bluuebunny/crossref_metadata_2025 huggingface dataset:
The Production of Food, Energy and Fresh Water From the Sea Through Artificial Upwelling
Authors: Roels O. A.
Published: April 2015

The tropical oceans are the world’s largest collector and storage system of solar energy. This heat can be utilized to generate mechanical energy and fresh water by using the cold deep water, only about 1000 m below this vast heat reservoir as the heat sink. After its utilization in the condenser of the power generating or desalination plant, the deep water can be utilized in a mariculture system to produce plant and animal protein. In a small shore-based pilot plant on the north shore of St. Croix, U. S. Virgin Islands, the technical feasibility of Artificial Upwelling mariculture has been demonstrated. Its economic potential is now under evaluation. The plant protein yield per unit surface area achieved in St. Croix is 8.1 tons/hectare/year. At current market prices, the gross sales value of the meat which can be obtained from a given volume of deep sea water pumped to the surface is considerably greater than that of the energy which can be generated from the same volume of deep water, according to OTEC power systems presently under consideration in the United States. The combined utilization of the ΔT and the nutrient content of deep water in the tropical ocean could be economical and would contribute to solving current shortages of food and energy.
Power Characteristics of a Continuous Crystallization Latent Heat Recovery System
Authors: Hallett J. , Keyser G.
Published: April 2015

A system for low quality heat storage through the latent heat of salt hydrates has been devised which gives only a slowly varying power output. This utilizes continuous generation and sedimentation of crystals. Heat transfer is accomplished by buoyant kerosene drops rising through a salt solution with concentration and size of suspended crystals controlled primarily by kerosene flow rate. The system has been investigated for sodium sulfate, sodium thiosulfate, and sodium acetate at working temperatures of 33, 48, 58 C, respectively. The sodium acetate system showed most promise and was studied quantitatively in a pilot unit.
On Air Conditioning With Photovoltaics
Authors: Kern E. C.
Published: April 2015

A simple solar photovoltaic power system comprised of photovoltaic modules and a vapor-compression air conditioner is described and its performance characteristics are analyzed. The mathematical model expresses the system’s cooling capacity as a function of insolation, ambient air temperature, and indoor air temperature. The economics of photovoltaic power systems are generally optimum when the power supply matches exactly the load demand, thus eliminating the need for on-site energy storage or backup power. Correlations between predicted cooling capacities and air conditioning loads are presented as one measure of the economics of air conditioning with photovoltaics.
Application of Solar Energy to Continuous Belt Dehydration
Authors: Graham B. J.
Published: April 2015

A solar system utilizing a 553-m2 (5950-ft2) array of evacuated tube collectors has been designed to augment the heat supplied by natural gas to a Proctor & Schwartz continuous belt dryer used for processing onions and garlic at the Gilroy Foods plant in Gilroy, California. It has been calculated that the array, which contains 3216 evacuated tubes, will contribute 2.47 × 1012 J/yr (2340 MBtu/yr) to the dehydration process. The system is currently being installed and will be operational for drying in May 1979. This project was sponsored by the U. S. Department of Energy under Contract No. E-(40-1)-5119.
Noncatalytic Conversion of Biomass to Gasoline
Authors: Diebold J. P. , Smith G. D.
Published: April 2015

This process involves three major steps: (a) a unique selective pyrolysis of biomass to form gases unusually rich in olefins, such as ethylene, propylene, and butylene; (b) compression and purification to concentrate the olefins; and (c) polymerization of the olefins to form primarily high octane gasoline. Preliminary economic evaluation by an independent third party has shown the process to be suitable for relatively small plant sizes. The process is currently in the bench-scale of development and has been funded by the Environmental Protection Agency (EPA).
Production of High Value Solid Fuels From Cellulosic Feed Materials by the Koppelman Process
Authors: Murray R. G.
Published: April 2015

When wet cellulosic material is heated to 500 C in an autoclave at 100 atmospheric pressure, the resulting solid product is dry and has a heating value ranging from 6700 to 7800 cal/g (12,00 to 14,00 Btu/lb). This treatment is the basis for the Koppelman Process covered in U.S. Patent 4,052,168. Test results and product characteristics are described.
Sputter deposition of thermochromic VO2 films on In2O3:Sn, SnO2, and glass: Structure and composition versus oxygen partial pressure
Authors: Montero José , Ji Yu-Xia , Li Shu-Yi , Niklasson Gunnar A. , Granqvist Claes G.
Published: April 2015

Thermochromic thin films of VO2 were produced by reactive DC magnetron sputtering and were characterized by atomic force microscopy, scanning electron microscopy, x-ray diffraction, spectrophotometry, and resistance measurements. Depositions took place onto substrates of glass with and without layers of electrically conducting ITO (i.e., In2O3:Sn) and nonconducting SnO2. The substrate conditions were of large importance; thus, VO2 could be prepared on ITO within a significantly wider process window of oxygen partial pressure than for the other substrates and could yield highly granular deposits. VO2 films on ITO typically showed some lattice compression. Our results are valuable for the preparation and implementation of thermochromic glazings, which are of importance for energy efficient buildings.
Complete Coding Sequences of Eastern Equine Encephalitis Virus and Venezuelan Equine Encephalitis Virus Strains Isolated from Human Cases
Authors: Yu Guo-Yun , Wiley Michael R. , Kugelman Jeffrey R. , Ladner Jason T. , Beitzel Brett F. , Eccleston Lori T. , Morazzani Elaine M. , Glass Pamela J. , Palacios Gustavo F.
Published: April 2015

