bluuebunny/crossref_metadata_2025 huggingface dataset:
An Approach to Model Based Testing of Multiagent Systems
Authors: Ur Rehman Shafiq , Nadeem Aamer
Published: March 2015

Autonomous agents perform on behalf of the user to achieve defined goals or objectives. They are situated in dynamic environment and are able to operate autonomously to achieve their goals. In a multiagent system, agents cooperate with each other to achieve a common goal. Testing of multiagent systems is a challenging task due to the autonomous and proactive behavior of agents. However, testing is required to build confidence into the working of a multiagent system. Prometheus methodology is a commonly used approach to design multiagents systems. Systematic and thorough testing of each interaction is necessary. This paper proposes a novel approach to testing of multiagent systems based on Prometheus design artifacts. In the proposed approach, different interactions between the agent and actors are considered to test the multiagent system. These interactions include percepts and actions along with messages between the agents which can be modeled in a protocol diagram. The protocol diagram is converted into a protocol graph, on which different coverage criteria are applied to generate test paths that cover interactions between the agents. A prototype tool has been developed to generate test paths from protocol graph according to the specified coverage criterion.
Biologic Roles of Estrogen Receptor-βand Insulin-Like Growth Factor-2 in Triple-Negative Breast Cancer
Authors: Hamilton Nalo , Márquez-Garbán Diana , Mah Vei , Fernando Gowry , Elshimali Yahya , Garbán Hermes , Elashoff David , Vadgama Jaydutt , Goodglick Lee , Pietras Richard
Published: March 2015

Triple-negative breast cancer (TNBC) occurs in 10–15% of patients yet accounts for almost half of all breast cancer deaths. TNBCs lack expression of estrogen and progesterone receptors and HER-2 overexpression and cannot be treated with current targeted therapies. TNBCs often occur in African American and younger women. Although initially responsive to some chemotherapies, TNBCs tend to relapse and metastasize. Thus, it is critical to find new therapeutic targets. A second ER gene product, termed ERβ, in the absence of ERαmay be such a target. Using human TNBC specimens with known clinical outcomes to assess ERβexpression, we find that ERβ1 associates with significantly worse 5-year overall survival. Further, a panel of TNBC cell lines exhibit significant levels of ERβprotein. To assess ERβeffects on proliferation, ERβexpression in TNBC cells was silenced using shRNA, resulting in a significant reduction in TNBC proliferation. ERβ-specific antagonists similarly suppressed TNBC growth. Growth-stimulating effects of ERβmay be due in part to downstream actions that promote VEGF, amphiregulin, and Wnt-10b secretion, other factors associated with tumor promotion.In vivo, insulin-like growth factor-2 (IGF-2), along with ERβ1, is significantly expressed in TNBC and stimulates high ERβmRNA in TNBC cells. This work may help elucidate the interplay of metabolic and growth factors in TNBC.
Development and Evaluation of Bus Operation Control System Based on Cooperative Speed Guidance
Authors: Teng Jing , Jin Weimin
Published: March 2015

Buses often have strong bunching or large interval tendency when traveling further along the route. To restrain this further deterioration of operation service, this paper developed a bus operation control system to dynamically adjust bus speed, bus dwell time, and traffic signal timings along the running path. In addition, a simulation platform was developed to evaluate the proposed control system with the actual data collected from bus route number 210 in Shanghai. The simulation results show that the proposed control system can mitigate the amplification trend of the headway deviation along the route to produce headways within a given tolerance.
A Novel Clustering Algorithm Inspired by Membrane Computing
Authors: Peng Hong , Luo Xiaohui , Gao Zhisheng , Wang Jun , Pei Zheng
Published: March 2015

P systems are a class of distributed parallel computing models; this paper presents a novel clustering algorithm, which is inspired from mechanism of a tissue‐like P system with a loop structure of cells, called membrane clustering algorithm. The objects of the cells express the candidate centers of clusters and are evolved by the evolution rules. Based on the loop membrane structure, the communication rules realize a local neighborhood topology, which helps the coevolution of the objects and improves the diversity of objects in the system. The tissue‐like P system can effectively search for the optimal partitioning with the help of its parallel computing advantage. The proposed clustering algorithm is evaluated on four artificial data sets and six real‐life data sets. Experimental results show that the proposed clustering algorithm is superior or competitive to k‐means algorithm and several evolutionary clustering algorithms recently reported in the literature.
A Novel Simple Phantom for Verifying the Dose of Radiation Therapy
Authors: Lee J. H. , Chang L. T. , Shiau A. C. , Chen C. W. , Liao Y. J. , Li W. J. , Lee M. S. , Hsu S. M.
Published: March 2015

A standard protocol of dosimetric measurements is used by the organizations responsible for verifying that the doses delivered in radiation-therapy institutions are within authorized limits. This study evaluated a self-designed simple auditing phantom for use in verifying the dose of radiation therapy; the phantom design, dose audit system, and clinical tests are described. Thermoluminescent dosimeters (TLDs) were used as postal dosimeters, and mailable phantoms were produced for use in postal audits. Correction factors are important for converting TLD readout values from phantoms into the absorbed dose in water. The phantom scatter correction factor was used to quantify the difference in the scattered dose between a solid water phantom and homemade phantoms; its value ranged from 1.084 to 1.031. The energy-dependence correction factor was used to compare the TLD readout of the unit dose irradiated by audit beam energies with60Co in the solid water phantom; its value was 0.99 to 1.01. The setup-condition factor was used to correct for differences in dose-output calibration conditions. Clinical tests of the device calibrating the dose output revealed that the dose deviation was within 3%. Therefore, our homemade phantoms and dosimetric system can be applied for accurately verifying the doses applied in radiation-therapy institutions.
Measuring Efficiency and Productivity Growth of New Technology‐Based Firms in Business Incubators: The Portuguese Case Study of Madan Parque
Authors: Grilo A. , Santos J.
Published: March 2015

