bluuebunny/crossref_metadata_2025 huggingface dataset:
Enhancement of tumor-associated antigen-specific T cell responses by radiofrequency ablation of hepatocellular carcinoma
Authors: Mizukoshi Eishiro , Yamashita Tatsuya , Arai Kuniaki , Sunagozaka Hajime , Ueda Teruyuki , Arihara Fumitaka , Kagaya Takashi , Yamashita Taro , Fushimi Kazumi , Kaneko Shuichi
Published: November 2012

Radiofrequency ablation (RFA) is one of the treatments for hepatocellular carcinoma (HCC) and is known to enhance host immune response. However, the epitopes to which enhanced immune responses occur, the impact on patient prognosis, and the functions and phenotype of T cells induced are still unclear. To address these issues, we analyzed immune responses before and after RFA in 69 HCC patients using 11 tumor-associated antigen (TAA)-derived peptides that we identified to be appropriate to analyze HCC-specific immune responses. The immune responses were analyzed using enzyme-linked immunospot (ELISPOT) assay and tetramer assays using peripheral blood mononuclear cells. An increase in the number of TAA-specific T cells detected by interferon-γ ELISPOT assays occurred in 62.3% of patients after RFA. The antigens and their epitope to which enhanced T cell responses occur were diverse, and some of them were newly induced. The number of TAA-specific T cells after RFA was associated with the prevention of HCC recurrence, and it was clarified to be predictive of HCC recurrence after RFA by univariate and multivariate analyses. The number of TAA-specific T cells after RFA was inversely correlated with the frequency of CD14+HLA-DR−/low myeloid-derived suppressor cells (MDSCs). The modification of T cell phenotype was observed after RFA. The number of TAA-specific T cells at 24 weeks after RFA was decreased.

Conclusion

: Although RFA can enhance various TAA-specific T cell responses and the T cells induced contribute to the HCC recurrence-free survival of patients, besides immunosuppression by MDSCs, the memory phenotype and lifetime of TAA-specific T cells are not sufficient to prevent HCC recurrence completely. Additional treatments by vaccine or immunomodulatory drugs might be useful to improve the immunological effect of RFA.
Sal-like protein 4 (SALL4), a stem cell biomarker in liver cancers
Authors: Oikawa Tsunekazu , Kamiya Akihide , Zeniya Mikio , Chikada Hiromi , Hyuck Ahn Dong , Yamazaki Yuji , Wauthier Eliane , Tajiri Hisao , Miller Lance D. , Wang Xin Wei , Reid Lola M. , Nakauchi Hiromitsu
Published: November 2012

Liver cancers, including hepatocellular carcinomas (HCCs), cholangiocarcinomas (CCs), and fibrolamellar HCCs (FL-HCCs) are among the most common cancers worldwide and are associated with a poor prognosis. Investigations of genes important in liver cancers have focused on Sal-like protein 4 (SALL4), a member of a family of zinc finger transcription factors. It is a regulator of embryogenesis, organogenesis, pluripotency, can elicit reprogramming of somatic cells, and is a marker of stem cells. We found it expressed in normal murine hepatoblasts, normal human hepatic stem cells, hepatoblasts and biliary tree stem cells, but not in mature parenchymal cells of liver or biliary tree. It was strongly expressed in surgical specimens of human HCCs, CCs, a combined hepatocellular and cholangiocarcinoma, a FL-HCC, and in derivative, transplantable tumor lines in immune-compromised hosts. Bioinformatics analyses indicated that elevated expression of SALL4 in tumors is associated with poor survival of HCC patients. Experimental manipulation of SALL4′s expression results in changes in proliferation versus differentiation in human HCC cell lines

in vitro

and

in vivo

in immune-compromised hosts. Virus-mediated gene transfer of SALL4 was used for gain- and loss-of-function analyses in the cell lines. Significant growth inhibition

in vitro

and

in vivo

, accompanied by an increase in differentiation occurred with down-regulation of SALL4. Overexpression of SALL4 resulted in increased cell proliferation

in vitro

, correlating with an increase in expression of cytokeratin19 (CK19), epithelial cell adhesion molecules (EpCAM), and adenosine triphosphate (ATP)-binding cassette-G2 (ABCG2).

Conclusion:

SALL4′s expression is an indicator of stem cells, a prognostic marker in liver cancers, correlates with cell and tumor growth, with resistance to 5-FU, and its suppression results in differentiation and slowed tumor growth. SALL4 is a novel therapeutic target for liver cancers.
Oxidative stress plays a major role in chlorpromazine-induced cholestasis in human HepaRG cells
Authors: Anthérieu Sébastien , Azzi Pamela Bachour-El , Dumont Julie , Abdel-Razzak Ziad , Guguen-Guillouzo Christiane , Fromenty Bernard , Robin Marie-Anne , Guillouzo André
Published: November 2012

Drugs induce cholestasis by diverse and still poorly understood mechanisms in humans. Early hepatic effects of chlorpromazine (CPZ), a neuroleptic drug known for years to induce intrahepatic cholestasis, were investigated using the differentiated human hepatoma HepaRG cells. Generation of reactive oxygen species (ROS) was detected as early as 15 minutes after CPZ treatment and was associated with an altered mitochondrial membrane potential and disruption of the pericanalicular distribution of F-actin. Inhibition of [3H]-taurocholic acid efflux was observed after 30 minutes and was mostly prevented by N-acetyl cysteine (NAC) cotreatment, indicating a major role of oxidative stress in CPZ-induced bile acid (BA) accumulation. Moreover, 24-hour treatment with CPZ decreased messenger RNA (mRNA) expression of the two main canalicular bile transporters, bile salt export pump (BSEP) and multidrug resistance protein 3 (MDR3). Additional CPZ effects included inhibition of Na+-dependent taurocholic cotransporting polypeptide (NTCP) expression and activity, multidrug resistance-associated protein 4 (MRP4) overexpression and CYP8B1 inhibition that are involved in BA uptake, basolateral transport, and BA synthesis, respectively. These latter events likely represent hepatoprotective responses which aim to reduce intrahepatic accumulation of toxic BA. Compared to CPZ effects, overloading of HepaRG cells with high concentrations of cholic and chenodeoxycholic acids induced a delayed oxidative stress and, similarly, after 24 hours it down-regulated BSEP and MDR3 in parallel to a decrease of NTCP and CYP8B1 and an increase of MRP4. By contrast, low BA concentrations up-regulated BSEP and MDR3 in the absence of oxidative stress.

