bluuebunny/crossref_metadata_2025 huggingface dataset:
Body size evolution during the Triassic archosauriform radiation
Authors: Turner Alan H. , Nesbitt Sterling J.
Published: April 2013

The first large (>1 m) diapsids appeared near the Permian–Triassic extinction and a subset of diapsids, the archosauriforms, expanded their body size range soon after in the Early–Middle Triassic. Here, we examine body size at key evolutionary events within Archosauriformes during the Triassic and through the end-Triassic extinction. Using femoral length as a body size proxy and a temporally calibrated phylogeny of Archosauriformes, we estimate ancestral body sizes using a maximum likelihood approach and test for the presence of an adapative radiation by comparing the fit of competing evolutionary models. Archosauriform body size is characterized by punctuated change with more change occurring early in the Triassic. Archosaurs crossing the Triassic–Jurassic boundary show a wide range in ancestral size, and dinosaurs (sauropodomorphs and theropods) are considerably larger in the Jurassic. Crocodylomorph origins are characterized by a drop in body size; however, both the relative amount of change and the rate of change are matched among other archosaur clades. Archosauriforms increase in absolute body size through the Triassic and evidence suggests that a directional trend in size increase occurred in the early Mesozoic. The morphological signature of adaptive radiation is rare in comparative data from extant animals but is present at the origination of Archosauriformes.
Thrombomodulin and the vascular endothelium: insights into functional, regulatory, and therapeutic aspects
Authors: Martin Fiona A. , Murphy Ronan P. , Cummins Philip M.
Published: April 2013

Thrombomodulin (TM) is a 557-amino acid protein with a broad cell and tissue distribution consistent with its wide-ranging physiological roles. When expressed on the lumenal surface of vascular endothelial cells in both large vessels and capillaries, its primary function is to mediate endothelial thromboresistance. The complete integral membrane-bound protein form displays five distinct functional domains, although shorter soluble (functional) variants comprising the extracellular domains have also been reported in fluids such as serum and urine. TM-mediated binding of thrombin is known to enhance the specificity of the latter serine protease toward both protein C and thrombin activatable fibrinolysis inhibitor (TAFI), increasing their proteolytic activation rate by almost three orders of magnitude with concomitant anticoagulant, antifibrinolytic, and anti-inflammatory benefits to the vascular wall. Recent years have seen an abundance of research into the cellular mechanisms governing endothelial TM production, processing, and regulation (including flow-mediated mechanoregulation)—from transcriptional and posttranscriptional (miRNA) regulation of TM gene expression, to posttranslational processing and release of the expressed protein—facilitating greater exploitation of its therapeutic potential. The goal of the present paper is to comprehensively review the endothelial/TM system from these regulatory perspectives and draw some fresh conclusions. This paper will conclude with a timely examination of the current status of TM's growing therapeutic appeal, from novel strategies to improve the clinical efficacy of recombinant TM analogs for resolution of vascular disorders such as disseminated intravascular coagulation (DIC), to an examination of the complex pleiotropic relationship between statin treatment and TM expression.
A low-carbohydrate/high-fat diet reduces blood pressure in spontaneously hypertensive rats without deleterious changes in insulin resistance
Authors: Bosse John D. , Lin Han Yi , Sloan Crystal , Zhang Quan-Jiang , Abel E. Dale , Pereira Troy J. , Dolinsky Vernon W. , Symons J. David , Jalili Thunder
Published: April 2013

Previous studies reported that diets high in simple carbohydrates could increase blood pressure in rodents. We hypothesized that the converse, a low-carbohydrate/high-fat diet, might reduce blood pressure. Six-week-old spontaneously hypertensive rats (SHR; n = 54) and Wistar-Kyoto rats (WKY; n = 53, normotensive control) were fed either a control diet (C; 10% fat, 70% carbohydrate, 20% protein) or a low-carbohydrate/high-fat diet (HF; 20% carbohydrate, 60% fat, 20% protein). After 10 wk, SHR-HF had lower ( P < 0.05) mean arterial pressure than SHR-C (148 ± 3 vs. 159 ± 3 mmHg) but a similar degree of cardiac hypertrophy (33.4 ± 0.4 vs. 33.1 ± 0.4 heart weight/tibia length, mg/mm). Mesenteric arteries and the entire aorta were used to assess vascular function and endothelial nitric oxide synthase (eNOS) signaling, respectively. Endothelium-dependent (acetylcholine) relaxation of mesenteric arteries was improved ( P < 0.05) in SHR-HF vs. SHR-C, whereas contraction (potassium chloride, phenylephrine) was reduced ( P < 0.05). Phosphorylation of eNOSSer1177 increased ( P < 0.05) in arteries from SHR-HF vs. SHR-C. Plasma glucose, insulin, and homoeostatic model of insulin assessment were lower ( P < 0.05) in SHR-HF vs. SHR-C, whereas peripheral insulin sensitivity (insulin tolerance test) was similar. After a 10-h fast, insulin stimulation (2 U/kg ip) increased ( P < 0.05) phosphorylation of AktSer473 and S6 in heart and gastrocnemius similarly in SHR-C vs. SHR-HF. In conclusion, a low-carbohydrate/high-fat diet reduced blood pressure and improved arterial function in SHR without producing signs of insulin resistance or altering insulin-mediated signaling in the heart, skeletal muscle, or vasculature.
Physiological cyclic strain promotes endothelial cell survival via the induction of heme oxygenase-1
Authors: Liu Xiao-ming , Peyton Kelly J. , Durante William
Published: April 2013