Business incubators can play a major role in helping to turn a business idea into a technology‐based organization that is economically efficient. However, there is a shortage in the literature regarding the efficiency evaluation and productivity evolution of the new technology‐based firms (NTBFs) in the incubation scope. This study develops a model based on the data envelopment analysis (DEA) methodology, which allows the incubated NTBFs to evaluate and improve the efficiency of their management. Moreover, the Malmquist index is used to examine productivity change. The index is decomposed into multiple components to give insights into the root sources of productivity change. The proposed model was applied in a case study with 13 NTBFs incubated. From that study, we conclude that inefficient firms invest excessively in research and development (R&D), and, on average, firms have a productivity growth in the period of study.
Enhanced Viscosity of Aqueous Palygorskite Suspensions through Physical and Chemical Processing
Authors: Zhou Feng-shan , Li Tian-qi , Yan Yun-hua , Cao Can , Zhou Lin , Liu Yang
Published: March 2015

Palygorskite has remarkable rheological properties and was used to increase the stability and viscosity of aqueous suspensions. The effects of different physical and chemical processing methods on the apparent viscosity and plastic viscosity of the palygorskite suspensions such as pressing, ultrasound scattering, acidification, and chemical additives have been released. The pressing and ultrasound scattering indicated that the dispersed state of palygorskite could be increased effectively after treatment, and the apparent viscosity of treated-palygorskite samples increased almost 2-3 times compared to that of before. The viscosity of the acid-treated palygorskite suspension was not increased. The viscosity increased with the content of bentonite in the mixture of bentonite and palygorskite in fresh water. It seemed to be not worthy to add a certain amount of bentonite to palygorskite in order to enhance viscosity and vice versa. Chemical additives appeared to have good effects on the rheological behavior of palygorskite suspension. Magnesium oxide revealed great contribution to viscosity enhancement. The main mechanism was the electrostatic attractive interaction between magnesium oxide particles with positive charges and the palygorskite rods with negative charges. This interacted force has an impact on the structural inversion of palygorskite rods and even caused the reinforcing of flocculation.
Feature Quantification and Abnormal Detection on Cervical Squamous Epithelial Cells
Authors: Zhao Mingzhu , Chen Lei , Bian Linjie , Zhang Jianhua , Yao Chunyan , Zhang Jianwei
Published: March 2015

Feature analysis and classification detection of abnormal cells from images for pathological analysis are an important issue for the realization of computer assisted disease diagnosis. This paper studies a method for cervical squamous epithelial cells. Based on cervical cytological classification standard and expert diagnostic experience, expressive descriptors are extracted according to morphology, color, and texture features of cervical scales epithelial cells. Further, quantificational descriptors related to cytopathology are derived as well, including morphological difference degree, cell hyperkeratosis, and deeply stained degree. The relationship between quantified value and pathological feature can be established by these descriptors. Finally, an effective method is proposed for detecting abnormal cells based on feature quantification. Integrated with clinical experience, the method can realize fast abnormal cell detection and preliminary cell classification.
Composition Optimization of Glass-Like Casing and Its Novel Application in Mending Instable Borehole Wall
Authors: Li Zhi-jun , Wang Yu , Liu Bao-lin , Yang Chun
Published: March 2015

A glass-like casing was developed to mend the instable borehole due to its great similarities in compositions and structure. In order to boost the casing’s mechanical properties and lower its cost, different wt% additions of aluminum and quartz sand are added into the composition. Based on the outcomes of differential scanning calorimeter (DSC), it is suggested to be sintered at the temperature of 700°C. The results of X-ray diffraction (XRD) show that aluminum and SiO2are its main crystalline phases. Its compression strength and the tensile strength range 5–14 Mpa and 0.5–4.5 Mpa, respectively, with the relative densities of between 1.00 g/cm3and 1.19 g/cm3. In the end, a glass-based formula with 30 wt% aluminum and 40 wt% quartz sand is developed and experimentally applied.
Reducing Hispanic Children’s Obesity Risk Factors in the First 1000 Days of Life: A Qualitative Analysis
Authors: Woo Baidal Jennifer A. , Criss Shaniece , Goldman Roberta E. , Perkins Meghan , Cunningham Courtney , Taveras Elsie M.
Published: March 2015

Objectives. Modifiable behaviors during the first 1000 days (conception age 24 months) mediate Hispanic children’s obesity disparities. We aimed to examine underlying reasons for early life obesity risk factors and identify potential early life intervention strategies.Methods. We conducted 7 focus groups with 49 Hispanic women who were pregnant or had children < age 24 months. Domains included influences on childhood obesity risk factors and future intervention ideas. We analyzed data with immersion-crystallization methods until no new themes emerged.Results. Themes included coping with pregnancy may trump healthy eating and physical activity; early life weight gain is unrelated to later life obesity; fear of infant hunger drives bottle and early solids introduction; beliefs about infant taste promote early solids and sugary beverage introduction; and belief that screen time promotes infant development. Mothers identified physicians, nutritionists, and relatives as important health information sources and expressed interest in mobile technology and group or home visits for interventions.Conclusion. Opportunities exist in the first 1000 days to improve Hispanic mothers’ understanding of the role of early life weight gain in childhood obesity and other obesity risk factors. Interventions that link health care and public health systems and include extended family may prevent obesity among Hispanic children.
3-(3-Pyridylmethylidene)-2-indolinone Reduces the Severity of Colonic Injury in a Murine Model of Experimental Colitis
Authors: Wang Kun-Ping , Zhang Chao , Zhang Shou-Guo , Liu En-Dong , Dong Lan , Kong Xiang-Zhen , Cao Peng , Hu Chun-Ping , Zhao Ke , Zhan Yi-Qun , Dong Xiao-Ming , Ge Chang-Hui , Yu Miao , Chen Hui , Wang Lin , Yang Xiao-Ming , Li Chang-Yan
Published: March 2015