Conclusion

: These data provide evidence that, among other mechanisms, oxidative stress plays a major role as both a primary causal and an aggravating factor in the early CPZ-induced intrahepatic cholestasis in human hepatocytes.
Constitutive Notch2 signaling induces hepatic tumors in mice
Authors: Dill Michael T. , Tornillo Luigi , Fritzius Thorsten , Terracciano Luigi , Semela David , Bettler Bernhard , Heim Markus H. , Tchorz Jan S.
Published: November 2012

Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCC) are the most common liver tumors and a leading cause for cancer-related death in men. Notch2 regulates cellular differentiation in the developing and adult liver. Although aberrant Notch signaling is implicated in various cancers, it is still unclear whether Notch2 regulates proliferation and differentiation in liver carcinogenesis and thereby contributes to HCC and CCC formation. Here, we investigated the oncogenic potential of constitutive Notch2 signaling in the liver. We show that liver-specific expression of the intracellular domain of Notch2 (N2ICD) in mice is sufficient to induce HCC formation and biliary hyperplasia. Specifically, constitutive N2ICD signaling in the liver leads to up-regulation of pro-proliferative genes and proliferation of hepatocytes and biliary epithelial cells (BECs). Using the diethylnitrosamine (DEN) HCC carcinogenesis model, we further show that constitutive Notch2 signaling accelerates DEN-induced HCC formation. DEN-induced HCCs with constitutive Notch2 signaling (DENN2ICD HCCs) exhibit a marked increase in size, proliferation, and expression of pro-proliferative genes when compared with HCCs from DEN-induced control mice (DENctrl HCCs). Moreover, DENN2ICD HCCs exhibit increased Sox9 messenger RNA (mRNA) levels and reduced Albumin and Alpha-fetoprotein mRNA levels, indicating that they are less differentiated than DENctrl HCCs. Additionally, DENN2ICD mice develop large hepatic cysts, dysplasia of the biliary epithelium, and eventually CCC. CCC formation in patients and DENN2ICD mice is accompanied by re-expression of hepatocyte nuclear factor 4α(HNF4α), possibly indicating dedifferentiation of BECs.

Conclusion

: Our data establish an oncogenic role for constitutive Notch2 signaling in liver cancer development.
High susceptibility to liver injury in IL-27 p28 conditional knockout mice involves intrinsic interferon-γ dysregulation of CD4+ T cells
Authors: Zhang Song , Liang Ruifang , Luo Wei , Liu Chang , Wu Xiaoli , Gao Yanan , Hao Jianlei , Cao Guangchao , Chen Xi , Wei Jun , Xia Siyuan , Li Zheng , Wen Ti , Wu Yunyun , Zhou Xinglong , Wang Puyue , Zhao Liqing , Wu Zhengzhou , Xiong Sidong , Gao Xiaoming , Gao Xiang , Chen Yongyan , Ge Qing , Tian Zhigang , Yin Zhinan
Published: November 2012

Interleukin (IL)-27, a newly discovered IL-12 family cytokine, is composed of p28 and EBI3. In this study,

CD11c-p28

f/f conditional knockout mice were generated to delete p28 specifically in dendritic cells (DCs). We demonstrated that in the absence of DC-derived p28, these mice were highly susceptible to both low and higher concentrations of concanavalin A (ConA) (5 mg/kg or 10 mg/kg), with extremely early and steady high levels of interferon-γ (IFN-γ) in sera. Neutralizing IFN-γ prevented ConA-induced liver damage in these mice, indicating a critical role of IFN-γ in this pathological process. Interestingly, the main source of the increased IFN-γ in

CD11c-p28

f/f mice was CD4+ T cells, but not natural killer T (NKT) cells. Depletion of CD4+, but not NK1.1+, cells completely abolished liver damage, whereas transferring CD4+ T cells from

CD11c-p28

f/f mice, but not from wild-type mice or

CD11c-p28

f/f
-
IFN

-γ−/− double knockout mice to CD4−/− mice, restored the increased liver damage. Further studies defined higher levels of IFN-γ and T-bet messenger RNA in naïve CD4+ T cells from

CD11c-p28

f/f mice, and these CD4+ T cells were highly responsive to both low and higher concentrations of anti-CD3, indicating a programmed functional alternation of CD4+ T cells.