Endothelial cells (ECs) are constantly subjected to cyclic strain that arises from periodic change in vessel wall diameter as a result of pulsatile blood flow. Application of physiological levels of cyclic strain inhibits EC apoptosis; however, the underlying mechanism is not known. Since heme oxygenase-1 (HO-1) is a potent inhibitor of apoptosis, the present study investigated whether HO-1 contributes to the antiapoptotic action of cyclic strain. Administration of physiological cyclic strain (6% at 1 Hz) to human aortic ECs stimulated an increase in HO-1 activity, protein, and mRNA expression. The induction of HO-1 was preceded by a rise in reactive oxygen species (ROS) and Nrf2 protein expression. Cyclic strain also stimulated an increase in HO-1 promoter activity that was prevented by mutating the antioxidant responsive element in the promoter or by overexpressing dominant-negative Nrf2. In addition, the strain-mediated induction of HO-1 and activation of Nrf2 was abolished by the antioxidant N-acetyl-l-cysteine. Finally, application of cyclic strain blocked inflammatory cytokine-mediated EC death and apoptosis. However, the protective action of cyclic strain was reversed by the HO inhibitor tin protoporphyrin-IX and was absent in ECs isolated from HO-1-deficient mice. In conclusion, the present study demonstrates that a hemodynamically relevant level of cyclic strain stimulates HO-1 gene expression in ECs via the ROS-Nrf2 signaling pathway to inhibit EC death. The ability of cyclic strain to induce HO-1 expression may provide an important mechanism by which hemodynamic forces promote EC survival and vascular homeostasis.
Mechanical and energetic properties of papillary muscle fromACTCE99K transgenic mouse models of hypertrophic cardiomyopathy
Authors: Song Weihua , Vikhorev Petr G. , Kashyap Mavin N. , Rowlands Christina , Ferenczi Michael A. , Woledge Roger C. , MacLeod Kenneth , Marston Steven , Curtin Nancy A.
Published: April 2013

We compared the contractile performance of papillary muscle from a mouse model of hypertrophic cardiomyopathy [α-cardiac actin ( ACTC) E99K mutation] with nontransgenic (non-TG) littermates. In isometric twitches, ACTC E99K papillary muscle produced three to four times greater force than non-TG muscle under the same conditions independent of stimulation frequency and temperature, whereas maximum isometric force in myofibrils from these muscles was not significantly different. ACTC E99K muscle relaxed slower than non-TG muscle in both papillary muscle (1.4×) and myofibrils (1.7×), whereas the rate of force development after stimulation was the same as non-TG muscle for both electrical stimulation in intact muscle and after a Ca2+jump in myofibrils. The EC50for Ca2+activation of force in myofibrils was 0.39 ± 0.33 μmol/l in ACTC E99K myofibrils and 0.80 ± 0.11 μmol/l in non-TG myofibrils. There were no significant differences in the amplitude and time course of the Ca2+transient in myocytes from ACTC E99K and non-TG mice. We conclude that hypercontractility is caused by higher myofibrillar Ca2+sensitivity in ACTC E99K muscles. Measurement of the energy (work + heat) released in actively cycling heart muscle showed that for both genotypes, the amount of energy turnover increased with work done but with decreasing efficiency as energy turnover increased. Thus, ACTC E99K mouse heart muscle produced on average 3.3-fold more work than non-TG muscle, and the cost in terms of energy turnover was disproportionately higher than in non-TG muscles. Efficiency for ACTC E99K muscle was in the range of 11–16% and for non-TG muscle was 15–18%.
Validation of a novel and existing algorithms for the estimation of pulse transit time: advancing the accuracy in pulse wave velocity measurement
Authors: Vardoulis Orestis , Papaioannou Theodore G. , Stergiopulos Nikolaos
Published: April 2013

The method used for pulse transit time (PTT) estimation critically affects the accuracy and precision of regional pulse wave velocity (PWV) measurements. Several methods of PTT estimation exist, often yielding substantially different PWV values. Since there is no analytic way to determine PTT in vivo, these methods cannot be validated except by using in silico or in vitro models of known PWV and PTT values. We aimed to validate and compare the most commonly used “foot-to-foot” algorithms, namely, the “ diastole-minimum,” “tangential,” “maximum first derivative,” and “maximum second derivative” methods. Also, we propose a new “diastole-patching” method aiming to increase the accuracy and precision in PWV measurements. We simulated 2,000 cases under different hemodynamic conditions using an accurate, validated, distributed, one-dimensional arterial model. The new algorithm detects and “matches” a specific region of the pressure wave foot between the proximal and distal waveforms instead of determining characteristic points. The diastole-minimum and diastole-patching methods showed excellent agreement compared with “real” PWV values of the model, as indicated by high values of the intraclass correlation coefficient (>0.86). The diastole-patching method resulted in low bias (absolute mean difference: 0.26 m/s). In contrast, PWV estimated by the maximum first derivative, maximum second derivative, and tangentia methods presented low to moderate agreement and poor accuracy (intraclass correlation coefficient: <0.79 and bias: >0.9 m/s). The diastole-patching method yielded PWV measurements with the highest agreement, accuracy, and precision and lowest variability.
Mechanisms that match ATP supply to demand in cardiac pacemaker cells during high ATP demand
Authors: Yaniv Yael , Spurgeon Harold A. , Ziman Bruce D. , Lyashkov Alexey E. , Lakatta Edward G.
Published: April 2013

