bluuebunny/crossref_metadata_2025_split huggingface dataset:
Improved squalene production through increasing lipid contents in Saccharomyces cerevisiae
Authors: Wei Liu‐Jing , Kwak Suryang , Liu Jing‐Jing , Lane Stephan , Hua Qiang , Kweon Dae‐Hyuk , Jin Yong‐Su 
Published: March 2018

AbstractSqualene, a valuable acyclic triterpene, can be used as a chemical commodity for pharmacology, flavor, and biofuel industries. Microbial production of squalene has been of great interest due to its limited availability, and increasing prices extracted from animal and plant tissues. Here we report genetic perturbations that synergistically improve squalene production in Saccharomyces cerevisiae. As reported previously, overexpression of a truncated HMG‐CoA reductase 1 (tHMG1) led to the accumulation 20‐fold higher squalene than a parental strain. In order to further increase squalene accumulation in the tHMG1 overexpressing yeast, we introduced genetic perturbations—known to increase lipid contents in yeast—to enhance squalene accumulation as lipid body is a potential storage of squalene. Specifically, DGA1 coding for diacylglycerol acyltranferase was overexpressed to enhance lipid biosynthesis, and POX1 and PXA2 coding for acyl‐CoA oxidase and a subunit of peroxisomal ABC transporter were deleted to reduce lipid β‐oxidation. Simultaneous overexpression of tHMG1 and DGA1 coding for rate‐limiting enzymes in the mevalonate and lipid biosynthesis pathways led to over 250‐fold higher squalene accumulation than a control strain. However, deletion of POX1 and PXA2 in the tHMG1 overexpressing yeast did not improve squalene accumulation additionally. Fed‐batch fermentation of the tHMG1 and DGA1 co‐overexpressing yeast strain resulted in the production of squalene at a titer of 445.6 mg/L in a nitrogen‐limited minimal medium. This report demonstrates that increasing storage capacity for hydrophobic compounds can enhance squalene production, suggesting that increasing lipid content is an effective strategy to overproduce a hydrophobic molecule in yeast.
Validated LC–MS/MS method for the quantification of sciadopitysin in rat plasma and its application to pharmacokinetic and bioavailability studies in vivo
Authors: Yang Shenbao , Qu Ruiying , Zhu Zhe , Li Wei , Zhao Chengliang , Li Liantai 
Published: March 2018

AbstractA sensitive and rapid LC–MS/MS method was developed and validated for quantitation of sciadopitysin in rat plasma using amentoflavone as an internal standard. Sample processing was accomplished after deproteinization with 150 μL aliquot of acetonitrile. Chromatographic separation was achieved using an Agela C18 column with an isocratic mobile phase comprising 2 mm ammonium acetate–acetonitrile (35:65, v/v) at a flow rate of 0.4 mL/min. Detection was performed by selection reaction monitoring on a triple‐quadrupole mass spectrometer following the transitions m/z 579 → 547 and 537 → 375 for sciadopitysin and internal standard, respectively, in the negative ionization mode. The calibration curve was linear from 2.90 to 1160 ng/mL for sciadopitysin. Intra‐ and inter‐day precisions were in the ranges 4.1–11.4 and 5.7–9.1% for sciadopitysin. Sciadopitysin was stable under different stability conditions. The validated assay was applied to pharmacokinetic and bioavailability studies in rats.
Simultaneous determination of twelve polar pteridines including dihydro‐ and tetrahydropteridine in human urine by hydrophilic interaction liquid chromatography with tandem mass spectrometry
Authors: Xiong Xin , Zhang Yuanyuan , Zhang Wenjing 
Published: March 2018