Conclusion

: We provide a unique model for studying the pathology of CD4+ T cell–mediated liver injury and reveal a novel function of DC-derived p28 on ConA-induced fulminant hepatitis through regulation of the intrinsic ability for IFN-γ production by CD4+ T cells.
Role of patatin-like phospholipase domain-containing 3 on lipid-induced hepatic steatosis and insulin resistance in rats
Authors: Kumashiro Naoki , Yoshimura Toru , Cantley Jennifer L. , Majumdar Sachin K. , Guebre-Egziabher Fitsum , Kursawe Romy , Vatner Daniel F. , Fat Ioana , Kahn Mario , Erion Derek M. , Zhang Xian-Man , Zhang Dongyan , Manchem Vara Prasad , Bhanot Sanjay , Gerhard Glenn S. , Petersen Kitt F. , Cline Gary W. , Samuel Varman T. , Shulman Gerald I.
Published: November 2012

Genome-wide array studies have associated the patatin-like phospholipase domain-containing 3 (PNPLA3) gene polymorphisms with hepatic steatosis. However, it is unclear whether PNPLA3 functions as a lipase or a lipogenic enzyme and whether PNPLA3 is involved in the pathogenesis of hepatic insulin resistance. To address these questions we treated high-fat-fed rats with specific antisense oligonucleotides to decrease hepatic and adipose pnpla3 expression. Reducing pnpla3 expression prevented hepatic steatosis, which could be attributed to decreased fatty acid esterification measured by the incorporation of [U-13C]-palmitate into hepatic triglyceride. While the precursors for phosphatidic acid (PA) (long-chain fatty acyl-CoAs and lysophosphatidic acid [LPA]) were not decreased, we did observe an ˜20% reduction in the hepatic PA content, ˜35% reduction in the PA/LPA ratio, and ˜60%-70% reduction in transacylation activity at the level of acyl-CoA:1-acylglycerol-sn-3-phosphate acyltransferase. These changes were associated with an ˜50% reduction in hepatic diacylglycerol (DAG) content, an ˜80% reduction in hepatic protein kinase Cε activation, and increased hepatic insulin sensitivity, as reflected by a 2-fold greater suppression of endogenous glucose production during the hyperinsulinemic-euglycemic clamp. Finally, in humans, hepatic PNPLA3 messenger RNA (mRNA) expression was strongly correlated with hepatic triglyceride and DAG content, supporting a potential lipogenic role of PNPLA3 in humans.

Conclusion:

PNPLA3 may function primarily in a lipogenic capacity and inhibition of PNPLA3 may be a novel therapeutic approach for treatment of nonalcoholic fatty liver disease-associated hepatic insulin resistance.
Contemporary fine‐grained bed sediment sources across the River Wensum Demonstration Test Catchment, UK
Authors: Collins A. L. , Zhang Y. S. , Hickinbotham R. , Bailey G. , Darlington S. , Grenfell S. E. , Evans R. , Blackwell M.
Published: November 2012

Because the sources of fine‐grained sediment problems in river systems are diffuse, it is essential to assemble catchment scale information for informing management strategies. Sediment source‐tracing procedures have increasingly been adopted in this respect. Accordingly, a recently refined composite tracing procedure was used to investigate contemporary sources of fine‐grained channel bed sediment in 11 sub‐catchments (364 km2) of the River Wensum Demonstration Test Catchment, in the eastern UK. The procedure incorporated a combination of statistical tests for discriminating source end members, plus numerical mass balance modelling incorporating weightings for within‐source tracer variations and tracer‐specific discriminatory power, as well as a combination of local and genetic algorithm optimisation coupled with Monte Carlo uncertainty analysis. Replicate Monte Carlo runs demonstrated the convergence of the modelling outputs within ±1% of the average medians. Relative frequency‐weighted average median source type contributions were estimated to range between 27%–69% (agricultural topsoils; predicted deviate median inputs 0%–98% and 9%–100%), 0%–38% (damaged road verges; predicted deviate median inputs 0%–58% and 0%–100%) and 21%–48% (channel banks/subsurface sources; predicted deviate median inputs 0%–50% and 4%–50%). The study provides further evidence of the importance of channel banks and damaged road verges as sediment sources and the need to include such areas in catchment sediment management strategies. Copyright © 2012 John Wiley & Sons, Ltd.
Age at menarche and risk of ovarian cancer: A meta‐analysis of epidemiological studies
Authors: Gong Ting‐Ting , Wu Qi‐Jun , Vogtmann Emily , Lin Bei , Wang Yong‐Lai
Published: November 2012

Epidemiological studies have reported inconsistent associations between menarcheal age and ovarian cancer risk. To our knowledge, a meta‐analysis for the association between menarcheal age and ovarian cancer has not been reported. Relevant published studies of menarcheal age and ovarian cancer were identified using MEDLINE, EMBASE and Web of Science through the end of April 2012. Two authors (T‐T.G. and Q‐J.W.) independently assessed eligibility and extracted data. We pooled the relative risks (RRs) from individual studies using a random‐effects model and performed heterogeneity and publication bias analyses. A total of 27 observational studies consisting of 22 case–control and five cohort studies were included in our analysis. In a pooled analysis of all studies, a statistically significant inverse association was observed between menarcheal age (for the oldest compared to the youngest category) and ovarian cancer risk (RR = 0.85; 95% confidence interval [CI] = 0.75–0.97). The pooled RRs of ovarian cancer for the oldest versus the youngest categories of menarcheal age in prospective and case–control studies were 0.89 (95% CI = 0.76–1.03) and 0.84 (95% CI = 0.70–0.99), respectively. Inverse associations between menarcheal age and ovarian cancer risk were observed in most subgroups; however, the significant association was restricted to invasive and borderline serous ovarian cancer. In conclusion, findings from this meta‐analysis support that menarcheal age was inversely associated with the risk of ovarian cancer. More large studies are warranted to stratify these results by different cancer grading and histotype of ovarian cancer.
Variation in PAH‐related DNA adduct levels among non‐smokers: The role of multiple genetic polymorphisms and nucleotide excision repair phenotype
Authors: Etemadi Arash , Islami Farhad , Phillips David H. , Godschalk Roger , Golozar Asieh , Kamangar Farin , Malekshah Akbar Fazel‐Tabar , Pourshams Akram , Elahi Seerat , Ghojaghi Farhad , Strickland Paul T. , Taylor Philip R. , Boffetta Paolo , Abnet Christian C. , Dawsey Sanford M. , Malekzadeh Reza , van Schooten Frederik J.
Published: November 2012