The spontaneous action potential (AP) firing rate of sinoatrial node cells (SANCs) involves high-throughput signaling via Ca2+-calmodulin activated adenylyl cyclases (AC), cAMP-mediated protein kinase A (PKA), and Ca2+/calmodulin-dependent protein kinase II (CaMKII)-dependent phosphorylation of SR Ca2+cycling and surface membrane ion channel proteins. When the throughput of this signaling increases, e.g., in response to β-adrenergic receptor activation, the resultant increase in spontaneous AP firing rate increases the demand for ATP. We hypothesized that an increase of ATP production to match the increased ATP demand is achieved via a direct effect of increased mitochondrial Ca2+(Ca2+m) and an indirect effect via enhanced Ca2+-cAMP/PKA-CaMKII signaling to mitochondria. To increase ATP demand, single isolated rabbit SANCs were superfused by physiological saline at 35 ± 0.5°C with isoproterenol, or by phosphodiesterase or protein phosphatase inhibition. We measured cytosolic and mitochondrial Ca2+and flavoprotein fluorescence in single SANC, and we measured cAMP, ATP, and O2consumption in SANC suspensions. Although the increase in spontaneous AP firing rate was accompanied by an increase in O2consumption, the ATP level and flavoprotein fluorescence remained constant, indicating that ATP production had increased. Both Ca2+mand cAMP increased concurrently with the increase in AP firing rate. When Ca2+mwas reduced by Ru360, the increase in spontaneous AP firing rate in response to isoproterenol was reduced by 25%. Thus, both an increase in Ca2+mand an increase in Ca2+activated cAMP-PKA-CaMKII signaling regulate the increase in ATP supply to meet ATP demand above the basal level.
Serotonin contributes to high pulmonary vascular tone in a sheep model of persistent pulmonary hypertension of the newborn
Authors: Delaney Cassidy , Gien Jason , Roe Gates , Isenberg Nicole , Kailey Jenai , Abman Steven H.
Published: April 2013

Although past studies demonstrate that altered serotonin (5-HT) signaling is present in adults with idiopathic pulmonary arterial hypertension, whether serotonin contributes to the pathogenesis of persistent pulmonary hypertension of the newborn (PPHN) is unknown. We hypothesized that 5-HT contributes to increased pulmonary vascular resistance (PVR) in a sheep model of PPHN and that selective 5-HT reuptake inhibitor (SSRI) treatment increases PVR in this model. We studied the hemodynamic effects of 5-HT, ketanserin (5-HT2Areceptor antagonist), and sertraline, an SSRI, on pulmonary hemodynamics of the late gestation fetal sheep with PPHN caused by prolonged constriction of the ductus arteriosis. Brief intrapulmonary infusions of 5-HT increased PVR from 1.0 ± 0.07 (baseline) to 1.4 ± 0.22 mmHg/ml per minute of treatment ( P < 0.05). Ketanserin decreased PVR from 1.1 ± 0.15 (baseline) to 0.82 ± 0.09 mmHg/ml per minute of treatment ( P < 0.05). Sertraline increased PVR from 1.1 ± 0.17 (baseline) to 1.4 ± 0.17 mmHg/ml per minute of treatment ( P = 0.01). In addition, we studied 5-HT production and activity in vitro in experimental PPHN. Compared with controls, pulmonary artery endothelial cells from fetal sheep with PPHN exhibited increased expression of tryptophan hydroxylase 1 and 5-HT production by twofold and 56%, respectively. Compared with controls, 5-HT2AR expression was increased in lung homogenates and pulmonary artery smooth muscle cell lysates by 35% and 32%, respectively. We concluded that increased 5-HT contributes to high PVR in experimental PPHN through activation of the 5-HT2Areceptor and that SSRI infusion further increases PVR in this model.
The Well-Posedness and Stability Analysis of a Computer Series System
Authors: Qiao Xing , Ma Dan , Zheng Fu , Zhu Guangtian
Published: April 2013

A repairable computer system model which consists of hardware and software in series is established in this paper. This study is devoted to discussing the unique existence of the solution and the stability of the studied system. In view ofc0semigroup theory, we prove the existence of a unique nonnegative solution of the system. Then by analyzing the spectra distribution of the system operator, we deduce that the transient solution of the system strongly converges to the nonnegative steady-state solution which is the eigenvector corresponding to eigenvalue 0 of the system operator. Finally, some reliability indices of the system are provided at the end of the paper with a new method.
β-Elemene-Attenuated Tumor Angiogenesis by Targeting Notch-1 in Gastric Cancer Stem-Like Cells
Authors: Yan Bing , Zhou Yuqi , Feng Shouhan , Lv Can , Xiu Lijuan , Zhang Yingcheng , Shi Jun , Li Yongjin , Wei Pinkang , Qin Zhifeng
Published: April 2013

Emerging evidence suggests that cancer stem cells are involved in tumor angiogenesis. The Notch signaling pathway is one of the most important regulators of these processes.β-Elemene, a naturally occurring compound extracted fromCurcumae Radix, has been used as an antitumor drug for various cancers in China. However, its underlying mechanism in the treatment of gastric cancer remains largely unknown. Here, we report that CD44+ gastric cancer stem-like cells (GCSCs) showed enhanced proliferation capacity compared to their CD44− counterparts, and this proliferation was accompanied by the high expression of Notch-1 (in vitro). These cells were also more superior in spheroid colony formation (in vitro) and tumorigenicity (in vivo) and positively associated with microvessel density (in vivo).β-Elemene was demonstrated to effectively inhibit the viability of GCSCs in a dose-dependent manner, most likely by suppressing Notch-1 (in vitro).β-Elemene also contributed to growth suppression and attenuated the angiogenesis capacity of these cells (in vivo) most likely by interfering with the expression of Notch-1 but not with Dll4. Our findings indicated that GCSCs play an important role in tumor angiogenesis, and Notch-1 is one of the most likely mediators involved in these processes.β-Elemene was effective at attenuating angiogenesis by targeting the GCSCs, which could be regarded as a potential mechanism for its efficacy in gastric cancer management in the future.
A Simple, Efficient Synthesis of 2-Aryl Benzimidazoles Using Silica Supported Periodic Acid Catalyst and Evaluation of Anticancer Activity
Authors: Sontakke Vyankat A. , Ghosh Sougata , Lawande Pravin P. , Chopade Balu A. , Shinde Vaishali S.
Published: April 2013

