bluuebunny/crossref_metadata_2025 huggingface dataset:
Bitumen Emulsion in Malaysia–A Conspectus
Authors: Yaacob Haryati , Hainin Mohd. Rosli , A. Aziz Md. Maniruzzaman , M. Warid Naqiuddin , Chang Fung-Lung , Ismail Che Ros , Abdul Hassan Norhidayah
Published: January 2014

Bitumen emulsion is an important building material, especially in highway pavement construction. It is a mixture of bitumen (asphalt), water and emulsifying agent, dispersed in tiny particles in an aqueous medium. It is an important material widely used in the pavement construction ever since the first introduction in the year 1900’s. This paper aims to provide an overview and an understanding among the practitioners on the bitumen emulsion from the manufacturing process, naming and categorizing to its potential application. Bitumen emulsion can be manufactured in a batch plant or in-line plant. Being water based, it is capable to be applied under ambient temperature besides being more environmental friendly. Categorizing the bitumen emulsion is simple but the naming may differs slightly according to local specification. Continuous research also has end up in the modification of conventional bitumen emulsion using polymers to produce polymer modified bitumen (PMB) emulsion which decreases thermal susceptibility and permanent deformation (rutting). It has resulted in even wider application of bitumen emulsion as in microsurfacing, slurry seal and cape seal.
Effect of Different Types of Microporous Layer Toward the Performance of Direct Formic Acid Fuel Cell
Authors: Mohamed Aslam Norraihanah , Masdar Mohd Shahbudin , Kamarudin Siti Kartom
Published: January 2014

Typical electrodes of anode and cathode are supported on macroporous backing layer with additional microporous carbon layer. The effect of the gas diffusion layer (GDL) on the cell performance in a direct formic acid fuel cell (DFAFC) has been characterized.Â  The performance of DFAFC might be hindered by mass transfer limitation due to hydrophilicity properties of the formic acid. By measuring the contact angle and SEM photograph, the physicochemical and surface morphology of different types of GDL can be classified. Meanwhile, the effects of carbon materials such as carbon black, carbon nanofibre and carbon nanotube as a microporous layer on the backing layer of carbon paper were investigated on the basis of the characterization and the performance. From the results, it was obtained that CNF was a good material as microporous layer due to the properties of in plane conductivity, high current in cyclic voltammetry and also had smoother surface on the morphology test.
Attenuation of Ground Penetrating Radar Signal Amplitude in Monitoring Reinforced Steel Corrosion
Authors: Abd. Ghani Azfaratul Hani , Senin Syahrul Fithry , Hamid R.
Published: January 2014

In this study, the reduction of ground penetrating radar (GPR) signal amplitude magnitudes were measured to monitor the reinforcing steel corrosion in concrete slab. Geophysical Survey System Incorporation (GSSI) BridgeScan system which includes a SIR-3000 Windows, based on portable GPR data collection with 1.6 GHz ground-couple antenna has been used to generate electromagnetic waves and analysis of the signal on a slab sample. Four 16 mm diameter reinforcing steel were embedded in a 255 mm x 455 mm x 60 mm grade 40 concrete slab in the transverse direction and three in the longitudinal. The slab was immersed in concentrated sodium chloride solution (8 g/l) for three months to simulate the corrosive environment on the reinforced slab. The average signal amplitude decreases from 1139.75 dB (at day 7) to -404.25 dB (at day 61) and finally drop to -782.75 dB (at day 93) as the corrosion process progressing. The presence of corrosion activity on the reinforcing steel was confirmed based on the potential difference reading by Half Cell (HC) which shows that the reinforcing steel experienced probability of corrosion level by more than 90 % after 61 and 93 days. GPR method is found to be a promising approach as it possesses high sensitivity towards changes in amplitude at par with high potential changes in HC method in corrosion detection.
Kesan Kenaikan Harga Bahan Bakar Terhadap Penggunaan Pengangkutan Awam
Authors: Nazri Borhan Muhamad , Abd. Rahman Nurul Aishah , O.K. Rahmat Riza Atiq Abdullah
Published: January 2014

This paper discusses the impact for the rise of the fuel price on public transports use. The Malaysian government provides fuel subsidies for petroleum, diesel, gas and electricity. This makes the price at the pump is among the lowest in the region with RM1.90 per litre for petrol. Provision of fuel subsidies helps motor vehicle users to pay less for the cost of travel. Besides, private car ownership will increase and would causes serious problem such as congestion, environmental pollution and accidents. Increasing fuel prices is seen as a significant way to reduce the use of private vehicles and to promote people to use public transports. In order to evaluate the impact of this factor, data are taken randomly during peak hours through stated preference (SP) survey method among the users of private transports. Logistic regression has been used to analyse the factors that influence users to switch their trips mode to public transports. It is concluded that with the rising of the fuel prices, it will directly effect the use of the public transports facility.
Refined FEM Analysis of Steel-Concrete Composite Beam Subjected to Negative Bending and Axial Compressive Forces
Authors: Bavan Mahesan , Baharom Shahrizan , Mutalib Azrul A.
Published: January 2014