Polycyclic aromatic hydrocarbons (PAHs) likely play a role in many cancers even in never‐smokers. We tried to find a model to explain the relationship between variation in PAH‐related DNA adduct levels among people with similar exposures, multiple genetic polymorphisms in genes related to metabolic and repair pathways, and nucleotide excision repair (NER) capacity. In 111 randomly selected female never‐smokers from the Golestan Cohort Study in Iran, we evaluated 21 SNPs in 14 genes related to xenobiotic metabolism and 12 SNPs in eight DNA repair genes. NER capacity was evaluated by a modified comet assay, and aromatic DNA adduct levels were measured in blood by32P‐postlabeling. Multivariable regression models were compared by Akaike's information criterion (AIC). Aromatic DNA adduct levels ranged between 1.7 and 18.6 per 108 nucleotides (mean: 5.8 ± 3.1). DNA adduct level was significantly lower in homozygotes for NAT2 slow alleles and ERCC5 non‐risk‐allele genotype, and was higher in the MPO homozygote risk‐allele genotype. The sum of risk alleles in these genes significantly correlated with the log‐adduct level (r = 0.4, p < 0.001). Compared with the environmental model, adding Phase I SNPs and NER capacity provided the best fit, and could explain 17% more of the variation in adduct levels. NER capacity was affected by polymorphisms in the MTHFR and ERCC1 genes. Female non‐smokers in this population had PAH‐related DNA adduct levels three to four times higher than smokers and occupationally‐exposed groups in previous studies, with large inter‐individual variation which could best be explained by a combination of Phase I genes and NER capacity.
microRNA and inflammatory gene expression as prognostic marker for overall survival in esophageal squamous cell carcinoma
Authors: Zhao Yiqiang , Schetter Aaron J. , Yang Geoffrey B. , Nguyen Giang , Mathé Ewy A. , Li Peng , Cai Hong , Yu Lei , Liu Fangfang , Hang Dong , Yang Haijun , Wang Xin Wei , Ke Yang , Harris Curtis C.
Published: November 2012

MicroRNAs (miRNAs) and inflammatory genes have a role in the initiation and development of esophageal squamous cell carcinoma (ESCC). In our study, we examined the potential of using miRNA and inflammatory gene expression patterns as prognostic classifiers for ESCC. Five miRNAs and 25 inflammatory‐related genes were measured by quantitative reverse transcriptase PCR in tumor tissues and adjacent noncancerous tissues from 178 Chinese patients with ESCC. The expression levels of miR‐21 (p = 0.027), miR‐181b (p = 0.002) and miR‐146b (p = 0.021) in tumor tissue and miR‐21 (p = 0.003) in noncancerous tissue were associated with overall survival of patients. These data were combined to generate a miRNA risk score that was significantly associated with worse prognosis (p = 0.0001), suggesting that these miRNAs may be useful prognostic classifiers for ESCC. To construct an inflammatory gene prognostic classifier, we divided the population into training (n = 124) and test cohorts (n = 54). The expression levels of CRY61, CTGF and IL‐18 in tumor tissue and VEGF in adjacent noncancerous tissue were modestly associated with prognosis in the training cohort |Z‐score| > 1.5 and were subsequently used to construct a Cox regression‐based inflammatory risk score (IRS). IRS was significantly associated with survival in both the training cohort (p = 0.002) and the test cohort (p = 0.005). Furthermore, Cox regression models combining both miRNA risk score and IRS performed significantly better than models with either alone (p < 0.001 likelihood ratio test). Therefore, miRNA and inflammatory gene expression patterns, alone or in combination, have potential as prognostic classifiers for ESCC and may help to guide therapeutic decisions.
Recent advances in laser tweezers Raman spectroscopy (LTRS) for label‐free analysis of single cells
Authors: Chan James W.
Published: November 2012

Laser tweezers Raman spectroscopy (LTRS), a technique that integrates optical tweezers with confocal Raman spectroscopy, is a variation of micro‐Raman spectroscopy that enables the manipulation and biochemical analysis of single biological particles in suspension. This article provides an overview of the LTRS method, with an emphasis on highlighting recent advances over the past several years in the development of the technology and several new biological and biomedical applications that have been demonstrated. A perspective on the future developments of this powerful cytometric technology will also be presented. (© 2013 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Raman spectroscopy coupled with advanced statistics for differentiating menstrual and peripheral blood
Authors: Sikirzhytskaya Aliaksandra , Sikirzhytski Vitali , Lednev Igor K.
Published: November 2012

Body fluids are a common and important type of forensic evidence. In particular, the identification of menstrual blood stains is often a key step during the investigation of rape cases. Here, we report on the application of near‐infrared Raman microspectroscopy for differentiating menstrual blood from peripheral blood. We observed that the menstrual and peripheral blood samples have similar but distinct Raman spectra. Advanced statistical analysis of the multiple Raman spectra that were automatically (Raman mapping) acquired from the 40 dried blood stains (20 donors for each group) allowed us to build classification model with maximum (100%) sensitivity and specificity. We also demonstrated that despite certain common constituents, menstrual blood can be readily distinguished from vaginal fluid. All of the classification models were verified using cross‐validation methods. The proposed method overcomes the problems associated with currently used biochemical methods, which are destructive, time consuming and expensive. (© 2014 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
An efficient method for computing the QTAIM topology of a scalar field: The electron density case
Authors: Rodríguez Juan I.
Published: November 2012