AbstractPteridines and their derivatives are important cofactors in the process of cell metabolism, and the level of urinary excretion of these compounds is considered as an important clinical criterion. In this work, a new separation method involving hydrophilic interaction chromatography (HILIC) with tandem mass spectrometric detection has been developed for the simultaneous analysis of 12 pteridines including oxidized, di‐ and tetrahydroforms, namely neopterin, 7,8‐dihydroneopterin, biopterin, 7,8‐dihydrobiopterin, 5,6,7,8‐tetrahydrobiopterin, dimethylpterin, dimethyltetrahydropterin, pterin, isoxanthopterin, xanthopterin, sepiapterin and pterin‐6‐carboxylic acid, in human urine without oxidative pretreatments. The stabilizing agent (dithiothreitol) at various concentrations and the stability of oxidized, di‐ and tetrahydroforms during the sample's short‐term storage and processing and of the extracts were tested. In the developed method, 12 pteridines were chromatographically separated on an ZIC‐HILIC column by gradient elution, and the run time was 20 min. Matrix effect was evaluated and several dilutions of urine were tested in order to study the evolution of signal suppression. Spiked recovery studies demonstrated that the technique was both accurate (83.1–116.7%) and precise (RSD 1.4–15.6%). Finally, several clinical urine specimens without oxidative pretreatments were examined with the new technique and compared with previous reports.
A simple and selective LC‐MS/MS method for quantification of ikarisoside A in rat plasma and its application to a pharmacokinetic study
Authors: Cong Yue , Wang Rui , Zhang Chen , Lin Hai 
Published: March 2018

AbstractIkarisoside A is a natural flavonoid isolated from Epimedium plants. To further evaluate its medicinal potential, a sensitive and robust LC–MS/MS method was developed and validated for the assay of ikarisoside A in rat plasma. Orientin was used as an internal standard. The electrospray ionization was operated in its negative ion mode while ikarisoside A and IS were measured by selected reaction monitoring using precursor‐to‐product ion transitions of m/z 499.1 → 353.0 and m/z 446.9 → 327.6, respectively. This LC–MS/MS method had good sensitivity (LLOQ = 1.5 ng/mL), accuracy (both intra‐ and inter‐day RE ≤ ±11.9%) and precision (both intra‐ and inter‐day RSD ≤8.5%). The pharmacokinetics of ikarisoside A was subsequently profiled in Sprague–Dawley rats. Following oral administration (35 mg/kg), ikarisoside A reached maximum plasma concentration (Cmax, 207.6 ± 96.7 ng/mL) attained at 1.10 ± 0.42 h. Following oral administration, the clearance and terminal half‐life were 42.9 ± 26.5 L/h/kg and 3.15 ± 0.80 h by oral route, respectively.
A robust LC–MS/MS method for the simultaneous determination of docetaxel and voriconazole in rat plasma and its application to pharmacokinetic studies
Authors: Pei Xuexue , Li Peijin , Jiang Wenjiao , Sun Yilin , Lu Li , Ding Fei , Wang Guangji , Hao Kun 
Published: March 2018

AbstractOpportunistic fungal infections are common in immunocompromised cancer patients, especially patients undergoing chemotherapy. Because antitumor agents are possible to combine with antifungal agents in clinical, it is necessary to study drug–drug interaction between antitumor agents and antifungal agents. The aim of the study was to explore a method for the simultaneous determination of voriconazole and docetaxel in plasma and investigate pharmacokinetic interaction of voriconazole and docetaxel in rats. A precise and reliable method using liquid chromatography tandem mass spectrometry (LC–MS/MS) was established for the simultaneous measure of docetaxel and voriconazole in rat plasma after liquid–liquid extraction with ethyl acetate. The method was fully validated and successfully applied to a pharmacokinetic interaction study of docetaxel and voriconazole in rats after single or combined administration. We found that the AUC of each drug after coadministration increased compared with that after the single administration, which might be caused by interaction at the absorption stage or the competitive inhibition on the metabolic enzymes. This established method can be utilized to study the detailed mechanism of the drug–drug interaction and guide rational drug use in the clinic.
An LC–MS/MS method for quantification of demethylzeylasteral, a novel immunosuppressive agent in rat plasma and the application to a pharmacokinetic study
Authors: Yang Luoluo , Xia Yan , An Lianhua , Zhou Dan 
Published: March 2018

AbstractIn this study, a sensitive liquid chromatography–tandem mass spectrometry (LC–MS/MS) method was developed and validated for the quantification of demethylzeylasteral in rat plasma. Electrospray ionization was operated in the negative ion mode while demethylzeylasteral and oleanolic acid (internal standard) were measured by selected reaction monitoring (demethylzeylasteral: m/z 479.2 → 436.0; oleanolic acid: m/z 454.9 → 407.2). This LC–MS/MS method had good selectivity, sensitivity, accuracy and precision. The pharmacokinetic profiles of demethylzeylasteral were subsequently examined in Wistar rats after oral or intravenous administration.
Fingolimod promotes blood–nerve barrier properties in vitro
Authors: Nishihara Hideaki , Maeda Toshihiko , Sano Yasuteru , Ueno Maho , Okamoto Nana , Takeshita Yukio , Shimizu Fumitaka , Koga Michiaki , Kanda Takashi 
Published: March 2018