A new, efficient method for the synthesis of 2-aryl substituted benzimidazole by using silica supported periodic acid (H5IO6-SiO2) as a catalyst has been developed. The salient feature of the present method includes mild reaction condition, short reaction time, high yield and easy workup procedure. The synthesized benzimidazoles exhibited potent anticancer activity against MCF7 and HL60 cell lines.
Stan Scheller: The Forerunner of Clinical Studies on Using Propolis for Poor and Chronic Nonhealing Wounds
Authors: Kucharzewski M. , Kubacka S. , Urbanek T. , Wilemska-Kucharzewska K. , Morawiec T.
Published: April 2013

For hundreds of years poor and chronic nonhealing wounds have constituted a serious problem to medicine. What is more, treating such wounds is an expensive let alone a long-lasting process. The following paper describes Professor Scheller's achievements in using propolis for poor and chronic non-healing wounds. The authors' intention was to present the results connected with the use of the ethanolic extract propolis, in the treatment of patients suffering from burns, venous crural ulceration, local sacral bone pressure ulcers, suppurative osteitis and arthritis, suppurative postoperative local wound complications, and infected traumatic wounds.
Tianma Gouteng Yin as Adjunctive Treatment for Essential Hypertension: A Systematic Review of Randomized Controlled Trials
Authors: Wang Jie , Feng Bo , Yang Xiaochen , Liu Wei , Liu Yongmei , Zhang Yun , Yu Gui , Li Shengjie , Zhang Yuqing , Xiong Xingjiang
Published: April 2013

Background. Tianma Gouteng Yin (TGY) is widely used for essential hypertension (EH) as adjunctive treatment. Many randomized clinical trials (RCTs) of TGY for EH have been published. However, it has not been evaluated to justify their clinical use and recommendation based on TCM zheng classification.Objectives. To assess the current clinical evidence of TGY as adjunctive treatment for EH with liver yang hyperactivity syndrome (LYHS) and liver-kidney yin deficiency syndrome (LKYDS).Search Strategy. 7 electronic databases were searched until November 20, 2012.Inclusion Criteria. RCTs testing TGY combined with antihypertensive drugs versus antihypertensive drugs were included.Data Extraction and Analyses. Study selection, data extraction, quality assessment, and data analyses were conducted according to the Cochrane standards.Results. 22 RCTs were included. Methodological quality was generally low. Except diuretics treatment group, blood pressure was improved in the other 5 subgroups; zheng was improved in angiotensin converting enzyme inhibitors (ACEIs), calcium channel blockers (CCBs), and “CCB + ACEI” treatment groups. The safety of TGY is still uncertain.Conclusions. No confirmed conclusion about the effectiveness and safety of TGY as adjunctive treatment for EH with LYHS and LKYDS could be made. More rigorous trials are needed to confirm the results.
Fault Diagnosis for Wireless Sensor by Twin Support Vector Machine
Authors: Ding Mingli , Yang Dongmei , Li Xiaobing
Published: April 2013

Various data mining techniques have been applied to fault diagnosis for wireless sensor because of the advantage of discovering useful knowledge from large data sets. In order to improve the diagnosis accuracy of wireless sensor, a novel fault diagnosis for wireless sensor technology by twin support vector machine (TSVM) is proposed in the paper. Twin SVM is a binary classifier that performs classification by using two nonparallel hyperplanes instead of the single hyperplane used in the classical SVM. However, the parameter setting in the TSVM training procedure significantly influences the classification accuracy. Thus, this study introduces PSO as an optimization technique to simultaneously optimize the TSVM training parameter. The experimental results indicate that the diagnosis results for wireless sensor of twin support vector machine are better than those of SVM, ANN.
Extendedℋ∞Estimation for Two-Dimensional Markov Jump Systems under Asynchronous Switching
Authors: Zhang Rui , Zhang Ying , Zhao Yan , Liao Jingsheng , Li Baopu
Published: April 2013

This paper is concerned with the problem of designingℋ∞filters for a class of two-dimensional (2D) Markov jump systems under asynchronous switching. The problem under consideration is primarily motivated by a realistic situation that the switching of candidate filters may have a lag to the switching of system modes. Different from conventional techniques, by a suitable augmentation, the jumping process of the error system is represented by a two-component Markov chain. Then, the extended transition probabilities are provided for the error system. A stochastic Lyapunov function approach is proposed for the design of desired filters that ensure a prescribedℋ∞performance for admissible asynchronous switching. Finally, a numerical example is given to illustrate the effectiveness of the developed method.
A Robust Weak Taylor Approximation Scheme for Solutions of Jump-Diffusion Stochastic Delay Differential Equations
Authors: Zhou Yanli , Wu Yonghong , Ge Xiangyu , Wiwatanapataphee B.
Published: April 2013