An efficient method for computing the quantum theory of atoms in molecules (QTAIM) topology of the electron density (or other scalar field) is presented. A modified Newton–Raphson algorithm was implemented for finding the critical points (CP) of the electron density. Bond paths were constructed with the second‐order Runge–Kutta method. Vectorization of the present algorithm makes it to scale linearly with the system size. The parallel efficiency decreases with the number of processors (from 70% to 50%) with an average of 54%. The accuracy and performance of the method are demonstrated by computing the QTAIM topology of the electron density of a series of representative molecules. Our results show that our algorithm might allow to apply QTAIM analysis to large systems (carbon nanotubes, polymers, fullerenes) considered unreachable until now. © 2012 Wiley Periodicals, Inc.
Complexes of 4‐substituted phenolates with HF and HCN: Energy decomposition and electronic structure analyses of hydrogen bonding
Authors: Szatyłowicz Halina , Krygowski Tadeusz M. , Fonseca Guerra Célia , Bickelhaupt F. Matthias
Published: November 2012

We have computationally studiedpara‐X‐substituted phenols and phenolates (X = NO, NO2, CHO, COMe, COOH, CONH2, Cl, F, H, Me, OMe, and OH) and their hydrogen‐bonded complexes with B−and HB (B = F and CN), respectively, at B3LYP/6‐311++G** and BLYP‐D/QZ4P levels of theory. Our purpose is to explore the structures and stabilities of these complexes. Moreover, to understand the emerging trends, we have analyzed the bonding mechanisms using the natural bond orbital scheme as well as Kohn–Sham molecular orbital (MO) theory in combination with quantitative energy decomposition analyses [energy decomposition analysis (EDA), extended transition state‐natural orbitals for chemical valence (ETS‐NOCV)]. These quantitative analyses allow for the construction of a simple physical model that explains all computational observations. © 2012 Wiley Periodicals, Inc.
Drug‐binding energetics of human α‐1‐acid glycoprotein assessed by isothermal titration calorimetry and molecular docking simulations
Authors: Huang Johnny X. , Cooper Matthew A. , Baker Mark A. , Azad Mohammad A. K. , Nation Roger L. , Li Jian , Velkov Tony
Published: November 2012

This study utilizes sensitive, modern isothermal titration calorimetric methods to characterize the microscopic thermodynamic parameters that drive the binding of basic drugs to α‐1‐acid glycoprotein (AGP) and thereby rationalize the thermodynamic data in relation to docking models and crystallographic structures of the drug–AGP complexes. The binding of basic compounds from the tricyclic antidepressant series, together with miaserine, chlorpromazine, disopyramide and cimetidine, all displayed an exothermically driven binding interaction with AGP. The impact of protonation/deprotonation events, ionic strength, temperature and the individual selectivity of the A and F1*S AGP variants on drug‐binding thermodynamics was characterized. A correlation plot of the thermodynamic parameters for all of the test compounds revealed that an enthalpy–entropy compensation is in effect. The exothermic binding energetics of the test compounds were driven by a combination of favorable (negative) enthalpic (∆Hº) and favorable (positive) entropic (∆Sº) contributions to the Gibbs free energy (∆Gº). Collectively, the data imply that the free energies that drive drug binding to AGP and its relationship to drug serum residency evolve from the complex interplay of enthalpic and entropic forces from interactions with explicit combinations of hydrophobic and polar side‐chain sub‐domains within the multi‐lobed AGP ligand binding cavity.Copyright © 2012 John Wiley & Sons, Ltd.
Comparison of lipid sinks in sequestering common intoxicating drugs
Authors: Lokajová Jana , Holopainen Juha M. , Wiedmer Susanne K.
Published: November 2012

Intravenous lipid emulsion is a recommended treatment for local anesthetic intoxication. The lipid sink theory hypothesizes that the mechanism behind the lipid treatment is the entrapment of toxic drugs in plasma, preventing them from reaching target receptors. Lipid sink treatment has also been used as a last refuge treatment for severe tricyclic antidepressant intoxication with seemingly beneficial results. We selected three drugs, i.e. amiodarone, ketamine, and amitriptyline, that can cause severe intoxication and compared their interactions with two commercial fat emulsions (Intralipid® and ClinOleic®) and one synthetic liposome (80:20 mol% phosphatidylcholine/phosphatidylglycerol) dispersion. The interaction studies were carried out by capillary electrokinetic chromatography and the retention factors and distributions constants of the drugs were calculated. The results demonstrate that there is stronger interaction between the drugs and the synthetic liposome dispersion than with the commercial emulsions.
Formal Semantics of Sign Languages
Authors: Zucchi Sandro
Published: November 2012

The paper discusses some issues that arise from research on sign languages in the area of formal semantics. Sign languages provide a unique standpoint to investigate semantic phenomena like donkey anaphora, indexical reference shift, and tense. Moreover, they pose a challenge for semantic theories, since movement verbs display gradient properties (semi‐continuous variations with semantic import). The paper presents and discusses some accounts that have been proposed.
Political Discourse Analysis: Exploring the Language of Politics and the Politics of Language
Authors: Dunmire Patricia L.
Published: November 2012

This essay overviews the body of research known as political discourse analysis (PDA). I begin by situating this work within the linguistic and political turns that took place in the latter part of the 20th century within the human and social sciences. I then discuss different conceptions of what comprisesthe politicaland the appropriate objects of study for PDA. Adopting an inclusive conception of politics and discourse, I consider the relationship between PDA and critical discourse analysis (CDA). I close with a review of studies of political discourse in terms of their theoretical and analytic frameworks and the socio‐political issues they address.
Structure and Substance in Artificial‐Phonology Learning, Part II: Substance
Authors: Moreton Elliott , Pater Joe
Published: November 2012