This paper presents modelling techniques with finite element method (FEM) for a composite beam subjected to combined negative bending and axial compressive forces. Flexural behaviours of composite beam were thoroughly analysed to determine the ultimate limit state due to vertical and axial compressive forces. Failure state of composite beam was revealed by the level of axial compressive forces and reduced negative moment due to axial compressive forces. The results obtained from FEM analysis were compared with the results of experimental analysis. Reliability agreement has been observed between the results of FEM and experimental analysis on ultimate state behavior and failure modes. Detailed numerical techniques such as loading strategies in combined vertical and axial compressive directions and potential convergence problems due to complicated contacts between the material components are discussed in this paper. Finally simplified numerical techniques for uncertainties in axially compressed composite beam subjected to negative bending are suggested.
Ultrafiltration Behavior of Organic Mixtures Simulating Sweetwater Solutions: Influence of Membrane Surface and Feed Chemistry
Authors: Mohd Amin Indok Nurul Hasyimah , Mohammad Abdul Wahab
Published: January 2014

One of the major drawbacks for the successful of ultrafiltration (UF) during pretreatment of glycerin-rich solution is membrane fouling due to the deposition of triglycerides (TG) and fatty acids (FA). In the present study, attempts were made to examine the filtration behaviour of organic mixtures (oleic acid-triglycerides) compared to single organic solute (triglycerides) contained in synthetic glycerol-water solutions (known as sweetwater). Furthermore, the rejections of individual solutes were studied. The TG-FA mixtures permeated preferentially when compared with single TG which is mainly due to the solubility as well as diffusivity of small fatty acid in the TG-FA mixtures. Furthermore, PVDF membrane provided higher fluxes and experienced less fouling than PES membrane for both cases. In case of PVDF membrane, the rejection of fatty acid was 6.20% while oil rejection in glycerol-water plus TG and TG-FA mixtures was 82.42% and 84.67%, respectively. However, PES membrane underwent higher fatty acid rejection (20.93%) as well as oil rejection in single TG (94.70%) and TG-FA mixtures (91.08%). It is noteworthy that the nature of the membrane and the feed characteristics had a significant effect on the fouling potential and filtration performance.
Understanding the Blended Learning Experiences of English Language Teachers in a Distance TESL Degree Programme in Malaysia
Authors: Kean Wah Lee , Choon Keong Tan , Lajium Denis , Shi Ing Ng
Published: January 2014

In an effort to improve the status and the professional qualification of non-graduate primary school teachers, the Ministry of Education, Malaysia recently mandated a large scale change effort to upgrade non-graduate teachers to become graduate teachers via a a specially designed distant education degree programme, called the Graduate Programme for Teachers (Program Pensiswazahan Guru also known as PPG in Malay language) using a blended format involving part face-to-face (F2F) and distance learning. This paper examines the learning experiences of the first cohort of TESL teachers undergoing the blended learning (BL) courses. Specifically, learning experiences were examined in the form of (1) the in-service teachersâ€™ perception towards the BL approach, and (2) the learning experiences supporting or impeding their learning using the BL approach. To gain an appreciation of the in-service teachersâ€™ experience with the BL system, both qualitative and quantitative techniques were used, namely a survey consisting of open and closed questions, focus groups interviews and reflective journals. Findings revealed the teachers generally have positive perceptions of the blended course design. However, when viewed through the theoretical lens of Activity Theory (AT), data revealed tensions both between and within the components of the activity system in the BL environment. The paper concludes that further fine-tuning needs to be taken to ameliorate the challenges faced, particularly the contradictions and tensions involving issues related to willingness and attitudes towards learning the courses (object/outcome component); Schoology and learning materials (Mediating tools); collaboration (Rules) and opinions related to â€˜teacherâ€™s presenceâ€™ (Division of Labour).
A Target Needs Analysis of the Written Communication Skills for Students of Writing for Professional Purposes Course
Authors: Vaghari Shaghayegh , Shuib Munir
Published: January 2014

The great demand for business communication skills among graduates has urged universities to develop English business communication courses, which lie under the domain of â€˜English for Specific Purposesâ€™. This paper aims to conduct a 'needs analysis' of Writing for Professional Purposes course students at the School of Humanities, Universiti Sains Malaysia (USM). It is part of a study which aims at gathering pertinent information from multiple sources including students, graduates of the Writing for Professional Purposes course, employers, and an ESP teacher. Hutchinson and Watersâ€™ model of needs analysis used in the present study to explorethe perceptions of graduates of the courseon the course studentsâ€™ target needs with regards to written business communication skills. The results demonstrate that a few written business communication skills such as writing emails, resumes and reportsare highly important in todayâ€™s workplace. Thus it is vital for students of Writing for Professional Purposes course to be prepared with the needed written business communication skills. The study indicates that generally the course is in line with the studentsâ€™ target needs.
Roles of Mentees via Virtual Mentoring
Authors: Fong Ng Siew , Zakaria Mohamad Hassan , Wan Mansor Wan Fara Adlina
Published: January 2014

This paper presents a case study that highlights online mentoring among pre-service teachers and in-service teachers from three local public tertiary institutions. Specifically, it investigates the roles of mentees during virtual mentoring sessions. Four groups of pre-service teachers from three local tertiary institutions mentored by four in-service teachers from Johor Bahru participated in the study. Each group was assigned an online newsletter and required to carry out writing of the online newsletter task by discussing through Nicenet, an online forum, when carrying out the task. The data obtained from the online postings on Nicenet was analyzed using Ambrosetti and Dekkersâ€™s (2010) roles of mentees. Findings implied that the e-mentees acted as supporters, active participants, collaborators, leaders, and role models. The findings also revealed three salient themes which are: i) collaboration as an inevitable practice, ii) the need for mentees to be actively involved in mentoring practice and iii) the lack of experience and self-esteem among mentees.
Development and review of the voluntary phase of a national BVD eradication programme in Ireland
Authors: Graham D. A. , Lynch M. , Coughlan S. , Doherty M. L. , O'Neill R. , Sammin D. , O'Flaherty J.
Published: January 2014