We obtained the complete coding genome of an eastern equine encephalitis virus (EEEV) strain, EEEV V105-00210, and the complete genome of a Venezuelan equine encephalitis virus (VEEV) strain, VEEV INH-9813. They were obtained from human cases and are proposed as reference challenge strains for vaccine and therapeutic development in animal models.
Complete Genome Sequence of a Hop Latent Virus Infecting Hop Plants
Authors: Jo Yeonhwa , Choi Hoseong , Cho Won Kyong
Published: April 2015

The hop latent virus is a single-stranded RNA virus that mainly infects hop plants. Here, we report the complete genome sequence of a hop latent virus, which was
de novo
assembled by RNA sequencing (RNA-seq). Our study indicates that transcriptome data are useful for identifying a complete viral genome.
Draft Genome Sequence of Clostridium beijerinckii Ne1, Clostridia from an Enrichment Culture Obtained from Australian Subterranean Termite,
Nasutitermes exitiosus
Authors: Wang Han , Lin Hai , Tran-Dinh Nai , Li Dongmei , Greenfield Paul , Midgley David J.
Published: April 2015

The draft genome of
Clostridium beijerinckii
strain Ne1 was reconstructed from the metagenomic sequence of a mixed-microbial consortium that produced commercially significant quantities of hydrogen from xylan as a sole feedstock. The organism possesses relatively limited hemicellulolytic capacity and likely requires the action of other organisms to completely degrade xylan.
Complete Genome Sequence of Streptococcus iniae YSFST01-82, Isolated from Olive Flounder in Jeju, South Korea
Authors: Rajoo Sasikumar , Jeon Wooyoung , Park Kyungmoon , Yoo Sungsik , Yoon Injung , Lee Hongweon , Ahn Jungoh
Published: April 2015

Streptococcus iniae
is associated with morbidity in commercial fish species, especially in olive flounders (
Paralichthys olivaceus
), and was recently identified as an emerging human pathogen. Here, we report the complete 2.09-Mb genome sequence of
S. iniae
strain YSFST01-82, isolated from an olive flounder with streptococcosis disease in Jeju, South Korea.
Draft Genome Sequences of Agrobacterium nepotum Strain 39/7
T
and
Agrobacterium
sp. Strain KFB 330
Authors: Kuzmanović Nemanja , Puławska Joanna , Prokić Anđelka , Ivanović Milan , Zlatković Nevena , Gašić Katarina , Obradović Aleksa
Published: April 2015

Tumorigenic strains of
Agrobacterium
spp. are responsible for crown gall disease of numerous plant species. We present here draft genome sequences of nonpathogenic
Agrobacterium nepotum
strain 39/7
T
(CFBP 7436
T
, LMG 26435
T
), isolated from crown gall tumor on
Prunus cerasifera
, and tumorigenic
Agrobacterium
sp. strain KFB 330 (CFBP 8308, LMG 28674), isolated from galls on raspberry.
Genome Sequence of Mucoid Pseudomonas aeruginosa Strain FRD1
Authors: Wang Di , Hildebrand Falk , Ye Lumeng , Wei Qing , Ma Luyan Z.
Published: April 2015

Pseudomonas aeruginosa
is an important opportunistic pathogen. Strain FRD1 is a mucoid isolate from the sputum of a cystic fibrosis patient. It has been widely studied and has many different phenotypes compared to nonmucoid strains. Here, we present the draft genome sequence of
P. aeruginosa
strain FRD1 to gain insight into mucoid isolates.
Terminology and definitions on groin pain in athletes: building agreement using a short Delphi method
Authors: Weir Adam , Hölmich Per , Schache Anthony G , Delahunt Eamonn , de Vos Robert-Jan
Published: April 2015

Background

Groin pain in athletes occurs frequently and can be difficult to treat, which may partly be due to the lack of agreement on diagnostic terminology.

Objective

To perform a short Delphi survey on terminology agreement for groin pain in athletes by a group of experts.

Methods

A selected number of experts were invited to participate in a Delphi questionnaire. The study coordinator sent a questionnaire, which consisted of demographic questions and two ‘real-life’ case reports of athletes with groin pain. The experts were asked to complete the questionnaire and to provide the most likely diagnosis for each case. Questionnaire responses were analysed by an independent researcher. The Cohen's κ statistic was used to evaluate the level of agreement between the diagnostic terms provided by the experts.

Results

Twenty-three experts participated (96% of those invited). For case 1, experts provided 9 different terms to describe the most likely diagnosis; for case 2, 11 different terms were provided to describe the most likely diagnosis. With respect to the terms provided for the most likely diagnosis, the Cohen's κ was 0.06 and 0.002 for case 1 and 2, respectively. This heterogeneous taxonomy reflects only a slight agreement between the various diagnostic terms provided by the selected experts.

Conclusions

This short Delphi survey of two ‘typical, straightforward’ cases demonstrated major inconsistencies in the diagnostic terminology used by experts for groin pain in athletes. These results underscore the need for consensus on definitions and terminology on groin pain in athletes.
The diagnostic performance evaluation of the SD BIOLINE HIV/syphilis Duo rapid test in southern Ethiopia: a cross-sectional study
Authors: Shimelis Techalew , Tadesse Endale
Published: April 2015

Objective

To determine the diagnostic performance of the SD BIOLINE HIV/syphilis Duo rapid test.

Design

A hospital-based cross-sectional study.

Setting

This evaluation was conducted at one of the largest hospitals in southern Ethiopia.