Artificial analogues of natural‐language phonological patterns can often be learned in the lab from small amounts of training or exposure. The difficulty of a featurally‐defined pattern has been hypothesized to be affected by two main factors, its formal structure (the abstract logical relationships between the defining features) and its phonetic substance (the concrete phonetic interpretation of the pattern). This paper, the second of a two‐part series, reviews the experimental literature on phonetic substance, which is hypothesized to facilitate the acquisition of phonological patterns that resemble naturally‐occurring phonetic patterns. The effects of phonetic substance on pattern learning turn out to be elusive and unreliable in comparison with the robust effects of formal complexity (reviewed in Part I). If natural‐language acquisition is guided by the same inductive biases as are found in the lab, these results support a theory in which inductive bias shapes only the form, and channel bias shapes the content, of the sound patterns of the worlds languages.
Telechelic Polymers by Visible‐Light‐Induced Radical Coupling
Authors: Iskin Birol , Yilmaz Gorkem , Yagci Yusuf
Published: November 2012

A simple and efficient method to prepare telechelics by visible‐light‐induced radical coupling is presented. Irradiation of the toluene solutions of bromo‐terminated polystyrenes prepared by atom transfer radical polymerization (ATRP) in the presence of an ester functional ATRP initiator and dimanganese decacarbonyl (Mn2(CO)10) at λ = 400–500 nm leads to the formation telechelic polymers through radical–radical coupling. Adaptability of the process for the preparation of mono‐ and bifunctional telechelics is demonstrated under variety of conditions of ATRP and coupling steps.
Ruthenium Ring‐Opening Metathesis Polymerization Catalysts Bearing o‐ Aryloxide‐N‐Heterocyclic Carbenes
Authors: Kong Yong , Tang Yungang , Wang Zunzhi , Xu Shansheng , Song Haibin , Wang Baiquan
Published: November 2012

A series of o‐aryloxide‐N‐heterocyclic carbene ruthenium complexes 2–4 is synthesized via sequential reactions of the o‐hydroxyaryl imidazolium proligands (2‐OH‐3,5‐tBu2C6H2)(R)(C3H3N2)+Br− (R = Me (1a), iPr (1b), Mes (1c)) with Ag2O and [(C6H6)RuCl2]2. All of the complexes are characterized by 1H and 13C NMR spectroscopy, high‐resolution mass spectrometry (HRMS), and elemental analysis. The molecular structure of 2 is determined by single‐crystal X‐ray diffraction analysis. The ring‐opening metathesis polymerization (ROMP) of norbornene (NBE) with 2–4 is studied. Among them, complex 4 exhibits the highest activity and efficiency toward ROMP of NBE at 85 °C without any cocatalyst, and the resultant polymers have very high molecular weight (>106 Da) and narrow molecular weight distributions. This complex can also efficiently catalyze the alternating copolymerization of NBE and cyclooctene.
High‐Performance Nanocomposites of Sodium Carboxymethylcellulose and Graphene Oxide
Authors: Layek Rama K. , Kundu Aniruddha , Nandi Arun K.
Published: November 2012

High‐performance nanocomposites of NaCMC with GO are produced by solution casting. FESEM images reveal a good homogeneous dispersion of GO in the NaCMC matrix. The composite formation is facilitated by H‐bonding interaction between GO and NaCMC. Tg of the composites increases with increasing GO concentration. The storage modulus (G′) exhibits a maximum 174% increase over NaCMC at 1 wt% GO. The mechanical properties of the composites exhibit highest increase of tensile stress and Young's modulus of 188 ± 4% and 154 ± 11%, respectively, for 1 wt% GO. Analysis of Young's modulus (Ey) data using the Halpin‐Tsai equation suggests that the Ey data are close to the unidirectional orientation at >0.5 wt% GO, indicating more efficient load transfer at these compositions.

magnified image
Mechanisms underlying the dualistic mode of action of major soy isoflavones in relation to cell proliferation and cancer risks
Authors: Rietjens Ivonne M. C. M. , Sotoca Ana M. , Vervoort Jacques , Louisse Jochem
Published: November 2012

Isoflavones are phytoestrogens that have been linked to both beneficial as well as adverse effects in relation to cell proliferation and cancer risks. The present article presents an overview of these seemingly contradicting health effects and of mechanisms that could be involved in this dualistic mode of action. One mechanism relates to the different ultimate cellular effects of activation of estrogen receptor (ER) α, promoting cell proliferation, and of ERβ, promoting apoptosis, with the major soy isoflavones genistein and daidzein activating especially ERβ. A second mode of action includes the role of epigenetics, including effects of isoflavones on DNA methylation, histone modification and miRNA expression patterns. The overview presented reveals that we are only at the start of unraveling the complex underlying mode of action for effects of isoflavones, both beneficial or adverse, on cell proliferation and cancer risks. It is evident that whatever model system will be applied, its relevance to human tissues with respect to ERα and ERβ levels, co‐repressor and co‐activator characteristics as well as its relevance to human exposure regimens, needs to be considered and defined.
Curcumin alleviates oxidative stress, inflammation, and renal fibrosis in remnant kidney through the Nrf2–keap1 pathway
Authors: Soetikno Vivian , Sari Flori R. , Lakshmanan Arun P. , Arumugam Somasundaram , Harima Meilei , Suzuki Kenji , Kawachi Hiroshi , Watanabe Kenichi
Published: November 2012

Scope

We hypothesized that curcumin, by increasing the expression of nuclear factor‐erythroid‐2‐related factor 2 (Nrf2), could reduce oxidative stress, inflammation, and renal fibrosis in remnant kidney.