Nrf2 is the key transcription factor regulating the antioxidant response which is crucial for cytoprotection against extracellular stresses. Numerousin vivostudies indicate that Nrf2 plays a protective role in anti-inflammatory response. 3-(3-Pyridylmethylidene)-2-indolinone (PMID) is a synthesized derivative of 2-indolinone compounds. Our previous study suggested that PMID induces the activation of Nrf2/ARE pathway, then protecting against oxidative stress-mediated cell death. However, little is known regarding the anti-inflammatory properties of PMID in severe inflammatory phenotypes. In the present study we determined if PMID treatment protects mice from dextran sodium sulphate- (DSS-) induced colitis. The result suggests that treatment with PMID prior to colitis induction significantly reduced body weight loss, shortened colon length, and decreased disease activity index compared to control mice. Histopathological analysis of the colon revealed attenuated inflammation in PMID pretreated animals. The levels of inflammatory markers in colon tissue and serum were reduced associated with inhibition of NF-κB activation. The expression levels of Nrf2-dependent genes such as HO-1, NQO1, and Nrf2 were increased in PMID pretreated mice. However, PMID pretreatment did not prevent DSS-induced colitis in Nrf2 knockout mice. These data indicate that PMID pretreatment in mice confers protection against DSS-induced colitis in Nrf2-dependent manner, suggesting a potential role of PMID in anti-inflammatory response.
Identification of Novel Thyroid Cancer-Related Genes and Chemicals Using Shortest Path Algorithm
Authors: Jiang Yang , Zhang Peiwei , Li Li-Peng , He Yi-Chun , Gao Ru-jian , Gao Yu-Fei
Published: March 2015

Thyroid cancer is a typical endocrine malignancy. In the past three decades, the continued growth of its incidence has made it urgent to design effective treatments to treat this disease. To this end, it is necessary to uncover the mechanism underlying this disease. Identification of thyroid cancer-related genes and chemicals is helpful to understand the mechanism of thyroid cancer. In this study, we generalized some previous methods to discover both disease genes and chemicals. The method was based on shortest path algorithm and applied to discover novel thyroid cancer-related genes and chemicals. The analysis of the final obtained genes and chemicals suggests that some of them are crucial to the formation and development of thyroid cancer. It is indicated that the proposed method is effective for the discovery of novel disease genes and chemicals.
Activating Transcription Factor 4 Promotes Angiogenesis of Breast Cancer through Enhanced Macrophage Recruitment
Authors: Liu Chen , Li Zongjin , Wang Lina , Tong Lingling , He Ningning , Chen Yanan , Liu Yanhua , Wu Zhongjun , Sun Peiqing , Xiang Rong , Ren Guosheng , Su Weijun
Published: March 2015

Angiogenesis plays an important role in the progression of tumor. Besides being regulated by tumor cells per se, tumor angiogenesis is also influenced by stromal cells in tumor microenvironment (TME), for example, tumor associated macrophages (TAMs). Activating transcription factor 4 (ATF4), a member of the ATF/CREB family, has been reported to be related to tumor angiogenesis. In this study, we found that exogenous overexpression of ATF4 in mouse breast cancer cells promotes tumor growth via increasing tumor microvascular density. However, ATF4 overexpression failed to increase the expression level of a series of proangiogenic factors including vascular endothelial growth factor A (VEGFA) in tumor cells in this model. Thus, we further investigated the infiltration of proangiogenic macrophages in tumor tissues and found that ATF4-overexpressing tumors could recruit more macrophages via secretion of macrophage colony stimulating factor (M-CSF). Overall, we concluded that exogenous overexpression of ATF4 in breast cancer cells may facilitate the recruitment of macrophages into tumor tissues and promote tumor angiogenesis and tumor growth indirectly.
Discrimination of Effects between Directional and Nondirectional Information of Auditory Warning on Driving Behavior
Authors: Zhang Yuting , Yan Xuedong , Yang Zhuo
Published: March 2015

This study examines the impacts of directional and nondirectional auditory warning information in a collision warning system (CWS) on driving behavior. The data on driving behavior is collected through experiment, with scenarios containing unexpected hazard events that include different warning content. As drivers approached the collision event, either a CWS auditory warning was given or no warning was given for a reference group. Discriminant analysis was used to investigate the relationship between directional auditory warning information and driving behavior. In the experiment, the CWS warnings significantly reduced brake reaction time and prompted drivers to press the brake pedal more heavily, demonstrating the effectiveness of CWS warnings in alerting drivers to avoid red-light running (RLR) vehicles when approaching a signalized intersection. Providing a clear warning with directional information about an urgent hazard event could give drivers adequate time to prepare for the potential collision. In terms of deceleration, a directional information warning was shown to greatly help drivers react to critical events at signalized intersections with more moderate braking. From these results, requirements can be derived for the design of effective warning strategies for critical intersections.
Stochastic Control of Inertial Sea Wave Energy Converter
Authors: Raffero Mattia , Martini Michele , Passione Biagio , Mattiazzo Giuliana , Giorcelli Ermanno , Bracco Giovanni
Published: March 2015