Participants

Serum samples obtained from clients attending the antiretroviral therapy and voluntary counselling and testing centres were used. Sera were originally collected for the purpose of investigating syphilis epidemiology. The performance of the test to detect HIV was evaluated using 400 sera (200 HIV positives and 200 HIV negatives). Also, its performance to detect syphilis was evaluated using 85 syphilis positive and 100 syphilis negative serum samples. Individuals <15 years of age or syphilis treated or those with ≤50 cells/µL CD4 cell count were originally excluded.

Outcome measures

HIV screening was carried out according to the national rapid diagnostic testing (RDT) algorithm: Shenghai Kehua Bioengineering (KHB) test kit as a screening test, followed by the HIV1/2 STAT-PAK assay if positive. Where the result of the STAT-PAK is discordant with KHB, Unigold HIV is used as a tiebreaker to determine the result. We also used ELISA to resolve discordant HIV results. Syphilis serostatus was determined using theTreponema pallidumhaemagglutination assay (TPHA).

Results

The respective sensitivity, specificity, positive predictive value and negative predictive value of the SD BIOLINE HIV/syphilis Duo test were 100, 99.5, 99.5 and 100% for HIV and 97.6, 96, 95.4 and 98% for syphilis testing, respectively. In reference to TPHA, the test kit reported 4 false positives and 2 false negative results for syphilis. The κ values were 0.99 for HIV testing and 0.94 for syphilis testing.

Conclusions

The excellent performance of the SD BIOLINE HIV/syphilis Duo test to detect HIV as well as syphilis facilitates the integration of syphilis testing and treatment to the already established HIV prevention programme, ultimately contributing to the dual HIV and syphilis elimination goal.
Rotation of principal axes and changes of stress due to mine-induced stresses
Authors: Ptáček J. , Konicek P. , Staš L. , Waclawik P. , Kukutsch R.
Published: April 2015

This research project comprises stress monitoring, primarily of the changes induced by longwall mining or destress blasting, which was realized in a mine of the Ostrava-Karviná Coalfields (Upper Silesian Coal Basin). Verification of the stress field response to stresses induced by different geological or mining factors was the main aim of the research project. Stress change monitoring in the region of the advanced longwall was carried out using seven stress probes. In all, seven boreholes were instrumented with compact conical ended borehole monitoring (CCBM) probes for continuous stress monitoring of the stress–strain changes due to mining and the destress blasting effect. Compact conical-ended borehole overcoring (CCBO) and CCBM probe installation were carried out before the start of the longwall mining. Data of the stress changes in all seven probes were recorded weekly and, after the longwall advanced, daily. Analysis of the stress changes was based on the idea of original stress distribution, which is based on long-term experiences in rock mass behavior in similar geological and mining conditions. For all probes, the magnitude of stress changes and principal axis direction changes were investigated. Analysis results to date indicate that stress changes ahead of the longwall face present not only the changes of stress magnitude, but the rotation of the axes of the stress components as well. Rotations of the principal axes emerged as very important factors of the stress tensor changes and their influence on rock mass deformation and stability of the workings. In addition, results show that the vertical to horizontal stress component ratio converges to 1 and in many cases horizontal stresses are higher than vertical ones. This of course relates to the impact of mine-induced stresses. This knowledge is basic for the purpose of prevention of rock burst because the actual stress state is fundamental to its proper and operative planning.
Identification of functional candidates amongst hypothetical proteins of Mycobacterium leprae Br4923, a causative agent of leprosy
Authors: Naqvi Ahmad Abu Turab , Ahmad Faizan , Hassan Md. Imtaiyaz
Published: April 2015

Mycobacterium leprae is an intracellular obligate parasite that causes leprosy in humans, and it leads to the destruction of peripheral nerves and skin deformation. Here, we report an extensive analysis of the hypothetical proteins (HPs) from M. leprae strain Br4923, assigning their functions to better understand the mechanism of pathogenesis and to search for potential therapeutic interventions. The genome of M. leprae encodes 1604 proteins, of which the functions of 632 are not known (HPs). In this paper, we predicted the probable functions of 312 HPs. First, we classified all HPs into families and subfamilies on the basis of sequence similarity, followed by domain assignment, which provides many clues for their possible function. However, the functions of 320 proteins were not predicted because of low sequence similarity with proteins of known function. Annotated HPs were categorized into enzymes, binding proteins, transporters, and proteins involved in cellular processes. We found several novel proteins whose functions were unknown for M. leprae. These proteins have a requisite association with bacterial virulence and pathogenicity. Finally, our sequence-based analysis will be helpful for further validation and the search for potential drug targets while developing effective drugs to cure leprosy.
Effective seeding strategy in evolutionary prisoner's dilemma games on online social networks
Authors: Xu Bo , Shi Huibin , Wang Jianwei , Huang Yun
Published: April 2015

This paper explores effective seeding strategies in prisoner's dilemma game (PDG) on online social networks, i.e. the optimal strategy to obtain global cooperation with minimum cost. Three distinct seeding strategies are compared by performing computer simulations on real online social network datasets. Our finding suggests that degree centrality seeding outperforms other strategies regardless of the initial payoff setting or network size. Celebrities of online social networks play key roles in preserving cooperation.
A promising nonlinear conjugate-gradient method proposed to design nonlinear domains with a disordered distribution
Authors: Zhao Li-Ming , Yue Gui-Kuan , Zhou Yun-Song , Wang Fu-He
Published: April 2015