The voluntary phase of an industry‐led national Bovine Viral Diarrhoea (BVD) eradication programme began in Ireland on January 1, 2012 with the goal of progressing to a compulsory programme in 2013. The development and implementation of the programme in 2012 was informed by a review of current and prior eradication programmes elsewhere in Europe and extensive stakeholder consultation. The programme was based on tissue tag testing of newborn calves in participating herds, with the status of the mothers of calves with positive or inconclusive results requiring clarification. Participating herd owners were required to comply with a series of guidelines, including not selling cattle suspected of being persistently infected. For herds compliant with the guidelines, the results from 2012 counted as one of three years of tag testing anticipated in the compulsory phase of the programme. Testing was carried out in laboratories designated for this purpose by the cross‐industry BVD Implementation Group that oversees the programme. Results were reported to a central database managed by the Irish Cattle Breeding Federation, and the majority of results were reported to farmers’ mobile telephones by SMS message. A detailed review of the programme was conducted, encompassing the period between January 1, 2012 and July 15, 2012, based on results from approximately 500,000 calves. This paper describes the establishment and structure of the programme, and the outcomes of the review, including findings at herd and animal level.
CHARGE STABILITY AND CONDUCTANCE ANALYSIS OF ANTHRACENE-BASED SINGLE ELECTRON TRANSISTOR
Authors: SRIVASTAVA ANURAG , SANTHIBHUSHAN BODDEPALLI , DOBWAL PANKAJ
Published: January 2014

The present paper discusses the investigation of electronic properties of anthracene-based single electron transistor (SET) operating in coulomb blockade region using Density Functional Theory (DFT) based Atomistix toolkit-Virtual nanolab. The charging energies of anthracene molecule in isolated as well as electrostatic SET environments have been calculated for analyzing the stability of the molecule for different charge states. Study also includes the analysis of SET conductance dependence on source/drain and gate potentials in reference to the charge stability diagram. Our computed charging energies for anthracene in isolated environment are in good agreement with the experimental values and the proposed anthracene SET shows good switching properties in comparison to other acene series SETs.
Key indicators for assessing the design of geocollaborative applications
Authors: Antunes Pedro , Zurita Gustavo , Baloian Nelson
Published: January 2014

A geocollaborative application integrates geographical information with collaboration support. Its implementation involves reasoning about the most adequate mix of technical features, human requirements and collaboration models. This paper proposes a framework for guiding and assessing the design of geocollaborative systems using a set of measurable indicators. We define five key indicators (KI): awareness, mobility, proximity, collaborative visualization and geographic relationships. These KI were derived from an extensive review of the state-of-the-art. The framework was validated in two case studies involving support to geologists working in the field and police agents evacuating crowded places. The case studies elucidate how the framework helps analyzing as-is and to-be collaborative scenarios, which constitute the design cycle posited by the design-science paradigm. This research is relevant to implementers in two ways: highlighting important qualities of geocollaboration systems and offering a structured mechanism to assess the design process.
FUNCTIONALIZED MULTIWALLED CARBON NANOTUBES BY GRAFTING HYPERBRANCHED POLYSILOXANE
Authors: YAN HONGXIA , JIA YUAN , MA LEI , WANG YANLI
Published: January 2014

Multi-walled carbon nanotubes (MWCNTs) are grafted with hyperbranched polysiloxane ( HBPSi ) by an efficient hydrosilylation method. In this hydrosilylation process, hydroxylated MWCNTs (HO-MWCNTs) are first functionalized by triethoxyvinylsilane to introduce carbon–carbon double bonds ( C = C ) on the surface of MWCNTs. The C = C is then reacted with the monomer of methylbis(dimethylvinylsiloxy)silane in the presence of the platinum–carbon catalyst, thus HBPSi is ultimately grafted on the surface of MWCNTs. Fourier transform infrared spectrometry (FTIR), Transmission electron microscope (TEM) and X-ray photoelectron spectroscopy (XPS) are employed to characterize the changes in MWCNTs surface morphology, chemistry and physical conditions at different processing stages. The content of HBPSi on the surface of MWCNTs was also measured by the thermogravimetric analysis (TGA). The results indicate that the HBPSi successfully grafted on the surface of MWCNTs, and the dispersion of MWCNTs in organic solvent is also improved after functionalization.
Cu-based materials as high-performance electrodes toward electrochemical energy storage
Authors: Chen Kunfeng , Xue Dongfeng
Published: January 2014