The ISWEC (inertial sea wave energy converter) is presented, its control problems are stated, and an optimal control strategy is introduced. As the aim of the device is energy conversion, the mean absorbed power by ISWEC is calculated for a plane 2D irregular sea state. The response of the WEC (wave energy converter) is driven by the sea‐surface elevation, which is modeled by a stationary and homogeneous zero mean Gaussian stochastic process. System equations are linearized thus simplifying the numerical model of the device. The resulting response is obtained as the output of the coupled mechanic‐hydrodynamic model of the device. A stochastic suboptimal controller, derived from optimal control theory, is defined and applied to ISWEC. Results of this approach have been compared with the ones obtained with a linear spring‐damper controller, highlighting the capability to obtain a higher value of mean extracted power despite higher power peaks.
Comparing Two Types of Rabbit ATG prior to Reduced Intensity Conditioning Allogeneic Hematopoietic SCT for Hematologic Malignancies
Authors: Paiano Sandra , Roosnek Eddy , Tirefort Yordanka , Nagy-Hulliger Monika , Masouridi Stavroula , Levrat Emmanuel , Bernimoulin Michael , Huguet Saadia , Casini Alessandro , Matthes Thomas , Samii Kaveh , Passweg Jakob R. , Chalandon Yves
Published: March 2015

Different rabbit polyclonal antilymphocyte globulins (ATGs) are used in allogeneic hematopoietic stem cell transplantation (alloHSCT) to prevent graft-versus-host disease (GvHD). We compared 2 different ATGs in alloHSCT after reduced intensity conditioning (RIC) for hematological malignancies. We reviewed 30 alloHSCT for hematologic malignancies performed between 2007 and 2010 with fludarabine and i.v. busulfan as conditioning regimen. Patients alternatingly received Thymoglobulin or ATG-F. Median followup was 3.3 (2.5–4.5) years. Adverse events appeared to occur more frequently during Thymoglobulin infusion than during ATG-F infusion but without statistical significance(P=0.14). There were also no differences in 3-year overall survival (OS), disease-free survival (DFS), relapse incidence, and transplant related mortality (TRM) in the Thymoglobulin versus ATG-F group: 45.7% versus 46.7%, 40% versus 33.7%, 40% versus 33.3%, and 20% versus 33.3%. The same held for graft failure, rejection, infectious complications, immune reconstitution, and acute or chronic GvHD. In patients transplanted for hematologic malignancies after RIC, the use of Thymoglobulin is comparable to that of ATG-F in all the aspects evaluated in the study. However due to the small number of patients in each group we cannot exclude a possible difference that may exist.
Evaluation of Sintering Behavior of Premix Al-Zn-Mg-Cu Alloy Powder
Authors: Rudianto Haris , Jang Gwang Joo , Yang Sang Sun , Kim Yong Jin , Dlouhy Ivo
Published: March 2015

Sintering of light aluminium alloys powder has been investigated as a way to substitute steels in automotive and aerospace industries. Premix Al-5.5Zn-2.5Mg-0.5Cu composite powder called Alumix 431D was analyzed in this research. Sintering was carried out under ultra high purity nitrogen gas and before reaching sintering temperature, green samples were delubricated at 400°C for 30 min. The powder possesses high sinterability by reaching 96% relative density at 580°C sintering temperature. Formation of liquid phase seems to support achieving high sintering density. Optimum mechanical properties also were obtained under those conditions. T6 heat treatment was done to improve the mechanical properties by formation of precipitation strengthening, and MgZn2appears to be dominant strengthening precipitate. X-ray diffraction, optical microscopy, and SEM-EDS were used to characterize powder, and sintered and heat treated samples.
Targeting Glutamine Metabolism in Breast Cancer with Aminooxyacetate
Authors: Korangath Preethi , Teo Wei Wen , Sadik Helen , Han Liangfeng , Mori Noriko , Huijts Charlotte M. , Wildes Flonne , Bharti Santosh , Zhang Zhe , Santa-Maria Cesar A. , Tsai Hualing , Dang Chi V. , Stearns Vered , Bhujwalla Zaver M. , Sukumar Saraswati
Published: March 2015

Purpose: Glutamine addiction in c-MYC–overexpressing breast cancer is targeted by the aminotransferase inhibitor, aminooxyacetate (AOA). However, the mechanism of ensuing cell death remains unresolved.

Experimental Design: A correlation between glutamine dependence for growth and c-MYC expression was studied in breast cancer cell lines. The cytotoxic effects of AOA, its correlation with high c-MYC expression, and effects on enzymes in the glutaminolytic pathway were investigated. AOA-induced cell death was assessed by measuring changes in metabolite levels by magnetic resonance spectroscopy (MRS), the effects of amino acid depletion on nucleotide synthesis by cell-cycle and bromodeoxyuridine (BrdUrd) uptake analysis, and activation of the endoplasmic reticulum (ER) stress–mediated pathway. Antitumor effects of AOA with or without common chemotherapies were determined in breast cancer xenografts in immunodeficient mice and in a transgenic MMTV-rTtA-TetO-myc mouse mammary tumor model.