AbstractObjectiveThe main effect of fingolimod is thought to be functional antagonism of lymphocytic S1P1 receptors and the prevention of lymphocyte egress from lymphoid tissues, thereby reducing lymphocyte infiltration into the nervous system. However, a growing number of reports suggest that fingolimod also has a direct effect on several cell types in the nervous system. Although we previously reported that fingolimod enhances blood–brain barrier (BBB) functions, there have been no investigations regarding the blood–nerve barrier (BNB). In this study, we examine how fingolimod affects the BNB.MethodsAn immortalized human peripheral nerve microvascular endothelial cell line (HPnMEC) was used to evaluate BNB barrier properties. We examined tight junction proteins and barrier functions of HPnMECs in conditioned medium with or without fingolimod‐phosphate and blood sera from patients with typical chronic inflammatory demyelinating polyneuropathy (CIDP).ResultsIncubation with fingolimod‐phosphate increased levels of claudin‐5 mRNA and protein as well as TEER values in HPnMECs. Conversely, typical CIDP sera decreased claudin‐5 mRNA/protein levels and TEER values in HPnMECs; however, pretreatment with fingolimod‐phosphate inhibited the effects of the typical CIDP sera.ConclusionsFingolimod‐phosphate directly modifies the BNB and enhances barrier properties. This mechanism may be a viable therapeutic target for CIDP, and fingolimod may be useful in patients with typical CIDP who have severe barrier disruption.
High expression of the HMGB1–TLR4 axis and its downstream signaling factors in patients with Parkinson's disease and the relationship of pathological staging
Authors: Yang Yi , Han Chenyang , Guo Li , Guan Qiaobin 
Published: March 2018

AbstractObjectiveTo detect the expression of high‐mobility group box protein 1 (HMGB1) and toll‐like receptor 4 (TLR4) and their downstream signaling factors—myeloid differentiation factor 88 (MyD88), nuclear factor kappa B (NF‐κB), and tumor necrosis factor alpha (TNF‐α)—in the sera of patients with Parkinson's disease (PD) in order to evaluate the relationship of the HMGB1–TLR4 axis with PD development and progression.MethodsThe serum HMGB1 and TLR4 protein levels of 120 patients with PD and 100 healthy volunteers were measured using double‐antibody sandwich ELISA, and their correlations with PD staging, disease duration, drug treatment effectiveness, and clinical classification were analyzed. In addition, their correlations with the key downstream factors of the HMGB1–TLR4 axis (MyD88, NF‐κB, and TNF‐α) were analyzed.ResultsHMGB1 and TLR4 expressions were higher in the peripheral blood of patients with PD than in healthy volunteers. PD patients with poor drug treatment outcomes had significantly higher HMGB1 and TLR4 expressions than PD patients with stable drug treatment outcomes. Higher HMGB1 and TLR4 expressions were found in patients at higher PD stages, and patients with >4‐year disease duration had significantly higher HMGB1 and TLR4 expressions than patients with <4‐year disease duration. No significant difference in HMGB1 and TLR4 expressions was found among patients with tremor‐dominant, akinetic‐rigid, and mixed subtypes of PD. NF‐κB and TNF‐α expressions were positively correlated with high expression of the HMGB1–TLR4 axis.ConclusionHigh expression of the HMGB1–TLR4 axis is closely associated with PD development, progression, drug treatment effectiveness, staging, and disease duration and has great significance for PD diagnosis and treatment.
Environmental, social and governance transparency and firm value
Authors: Yu Ellen Pei‐yi , Guo Christine Qian , Luu Bac Van 
Published: March 2018