Cu -based materials, including metal Cu and semiconductors of Cu 2 O and CuO , are promising and important candidates toward practical electrochemical energy storage devices due to their abundant, low cost, easy synthesis and environmentally friendly merits. This review presents an overview of the applications of Cu -based materials in the state-of-art electrochemical energy storage, including both lithium-ion batteries and supercapacitors. The synthesis chemistry, structures and the corresponding electrochemical performances of these materials are summarized and compared. During chemical synthesis and electroactive performance measurement of Cu -based materials, we found that Cu – Cu 2 O – CuO sequence governs all related transformations. Novel water-soluble CuCl 2 supercapacitors with ultrahigh capacitance were also reviewed which can advance the understanding of intrinsic mechanism of inorganic pseudocapacitors. The major goal of this review is to highlight some recent progresses in using Cu -based materials for electrochemical energy storage.
Balloon-Assisted Tracking to Overcome Radial Spasm during Transradial Coronary Angiography: A Case Report
Authors: Verouden N. J. W. , Kiemeneij F.
Published: January 2014

Spasm of the radial artery is the most important cause of failure to perform coronary angiography via the transradial approach. Spasmolytic cocktail may prevent radial artery spasm but is relatively contraindicated in patients with aortic stenosis or diminished left ventricular function. In this case report we describe a recently published technique to overcome severe radial spasm during transradial coronary angiography in a patient with moderate aortic valve stenosis.
ZnTe Semiconductor‐Polymer Gel Composited Electrolyte for Conversion of Solar Energy
Authors: Promnopas Wonchai , Thongtem Titipun , Thongtem Somchai
Published: January 2014

Nanostructured cubic p‐type ZnTe for dye sensitized solar cells (DSSCs) was synthesized from 1 : 1 molar ratio of Zn : Te by 600 W and 900 W microwave plasma for 30 min. In this research, their green emissions were detected at the same wavelengths of 563 nm, the energy gap (Eg) at 2.24 eV, and three Raman shifts at 205, 410, and 620 cm−1. The nanocomposited electrolyte of quasisolid state ZnO‐DSSCs was in correlation with the increase in the JSC, VOC, fill factor (ff), and efficiency (η) by increasing the wt% of ZnTe‐GPE (gel polymer electrolyte) to an optimum value and decreased afterwards. The optimal ZnO‐DSSC performance was achieved for 0.20 wt% ZnTe‐GPE with the highest photoelectronic energy conversion efficiency at 174.7% with respect to that of the GPE without doping of p‐type ZnTe.
Jejunal Choristoma: A Very Rare Cause of Abdominal Pain in Children
Authors: Olajide T. A. , Agodirin S. O. , Ojewola R. W. , Akanbi O. O. , Solaja T. O. , Odesanya Johnson Oluremi , Ariyibi O. O.
Published: January 2014

Choristoma is development of a normal tissue in an aberrant location. This report describes jejunal salivary choristoma (JSC) causing recurring episodes of abdominal discomfort in a 5-year-old girl. Exploratory laporatomy revealed a pale yellow subserosal jejunal lesion. Wedge resection of the lesion and repair of the bowel were performed. The child did well postoperatively and has since that time been free of pain at follow-up. Histopathological examination of the resected lesion revealed salivary gland choriostoma. Literature review (PUBMED search engine) revealed no previous report of this rare clinicopathologic entity. We conclude that choriostoma should be considered a possible differential when evaluating abdominal complaint in children.
Environmental Temperature and Thermal Indices: What Is the Most Effective Predictor of Heat-Related Mortality in Different Geographical Contexts?
Authors: Morabito Marco , Crisci Alfonso , Messeri Alessandro , Capecchi Valerio , Modesti Pietro Amedeo , Gensini Gian Franco , Orlandini Simone
Published: January 2014

The aim of this study is to identify the most effective thermal predictor of heat-related very-elderly mortality in two cities located in different geographical contexts of central Italy. We tested the hypothesis that use of the state-of-the-art rational thermal indices, the Universal Thermal Climate Index (UTCI), might provide an improvement in predicting heat-related mortality with respect to other predictors. Data regarding very elderly people (≥75 years) who died in inland and coastal cities from 2006 to 2008 (May–October) and meteorological and air pollution were obtained from the regional mortality and environmental archives. Rational (UTCI) and direct thermal indices represented by a set of bivariate/multivariate apparent temperature indices were assessed. Correlation analyses and generalized additive models were applied. The Akaike weights were used for the best model selection. Direct multivariate indices showed the highest correlations with UTCI and were also selected as the best thermal predictors of heat-related mortality for both inland and coastal cities. Conversely, the UTCI was never identified as the best thermal predictor. The use of direct multivariate indices, which also account for the extra effect of wind speed and/or solar radiation, revealed the best fitting with all-cause, very-elderly mortality attributable to heat stress.
Impact of Vagal Nerve Stimulation on Left Atrial Structure and Function in a Canine High-Rate Pacing Model
Authors: Kusunose Kenya , Zhang Youhua , Mazgalev Todor N. , Van Wagoner David R. , Thomas James D. , Popović Zoran B.
Published: January 2014

Background—

Cervical vagal nerve stimulation (VNS) can improve left ventricular dysfunction in the setting of heart failure (HF). However, little is known about the impact of VNS on left atrial (LA) function. The aim of this study was to compare LA mechanics and histology between control and VNS-treated animals during HF development.