Methods and results

Sprague‐Dawley rats were subjected to 5/6 nephrectomy and randomly assigned to untreated (Nx), curcumin‐treated (75 mg/kg/day, orally), and telmisartan‐treated groups (10 mg/kg/day, orally; as positive control). Sham‐operated rats also served as controls. Five/sixth nephrectomy caused renal dysfunction, as evidenced by elevated proteinuria, blood urea nitrogen, and plasma creatinine, and decreased creatinine clearance that were ameliorated by curcumin or telmisartan treatment. The Nx rats demonstrated reduced Nrf2 protein expression, whereas the Kelch‐like ECH‐associated protein 1 was upregulated and heme oxygenase‐1 level was significantly diminished. Consequently, Nx animals had significantly higher kidney malondialdehyde concentration and lower glutathione peroxidase activity, which was associated with the upregulation of nicotinamide adenine dinucleotide phosphatase oxidase subunit (p67phox and p22phox), NF‐kappaB p65, TNF‐α, TGF‐β1, cyclooxygenase‐2, and fibronectin accumulation in remnant kidney. Interestingly, all of these changes were ameliorated by curcumin or telmisartan.

Conclusion

These findings demonstrate that, by modulating Nrf2‐Keap1 pathway, the curcumin effectively attenuates oxidative stress, inflammation, and renal fibrosis, which suggest that curcumin hold promising potential for safe treatment of chronic kidney disease.
Relationship between maximum principle and dynamic programming principle for stochastic recursive optimal control problems of jump diffusions
Authors: Shi Jingtao
Published: November 2012

This paper is concerned with the relationship between maximum principle and dynamic programming principle for stochastic recursive optimal control problems of jump diffusions. Under the assumption that the value function is smooth, relations among the adjoint processes, the generalized Hamiltonian function, and the value function are given. A linear quadratic recursive utility portfolio optimization problem in the financial market is discussed to show the applications of the main result. Copyright © 2012 John Wiley & Sons, Ltd.
Structural health monitoring of metal components: A new approach based on electrochemical measurements
Authors: Astarita A. , Scala A. , Paradiso V. , Squillace A. , Iodice M. , Indolfi M. , Monetta T. , Bellucci F.
Published: November 2012

Corrosion fatigue is defined as the sequential stages of metal damage that evolve with accumulated load cycling, in an aggressive environment, and resulting from the interaction of irreversible cyclic plastic deformation with localized chemical or electrochemical reactions. It appears then evident the need to know and understand all phenomena that are involved in pit formation and growth in the presence of both an aggressive environment and a cyclic load. Although each single effect of both fatigue and corrosion have been extensively documented for aluminium alloys, their synergic action is not thoroughly understood and it continues to be an area of considerable scientific and industrial interest. Fatigue experiments were conducted on bare AA 2024 T3 aluminium alloy specimens in the presence of an aggressive environment consisting of a water aerated solution with 3.5% of NaCl in weight. The specimen was stressed in a four‐point bending test; the upper surface of the specimen, experiencing only tensile stress, was the monitored one. True strain on this surface was monitored by means of fibre optic Bragg grating. The strain and open circuit potential variations observed as a function of number of cycles are interpreted as a result, and taking into account the numerous and complex phenomena occurring as time goes on. The pits birth and their subsequent growth seem to play a significant role in crack initiation and subsequent propagation up to final catastrophic failure. This has been verified also by means of finite element method analysis. Copyright © 2012 John Wiley & Sons, Ltd.
Performance effects of top management team demographic faultlines in the process of product diversification
Authors: Hutzschenreuter Thomas , Horstkotte Julian
Published: November 2012

Expanding into new product areas is an important part of the growth strategy of many firms, but there is still more to learn about how it affects firm performance. We believe that as the top management team (TMT) is responsible for coordinating product expansion, looking there can yield valuable clues. We argue that diversification entails significant additional information processing and that this strains top managerial resources. We hypothesize that task‐related faultlines within the TMT may help it cope with product expansion while bio‐demographic faultlines may hinder it. We find support for these hypotheses on a longitudinal sample of 2,730 expansion steps made by 61 German firms between 1985 and 2007: task related faultline strength increases performance when diversifying, while bio‐demographic faultline strength decreases it. Copyright © 2012 John Wiley & Sons, Ltd.
Facile and Clean Release of Vertical Si Nanowires by Wet Chemical Etching Based on Alkali Hydroxides
Authors: Yoon Sung‐Soo , Khang Dahl‐Young
Published: November 2012

A simple method to release Si nanowires (SiNWs) from a substrate, with their original length almost intact, is demonstrated. By exploiting the unique chemistry involved for the fabrication of vertical arrays of SiNWs in metal‐assisted chemical etching (MaCE) based either on HF/AgNO3 or HF/H2O2 chemistries, wet etching with alkali hydroxides such as NaOH or KOH preferentially attacks the bottom part of the vertical SiNWs. A protective layer of Si oxide is found to exist on the outer wall of the SiNWs and to play the key role of etch mask during the release‐etching by alkali hydroxides. The clean release of SiNWs also enables the repeated use of the Si substrate for the fabrication of vertical SiNW arrays by MaCE. The released SiNWs are further used for the fabrication of field‐effect transistors on a flexible plastic substrate. The method developed here, when combined with a suitable assembling technique, can be very useful in implementing flexible electronics, or in the fabrication of SiNW composites with other functional materials.
NLRP3 Inflammasome Activation Induced by Engineered Nanomaterials
Authors: Sun Bingbing , Wang Xiang , Ji Zhaoxia , Li Ruibin , Xia Tian
Published: November 2012