Stochastic delay differential equations with jumps have a wide range of applications, particularly, in mathematical finance. Solution of the underlying initial value problems is important for the understanding and control of many phenomena and systems in the real world. In this paper, we construct a robust Taylor approximation scheme and then examine the convergence of the method in a weak sense. A convergence theorem for the scheme is established and proved. Our analysis and numerical examples show that the proposed scheme of high order is effective and efficient for Monte Carlo simulations for jump-diffusion stochastic delay differential equations.
Nkx2-8 Downregulation Promotes Angiogenesis and Activates NF-κB in Esophageal Cancer
Authors: Lin Chuyong , Song Libing , Gong Hui , Liu Aibin , Lin Xi , Wu Jueheng , Li Mengfeng , Li Jun
Published: April 2013

Angiogenesis is a major clinical feature of esophageal squamous cell carcinoma (ESCC), an aggressive disease of increasing incidence in developed countries. In ESCCs, the proangiogenic factor VEGF-C is an independent prognostic factor for ESCC, where understanding the mechanisms of VEGF-C upregulation may cue possible therapeutic insights. Here, we report that expression of the transcription factor Nkx2-8 is downregulated in ESCCs where it inversely correlates with progression and VEGF-C upregulation. Patients with ESCCs with lower Nkx2-8 expression exhibited reduced overall survival. Modulating expression of Nkx2-8 up or down inhibited or enhanced, respectively, proangiogenic activity in vitro and in vivo. Mechanistic investigations showed that Nkx2-8 repressed NF-κB activity by restraining nuclear localization of NF-κB p65 via downregulation of AKIP1, a NF-κB p65 binding partner, and also by directly targeting the AKIP1 promoter. We confirmed evidence for the importance of the Nkx2-8/AKIP1/NF-κB axis identified in ESCC cell models through an immunohistochemical analysis of a large cohort of human ESCC specimens. Taken together, our results showed that Nkx2-8 functions as a tumor suppressor in ESCCs, the downregulation of which contributes to NF-κB activation and ESCC angiogenesis. Cancer Res; 73(12); 3638–48. ©2013 AACR.
Reduced Nicotine Content Cigarettes and Nicotine Patch
Authors: Hatsukami Dorothy K. , Hertsgaard Louise A. , Vogel Rachel I. , Jensen Joni A. , Murphy Sharon E. , Hecht Stephen S. , Carmella Steven G. , al'Absi Mustafa , Joseph Anne M. , Allen Sharon S.
Published: April 2013

Background: Reduced nicotine content (RNC) cigarettes have led to smoking fewer cigarettes, withdrawal relief, and facilitation of cessation. The aim of this study is to examine the effects RNC cigarettes with and without nicotine patch and patch alone on smoking behavior, toxicant exposure, withdrawal discomfort, and as an exploratory analysis, on long-term abstinence.

Methods: This study involved a randomized, parallel arm design and six weeks of: (i) 0.05–0.09 mg nicotine yield cigarettes (N = 79); (ii) 21 mg nicotine patch (N = 80), or (iii) 0.05–0.09 nicotine yield cigarettes with 21 mg nicotine patch (N = 76); all groups received six weeks of additional behavioral treatment with follow-ups up to six months.

Results: Combination approach led to lower rates of smoking assigned cigarettes and hence lower carbon monoxide levels than RNC cigarettes alone. In addition, the combination approach was associated with less withdrawal severity when switching from usual brand to assigned product, and less smoking of usual brand cigarettes during treatment, but not after treatment compared with the other approaches.

Conclusion: Combining very low nicotine content cigarettes with nicotine patch may improve the acute effects resulting from switching to either of these products alone.

Impact: These findings may have implications for smoking cessation treatment or a policy measure to reduce nicotine content in cigarettes. Cancer Epidemiol Biomarkers Prev; 22(6); 1015–24. ©2013 AACR.
Mouse Models of Kras-Mutant Colorectal Cancer: Valuable GEMMs for Drug Testing?
Authors: Di Nicolantonio Federica , Bardelli Alberto
Published: April 2013

The development of effective therapies for colorectal cancer depends on the ability of preclinical models to faithfully recapitulate the molecular and biologic behavior of human tumors. This study reports on the characterization of colorectal genetically engineered mouse models and their derivative cell lines carrying wild-type or oncogenic Kras with concomitant Apc and p53 loss. Clin Cancer Res; 19(11); 2794–6. ©2013 AACR.
A Novel Monoclonal Antibody to Secreted Frizzled-Related Protein 2 Inhibits Tumor Growth
Authors: Fontenot Emily , Rossi Emma , Mumper Russell , Snyder Stephanie , Siamakpour-Reihani Sharareh , Ma Ping , Hilliard Eleanor , Bone Bradley , Ketelsen David , Santos Charlene , Patterson Cam , Klauber-DeMore Nancy
Published: April 2013

Secreted frizzled-related protein 2 (SFRP2) is overexpressed in human angiosarcoma and breast cancer and stimulates angiogenesis via activation of the calcineurin/NFATc3 pathway. There are conflicting reports in the literature as to whether SFRP2 is an antagonist or agonist of β-catenin. The aims of these studies were to assess the effects of SFRP2 antagonism on tumor growth and Wnt-signaling and to evaluate whether SFRP2 is a viable therapeutic target. The antiangiogenic and antitumor properties of SFRP2 monoclonal antibody (mAb) were assessed using in vitro proliferation, migration, tube formation assays, and in vivo angiosarcoma and triple-negative breast cancer models. Wnt-signaling was assessed in endothelial and tumor cells treated with SFRP2 mAb using Western blotting. Pharmacokinetic and biodistribution data were generated in tumor-bearing and nontumor-bearing mice. SFRP2 mAb was shown to induce antitumor and antiangiogenic effects in vitro and inhibit activation of β-catenin and nuclear factor of activated T-cells c3 (NFATc3) in endothelial and tumor cells. Treatment of SVR angiosarcoma allografts in nude mice with the SFRP2 mAb decreased tumor volume by 58% compared with control (P = 0.004). Treatment of MDA-MB-231 breast carcinoma xenografts with SFRP2 mAb decreased tumor volume by 52% (P = 0.03) compared with control, whereas bevacizumab did not significantly reduce tumor volume. Pharmacokinetic studies show the antibody is long circulating in the blood and preferentially accumulates in SFRP2-positive tumors. In conclusion, antagonizing SFRP2 inhibits activation of β-catenin and NFATc3 in endothelial and tumor cells and is a novel therapeutic approach for inhibiting angiosarcoma and triple-negative breast cancer. Mol Cancer Ther; 12(5); 685–95. ©2013 AACR.
miR-150 Blocks MLL-AF9–Associated Leukemia through Oncogene Repression
Authors: Bousquet Marina , Zhuang Guoqing , Meng Cong , Ying Wei , Cheruku Patali S. , Shie Andrew T. , Wang Stephanie , Ge Guangtao , Wong Piu , Wang Gang , Safe Stephen , Zhou Beiyan
Published: April 2013