Methods and Results—

Fifteen mongrel dogs were randomized into control (n=7) and VNS (n=8) groups. All dogs underwent 8 weeks of high-rate ventricular pacing (at 220 beats per minute for the first 4 weeks to develop HF and another 4 weeks at 180 beats per minute to maintain HF). LA contractile function (LA negative peak strain), conduit function (LA positive peak strain), and reservoir function (LA total strain) were measured from speckle tracking in 2 groups. At the end of the terminal study, the LA appendage was obtained. Baseline LA strains were comparable in the control and VNS-treated dogs. At 4 and 8 weeks of ventricular pacing, all LA strains were decreased and LA volumes were increased in the control group compared with the VNS group (
P
<0.05). Histological evaluation of the left atrium revealed that percent fibrosis was significantly lower in the VNS versus the control group (8±1% versus 13±1%;
P
<0.001). Finally, transmitral flow showed decreased atrial contribution to left ventricular filling in the control group (
P
<0.05).

Conclusions—

VNS improved LA function and volumes and suppressed LA fibrosis in the canine high-rate ventricular pacing model. VNS is a novel and potentially useful therapy for improving LA function during HF.
Pregnancy outcomes following recovery from acquired thrombotic thrombocytopenic purpura
Authors: Jiang Yang , McIntosh Jennifer J. , Reese Jessica A. , Deford Cassandra C. , Kremer Hovinga Johanna A. , Lämmle Bernhard , Terrell Deirdra R. , Vesely Sara K. , Knudtson Eric J. , George James N.
Published: January 2014

Key Points

Recurrent TTP complicating a subsequent pregnancy may be uncommon; most pregnancies result in normal children. The frequency of preeclampsia may be increased in pregnancies following recovery from TTP.
Surgical treatment of an invasive thymoma extending into the superior vena cava and right atrium
Authors: Dong Yong-Qiang , Liang Jiang-Shui , Zhang Xiao-Ming , Zhu Shui-Bo , Xu Jia-Hang , Ji Tao , Yin Gui-Lin
Published: January 2014

Although invasive thymoma commonly infiltrates neighbouring mediastinal structures, its extension into the superior vena cava (SVC) and consequent SVC occlusion are rare. In such cases, the urgent removal of the thymoma and radical resection of the infiltrated SVC representreasonable options, since induction therapy is time-consuming and useless for symptom resolution. A case of invasive thymoma extending into the SVC and right atrium (RA) with SVC syndrome is reported. The patient underwent a combined resection of the invasive tumor and SVC under cardiopulmonary bypass (CPB), and the SVC and bilateral brachiocephalic vein (BCV) were reconstructed with an autologous pericardial ‘Y’ conduit. After 40 months of follow-up, the patient showed a patent graft and no tumor recurrence.
Antiresorptive Treatment of Postmenopausal Osteoporosis: Comparison of Study Designs and Outcomes in Large Clinical Trials with Fracture as an Endpoint
Authors: Marcus Robert , Wong Mayme , Heath Hunter , Stock John L.
Published: January 2014

Antiresorptive treatments for postmenopausal osteoporosis have been studied extensively, but due to the volume of published data and lack of head-to-head trials, it is difficult to evaluate and compare their fracture reduction efficacy. The objective of this review is to summarize the results from clinical trials that have fracture as an endpoint and to discuss the factors in study design and populations that can affect the interpretation of the results. Although there are numerous observational studies suggesting that estrogen and hormone replacement therapies may reduce the risk of vertebral and nonvertebral fractures, there is no large, prospective, randomized, placebo-controlled, double-blind clinical trial demonstrating fracture efficacy. The effects of raloxifene, alendronate, risedronate, and salmon calcitonin on increasing bone mineral density (BMD) and decreasing fracture risk have been shown in randomized, placebo-controlled, double-blind clinical trials of postmenopausal women with osteoporosis. Although the increases in lumbar spine BMD vary greatly in these trials, the decrease in relative risk of vertebral fractures is similar among therapies. However, nonvertebral fracture efficacy has not been consistently demonstrated. Combined administration of two antiresorptive therapies results in greater BMD increases, but the effects on fracture risk are unknown. Direct comparisons of clinical trial results should be considered carefully, given the differences in study design and populations. Differences in study design that may influence the efficacy of fracture risk reduction include calcium and vitamin D supplementation, primary fracture endpoints, definition of vertebral deformity or fracture, discontinuation rates, and statistical power. Factors in the study population that may influence fracture efficacy include the age of the population and the proportion of subjects with prevalent fractures. The use of surrogate endpoints such as BMD to predict fracture risk should be approached with caution, as the relationship between BMD changes and fracture risk reduction with antiresorptive therapies is uncertain. Consideration of these results from clinical trials can contribute to clinical judgment in selecting the best treatment option for postmenopausal osteoporosis.
Fasting-Induced Hepatic Production of DHEA is Regulated by PGC-1α, ERRα and HNF4α
Authors: Grasfeder Linda L. , Gaillard Stephanie , Hammes Stephen R. , Ilkayeva Olga , Newgard Christopher B. , Hochberg Richard B. , Dwyer Mary A. , Chang Ching-yi , McDonnell Donald P.
Published: January 2014