Results: We established a direct correlation between c-MYC overexpression, suppression of glutaminolysis, and AOA sensitivity in most breast cancer cells. MRS, cell-cycle analysis, and BrdUrd uptake measurements indicated depletion of aspartic acid and alanine leading to cell-cycle arrest at S-phase by AOA. Activation of components of the ER stress–mediated pathway, initiated through GRP78, led to apoptotic cell death. AOA inhibited growth of SUM159, SUM149, and MCF-7 xenografts and c-myc–overexpressing transgenic mouse mammary tumors. In MDA-MB-231, AOA was effective only in combination with chemotherapy.

Conclusions: AOA mediates its cytotoxic effects largely through the stress response pathway. The preclinical data of AOA's effectiveness provide a strong rationale for further clinical development, particularly for c-MYC–overexpressing breast cancers. Clin Cancer Res; 21(14); 3263–73. ©2015 AACR.
The p53 Target Gene SIVA Enables Non–Small Cell Lung Cancer Development
Authors: Van Nostrand Jeanine L. , Brisac Alice , Mello Stephano S. , Jacobs Suzanne B.R. , Luong Richard , Attardi Laura D.
Published: March 2015

Although p53 transcriptional activation potential is critical for its ability to suppress cancer, the specific target genes involved in tumor suppression remain unclear. SIVA is a p53 target gene essential for p53-dependent apoptosis, although it can also promote proliferation through inhibition of p53 in some settings. Thus, the role of SIVA in tumorigenesis remains unclear. Here, we seek to define the contribution of SIVA to tumorigenesis by generating Siva conditional knockout mice. Surprisingly, we find that SIVA loss inhibits non–small cell lung cancer (NSCLC) development, suggesting that SIVA facilitates tumorigenesis. Similarly, SIVA knockdown in mouse and human NSCLC cell lines decreases proliferation and transformation. Consistent with this protumorigenic role for SIVA, high-level SIVA expression correlates with reduced NSCLC patient survival. SIVA acts independently of p53 and, instead, stimulates mTOR signaling and metabolism in NSCLC cells. Thus, SIVA enables tumorigenesis in a p53-independent manner, revealing a potential new cancer therapy target.

Significance: These findings collectively reveal a novel role for the p53 target gene SIVA both in regulating metabolism and in enabling tumorigenesis, independently of p53. Importantly, these studies further identify SIVA as a new prognostic marker and as a potential target for NSCLC cancer therapy. Cancer Discov; 5(6); 622–35. ©2015 AACR.

See related commentary by Resnick-Silverman and Manfredi, p. 581

This article is highlighted in the In This Issue feature, p. 565
BRAFV600E Co-opts a Conserved MHC Class I Internalization Pathway to Diminish Antigen Presentation and CD8+ T-cell Recognition of Melanoma
Authors: Bradley Sherille D. , Chen Zeming , Melendez Brenda , Talukder Amjad , Khalili Jahan S. , Rodriguez-Cruz Tania , Liu Shujuan , Whittington Mayra , Deng Wanleng , Li Fenge , Bernatchez Chantale , Radvanyi Laszlo G. , Davies Michael A. , Hwu Patrick , Lizée Gregory
Published: March 2015

Oncogene activation in tumor cells induces broad and complex cellular changes that contribute significantly to disease initiation and progression. In melanoma, oncogenic BRAFV600E has been shown to drive the transcription of a specific gene signature that can promote multiple mechanisms of immune suppression within the tumor microenvironment. We show here that BRAFV600E also induces rapid internalization of MHC class I (MHC-I) from the melanoma cell surface and its intracellular sequestration within endolysosomal compartments. Importantly, MAPK inhibitor treatment quickly restored MHC-I surface expression in tumor cells, thereby enhancing melanoma antigen-specific T-cell recognition and effector function. MAPK pathway–driven relocalization of HLA-A*0201 required a highly conserved cytoplasmic serine phosphorylation site previously implicated in rapid MHC-I internalization and recycling by activated immune cells. Collectively, these data suggest that oncogenic activation of BRAF allows tumor cells to co-opt an evolutionarily conserved MHC-I trafficking pathway as a strategy to facilitate immune evasion. This link between MAPK pathway activation and the MHC-I cytoplasmic tail has direct implications for immunologic recognition of tumor cells and provides further evidence to support testing therapeutic strategies combining MAPK pathway inhibition with immunotherapies in the clinical setting. Cancer Immunol Res; 3(6); 602–9. ©2015 AACR.
Endothelial Uncoupling Protein 2 Regulates Mitophagy and Pulmonary Hypertension During Intermittent Hypoxia
Authors: Haslip Maria , Dostanic Iva , Huang Yan , Zhang Yi , Russell Kerry S. , Jurczak Michael J. , Mannam Praveen , Giordano Frank , Erzurum Serpil C. , Lee Patty J.
Published: March 2015

Objectives—

Pulmonary hypertension (PH) is a process of lung vascular remodeling, which can lead to right heart dysfunction and significant morbidity. The underlying mechanisms leading to PH are not well understood, and therapies are limited. Using intermittent hypoxia (IH) as a model of oxidant-induced PH, we identified an important role for endothelial cell mitophagy via mitochondrial uncoupling protein 2 (Ucp2) in the development of IH-induced PH.