Engineered nanomaterials (ENMs) continue to attract significant attention because they have novel physicochemical properties that can improve the functions of products that will benefit human lives. However, the physicochemical properties that make ENMs attractive could interact with biological systems and induce cascades of events that cause toxicological effects. Recently, there have been more studies suggesting inflammasome activation may play an important role in ENM‐induced biological responses. Inflammasomes are a family of multiprotein complexes that are increasingly recognized as major mediators of the host immune system. Among these, NLRP3 inflammasome is the most studied that could directly interact with ENMs to generate inflammatory responses. In this review, the ENM physicochemical properties are linked to NLRP3 inflammasome activation. An understanding of the mechanisms of ENM–NLRP3 inflammasome interactions will provide us with strategies for safer nanomaterial design and therapy.
Characterizing the Lateral Friction of Nanoparticles on On‐Chip Integrated Black Lipid Membranes
Authors: Chen Tianhong , Reinhard Björn M.
Published: November 2012

The use of nanoparticles (NPs) in biomedical applications creates a need for appropriate model systems to systematically investigate NP–membrane interactions under well‐defined conditions. Black lipid membranes (BLMs) are free‐floating membranes with defined composition that are ideally suited for characterizing NP–membrane interactions free of any potential perturbation through a supporting substrate. Herein, arrays of microfabricated BLMs are integrated into a chip‐based platform that is compatible with high‐speed optical NP tracking. This system is used to investigate the lateral diffusion of 40 nm gold spheres tethered to biotinylated lipids through antibody‐functionalized ligands (single‐stranded DNA or polyethylene glycol). Although the NPs show an almost free and ergodic diffusion, their lateral motion is subject to substantial drag at the membrane surface, which leads to systematically smaller diffusion coefficients than those obtained for lipids in the membrane through fluorescence recovery after photobleaching. The lateral mobility of the NPs is influenced by the chemical composition and salt concentration at the NP‐membrane interface, but is independent of the ligand density in the membrane. Together with the observation that nanoprisms, which have a larger relative contact area with the membrane than spherical NPs, show an even slower diffusion, these findings indicate that the lateral mobility of NPs tethered in close vicinity to a membrane is significantly reduced by the friction at the NP‐membrane interface.
Zebrafish High‐Throughput Screening to Study the Impact of Dissolvable Metal Oxide Nanoparticles on the Hatching Enzyme, ZHE1
Authors: Lin Sijie , Zhao Yan , Ji Zhaoxia , Ear Jason , Chang Chong Hyun , Zhang Haiyuan , Low‐Kam Cecile , Yamada Kristin , Meng Huan , Wang Xiang , Liu Rong , Pokhrel Suman , Mädler Lutz , Damoiseaux Robert , Xia Tian , Godwin Hilary A. , Lin Shuo , Nel André E.
Published: November 2012

The zebrafish is emerging as a model organism for the safety assessment and hazard ranking of engineered nanomaterials. In this Communication, the implementation of a roboticized high‐throughput screening (HTS) platform with automated image analysis is demonstrated to assess the impact of dissolvable oxide nanoparticles on embryo hatching. It is further demonstrated that this hatching interference is mechanistically linked to an effect on the metalloprotease, ZHE 1, which is responsible for degradation of the chorionic membrane. The data indicate that 4 of 24 metal oxide nanoparticles (CuO, ZnO, Cr2O3, and NiO) could interfere with embryo hatching by a chelator‐sensitive mechanism that involves ligation of critical histidines in the ZHE1 center by the shed metal ions. A recombinant ZHE1 enzymatic assay is established to demonstrate that the dialysates from the same materials responsible for hatching interference also inhibit ZHE1 activity in a dose‐dependent fashion. A peptide‐based BLAST search identifies several additional aquatic species that express enzymes with homologous histidine‐based catalytic centers, suggesting that the ZHE1 mechanistic paradigm could be used to predict the toxicity of a large number of oxide nanoparticles that pose a hazard to aquatic species.
Indirect pump: unique presentation of a monochorionic–triamniotic triplet gestation complicated by TRAP sequence and successfully managed with radiofrequency ablation of the acardiac fetus
Authors: Argoti P. S. , Bebbington M. W. , Johnson A. , Moise K. J.
Published: November 2012

Twin reversed arterial perfusion (TRAP) sequence is a rare complication of multiple gestations. Only a few cases of TRAP sequence in monochorionic triplets have been reported. Here we report a case of TRAP sequence in a monochorionic–triamniotic triplet gestation treated with radiofrequency ablation of the acardiac fetus. The response to the radiofrequency ablation procedure and subsequent examination of the placenta support the hypothesis of an ‘indirect’ pump triplet. Copyright © 2013 ISUOG. Published by John Wiley & Sons Ltd.
Myrmecophilous aphids produce cuticular hydrocarbons that resemble those of their tending ants
Authors: Endo Shintaro , Itino Takao
Published: November 2012

Aphid‐tending ants protect aphids from natural enemies and collect honeydew secreted by the aphids. However, ants also often prey on the aphids they attend. Aphids, therefore, like social parasites of ants, may well have evolved chemical mimicry as an anti‐predation strategy. In this study, we aimed to determine whether the aphid Stomaphis yanonis actively produces cuticular hydrocarbons (CHCs) that resemble those of the tending ant Lasius fuji. In the wild, ants put their CHCs on the aphids that they are tending, so in this study we analyzed “ant‐free” aphids. Mature aphids that exuviated in the absence of ant attendance had almost all of the hydrocarbon components that the ants’ CHCs had. Moreover, hydrocarbons artificially applied to the aphids’ body surface were lost by exuviation. Taken together, these findings indicate that mature aphids actively produced ant‐like CHCs, and they constitute the first documentation of a chemical resemblance between aphids and ants in a specific aphid–ant association.