The transcriptional coactivator PGC-1α is involved in the coordinate induction of changes in gene expression in the liver that enable a homeostatic response to alterations in metabolic state, environmental cues and nutrient availability. In exploring the specific pathways under PGC-1α regulation in the liver, we have made the surprising observation that this coactivator can induce the expression of CYP11A1 and CYP17A1, key rate limiting enzymes involved in the initial steps of steroidogenesis. Both of these enzymes function to produce C19-steroids, converting cholesterol into pregnenolone, and then to DHEA. ERRa mediates PGC-1α’s induction of CYP11A1 and binds within the first intron of the CYP11A1 gene. Both ERRa and HNF4a are required for PGC-1α-mediated induction of CYP17A1 and specific binding sites for these receptors have been identified in the regulatory regions of this gene. The potential physiological significance of these observations was highlighted in rats where fasting induced hepatic expression of PGC-1α and CYP17A1 and was associated with an increase in hepatic levels of DHEA. These data suggest that DHEA could be playing a role as an intracellular signaling molecule involved in modulating hepatic activity in response to fasting conditions.
Pegylated Leptin Antagonist Is a Potent Orexigenic Agent: Preparation and Mechanism of Activity
Authors: Elinav Eran , Niv-Spector Leonora , Katz Meirav , Price Tulin O. , Ali Mohammed , Yacobovitz Michal , Solomon Gili , Reicher Shay , Lynch Jessica L. , Halpern Zamir , Banks William A. , Gertler Arieh
Published: January 2014

Leptin, a pleiotropic adipokine, is a central regulator of appetite and weight and a key immunomodulatory protein. Although inborn leptin deficiency causes weight gain, it is unclear whether induced leptin deficiency in adult wild-type animals would be orexigenic. Previous work with a potent competitive leptin antagonist did not induce a true metabolic state of leptin deficiency in mice because of a short circulating half-life. In this study, we increased the half-life of the leptin antagonist by pegylation, which resulted in significantly increased bioavailability and retaining of antagonistic activity. Mice administered the pegylated antagonist showed a rapid and dramatic increase in food intake with weight gain. Resulting fat was confined to the mesenteric region with no accumulation in the liver. Serum cholesterol, triglyceride, and hepatic aminotransferases remained unaffected. Weight changes were reversible on cessation of leptin antagonist treatment. The mechanism of severe central leptin deficiency was found to be primarily caused by blockade of transport of circulating leptin across the blood-brain barrier with antagonisms at the arcuate nucleus playing a more minor role. Altogether we introduce a novel compound that induces central and peripheral leptin deficiency. This compound should be useful in exploring the involvement of leptin in metabolic and immune processes and could serve as a therapeutic for the treatment of cachexia.
Role of Insulin-Like Growth Factor-Binding Protein 5 (IGFBP5) in Organismal and Pancreatic β-Cell Growth
Authors: Gleason Catherine E. , Ning Yun , Cominski Tara P. , Gupta Rana , Kaestner Klaus H. , Pintar John E. , Birnbaum Morris J.
Published: January 2014

A family of IGF-binding proteins (IGFBP) exerts biological actions both dependent on and independent of IGF-I. A major effector of the insulin/IGF-I signaling pathway, the serine/threonine protein kinase Akt, mediates cellular processes such as glucose uptake, protein synthesis, cell survival, and growth. IGF-I is required for normal organismal growth, and in the pancreatic β-cell, the insulin/IGF-I signaling pathway is critical for normal and adaptive maintenance of β-cell mass. Expression of myrAkt1, an activated form of Akt, in the endocrine pancreas drives β-cell expansion through dramatic increases in both islet and β-cell size and number. Herein we present a comparative expression profiling of myrAkt1 transgenic islets that demonstrates the increased abundance of transcripts encoding proteins associated with growth, suppression of apoptosis, RNA processing, and metabolism. Although IGFBP5 is identified as a gene induced by Akt1 activation in the β-cell, Igfbp5 expression is not necessary for myrAkt1 to augment β-cell size or mass in vivo. However, in the absence of Igfbp5, mice demonstrate an increase in size and mild glucose intolerance. This is accentuated during diet-induced obesity, when Igfbp5-deficient mice have increased adiposity compared with wild-type mice on the same diet. These studies reveal a novel role for Igfbp5 in the control of growth and metabolism.
Acute Tissue Injury Caused by Subcutaneous Fat Biopsies Produces Endoplasmic Reticulum Stress
Authors: Boden Guenther , Silviera Matthew , Smith Brian , Cheung Peter , Homko Carol
Published: January 2014

Background

It is not known whether acute tissue injury is associated with endoplasmic reticulum (ER) stress.

Objective

Our objective was to determine whether open, sc fat biopsies cause ER stress.

Approach

Five healthy subjects underwent three open sc fat biopsies. The first biopsy, taken from the lateral aspect of a thigh, was followed 4 h later by a second biopsy from the same incision site and a third biopsy from the contralateral leg. Expression markers of ER stress, inflammation, hypoxia, and adipokines were measured in these fat biopsies. In addition, we tested for signs of systemic ER stress and inflammation in plasma and in circulating monocytes.

Results

mRNA/18s ratios of IL-6, monocyte chemoattractant protein-1, CD-14, hypoxia-induced factor 1-α, the spliced form of Xbox protein-1, glucose-regulated protein 78, CEBP homologous protein, and activating factor-4 were all severalfold higher, whereas mRNA/18s ratios of adiponectin and leptin were lower in fat biopsies taken from the same site 4 h after the first biopsy but were unchanged in the second biopsy that was taken from the contralateral site. The biopsies were not associated with changes in plasma and monocyte IL-6 concentrations or in monocyte ER stress markers. Also, whole-body insulin-stimulated glucose uptake was the same in 15 subjects who had biopsies compared with 15 different subjects who did not.