A new method, namely the nonlinear conjugate-gradient (NCG) method, is proposed to design nonlinear domains with a disordered distribution, in which an efficient broadband second harmonic generation can be achieved simultaneously with high conversion efficiency. It is demonstrated by numerical simulation that the NCG method has obvious advantages in realizing the optimal quasi-phase-matching, in comparison with the traditional simulated annealing method.
Gravitational microlensing I: A unique astrophysical tool
Authors: Rahvar Sohrab
Published: April 2015

In this paper, we review the astrophysical application of gravitational microlensing. After introducing the history of gravitational lensing, we present the key equations and concept of microlensing. The most frequent microlensing events are single-lens events and historically it has been used for searching dark matter in the form of compact astrophysical halo objects in the Galactic halo. We discuss about the degeneracy problem in the parameters of lens and perturbation effects that can partially break the degeneracy between the lens parameters. The rest of paper is about the astrophysical applications of microlensing. One of the important applications is in the stellar physics by probing the surface of source stars in the high magnification microlensing events. The astrometric and polarimetric observations will be complimentary for probing the atmosphere and stellar spots on the surface of source stars. Finally we discuss about the future projects as space-based telescopes for parallax and astrometry observations of microlensing events. With this project, we would expect to produce a complete stellar and remnant mass function and study the structure of Galaxy in term of distribution of stars along our line of sight towards the center of galaxy.
EMD-BASED ECG DENOISING USING SOURCE SEPARATION
Authors: TALBI MOURAD , ABID SABEUR , CHERIF ADNEN
Published: April 2015

We consider the problem of electrocardiogram (ECG) denoising using source separation. In this study, a hybrid technique using empirical mode decomposition (EMD) and source separation, is proposed. This technique consists of two steps, the first step consists in applying the EMD to two different mixtures. These mixtures are obtained by corrupting in additive manner, the same ECG signal by a white Gaussian noise with two different values of the signal-to-noise ratio (SNR). The second step consists in computing the entropy of each obtained intrinsic mode function (IMF) and finds the two IMFs having the minimal entropy. These two IMFs are used to estimate the separation matrix of the ECG signal from noise by using the source separation. The proposed technique is evaluated by comparing it to the denoising technique based on source separation in time domain using runica and the technique based on Bionic wavelet transform (BWT) and also using source separation. The obtained results from SNR and the mean square error (MSE) computations, show that the proposed technique outperforms the other two techniques used in this evaluation.
Wigner rotation via Fermi–Walker transport and relativistic EPR correlations in the Schwarzschild spacetime
Authors: Bakke K. , Furtado C. , Carvalho A. M. de M.
Published: April 2015

The Wigner rotation angle for a particle in a circular motion in the Schwarzschild spacetime is obtained via the Fermi–Walker transport of spinors. Then, by applying the Wentzel, Kramers, Brillouin (WKB) approximation, a possible application of the Fermi–Walker transport of spinors in relativistic Einstein–Podolsky–Rosen (EPR) correlations is discussed, where it is shown that the spins of the correlated particle undergo a precession in an analogous way to that obtained by Terashima and Ueda [H. Terashima and M. Ueda, Phys. Rev. A 69, 032113 (2004)] via the application of successive infinitesimal Lorentz transformations. Moreover, from the WKB approach, it is also shown that the degree of violation of the Bell inequality depends on the Wigner rotation angle obtained via the Fermi–Walker transport. Finally, the relativistic effects from the geometry of the spacetime and the accelerated motion of the correlated particles is discussed in the nonrelativistic limit.
Quantum stabilizer codes from Abelian and non-Abelian groups association schemes
Authors: Naghipour Avaz , Jafarizadeh Mohammad Ali , Shahmorad Sedaghat
Published: April 2015

A new method for the construction of the binary quantum stabilizer codes is provided, where the construction is based on Abelian and non-Abelian groups association schemes. The association schemes based on non-Abelian groups are constructed by bases for the regular representation from U6n, T4n, V8n and dihedral D2n groups. By using Abelian group association schemes followed by cyclic groups and non-Abelian group association schemes a list of binary stabilizer codes up to 40 qubits is given in tables 4, 5 and 10. Moreover, several binary stabilizer codes of minimum distances 5, 7 and 8 with good quantum parameters is presented. The preference of this method specially for Abelian group association schemes is that one can construct any binary quantum stabilizer code with any distance by using the commutative structure of association schemes.
LEGITIMACY, ATTITUDES AND INTENDED PATRONAGE: UNDERSTANDING CHALLENGES FACING BLACK ENTREPRENEURS
Authors: OGBOLU MICHAEL N. , SINGH ROBERT P. , WILBON ANTHONY
Published: April 2015

Traditional research on the reasons for the depressed rate of black entrepreneurship has focused on differences between black [note: The term "blacks" is used to represent the broader groups of blacks in the United States, which include African-Americans and also black people from African countries, the Caribbean and other countries.] and white entrepreneurs. In this paper, we move beyond the individual entrepreneur and study consumers' perceptual differences of black and white entrepreneurs. Using a multi-disciplinary theoretical framework to study 846 participants, we found empirical evidence that there are significant relationships between perceptions of legitimacy and consumer attitudes toward entrepreneurs and intended patronage. In addition, there appears to be differences in the way consumers perceive black and white entrepreneurs, which suggest significant challenges facing black entrepreneurs. Implications and future research directions are discussed.
Topical protection of human esophageal mucosal integrity
Authors: Woodland P. , Batista-Lima F. , Lee C. , Preston S. L. , Dettmar P. , Sifrim D.
Published: April 2015