Approach and Results—

Ucp2 endothelial knockout (VE-KO) and Ucp2 Flox (Flox) mice were subjected to 5 weeks of IH. Ucp2 VE-KO mice exhibited higher right ventricular systolic pressure and worse right heart hypertrophy, as measured by increased right ventricle weight/left ventricle plus septal weight (RV/LV+S) ratio, at baseline and after IH. These changes were accompanied by increased mitophagy. Primary mouse lung endothelial cells transfected with Ucp2 siRNA and subjected to cyclic exposures to CoCl
2
(chemical hypoxia) showed increased mitophagy, as measured by PTEN-induced putative kinase 1 and LC3BII/I ratios, decreased mitochondrial biogenesis, and increased apoptosis. Similar results were obtained in primary lung endothelial cells isolated from VE-KO mice. Moreover, silencing PTEN-induced putative kinase 1 in the endothelium of Ucp2 knockout mice, using endothelial-targeted lentiviral silencing RNA in vivo, prevented IH-induced PH. Human pulmonary artery endothelial cells from people with PH demonstrated changes similar to Ucp2-silenced mouse lung endothelial cells.

Conclusions—

The loss of endothelial Ucp2 leads to excessive PTEN-induced putative kinase 1–induced mitophagy, inadequate mitochondrial biosynthesis, and increased apoptosis in endothelium. An endothelial Ucp2–PTEN-induced putative kinase 1 axis may be effective therapeutic targets in PH.
Getting to the Heart of the Matter
Authors: Leask Andrew
Published: March 2015

Fibrotic diseases are a significant global burden for which there are limited treatment options. The effector cells of fibrosis are activated fibroblasts called myofibroblasts, a highly contractile cell type characterized by the appearance of α-smooth muscle actin stress fibers. The underlying mechanism behind myofibroblast differentiation and persistence has been under much investigation and is known to involve a complex signaling network involving transforming growth factor-β, endothelin-1, angiotensin II, CCN2 (connective tissue growth factor), and platelet-derived growth factor. This review addresses the contribution of these signaling molecules to cardiac fibrosis.
Poorly Cited Articles in Peer-Reviewed Cardiovascular Journals from 1997 to 2007
Authors: Ranasinghe Isuru , Shojaee Abbas , Bikdeli Behnood , Gupta Aakriti , Chen Ruijun , Ross Joseph S. , Masoudi Frederick A. , Spertus John A. , Nallamothu Brahmajee K. , Krumholz Harlan M.
Published: March 2015

Background—

The extent to which articles are cited is a surrogate of the impact and importance of the research conducted; poorly cited articles may identify research of limited use and potential wasted investments. We assessed trends in the rates of poorly cited articles and journals in the cardiovascular literature from 1997 to 2007.

Methods and Results—

We identified original articles published in cardiovascular journals and indexed in the Scopus citation database from 1997 to 2007. We defined poorly cited articles as those with ≤5 citations in the 5 years following publication and poorly cited journals as those with >75% of journal content poorly cited. We identified 164 377 articles in 222 cardiovascular journals from 1997 to 2007. From 1997 to 2007, the number of cardiovascular articles and journals increased by 56.9% and 75.2%, respectively. Of all the articles, 75 550 (46.0%) were poorly cited, of which 25 650 (15.6% overall) had no citations. From 1997 to 2007, the proportion of poorly cited articles declined slightly (52.1%–46.2%, trend
P
<0.001), although the absolute number of poorly cited articles increased by 2595 (trend
P
<0.001). At a journal level, 44% of cardiovascular journals had more than three-fourths of the journal’s content poorly cited at 5 years.

Conclusion—

Nearly half of all peer-reviewed articles published in cardiovascular journals are poorly cited 5 years after publication, and many are not cited at all. The cardiovascular literature and the number of poorly cited articles both increased substantially from 1997 to 2007. The high proportion of poorly cited articles and journals suggests inefficiencies in the cardiovascular research enterprise.
Fibroblast Growth Factor 21 Prevents Atherosclerosis by Suppression of Hepatic Sterol Regulatory Element-Binding Protein-2 and Induction of Adiponectin in Mice
Authors: Lin Zhuofeng , Pan Xuebo , Wu Fan , Ye Dewei , Zhang Yi , Wang Yu , Jin Leigang , Lian Qizhou , Huang Yu , Ding Hong , Triggle Chris , Wang Kai , Li Xiaokun , Xu Aimin
Published: March 2015

Background—

Fibroblast growth factor 21 (FGF21) is a metabolic hormone with pleiotropic effects on glucose and lipid metabolism and insulin sensitivity. It acts as a key downstream target of both peroxisome proliferator-activated receptor α and γ, the agonists of which have been used for lipid lowering and insulin sensitization, respectively. However, the role of FGF21 in the cardiovascular system remains elusive.

Methods and Results—

The roles of FGF21 in atherosclerosis were investigated by evaluating the impact of FGF21 deficiency and replenishment with recombinant FGF21 in apolipoprotein E
−/−
mice. FGF21 deficiency causes a marked exacerbation of atherosclerotic plaque formation and premature death in apolipoprotein E
−/−
mice, which is accompanied by hypoadiponectinemia and severe hypercholesterolemia. Replenishment of FGF21 protects against atherosclerosis in apolipoprotein E
−/−
mice via 2 independent mechanisms, inducing the adipocyte production of adiponectin, which in turn acts on the blood vessels to inhibit neointima formation and macrophage inflammation, and suppressing the hepatic expression of the transcription factor sterol regulatory element-binding protein-2, thereby leading to reduced cholesterol synthesis and attenuation of hypercholesterolemia. Chronic treatment with adiponectin partially reverses atherosclerosis without obvious effects on hypercholesterolemia in FGF21-deficient apolipoprotein E
−/−
mice. By contrast, the cholesterol-lowering effects of FGF21 are abrogated by hepatic expression of sterol regulatory element-binding protein-2.