Conclusion

Open, sc fat biopsies produced inflammation, hypoxia, ER stress, and decreased expression of adiponectin and leptin. These changes remained confined to the biopsy site for at least 4 h.
Precursor Cells in Mouse Islets Generate New β-Cells in Vivo during Aging and after Islet Injury
Authors: Liu H. , Guz Y. , Kedees M. H. , Winkler J. , Teitelman G.
Published: January 2014

Whereas it is believed that the pancreatic duct contains endocrine precursors, the presence insulin progenitor cells residing in islets remain controversial. We tested whether pancreatic islets of adult mice contain precursor β-cells that initiate insulin synthesis during aging and after islet injury. We used bigenic mice in which the activation of an inducible form of cAMP response element recombinase by a one-time pulse of tamoxifen results in the permanent expression of a floxed human placental alkaline phosphatase (PLAP) gene in 30% of pancreatic β-cells. If islets contain PLAP− precursor cells that differentiate into β-cells (PLAP−IN+), a decrease in the percentage of PLAP+IN+ cells per total number of IN+ cells would occur. Conversely, if islets contain PLAP+IN− precursors that initiate synthesis of insulin, the percentage of PLAP+IN+ cells would increase. Confocal microscope analysis revealed that the percentage of PLAP+IN+ cells in islets increased from 30 to 45% at 6 months and to 60% at 12 months. The augmentation in the level of PLAP in islets with time was confirmed by real time-PCR. Our studies also demonstrate that the percentage of PLAP+IN+ cells in islets increased after islet injury and identified putative precursors in islets. We postulate that PLAP+IN− precursors differentiate into insulin-positive cells that participate in a slow renewal of the β-cell mass during aging and replenish β-cells eliminated by injury.
Minireview: A Tiny Touch: Activation of Cell Signaling Pathways with Magnetic Nanoparticles
Authors: Sniadecki Nathan J.
Published: January 2014

Magnetic nanoparticles can be coated with specific ligands that enable them to bind to receptors on a cell’s surface. When a magnetic field is applied, it pulls on the particles so that they deliver nanoscale forces at the ligand-receptor bond. It has been observed that mechanical stimulation in this manner can activate cellular signaling pathways that are known as mechanotransduction pathways. Integrin receptors, stretch-activated ion channels, focal adhesions, and the cytoskeleton are key players in activating these pathways, but there is still much we do not know about how these mechanosensors work. Current evidence indicates that applied forces at these structures can activate Ca2+ signaling, Src family protein kinase, MAPK, and RhoGTPase pathways. The techniques of magnetic twisting and magnetic tweezers, which use magnetic particles to apply forces to cells, afford a fine degree of control over how cells are stimulated and hold much promise in elucidating the fundamentals of mechanotransduction. The particles are generally not harmful to cellular health, and their nanoscale dimensions make them advantageous for probing a cell’s molecular-scale sensory structures. This review highlights the basic aspects of magnetic nanoparticles, magnetic particle techniques and the structures and pathways that are involved in mechanotransduction.
A Novel Bile Acid-Activated Vitamin D Receptor Signaling in Human Hepatocytes
Authors: Han Shuxin , Li Tiangang , Ellis Ewa , Strom Steven , Chiang John Y. L.
Published: January 2014

Vitamin D receptor (VDR) is activated by natural ligands, 1α, 25-dihydroxy-vitamin D3 (1α, 25(OH)2-D3) and lithocholic acid (LCA). Our previous study shows that VDR is expressed in human hepatocytes, and VDR ligands inhibit bile acid synthesis and transcription of the gene encoding cholesterol 7α-hydroxylase (CYP7A1). Primary human hepatocytes were used to study LCA and 1α, 25(OH)2-D3 activation of VDR signaling. Confocal immunofluorescent microscopy imaging and immunoblot analysis showed that LCA and 1α, 25(OH)2-D3 induced intracellular translocation of VDR from the cytosol to the nucleus, and also plasma membrane where VDR co-localized with caveolin-1. VDR ligands induced tyrosine phosphorylation of c-Src and VDR, and their interaction. Inhibition of c-Src abrogated VDR ligand-dependent inhibition of CYP7A1 mRNA expression. Kinase assays showed that VDR ligands specifically activated the c-Raf/MEK1/2/ERK1/2 pathway, which stimulates serine phosphorylation of VDR and HNF4α, and their interaction. Mammalian two-hybrid assays showed a VDR ligand dependent interaction of nuclear receptor corepressor-1 (NCoR-1) and silencing mediator of retinoid and thyroid (SMRT) with VDR/RXRα. Chromatin immunoprecipitation assays revealed that an ERK1/2 inhibitor reversed VDR ligand-induced recruitment of VDR, RXRα and corepressors to human CYP7A1 promoter. In conclusion, VDR ligands activate membrane VDR signaling to activate the MEK1/2/ERK1/2 pathway, which stimulates nuclear VDR/RXRα recruitment of co-repressors to inhibit CYP7A1 gene transcription in human hepatocytes. This membrane VDR signaling pathway may be activated by bile acids to inhibit bile acid synthesis as a rapid response to protect hepatocytes from cholestatic liver injury.
Novel Corticosteroid-Binding Globulin Variant That Lacks Steroid Binding Activity
Authors: Perogamvros I. , Underhill C. , Henley D. E. , Hadfield K. D. , Newman W. G. , Ray D. W. , Lightman S. L. , Hammond G. L. , Trainer P. J.
Published: January 2014

Background:

Corticosteroid-binding globulin (CBG) is the principal carrier for glucocorticoids in the circulation and a regulator of their bioavailability. Inherited CBG deficiencies are rarely reported, and only three causative mutations in four families have been described.