Patients with nonerosive reflux disease exhibit impaired esophageal mucosal integrity, which may underlie enhanced reflux perception. In vitro topical application of an alginate solution can protect mucosal biopsies against acid-induced changes in transepithelial electrical resistance (TER). We aimed to confirm this finding in a second model using 3D cell cultures and to assess prolonged protection in a biopsy model. We assessed the protective effect of a topically applied alginate solution 1 h after application. 3D cell cultures were grown by using an air-liquid interface and were studied in Ussing chambers. The apical surface was “protected” with 200 μl of either alginate or viscous control or was unprotected. The tissue was exposed to pH 3 + bile acid solution for 30 min and TER change was calculated. Distal esophageal mucosal biopsies were taken from 12 patients and studied in Ussing chambers. The biopsies were coated with either alginate or viscous control solution. The biopsies were then bathed in pH 7.4 solution for 1 h. The luminal chamber solution was replaced with pH 2 solution for 30 min. Percentage changes in TER were recorded. In five biopsies fluorescein-labeled alginate solution was used to allow immunohistological localization of the alginate after 1 h. In the cell culture model, alginate solution protected tissue against acid-induced change in TER. In biopsies, 60 min after protection with alginate solution, the acidic exposure caused a −8.3 ± 2.2% change in TER compared with −25.1 ± 4.5% change after protection with the viscous control ( P < 0.05). Labeled alginate could be seen coating the luminal surface in all cases. In vitro, alginate solutions can adhere to the esophageal mucosa for up to 1 h and exert a topical protectant effect. Durable topical protectants can be further explored as first-line/add-on therapies for gastroesophageal reflux disease.
Therapeutic potential of sustained-release sodium nitrite for critical limb ischemia in the setting of metabolic syndrome
Authors: Polhemus David J. , Bradley Jessica M. , Islam Kazi N. , Brewster Luke P. , Calvert John W. , Tao Ya-Xiong , Chang Carlos C. , Pipinos Iraklis I. , Goodchild Traci T. , Lefer David J.
Published: April 2015

Nitrite is a storage reservoir of nitric oxide that is readily reduced to nitric oxide under pathological conditions. Previous studies have demonstrated that nitrite levels are significantly reduced in cardiovascular disease states, including peripheral vascular disease. We investigated the cytoprotective and proangiogenic actions of a novel, sustained-release formulation of nitrite (SR-nitrite) in a clinically relevant in vivo swine model of critical limb ischemia (CLI) involving central obesity and metabolic syndrome. CLI was induced in obese Ossabaw swine ( n = 18) by unilateral external iliac artery deployment of a full cross-sectional vessel occlusion device positioned within an endovascular expanded polytetrafluoroethylene-lined nitinol stent-graft. At post-CLI day 14, pigs were randomized to placebo ( n = 9) or SR-nitrite (80 mg, n = 9) twice daily by mouth for 21 days. SR-nitrite therapy increased nitrite, nitrate, and S-nitrosothiol in plasma and ischemic skeletal muscle. Oxidative stress was reduced in ischemic limb tissue of SR-nitrite- compared with placebo-treated pigs. Ischemic limb tissue levels of proangiogenic growth factors were increased following SR-nitrite therapy compared with placebo. Despite the increases in cytoprotective and angiogenic signals with SR-nitrite therapy, new arterial vessel formation and enhancement of blood flow to the ischemic limb were not different from placebo. Our data clearly demonstrate cytoprotective and proangiogenic signaling in ischemic tissues following SR-nitrite therapy in a very severe model of CLI. Further studies evaluating longer-duration nitrite therapy and/or additional nitrite dosing strategies are warranted to more fully evaluate the therapeutic potential of nitrite therapy in peripheral vascular disease.
Pan-HER, an Antibody Mixture Simultaneously Targeting EGFR, HER2, and HER3, Effectively Overcomes Tumor Heterogeneity and Plasticity
Authors: Jacobsen Helle J. , Poulsen Thomas T. , Dahlman Anna , Kjær Ida , Koefoed Klaus , Sen Jette W. , Weilguny Dietmar , Bjerregaard Bolette , Andersen Christina R. , Horak Ivan D. , Pedersen Mikkel W. , Kragh Michael , Lantto Johan
Published: April 2015

Purpose: Accumulating evidence indicates a high degree of plasticity and compensatory signaling within the human epidermal growth factor receptor (HER) family, leading to resistance upon therapeutic intervention with HER family members.

Experimental Design/Results: We have generated Pan-HER, a mixture of six antibodies targeting each of the HER family members EGFR, HER2, and HER3 with synergistic pairs of antibodies, which simultaneously remove all three targets, thereby preventing compensatory tumor promoting mechanisms within the HER family. Pan-HER induces potent growth inhibition in a range of cancer cell lines and xenograft models, including cell lines with acquired resistance to therapeutic antibodies. Pan-HER is also highly efficacious in the presence of HER family ligands, indicating that it is capable of overcoming acquired resistance due to increased ligand production. All three target specificities contribute to the enhanced efficacy, demonstrating a distinct benefit of combined HER family targeting when compared with single-receptor targeting.

Conclusions: Our data show that simultaneous targeting of three receptors provides broader efficacy than targeting a single receptor or any combination of two receptors in the HER family, especially in the presence of HER family ligands. Pan-HER represents a novel strategy to deal with primary and acquired resistance due to tumor heterogeneity and plasticity in terms of HER family dependency and as such may be a viable alternative in the clinic. Clin Cancer Res; 21(18); 4110–22. ©2015 AACR.

