Moreover, a chemically induced liver fibrosis animal model was used to evaluate the functionality of these rescued cells in vivo. Liver dysfunction was established by injecting 200 mg/kg thioacetamide (TAA) intraperitoneally into Wistar rats every third day for 60 days. The experimental rats were separated into groups: normal group (rats without TAA induction), sham group (without ADSC transplantation), positive control group (transplanted with normal ADSCs), H2O2 group (transplanted with H2O2-induced senescent ADSCs), and H2O2 + TC group (transplanted with ADSCs pretreated with H2O2 and then further treated with TC). In the transplantation group, 1 × 106 human ADSCs were introduced into each rat via direct liver injection. Based on the biochemical analysis and immunohistochemical staining results, it was determined that the therapeutic effects on liver fibrosis by the induced senescent ADSCs (H2O2 group) were not as significant as those exerted by the normal ADSCs (the positive control group). However, the H2O2 + TC group showed significant reversal of liver damage when compared to the H2O2 group 1 week posttransplantation. These data confirmed that the TC treatment had the potential to reduce the effects of H2O2-induced senescence and to restore in vivo functionality of the induced senescent ADSCs. It is therefore suggested that TC has potential applications in maintaining the quality of stem cells and could aid in treating senescence-related disorders.

Protein sequences evolve under selection pressures imposed by functional and biophysical requirements, resulting in site-dependent rates of amino acid substitution. Relative solvent accessibility (RSA) and local packing density (LPD) have emerged as the best candidates to quantify structural constraint. Recent research assumes that RSA is the main determinant of sequence divergence. However, it is not yet clear which is the best predictor of substitution rates. To address this issue, we compared RSA and LPD with site-specific rates of evolution for a diverse data set of enzymes. In contrast with recent studies, we found that LPD measures correlate better than RSA with evolutionary rate. Moreover, the independent contribution of RSA is minor. Taking into account that LPD is related to backbone flexibility, we put forward the possibility that the rate of evolution of a site is determined by the ease with which the backbone deforms to accommodate mutations. Fil: Yeh, So Wei. National Chiao Tung University; China Fil: Liu, Jen Wei. National Chiao Tung University; China Fil: Yu, Sung Huan. National Chiao Tung University; China Fil: Yih, Chien Hua. National Chiao Tung University; China Fil: Hwang, Jenn Kang. National Chiao Tung University; China Fil: Echave, Julián. Universidad Nacional de San Martín. Escuela de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina

This paper discusses about EMI behaviors of a simple microcontroller under different machine code combinations. It's known that a microcontroller has different EMI behaviors under different machine code sequences. To the best of our knowledge, little research addresses its attention on the relationship between the machine code sequence and the EMI behaviors. In this paper, we try to find it by theoretical deduction and measurement verification. From the me asured result, the deduction is able to predict the EMI behavior for several machine codes. This research can be the foundation of software- level EMI optimization techniques.

A novel process corner detection technique as well as process and temperature compensation method for sub-2×VDD output buffer is proposed. The threshold voltage (Vth) of PMOSs and NMOSs varying with process and temperature deviation could be detected, respectively. By adjusting output currents, the slew rate of output signal could be compensated over 117 %. The maximum data rate with compensation is 120 MHz in contrast with 95 MHz without compensation, which is measured on silicon with an equivalent probe capacitive load of 10 pF.

A 60 V battery charger implemented using TSMC 0.25 µm Bipolar-CMOS-DMOS (BCD) 60 V process is presented in this work. A novel transition method is proposed to ensure smooth transitions between constant current (CC) and constant voltage (CV) modes. Since the proposed approach would require only additional diodes, power consumption and chip area are conserved in comparison with other sophisticated methods proposed in prior works. The charger sources a current of 50 mA in CC mode and has an efficiency of 75% ∼ 80% throughout the charging sequence. The supply voltage is kept at 3 volts higher than the battery voltage throughout the charging sequence to maintain charging efficiency. A thermal protection circuit is included in this design to prevent the charger from operating at a temperature over the maximum allowed temperature.

A 1.0 V to 1.8 V mixed-voltage I/O buffer implemented with 90-nm 1-V standard CMOS devices is proposed. By using a dynamic gate bias generator to provide appropriate gate drive voltages for the output stage, the I/O buffer can transmit 2×VDD voltage level signal without any gate-oxide overstress hazard. Besides, the leakage current is eliminated by adopting a floating N-well circuit. The maximum data rate is simulated to be 340 MHz and 450 MHz for 1.8 V and 1.0 V, respectively, with a given capacitive load of 20 pF.

A 0.9 V to 5 V (0.9/1.2/1.8/2.5/3.5/5 V) mixed-voltage I/O buffer with NMOS clamping technique is proposed. By using a dynamic gate bias generator to provide appropriate gate drive voltages for the output stage, the I/O buffer can transmit 3×VDD voltage level signal without gate-oxide overstress hazard. Besides, the leakage current effect is eliminated by adopting a floating N-well circuit. The maximum data rate is simulated to 140/120/120/120/80/40 Mbps for 5/3.3/2.5/1.8/1.2/0.9 V, respectively, with a given capacitive load of 10 pF.