Conclusions—

FGF21 protects against atherosclerosis via fine tuning the multiorgan crosstalk among liver, adipose tissue, and blood vessels.
Myocardial Fibrosis Burden Predicts Left Ventricular Ejection Fraction and Is Associated With Age and Steroid Treatment Duration in Duchenne Muscular Dystrophy
Authors: Tandon Animesh , Villa Chet R. , Hor Kan N. , Jefferies John L. , Gao Zhiqian , Towbin Jeffrey A. , Wong Brenda L. , Mazur Wojciech , Fleck Robert J. , Sticka Joshua J. , Benson D. Woodrow , Taylor Michael D.
Published: March 2015

Background

Patients with Duchenne muscular dystrophy exhibit progressive cardiac and skeletal muscle dysfunction. Based on prior data, cardiac dysfunction in Duchenne muscular dystrophy patients may be influenced by myocardial fibrosis and steroid therapy. We examined the longitudinal relationship of myocardial fibrosis and ventricular dysfunction using cardiac magnetic resonance in a large Duchenne muscular dystrophy cohort.

Methods and Results

We reviewed 465 serial cardiac magnetic resonance studies (98 Duchenne muscular dystrophy patients with ≥4 cardiac magnetic resonance studies) for left ventricular ejection fraction (
LVEF
) and presence of late gadolinium enhancement (
LGE
), a marker for myocardial fibrosis.
LVEF
was modeled by examining
LGE
status, myocardial fibrosis burden (as assessed by the number of
LGE
‐positive left ventricular segments), patient age, and steroid treatment duration. An age‐only model demonstrated that
LVEF
declined 0.58±0.10% per year. In patients with both
LGE
‐negative and
LGE
‐positive studies (n=51),
LVEF
did not decline significantly over time if
LGE
was absent but declined 2.2±0.31% per year when
LGE
was present. Univariate modeling showed significant associations between
LVEF
and steroid treatment duration, presence of
LGE
, and number of
LGE
‐positive left ventricular segments; multivariate modeling showed that
LVEF
declined by 0.93±0.09% for each
LGE
‐positive left ventricular segment, whereas age and steroid treatment duration were not significant. The number of
LGE
‐positive left ventricular segments increased with age, and longer steroid treatment duration was associated with lower age‐related increases.

Conclusion

Progressive myocardial fibrosis, as detected by
LGE
, was strongly correlated with the
LVEF
decline in Duchenne muscular dystrophy patients. Longer steroid treatment duration was associated with a lower age‐related increase in myocardial fibrosis burden.
A Change in Inflammatory Footprint Precedes Plaque Instability: A Systematic Evaluation of Cellular Aspects of the Adaptive Immune Response in Human Atherosclerosis
Authors: van Dijk R. A. , Duinisveld A. J. F. , Schaapherder A. F. , Mulder‐Stapel A. , Hamming J. F. , Kuiper J. , de Boer O. J. , van der Wal A. C. , Kolodgie F. D. , Virmani R. , Lindeman J. H. N.
Published: March 2015

Background

Experimental studies characterize adaptive immune response as a critical factor in the progression and complications of atherosclerosis. Yet, it is unclear whether these observations translate to the human situation. This study systematically evaluates cellular components of the adaptive immune response in a biobank of human aortas covering the full spectrum of atherosclerotic disease.

Methods and Results

A systematic analysis was performed on 114 well‐characterized perirenal aortic specimens with immunostaining for T‐cell subsets (CD3/4/8/45RA/45RO/FoxP3) and the Th1/non‐Th1/Th17 ratio (CD4
+
T‐bet
+
/CD4
+
T‐bet
−
/CD4
+
/interleukin‐17
+
double staining). CD20 and CD138 were used to identify B cells and plasma cells, while B‐cell maturation was evaluated by AID/CD21 staining and expression of lymphoid homeostatic CXCL13. Scattered CD4 and CD8 cells with a T memory subtype were found in normal aorta and early, nonprogressive lesions. The total number of T cells increases in progressive atherosclerotic lesions (≈1:5 CD4/CD8 T‐cell ratio). A further increase in medial and adventitial T cells is found upon progression to vulnerable lesions.

This critical stage is further hallmarked by de novo formation of adventitial lymphoidlike structures containing B cells and plasma cells, a process accompanied by transient expression of CXCL13. A dramatic reduction of T‐cell subsets, disappearance of lymphoid structures, and loss of CXCL13 expression characterize postruptured lesions. FoxP3 and Th17 T cells were minimally present throughout the atherosclerotic process.

Conclusions

Transient CXCL13 expression, restricted presence of B cells in human atherosclerosis, along with formation of nonfunctional extranodal lymphoid structures in the phase preceding plaque rupture, indicates a “critical” change in the inflammatory footprint before and during plaque destabilization.
Lower Serum Calcium Level Is Associated With Hemorrhagic Transformation After Thrombolysis
Authors: Guo Yang , Yan Shenqiang , Zhang Sheng , Zhang Xiaocheng , Chen Qingmeng , Liu Keqin , Liebeskind David S. , Lou Min
Published: March 2015

Background and Purpose—

We aim to investigate whether lower admission serum calcium levels are associated with hemorrhagic transformation (HT) after intravenous thrombolysis (IVT).

Methods—

A total of 362 patients treated with IVT was divided into 4 quartiles based on admission serum calcium levels (Q1[<2.16], Q2[2.16, 2.23], Q3[2.24, 2.31], and Q4[>2.31] mmol/L). HT was classified as hemorrhagic infarction and parenchymal hemorrhage. Logistic regression was applied to assess the association between serum calcium levels and the incidence of HT.