See related commentary by Yarden and Sela, p. 4030
Modulation of Pulmonary Vascular Remodeling in Hypoxia: Role of 15-LOX-2/15-HETE-MAPKs Pathway
Authors: Yu Xiufeng , Li Tingting , Liu Xia , Yu Hao , Hao Zhongfei , Chen Yingli , Zhang Chen , Liu Yumei , Li Qian , Mao Min , Zhu Daling
Published: April 2015

Background: We have previously shown that 15-hydroxyeicosatetraenoic acid (15-HETE) plays a critical role in pulmonary hypertension (PH)-associated vascular remodeling. However, the signaling mechanisms remain unclear. The purpose of this study was to investigate the role of 15-lipoxygenase-2 (15-LO-2)/15-HETE-mitogen-activated protein kinases (MAPKs) pathway in hypoxia-induced pulmonary vascular remodeling and the underlying mechanisms. Methods: The arterial wall thickness was measured by hematoxylin and eosin (HE) staining in distal pulmonary arteries isolated from normal and PAH patient-derived lungs. The protein expression of phosphorylated extracellular signal-regulated kinase (p-ERK) and phosphorylated p38 mitogen-activated protein kinases (p-p38MAPK) were measured by Western blot in the lungs of PAH patients and hypoxia-induced rats. The apoptosis of cultured rat pulmonary arterial smooth muscle cells (PASMCs) was determined by Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and Flow cytometry. The cell proliferation and cell cycle in PASMCs following hypoxia were analyzed by bromodeoxyuridine incorporation and flow cytometry, respectively. Results: Our results showed that the levels of p-ERK and p-p38MAPK were both drastically elevated in lungs from human patients and hypoxic rats. The HE staining revealed that the medial wall thickness was higher in patients with PAH than normal humans. In cultured PASMCs, Hypoxia stimulated the cell proliferation, the cell cycle progression, and subsequently promoted cell differentiation and cell migration leading to the suppressed cell apoptosis. Furthermore, MAPKs- induced cell proliferation and anti-apoptosis in PASMCs is 15-LO-2/15HETE activation-dependent. Conclusion: Our study indicates that hypoxia-induced pulmonary vascular remodeling is associated with increased levels of 15-LO-2 and 15-HETE. 15-LO-2/15-HETE stimulates the cell proliferation and anti-apoptosis in PASMCs through phosphorylation of ERK and p38MAPK, which subsequently contributing to hypoxia-induced pulmonary vascular remodeling.
Depletion of Neutrophils Protects Against L-Arginine-Induced Acute Pancreatitis in Mice
Authors: Chen Guolin , Xu Feng , Li Jing , Lu Shiqi
Published: April 2015

Background/Aims: Acute pancreatitis (AP) is an inflammatory disease characterized by acinar cell damage and inflammation of the pancreas with infiltration of leukocytes, predominantly neutrophils. We investigated whether neutrophil depletion protects against experimental AP induced by L-arginine. Methods: AP was induced in C57BL/6 mice via two intraperitoneal L-arginine (4 g/kg) injections. Mice were pretreated with 250 and 100 µg anti-Gr-1 antibody via intraperitoneal injection at 24 and 4 h, respectively, before L-arginine challenge for neutrophil depletion. At 48 and 72 h after injection, the severity of AP was determined with the aid of biochemical and histological analyses. Amylase and MPO activity was detected using specific assay kits. The plasma cytokines levels were detected using ELISA. Results: Neutrophil depletion resulted in significantly reduced plasma amylase levels in pancreas, myeloperoxidase (MPO) activity in pancreas and lung, reactive oxygen species (ROS) generation and cell apoptosis, and decreased circulating neutrophil, tissue damage as well as expression levels of nuclear factor NF-κB. Conclusion: Neutrophil depletion is capable of reducing tissue damage of pancreas and lung in mice with acute pancreatitis.
Exercise Prevents Cardiac Injury and Improves Mitochondrial Biogenesis in Advanced Diabetic Cardiomyopathy with PGC-1α and Akt Activation
Authors: Wang Hui , Bei Yihua , Lu Yan , Sun Wei , Liu Qi , Wang Yalong , Cao Yujie , Chen Ping , Xiao Junjie , Kong Xiangqing
Published: April 2015

Background/Aims: Diabetic cardiomyopathy (DCM) represents the major cause of morbidity and mortality among diabetics. Exercise has been reported to be effective to protect the heart from cardiac injury during the development of DCM. However, the potential cardioprotective effect of exercise in advanced DCM remains unclear. Methods: Seven-week old male C57BL/6 wild-type or db/db mice were either subjected to a running exercise program for 15 weeks or kept sedentary. Cardiac function, myocardial apoptosis and fibrosis, and mitochondrial biogenesis were examined for evaluation of cardiac injury. Results: A reduction in ejection fraction and fractional shortening in db/db mice was significantly reversed by exercise training. DCM induced remarkable cardiomyocyte apoptosis and increased ratio of Bax/Bcl-2 at the protein level. Meanwhile, DCM caused slightly myocardial fibrosis with elevated mRNA levels of collagen I and collagen III. Also, DCM resulted in a reduction of mitochondrial DNA (mtDNA) replication and transcription, together with reduced mtDNA content and impaired mitochondrial ultrastructure. All of these changes could be abolished by exercise training. Furthermore, DCM-associated inhibition of PGC-1α and Akt signaling was significantly activated by exercise, indicating that exercise-induced activation of PGC-1α and Akt signaling might be responsible for mediating cardioprotective effect of exercise in DCM. Conclusion: Exercise preserves cardiac function, prevents myocardial apoptosis and fbrosis, and improves mitochondrial biogenesis in the late stage of DCM. Exercise-induced activation of PGC-1α and Akt signaling might be promising therapeutic targets for advanced DCM.
Obesity-Associated MiR-342-3p Promotes Adipogenesis of Mesenchymal Stem Cells by Suppressing CtBP2 and Releasing C/EBPα from CtBP2 Binding
Authors: Wang Liang , Xu Lei , Xu Min , Liu Guoqiang , Xing Jian , Sun Caifeng , Ding Huifang
Published: April 2015