The microRNA miR-150, a critical regulator of hematopoiesis, is downregulated in mixed-lineage leukemia (MLL). In this study, miR-150 acts as a potent leukemic tumor suppressor by blocking the oncogenic properties of leukemic cells. By using MLL-AF9–transformed cells, we demonstrate that ectopic expression of miR-150 inhibits blast colony formation, cell growth, and increases apoptosis in vitro. More importantly, ectopic expression of miR-150 in MLL-AF9–transformed cells completely blocked the development of myeloid leukemia in transplanted mice. Furthermore, gene expression profiling revealed that miR-150 altered the expression levels of more than 30 “stem cell signature” genes and many others that are involved in critical cancer pathways. In addition to the known miR-150 target Myb, we also identified Cbl and Egr2 as bona fide targets and shRNA-mediated suppression of these genes recapitulated the pro-apoptotic effects observed in leukemic cells with miR-150 ectopic expression. In conclusion, we demonstrate that miR-150 is a potent leukemic tumor suppressor that regulates multiple oncogenes.

Implications: These data establish new, key players for the development of therapeutic strategies to treat MLL-AF9–related leukemia. Mol Cancer Res; 11(8); 912–22. ©2013 AACR.
Pupillometric Assessment of Autonomic Nervous System in Children with Allergic Rhinitis
Authors: Ozsutcu Mustafa , Ozkaya Emin , Demir Aysegul , Erenberk Ufuk , Sogut Ayhan , Dundaroz Rusen
Published: April 2013

Objective: The purpose of this study was to investigate autonomic nervous system dysfunction by measuring pupil sizes in pediatric patients with allergic rhinitis. Subjects and Methods: The study group consisted of 60 children (28 girls and 32 boys) who were age and gender matched with the control group, which also consisted of 60 children (26 girls and 34 boys). The diagnosis of allergic rhinitis was based on the history, physical examination and skin prick test performed by an allergologist. Pupil diameter measurements were performed using the pupillometer incorporated in the NİDEK OPD-Scan. Results: In the allergic rhinitis group, mean photopic and mesopic pupil diameters were 3.52 ± 0.07 and 5.98 ± 0.21, respectively, while in the control group, corresponding measurements were 4.03 ± 0.18 and 6.55 ± 0.16. There was a significant difference for photopic and mesopic pupil diameter between the groups (p < 0.001). Conclusion: This study showed that the pupil size in response to a light stimulus in children with allergic rhinitis was smaller than that of the control group and may indicate parasympathetic hyperactivity and sympathetic hypoactivity.
Evidence for Two Karyotypic Variants of the Lesser Horseshoe Bat (Rhinolophus hipposideros, Chiroptera, Mammalia) in Central Europe
Authors: Volleth M. , Biedermann M. , Schorcht W. , Heller K.-G.
Published: April 2013

Three different diploid chromosome numbers (2n = 54, 56 and 58) have been reported in the lesser horseshoe bat, Rhinolophus hipposideros. Asia Minor and the Middle East are inhabited by R. hipposideros specimens with 58 chromosomes. In Europe, specimens with 56 chromosomes have been recorded from several localities in the Czech Republic, Slovakia, Italy and Greece. Up to now, specimens with 54 chromosomes have been reported only from Spain and possibly from Switzerland. With the record of 54 chromosomes in specimens from Germany presented here, the distributional area of this variant is expanded into Central Europe. According to the cytogenetic data presently available, we presume that the European R. hipposideros population is divided into a western form (from Spain to Germany) with a 2n = 54 karyotype and an eastern form (from the Czech Republic to Greece) with a 2n = 56 karyotype. This study presents banded karyotypes for the 2n = 54 and 2n = 56 variants for the first time. In addition, chromosomal arm homology to the vespertilionid bat species Myotis myotis revealed by chromosome painting is reported. Whether the variants could represent separate species is also discussed.
D2MOPSO: MOPSO Based on Decomposition and Dominance with Archiving Using Crowding Distance in Objective and Solution Spaces
Authors: Al Moubayed N. , Petrovski A. , McCall J.
Published: April 2013