AbstractWe investigate whether environmental, social and governance (ESG) transparency, the extent of ESG disclosure, has an impact on firm value. Reducing investors’ information symmetry and agency costs is the mechanism by which better ESG transparency potentially impacts firm value. Using Bloomberg ESG disclosure scores to assess a firm's ESG transparency, we look at a sample of 1996 large cap companies across 47 developed and emerging countries and territories. Our empirical analyses suggest that the benefits from ESG disclosure outweigh their costs for the average listed firm. We find supporting evidence for greater disclosure of ESG issues boosting firm valuation measures, such as Tobin's Q. Furthermore, our results suggest that firms with greater asset size, better liquidity, higher R&D intensity, fewer insider holdings and good past financial performance will be more transparent in ESG issues.
Android smartphones network implementation in the absence of internet
Authors: El‐Bayaa Ahmed S. , Khedr Mohamed E. , Aly Moustafa H. 
Published: March 2018

AbstractIn this paper, Mobile Delay Tolerant Network service is implemented in Android application that allows the use of smartphones for broadcasting messages to nearby smartphones without Internet. A simple experiment is carried out with simple facilities and one type of routing protocols. This is implemented with only one router and eleven smartphones.
Germline MLH1, MSH2 and MSH6 variants in Brazilian patients with colorectal cancer and clinical features suggestive of Lynch Syndrome
Authors: Schneider Nayê Balzan , Pastor Tatiane , Paula André Escremim de , Achatz Maria Isabel , Santos Ândrea Ribeiro dos , Vianna Fernanda Sales Luiz , Rosset Clévia , Pinheiro Manuela , Ashton‐Prolla Patricia , Moreira Miguel Ângelo Martins , Palmero Edenir Inêz ,   Brazilian Lynch Syndrome Study Group
Published: March 2018

AbstractLynch syndrome (LS) is the most common hereditary colorectal cancer syndrome, caused by germline mutations in one of the major genes involved in mismatch repair (MMR): MLH1, MSH2, MSH6 and more rarely, PMS2. Recently, germline deletions in EPCAM have been also associated to the syndrome. Most of the pathogenic MMR mutations found in LS families occur in MLH1 or MSH2. Gene variants include missense, nonsense, frameshift mutations, large genomic rearrangements and splice‐site variants and most of the studies reporting the molecular characterization of LS families have been conducted outside South America. In this study, we analyzed 60 unrelated probands diagnosed with colorectal cancer and LS criteria. Testing for germline mutations and/or rearrangements in the most commonly affected MMR genes (MLH1, MSH2, EPCAM and MSH6) was done by Sanger sequencing and MLPA. Pathogenic or likely pathogenic variants were identified in MLH1 or MSH2 in 21 probands (35.0%). Of these, approximately one‐third were gene rearrangements. In addition, nine variants of uncertain significance (VUS) were identified in 10 (16.6%) of the sixty probands analyzed. Other four novel variants were identified, only in MLH1. Our results suggest that MSH6 pathogenic variants are not common among Brazilian LS probands diagnosed with CRC and that MMR gene rearrangements account for a significant proportion of the germline variants in this population underscoring the need to include rearrangement analysis in the molecular testing of Brazilian individuals with suspected Lynch syndrome.
The influence of insurance type on stage at presentation, treatment, and survival between Asian American and non‐Hispanic White lung cancer patients
Authors: Tantraworasin Apichat , Taioli Emanuela , Liu Bian , Flores Raja M. , Kaufman Andrew J. 
Published: March 2018

AbstractThe effect of insurance type on lung cancer diagnosis, treatment, and survival in Asian patients living in the United States is still under debate. We have analyzed this issue using the Surveillance, Epidemiology, and End Results database. There were 102,733 lung cancer patients age 18–64 years diagnosed between 2007 and 2013. Multilevel regression analysis was performed to identify the association between insurance types, stage at diagnosis, treatment modalities, and overall mortality in Asian and non‐Hispanic White (NHW) patients. Clinical characteristics were significantly different between Asian and NHW patients, except for gender. Asian patients were more likely to present with advanced disease than NHW patients (ORadj = 1.12, 95% CI = 1.06–1.19). Asian patients with non‐Medicaid insurance underwent lobectomy more than NHW patients with Medicaid or uninsured; were more likely to undergo mediastinal lymph node evaluation (MLNE) (ORadj = 1.98, 95% CI = 1.72–2.28) and cancer‐directed surgery and/or radiation therapy (ORadj = 1.41, 95% CI = 1.20–1.65). Asian patients with non‐Medicaid insurance had the best overall survival. Uninsured or Medicaid‐covered Asian patients were more likely to be diagnosed with advanced disease, less likely to undergo MLNE and cancer‐directed treatments, and had shorter overall survival than their NHW counterpart.
Functional transcriptomic annotation and protein–protein interaction analysis identify EZH2 and UBE2C as key upregulated proteins in ovarian cancer
Authors: Martínez‐Canales Sandra , López de Rodas Miguel , Nuncia‐Cantarero Miriam , Páez Raquel , Amir Eitan , Győrffy Balázs , Pandiella Atanasio , Galán‐Moya Eva María , Ocaña Alberto 
Published: March 2018