Background/Aims: The elucidation of the molecular mechanism of adipocyte differentiation in mesenchymal stem cells is of essential importance for the development of treatments for metabolic diseases, such as obesity and diabetes. Methods: The expression levels of miR-342-3p and carboxy-terminal binding protein 2 (CtBP2) were regulated by oligonucleotide transfection. Adipogenic differentiation was induced by adipogenic medium containing indomethacin, dexamethasone and 3-isobutyl-1-methylxanthine on day 12, as determined by Oil Red O staining and triglyceride concentration assay to assess intracellular lipid accumulation. The induction of adipocyte-specific transcription factors and markers was detected by qRT-PCR and western blot. The regulation of CtBP2 expression by miR-342-3p was determined by western blot, qRT-PCR, luciferase reporter assay, ChIP assay and functional experiments. Results: We revealed that miR-342-3p was enriched in the adipose tissue of obese mice, and its expression was significantly elevated during adipogenic differentiation in both human mesenchymal stem cells (hMSCs) and 3T3L1 cells. Using gain- and loss-of-function assays, we demonstrated that the overexpression of miR-342-3p markedly promoted the differentiation of hMSCs into an adipogenic lineage. Adipogenesis was significantly blocked by miR-342-3p downregulation. We identified and validated that CtBP2 was a direct target of miR-342-3p in this process. The effects of the inhibition of CtBP2 were similar to those of miR-342-5p overexpression on adipogenic differentiation, promoting the release of C/EBPα from CtBP2 binding. Conclusion: miR-342-3p is a powerful enhancer of the adipogenesis of human adipose-derived MSCs that acts by inhibiting CtBP2 and releasing the key adipogenic regulator C/EBPα from CtBP2 binding, subsequently activating the expression of adipogenic transcription factors and markers.
GFP Labeling and Hepatic Differentiation Potential of Human Placenta-Derived Mesenchymal Stem Cells
Authors: Yu Jiong , Su Xiaoru , Zhu Chengxing , Pan Qiaoling , Yang Jinfeng , Ma Jing , Shen Leyao , Cao Hongcui , Li Lanjuan
Published: April 2015

Background: Stem cell-based therapy in liver diseases has received increasing interest over the past decade, but direct evidence of the homing and implantation of transplanted cells is conflicting. Reliable labeling and tracking techniques are essential but lacking. The purpose of this study was to establish human placenta-derived mesenchymal stem cells (hPMSCs) expressing green fluorescent protein (GFP) and to assay their hepatic functional differentiation in vitro. Methods: The GFP gene was transduced into hPMSCs using a lentivirus to establish GFP+ hPMSCs. GFP+ hPMSCs were analyzed for their phenotypic profile, viability and adipogenic, osteogenic and hepatic differentiation. The derived GFP+ hepatocyte-like cells were evaluated for their metabolic, synthetic and secretory functions, respectively. Results: GFP+ hPMSCs expressed high levels of HLA I, CD13, CD105, CD73, CD90, CD44 and CD29, but were negative for HLA II, CD45, CD31, CD34, CD133, CD271 and CD79. They possessed adipogenic, osteogenic and hepatic differentiation potential. Hepatocyte-like cells derived from GFP+ hPMSCs showed typical hepatic phenotypes. Conclusions: GFP gene transduction has no adverse influences on the cellular or biochemical properties of hPMSCs or markers. GFP gene transduction using lentiviral vectors is a reliable labeling and tracking method. GFP+ hPMSCs can therefore serve as a tool to investigate the mechanisms of MSC-based therapy, including hepatic disease therapy.
Toll-Like Receptor 4/Spleen Tyrosine Kinase Complex in High Glucose Signal Transduction of Proximal Tubular Epithelial Cells
Authors: Yang Won Seok , Kim Joon-Seok , Han Nam Jeong , Lee Mee Jeong , Park Su-Kil
Published: April 2015

Background/Aims: High glucose activates spleen tyrosine kinase (Syk) in human proximal tubular epithelial cells (HK-2 cells), which leads to NF-κB activation and transforming growth factor-ß1 (TGF-ß1) production. We explored the signal transduction pathway from high glucose to Syk activation. Methods: The pathway was evaluated by siRNA transfection, immunoprecipitation and Western blot. Results: High glucose stimulated Syk activation within 10 min. Depletion of toll-like receptor 4 (TLR4) attenuated high glucose-induced Syk activation, NF-κB p65 nuclear translocation, and TGF-ß1 production. In addition, TLR4 inhibitor (CLI-095), TLR4-neutralizing antibody, and depletion of myeloid differentiation factor 88 (MyD88) all attenuated high glucose-induced Syk activation. As an evidence of TLR4 activation, interleukin-1 receptor-associated kinase 1 was recruited to MyD88 and TLR4 upon exposure to high glucose. Syk was co-immunoprecipitated with TLR4, and Syk bound to TLR4 was activated by high glucose. High-mobility group box-1 (HMGB-1), an endogenous activator of TLR4, rapidly increased in TLR4 immunoprecipitates upon high glucose stimulation, and this association was reduced by N-acetylcysteine, an antioxidant. An HMGB-1 inhibitor glycyrrhizin suppressed high glucose-induced Syk activation. Conclusion: Syk is constitutively associated with TLR4. High glucose induces an immediate, reactive oxygen species-dependent, extracellular release of HMGB-1 which binds to TLR4 and activates it, leading to Syk activation.
Baicalin Attenuates High Fat Diet-Induced Obesity and Liver Dysfunction: Dose-Response and Potential Role of CaMKKβ/AMPK/ACC Pathway
Authors: Xi Youli , Wu Miaozong , Li Hongxia , Dong Siqi , Luo Erfei , Gu Mingbo , Shen Xiao , Jiang Yabo , Liu Yaqun , Liu Hua
Published: April 2015