This paper improves a recently developed multi-objective particle swarm optimizer ([Formula: see text]) that incorporates dominance with decomposition used in the context of multi-objective optimization. Decomposition simplifies a multi-objective problem (MOP) by transforming it to a set of aggregation problems, whereas dominance plays a major role in building the leaders’ archive. [Formula: see text] introduces a new archiving technique that facilitates attaining better diversity and coverage in both objective and solution spaces. The improved method is evaluated on standard benchmarks including both constrained and unconstrained test problems, by comparing it with three state of the art multi-objective evolutionary algorithms: MOEA/D, OMOPSO, and dMOPSO. The comparison and analysis of the experimental results, supported by statistical tests, indicate that the proposed algorithm is highly competitive, efficient, and applicable to a wide range of multi-objective optimization problems.
The Revival of Comparative Law in a Socialist Country: The Impact of Imre Szabó and Gyula Eörsi on the Development of Hungarian Comparative Law
Authors: Fekete Balázs
Published: April 2013

This article discusses the revival of comparative law in Hungarian Socialist jurisprudence. Prior to World War II, the development of comparative law generally had followed international trends; however, it was disrupted at both a personal and an institutional level at the end of the 1940s due to the Marxist-Leninist turn of legal thinking that accompanied the introduction of a Communist regime in the country. Nonetheless, this rejection of comparative law was gradually replaced by a more open attitude that strongly supported participation in the international comparative-law movement from the 1960s. Imre Szabó and Gyula Eörsi played a prominent role in this transformation. They legitimized the use of comparative methods in Socialist jurisprudence and, also, created a plausible conceptual framework for Socialist comparative law.
The ‘Iukos Affair’. The Russian Judiciary and the European Court of Human Rights
Authors: Groen Laurence A.
Published: April 2013

This note analyzes the functioning of the Russian judiciary on the basis of the European Court of Human Rights’ judgments in the cases of OAO Neftianaia Kompaniia Iukos and three of the company’s former leading executives, Mikhail Borisovich Khodorkovskii, Platon Leonidovich Lebedev and the late Vasilii Aleksanian. The analysis turns to the breaches by the Russian state of Articles 5 (right to liberty and security), 6 (right to a fair trial) and 18 (permissible restrictions to the rights guaranteed) of the 1950 European Convention for the Protection of Human Rights and Fundamental Freedoms, as established by the Court in the aforementioned cases, and the role of the Russian judiciary therein. In light of the fundamental flaws and structural nature characterizing the violations found, the conclusion is reached that the Russian judiciary (still) appears not to be entirely free from undue influence by the other branches of government.
“It Is No Longer I Who Live”: Christ’s Faith and Christian Faith
Authors: Allen Michael
Published: April 2013

Abstract

I offer a dogmatic analysis of Galatians 2:20 in three parts. First, Christ lives for us. Second, by faith we really do live in Christ. Third, there is an order and sequence to these two statements, and they require a theological framework within which they can be related. To that end, I point to two ways in which the common Reformational teaching on imputation was teased out in Luther’s definition of Christian freedom and the Reformed tradition of distinguishing between the covenant of works and the covenant of grace. These are not the only possible constructions which could maintain this order and sequence, but they have great historical prominence and a greater than commonly appreciated viability.
Divine Hiddenness and Human Sin: The Noetic Effect of Sin
Authors: Azadegan Ebrahim
Published: April 2013

Abstract

This paper examines the relationship between human sin and divine hiddenness, drawing on views that are widely acknowledged within the Reformed tradition. It argues, first, that according to these views there is no inculpable nonbelief, and thus, second, that a crucial premise in the atheistic argument from divine hiddenness is untenable. The overarching question here is: If there is a sensus divinitatis, is it possible to be an inculpable nonbeliever? To answer this question, the cognitive effects of sin on our sensus divinitatis as a faculty of producing basic beliefs about God will be assessed. I conclude that the premise which many find plausible—that there is inculpable nonbelief—is in fact controversial and dubious.
Scientific Theology? Herman Bavinck and Adolf Schlatter on the Place of Theology in the University
Authors: Eglinton James , Bräutigam Michael
Published: April 2013

Abstract

This article, primarily historical in focus, explores the contributions of Herman Bavinck (1854-1921) and Adolf Schlatter (1852-1938) to discussion on the place of theology within the university. Schlatter’s belief that theology is a science belonging within the academy is explored via his debate with Paul Jäger on the possibility of ‘atheistic theology’. Bavinck’s similar convictions, it is seen, were formed in response to the Higher Education Act (1876), a piece of legislation which sought to marginalise theology in a Dutch academic context. The article concludes by tentatively encouraging twenty-first century theology to see itself as a necessary subject (on the grounds of its divine object and power to bring coherence among the sciences) within the contemporary university.
Colin Gunton, Divine Love, and Univocal Predication
Authors: Wessling Jordan
Published: April 2013

Abstract

In this paper I draw from Colin Gunton and argue that the scriptures teach, or else presuppose, that univocity is true—specifically, that the term ‘love’ can possess the same meaning when applied to God and humans. My argument for this conclusion has three stages. In the first stage I survey the three major views of theological predication relevant to my Gunton-inspired argument—univocity, equivocity, and analogy. From there I attempt to assuage the worry that one cannot adjudicate between theories of predication by appealing to the biblical texts. Finally, I contend that univocity, in contrast to analogy and equivocity, best undergirds Jesus’ command in John 15:9-12 to love others as the Father has loved him.
Pneumatological Feminist/Womanist Theologies: The Importance of Discernment
Authors: Macchia Frank D.
Published: April 2013

Abstract

The pneumatological point of departure in the spiritually-gifted community of faith holds promise for a feminist/womanist theology that respects the changing diversity of voices in the body of Christ. This point of departure will reach for discernment, which will lead us to the second article of the Creed. In the process of exploring this discernment, my response addresses related issues, such as gender, the appeal to experience, and the Trinity.
Training Tennis Players through Natural Philosophy: From Scaino’s Trattato to Garsault’s Art du paumier
Authors: Beretta Marco
Published: April 2013