Patients, Methods, and Results:

In a 26-yr-old female with hypotension, fatigue, and undetectable serum cortisol at presentation, we have identified a novel homozygous c.776g>t transversion in exon 3 of the CBG (SERPINA6) gene. This results in a p.Gly237Val substitution that is predicted to influence the positioning of two β-sheets that constitute part of the CBG steroid-binding site. Two siblings were also homozygous for the variant, whereas her mother and an unaffected sibling were heterozygous. No other symptomatic family members were identified apart from the proband. Individuals homozygous for the variant had serum CBG levels below the reference range when measured by RIA, but CBG was unmeasurable in cortisol-binding capacity assays. In the same individuals, we observed very low baseline and stimulated serum cortisol levels but normal free serum and salivary cortisol and plasma ACTH. In a study of ultradian cortisol pulsatility, increased pulse frequency was only observed in the proband.

Conclusion:

We describe a novel CBG variant that lacks steroid binding. All mutant homozygotes have very low serum cortisol, but normal free cortisol levels. The only biochemical feature to distinguish the symptomatic subject was increased cortisol pulsatility, and we suggest that this may influence glucocorticoid signaling and contribute to symptoms previously associated with CBG deficiency.
Familial Glucocorticoid Resistance Caused by a Novel Frameshift Glucocorticoid Receptor Mutation
Authors: Trebble P. , Matthews L. , Blaikley J. , Wayte A. W. O. , Black G. C. M. , Wilton A. , Ray D. W.
Published: January 2014

Context

Familial glucocorticoid resistance is a rare condition with a typical presentation of women with hirsutism and hypertension, with or without hypokalemia.

Objective

The aim was to determine the cause of apparent glucocorticoid resistance in a young woman.

Patients and Methods

We studied a family with a novel glucocorticoid receptor (GR) mutation and a surprisingly mild phenotype. Their discovery resulted from serendipitous measurement of serum cortisol with little biochemical or clinical evidence for either hyperandrogenism or mineralocorticoid excess.

Results

The causative mutation was identified as a frameshift mutation in exon 6. Transformed peripheral blood lymphocytes were generated to analyze GR expression in vitro. Carriers of the mutation had less full-length GR, but the predicted mutant GR protein was not detected. However, this does not exclude expression in vivo, and so the mutant GR (D612GR) was expressed in vitro. Simple reporter gene assays suggested that Δ612GR has dominant negative activity. Δ612GR was not subject to ligand-dependent Ser211 phosphorylation or to ligand-dependent degradation. A fluorophore-tagged construct showed that Δ612GR did not translocate to the nucleus in response to ligand and retarded translocation of the wild-type GR. These data suggest that Δ612GR is not capable of binding ligand and exerts dominant negative activity through heterodimerization with wild-type GR.

Conclusion

Therefore, we describe a novel, naturally occurring GR mutation that results in familial glucocorticoid resistance. The mutant GR protein, if expressed in vivo, is predicted to exert dominant negative activity by impairing wild-type GR nuclear translocation.
GH (Growth Hormone)-Dependent STAT5 Signaling Plays an Important Role in Hepatic Lipid Metabolism
Authors: Barclay Johanna L. , Nelson Caroline N. , Ishikawa Mayumi , Murray Lauren A. , Kerr Linda M. , McPhee Timothy R. , Powell Elizabeth E. , Waters Michael J.
Published: January 2014

GH deficiency is known to be clinically associated with a high incidence of nonalcoholic fatty liver disease, and this can be reversed by GH administration. Here we investigated the mechanistic basis for this phenomenon using engineered male mice lacking different signaling elements of the GH receptor, hepatic stat5a/b−/− mice and a mouse hepatoma line. We found deficient GH-dependent signal transducer and activator of transcription (STAT)-5 signaling correlates with steatosis, and through microarray analysis, quantitative PCR, and chromatin immunoprecipitation, identifies putative targets of STAT5 signaling responsible for the steatosis seen on a normal diet. These targets were verified with liver-specific stat5a/b deletion in vivo, and in vitro we show that dominant-negative (DN) STAT5 increases lipid uptake in a mouse hepatoma line. Because loss of STAT5 signaling results in elevated STAT1 and STAT3 activity and intracellular lipid accumulation, we have used the hepatoma line DN-STAT5a/b, DN-STAT1, CA-STAT3, or addition of oleate/palmitate to assign which of these apply to individual targets in active STAT5 deficiency. These findings and published mouse models of steatosis enable us to propose elevated cd36, pparγ, and pgc1α/β expression as primary instigators of the steatosis along with elevated fatty acid synthase, lipoprotein lipase, and very low-density lipoprotein receptor expression. Decreased fgf21 and insig2 expression may also contribute. In conclusion, despite normal plasma free fatty acids and minimal obesity, absent GH activation leads to steatosis because phosphorylated STAT5 prevents hepatic steatosis. These results raise the possibility of low-dose GH treatment for nonalcoholic fatty liver disease.