Background/Aims: Obesity-associated fatty liver disease affects millions of individuals. This study aimed to evaluate the therapeutic effects of baicalin to treat obesity and fatty liver in high fat diet-induced obese mice, and to study the potential molecular mechanisms. Methods: High fat diet-induced obese animals were treated with different doses of baicalin (100, 200 and 400 mg/kg/d). Whole body, fat pad and liver were weighed. Hyperlipidemia, liver steatosis, liver function, and hepatic Ca2+/CaM-dependent protein kinase kinase β (CaMKKβ) / AMP-activated protein kinase (AMPK) / acetyl-CoA carboxylase (ACC) were further evaluated. Results: Baicalin significantly decreased liver, epididymal fat and body weights in high fat diet-fed mice, which were associated with decreased serum levels of triglycerides, total cholesterol, LDL, alanine transaminase and aspartate transaminase, but increased serum HDL level. Pathological analysis revealed baicalin dose-dependently decreased the degree of hepatic steatosis, with predominantly diminished macrovesicular steatosis at lower dose but both macrovesicular and microvesicular steatoses at higher dose of baicalin. Baicalin dose-dependently inhibited hepatic CaMKKβ/AMPK/ACC pathway. Conclusion: These data suggest that baicalin up to 400 mg/kg/d is safe and able to decrease the degree of obesity and fatty liver diseases. Hepatic CaMKKβ/AMPK/ACC pathway may mediate the therapeutic effects of baicalin in high fat diet animal model.
Salicylate Inhibits Thrombopoiesis in Rat Megakaryocytes by Changing the Membrane Micro-Architecture
Authors: Kazama Itsuro , Baba Asuka , Endo Yasuhiro , Toyama Hiroaki , Ejima Yutaka , Matsubara Mitsunobu , Tachi Masahiro
Published: April 2015

Background/Aims: Salicylate causes drug-induced immune thrombocytopenia. However, some clinical studies indicate the presence of additional mechanisms in the drug-induced thrombocytopenia, by which the platelet production from megakaryocytes may directly be affected. Since salicylate is amphiphilic and preferentially partitioned into the lipid bilayers of the plasma membrane, it can induce some structural changes in the megakaryocyte membrane surface and thus affect the process of thrombopoiesis. Methods: Employing the standard patch-clamp whole-cell recording technique, we examined the effects of salicylate on the membrane capacitance in rat megakaryocytes. Taking electron microscopic imaging of the cellular surface, we also examined the effects of salicylate on the membrane micro-architecture of megakaryocytes. Results: Salicylate significantly decreased the membrane capacitance of megakaryocytes, indicating the decreased number of invaginated plasma membranes, which was not detected by the fluorescent imaging technique. As shown by electron microscopy, salicylate actually halted the process of pro-platelet formation in megakaryocytes. Conclusion: This study demonstrated for the first time that salicylate inhibits the process of thrombopoiesis in megakaryocytes, as detected by the decrease in the membrane capacitance. Salicylate-induced changes in the membrane micro-architecture are thought to be responsible for its effects.
Forkhead Box O-1 Modulation Improves Endothelial Insulin Resistance in Human Obesity
Authors: Karki Shakun , Farb Melissa G. , Ngo Doan T.M. , Myers Samantha , Puri Vishwajeet , Hamburg Naomi M. , Carmine Brian , Hess Donald T. , Gokce Noyan
Published: April 2015

Objective—

Increased visceral adiposity has been closely linked to insulin resistance, endothelial dysfunction, and cardiometabolic disease in obesity, but pathophysiological mechanisms are poorly understood. We sought to investigate mechanisms of vascular insulin resistance by characterizing depot-specific insulin responses and gain evidence that altered functionality of transcription factor forkhead box O-1 (FOXO-1) may play an important role in obesity-related endothelial dysfunction.

Approach and Results—

We intraoperatively collected paired subcutaneous and visceral adipose tissue samples from 56 severely obese (body mass index, 43±7 kg/m
2
) and 14 nonobese subjects during planned surgical operations, and characterized depot-specific insulin-mediated responses using Western blot and quantitative immunofluorescence techniques. Insulin signaling via phosphorylation of FOXO-1 and consequent endothelial nitric oxide synthase stimulation was selectively impaired in the visceral compared with subcutaneous adipose tissue and endothelial cells of obese subjects. In contrast, tissue actions of insulin were preserved in nonobese individuals. Pharmacological antagonism with AS1842856 and biological silencing using small interfering RNA–mediated FOXO-1 knockdown reversed insulin resistance and restored endothelial nitric oxide synthase activation in the obese.

Conclusions—

We observed profound endothelial insulin resistance in the visceral adipose tissue of obese humans which improved with FOXO-1 inhibition. FOXO-1 modulation may represent a novel therapeutic target to diminish vascular insulin resistance. In addition, characterization of endothelial insulin resistance in the adipose microenvironment may provide clues to mechanisms of systemic disease in human obesity.