The motion of tennis balls has always been taken as a particularly interesting example of the complexity of the laws of motion. In this essay I survey the historical and cultural background of the use of the tennis ball as a scientific example of motion and its laws from the late Italian Renaissance onwards. I have examined in particular Antonio Scaino’s Trattato del giuco della palla (1555) and its scientific sources. Scaino’s effort to provide his readers with a scientific explanation of various tennis shots inspired the authors of other texts on sports to adopt an approach that combined science and leisure activities. However, the mysterious irregular trajectory of the tennis ball remained unexplained until 1852 when the German physicist Heinrich Gustav Magnus demonstrated mathematically how the action of air was the cause of the variation in motion of projectiles.
Jeu de la paume: Health of the Body and the Mind in Early Modern Medicine
Authors: Pennuto Concetta
Published: April 2013

This article deals with the role that gymnastics and particularly the game of handball (pila palmaria) played in early modern medicine. The game was seen as useful in order to foster good health, both of the body and the mind. Following the tradition of ancient medical sources, early modern philosophers, physicians, ball players and authors – such as Erasmus, Mercuriale, Scaino, Valleriola, Forbet and Hulpeau – elaborated a rich repertory of ideas demonstrating the impact of ball games on the education of young people, on the therapy for various diseases, and on the prevention of illness. Pila palmaria thus enjoyed a dual status, since it could act on the body through physical exercise and on the mind thanks to the pleasure produced in the player’s spirit.
Base-State Substitution: An Idealized Modeling Technique for Approximating Environmental Variability
Authors: Letkewicz Casey E. , French Adam J. , Parker Matthew D.
Published: April 2013

Base-state substitution (BSS) is a novel modeling technique for approximating environmental heterogeneity in idealized simulations. After a certain amount of model run time, base-state substitution replaces the original horizontally homogeneous background environment with a new horizontally homogeneous environment while maintaining any perturbations that have developed during the preceding simulation. This allows the user to independently modify the kinematic or thermodynamic environments, or replace the entire sounding without altering the structure of the perturbation fields. Such an approach can provide a powerful hypothesis test, for example, in a study of how an isolated convective storm would respond to a different environment within a horizontally homogeneous setting. The BSS modifications can be made gradually or instantaneously, depending on the needs of the user. In this paper both the gradual and instantaneous BSS procedures are demonstrated for simulations of deep moist convection, using first a wholly idealized setup and then a pair of observed near-storm soundings. Examination of domainwide model statistics demonstrates that model stability is maintained following the introduction of the new background environment. Following BSS, domain total mass and energy exhibit the expected instantaneous jumps upward or downward as a result of the imposed changes to the mean thermal and wind profiles, after which they remain steady during the subsequent simulation. The gridded model fields are well behaved and change gradually as the simulated storms respond meteorologically to their new environments. The paper concludes with a discussion of several unique aspects of the BSS approach.
Capsaicin Regulates the NF-κB Pathway in Salivary Gland Inflammation
Authors: Shin Y.-H. , Namkoong E. , Choi S. , Bae J.-S. , Jin M. , Hwang S.-M. , Arote R. , Choi S.-Y. , Park K.
Published: April 2013

Salivary gland epithelial cells (SGEC) release several cytokines that play important roles in the inflammatory process. In this study, we examined whether capsaicin can modulate cytokine release in SGEC. After cells were stimulated with polyinosinic-polycytidylic acid [poly(I:C)] or lipopolysaccharide (LPS), mRNA transcript and protein levels were detected by reverse-transcriptase-polymerase chain-reaction (RT-PCR), real-time PCR, and enzyme-linked immunosorbent assay (ELISA). These findings demonstrated that the increases in TNFα and IL-6 mRNA transcripts were highest at 3 hrs and 1 hr after incubation with poly(I:C) and LPS, respectively. Pre-treatment of the cells with 10 μµ capsaicin, however, significantly inhibited mRNA transcripts and its protein levels. The simultaneous application of 10 μµ capsazepine with capsaicin did not block the inhibitory effect of capsaicin. Furthermore, the inhibitory effect of capsaicin was also shown in primary cultured cells from TRPV1−/− mice. We found that both poly(I:C) and LPS induced IκB-α degradation and phosphorylation, which resulted in NF-κB activation, and capsaicin inhibited this NF-κB pathway. These results demonstrate that SGEC release pro-inflammatory cytokines mediated by TLR, and capsaicin inhibits this process through the NF-κB pathway. This study suggests that capsaicin could potentially alleviate inflammation in salivary glands.
Design of orthopedic support material containing diclofenac sodium microparticles: preparation and characterization of microparticles and application to orthopedic support material
Authors: Sarıışık Merih , Arıcı Mesut , Topbaş Özlem , Karavana Sinem Yaprak , Öztürk Cihat , Ertan Gökhan
Published: April 2013

The aim of this study is preparation and characterization of diclofenac sodium microparticles and their application to the orthopedic support materials. The microparticles were obtained using spray drying method involving ethyl cellulose as shell material. The morphology, particle size, drug loading capacity and in vitro release characteristics of the drug microparticles were optimized for impregnation diclofenac sodium microparticles onto the orthopedic support materials. Scanning electron microscopy (SEM) was used to characterize the drug microparticles and the treated fabrics with microparticles. SEM images illustrated that the microparticles were spherical in shape and also fixed onto the orthopedic support materials. Furthermore, the resistance of materials containing microparticles to washing were also investigated. Finally, in vitro drug release studies of microparticles and textile impregnated with microparticles were done. This study suggested that textile systems containing diclofenac sodium microparticles could have a potential for long-term therapy for rheumatic disorders.