Results—

Compared with Q4, HT was more common in Q1 (odds ratio, 2.580; 95% CI, [1.258–5.292];
P
=0.010), Q2 (odds ratio, 2.382; 95% CI, [1.163–4.877];
P
=0.018), and Q3 (odds ratio, 2.293; 95% CI, [1.133–4.637];
P
=0.021). Hemorrhagic infarction was more common in Q1 (
P
=0.037), and Q2 (
P
=0.018), compared with Q4, and parenchymal hemorrhage was more common in Q1 (
P
=0.029) than Q4.

Conclusions—

Lower admission serum calcium level is independently associated with HT after IVT, and this hypothesis needs larger confirmatory trials.
When is an Out-of-Body Experience (Not) an Out-of-Body Experience? Reflections about Out-of-Body Phenomena in Neuroscientific Research
Authors: Craffert Pieter F.
Published: March 2015

In recent years there has been an increased interest in the study of out-of-body experiences (obes) by cognitive and neuro-scientists. Nowadays, far-reaching claims regarding the uncovering of the neural mechanisms and pathways, as well as the mystery ofobes in the anthropological and historical record are on offer. In this article the implicit assumption thatobes are much better understood and that real progress has been made are questioned on the basis of the definitional and conceptual problems that still haunt this area of research. It is suggested that progress will only be registered once the spectrum of out-of-body phenomena (obp) is recognized and attention is paid to the neurocultural complexity of distinct instances ofobes.
What Made Sahar Scared?: Imaginary and Realistic Causes in Palestinian and American Children’s Concept for Fear
Authors: Kayyal Mary H. , Widen Sherri C.
Published: March 2015

Young children associate fear with monsters, ghosts, and other imaginary creatures more than with real threats to safety, such as robbers or bullies – at least in Western societies. Cross-cultural studies are rare, are limited to older children, and have not asked if the role of the imagination extends to emotions other than fear. In this study, young Palestinian and American children (60 in each group, 3–7 years, age- and sex-matched) were asked to tell stories in which they generated a cause for fear as well as happiness, sadness, anger and surprise. Imaginary creatures were rarely cited as the cause of any emotion other than fear, but were cited frequently for fear by both Palestinians and Americans. There was also a cultural difference: Palestinians generated significantly fewer imaginary and more realistic causes for fear than did Americans. Thus, imaginary causes are a part of Palestinian children’s fear concept, but imaginary causes are not primary as they are for American children; for Palestinian children, realistic causes are primary in their fear concept.
A Clash of Treaties: The Lawfulness of Countermeasures in International Trade Law and International Investment Law
Authors: Losari Junianto James , Ewing-Chow Michael
Published: March 2015

Countermeasures are part of customary international law and have been incorporated into the WTO as a mechanism to facilitate compliance. In the NAFTA sugar disputes, Mexico claimed that the measure in dispute was a countermeasure against a breach of NAFTA by the United States. Three US investors also claimed against Mexico under the investment chapter of NAFTA. All three ICSID tribunals held, for different reasons, that trade countermeasures affecting investor rights would be unlawful. Some of the tribunals’ reasoning that investors have direct rights could set up a clash between the trade and investment regimes. We argue that an authorized trade countermeasure should also be lawful in the investment law context. Coherence between the trade and investment regimes is essential in this age of global value chains in which investors are part of a complex trade network. We suggest ways to improve the jurisprudence and existing investment treaties.
Toward a phylogenetic-based Generic Classification of Neotropical Lecythidaceae—I. Status of Bertholletia, Corythophora, Eschweilera and Lecythis
Authors: Huang Ya-Yi , Mori Scott A. , Kelly Lawrence M.
Published: March 2015

Lecythidaceae subfam. Lecythidoideae is limited to the Neotropics and is the only naturally occurring subfamily of Lecythidaceae in the New World. A subset of genera with zygomorphic flowers—Bertholletia, Corythophora, Eschweilera and Lecythis—comprises a group of about 125 species called the Bertholletia clade. A previous study based on plastid ndhF and trnL-F genes supported the monophyly of Corythophora but suggested that Eschweilera and Lecythis are not monophyletic. Using this study as a baseline, we sampled more taxa and sequenced more loci to address the taxonomic problems of the ambiguous genera and to determine relationships within the Bertholletia clade. Our results support the monophyly of the Bertholletia clade as previously circumscribed. In addition, Corythophora is monophyletic, and the two accessions of Bertholletia excelsa come out together on the tree. Results of the simultaneous analysis do not support the monophyly of Lecythis or Eschweilera. Lecythis consists of four main groups (the Lecythis pisonis, L. poiteaui, L. chartacea, and L. corrugata clades), the last of which is nested within Eschweilera, and Eschweilera consists of three clades (the Eschweilera integrifolia, E. tetrapetala, and Eschweilera parvifolia clades). We compare our results with the generic classification presented in the latest monograph of neotropical Lecythidaceae and make recommendations for a revised generic classification of the Bertholletia clade of Lecythidaceae.
Pueraria grandiflora (Fabaceae), a new species from Southwest China
Authors: Pan Bo , LIU BING , YU ZHI-XIANG , YANG YONG-QIONG
Published: March 2015

A new species, Pueraria grandiflora, (Fabaceae, Phaseoleae), is described and illustrated. It resembles Pueraria tuberosa, but differs in lobed leaflets, larger flowers, single or once branched inflorescences, and flowering and fruiting season. This species is only known from dry-hot valleys in Sichuan and Yunnan, and is rare and narrowly distributed.