AbstractAlthough early stage ovarian cancer is in most cases a curable disease, some patients relapse even with appropriate adjuvant treatment. Therefore, the identification of patient and tumor characteristics to better stratify risk and guide rational drug development is desirable. Using transcriptomic functional annotation followed by protein–protein interacting (PPI) network analyses, we identified functions that were upregulated and associated with detrimental outcome in patients with early stage ovarian cancer. Some of the identified functions included cell cycle, cell division, signal transduction/protein modification, cellular response to extracellular stimuli or transcription regulation, among others. Genes within these functions included AURKA, AURKB, CDK1, BIRC5, or CHEK1 among others. Of note, the histone‐lysine N‐methyltransferase (EZH2) and the ubiquitin‐conjugating enzyme E2C (UBE2C) genes were found to be upregulated and amplified in 10% and 6% of tumors, respectively. Of note, EZH2 and UBE2C were identified as principal interacting proteins of druggable networks. In conclusion, we describe a set of genes overexpressed in ovarian cancer with potential for therapeutic intervention including EZH2 and UBE2C.
‘Nobody else can lead your life’: What adolescents need from psychotherapists in change processes
Authors: Lavik Kristina O. , Veseth Marius , Frøysa Helga , Binder Per‐Einar , Moltu Christian 
Published: March 2018

AbstractAimA startling number of adolescents have mental health problems, yet research on the effect of routine care shows sobering effect sizes and high dropout rates. This study's objective was to gain in‐depth, first‐person knowledge about what adolescents need from their therapists to engage therapeutically and benefit from treatment.MethodA total of 22 adolescents aged 14–19 years participated in qualitative focus groups or individual interviews of their own choosing. The data material was analysed using a systematic, step‐wise and consensual qualitative research framework for team‐based analysis.FindingsSix themes emerged from the analysis, named from the words of the adolescent participants: (1) facing a scary situation: Attend to the adolescent's starting point, (2) be warm, invested and emotionally engaged, (3) offer live company and presence as a real human being, (4) have integrity as an adult and a professional, (5) know the world of a teenager and get into their stories and (6) have mutuality as a virtue and treat the adolescent as an equal.Discussion and implicationsOverall, adolescents regard the quality of the therapeutic relationship with their therapist as essential for the success of psychotherapy. In terms of their needs in treatment, therapists need to overcome the adolescents’ initial misgivings and scepticism towards therapy through establishing trust and accommodating their developmental desire for autonomy and connectedness.
Social inequalities in the demand, supply and utilisation of psychological treatment
Authors: Delgadillo Jaime , Farnfield Amy , North Alice 
Published: March 2018

AbstractIntroductionSocio‐economic deprivation is associated with higher prevalence of mental disorders but poor access to care. We conducted a national workforce survey to examine the demand, supply and utilisation of primary care psychological services.AimTo understand the variability in the rates of access to psychological care in different geographical areas.MethodThis was a cross‐sectional survey of Improving Access to Psychological Therapies (IAPT) services. Data were collected from 144 services covering 180 local areas in England, using a freedom of information request. The access gap (AG) was defined as the percentage of cases that did not receive treatment, from the wider pool of cases referred for psychological care. We examined correlations between the demand (number of referrals) and supply (workforce size) of psychological care with local area prevalence rates of common mental disorders and the index of multiple deprivation (IMD). Regression analyses were used to assess if the variability in the AG may be explained by IMD and workforce size, controlling for local population statistics.ResultsWorkforce size was weakly correlated with the IMD (r = .16, p = .04) and prevalence rates (r = .16, p = .03). The AG was significantly associated with IMD, number of referrals, prevalence rates and treatment waiting times, but not with workforce size. Together, these variables explained approximately 26% of variance in the AG.ConclusionsSocio‐economic deprivation is associated with psychological service utilisation, irrespective of the demand–supply function, particularly when contrasting the poorest and most affluent areas.