bluuebunny/crossref_metadata_2025 huggingface dataset:
Peer mentoring for core medical trainees: uptake and impact
Authors: Webb Jessica , Brightwell Alexandra , Sarkar Pamela , Rabbie Roy , Chakravorty Indranil
Published: February 2015

Objective

To assess the uptake and impact of a peer mentoring scheme for core medical trainees on both mentors and mentees.

Method

All second year core medical trainees in the Southwest London Training programme in September 2012 were invited to mentor a first year core medical trainee. In parallel, all first year core medical trainees were invited to be mentored. Both potential mentors and mentees were asked to submit personal statements, to attend a three-session mentoring training programme and to be matched into mentoring pairs. The impact of the mentoring scheme on trainees’ behaviour and outlook was assessed through questionnaires distributed at the start and at the end of the year.

Results

31 of 72 (43%) core medical trainees submitted personal statements and 40 of 72 (56%) attended training sessions. 42 trainees (58%) participated in the scheme (21 mentor/mentee pairs were established). Of the trainees who participated, 23 of 42 (55%) completed the end of year questionnaire. Participating trainees viewed the scheme positively. Reported benefits included changes in their behaviour and acquiring transferable skills that might help them in later career roles, such as an educational supervisor. The end of year questionnaire was sent to all trainees and 10 responded who had not participated. They were asked why they had not participated and their reasons included lack of time, lack of inclination and a desire for more senior mentors. Their suggestions for improvement included more structured sessions to allow the mentor/mentee pairs to meet.

Conclusions

This simple peer mentoring scheme was popular despite busy workloads and benefited all concerned. It is a simple effective way of supporting doctors. More work is needed to improve training for mentors and to improve access to mentoring.
Quasi-classical trajectory study of the reaction dynamics of calcium ground state and metastable atoms with CH2Cl2
Authors: Ding Yang , Xia Wenwen , Song Liguo , Yao Li
Published: February 2015

The dynamics properties of the Ca(1S0,3P) + CH2Cl2 reaction system have been calculated by means of the quasi-classical trajectory method based on the extended London–Eyring–Polanyi–Sato potential energy surface. By the calculations, the vibrational distribution, reaction cross section, rotational alignment, and reaction rate constant are obtained. The peak location of vibrational quantum numbers is at ν = 0 when the collision energy is 2.302 kcal/mol, whether the calcium atom is at the ground state or metastable state. The product vibrational distribution agrees well with the experiment value in Han, K. L.; He, G. Z.; Lou, N. Q. Chem. Phys. Lett. 1991, 178, 528. The cross section thoroughly decreases with the increase of the collision energy. The rotational alignment of the product greatly deviates from –0.5. The reaction rate constant increases with rising temperature.
Dynamic behavior of photo-induced orientation of poly(methyl methacrylate) – Solvent Red 23 thin films
Authors: Abbas B. , Salman Y.T. , EL-Dahr M.S.
Published: February 2015

We investigate the effect of the photo-orientation and stability of the Solvent Red 23 dye incorporated in poly(methyl methacrylate) thin films as a guest–host system. A probe–pump optical system was used to investigate the dichroic behavior of the samples. Orthogonally polarized laser lights induce a smaller increase in the transmitted beam intensity. A stronger polar order was induced using a parallel probe–pump laser light compared to that of the perpendicular state. It was found that the dichroic ratio value of the poly(methyl methacrylate) – Solvent Red 23 thin film increased by 0.174 at the photostationary state, indicating that the net orientation of Solvent Red 23 molecules has increased 17.4% in the direction perpendicular to the applied beam field. The dynamic evolution of the dichroic ratio showed that the relaxation is rather slow, and it deteriorates in a slow exponential fashion, which may take a very long time to reach the isotropic state. The contrast ratios were 0.449 and 0.267 in parallel and orthogonal probe–pump configurations, respectively. The order parameter calculations reveal that about 70% of photo-induced anisotropy remains after relaxation for a long time.
Classification of Obsessive Compulsive Disorder by EEG Complexity and Hemispheric Dependency Measurements
Authors: Aydin Serap , Arica Nafiz , Ergul Emrah , Tan Oğuz
Published: February 2015

In the present study, both single channel electroencephalography (EEG) complexity and two channel interhemispheric dependency measurements have newly been examined for classification of patients with obsessive–compulsive disorder (OCD) and controls by using support vector machine classifiers. Three embedding entropy measurements (approximate entropy, sample entropy, permutation entropy (PermEn)) are used to estimate single channel EEG complexity for 19-channel eyes closed cortical measurements. Mean coherence and mutual information are examined to measure the level of interhemispheric dependency in frequency and statistical domain, respectively for eight distinct electrode pairs placed on the scalp with respect to the international 10–20 electrode placement system. All methods are applied to short EEG segments of 2 s. The classification performance is measured 20 times with different 2-fold cross-validation data for both single channel complexity features (19 features) and interhemispheric dependency features (eight features). The highest classification accuracy of 85 ±5.2% is provided by PermEn at prefrontal regions of the brain. Even if the classification success do not provided by other methods as high as PermEn, the clear differences between patients and controls at prefrontal regions can also be obtained by using other methods except coherence. In conclusion, OCD, defined as illness of orbitofronto-striatal structures [Beucke et al., JAMA Psychiatry 70 (2013) 619–629; Cavedini et al., Psychiatry Res. 78 (1998) 21–28; Menzies et al., Neurosci. Biobehav. Rev. 32(3) (2008) 525–549], is caused by functional abnormalities in the pre-frontal regions. Particularly, patients are characterized by lower EEG complexity at both pre-frontal regions and right fronto-temporal locations. Our results are compatible with imaging studies that define OCD as a sub group of anxiety disorders exhibited a decreased complexity (such as anorexia nervosa [Toth et al., Int. J. Psychophysiol. 51(3) (2004) 253–260] and panic disorder [Bob et al., Physiol. Res. 55 (2006) S113–S119]).
Macroscopic modeling for traffic flow on three-lane highways
Authors: Chen Jianzhong , Fang Yuan
Published: February 2015

In this paper, a macroscopic traffic flow model for three-lane highways is proposed. The model is an extension of the speed gradient model by taking into account the lane changing. The new source and sink terms of lane change rate are added into the continuity equations and the speed dynamic equations to describe the lane-changing behavior. The result of the steady state analysis shows that our model can describe the lane usage inversion phenomenon. The numerical results demonstrate that the present model effectively reproduces several traffic phenomena observed in real traffic such as shock and rarefaction waves, stop-and-go waves and local clusters.
Review of physics results from the Tevatron: Heavy flavor physics
Authors: Lewis Jonathan , Van Kooten Rick
Published: February 2015

We present a review of heavy flavor physics results from the CDF and DØ Collaborations operating at the Fermilab Tevatron Collider. A summary of results from Run 1 is included, but we concentrate on legacy results of charm and b physics from Run 2, including results up to Summer 2014.
Efficient Audio Filter Using Folded Pipelining Architecture Based on Retiming Using Evolutionary Computation
Authors: Yagain Deepa , Balla Sivanag , Krishna Vijaya
Published: February 2015

It is important in digital signal processing (DSP) architectures to minimize the silicon area of the integrated circuits. This can be achieved by reducing the number of functional units such as adders and multipliers. In literature, folding technique is used to reduce the functional units by executing multiple algorithm operations on a single functional unit. Register minimization techniques are used to reduce the number of registers in a folded architecture. Retiming is a technique that needs to be performed before applying folding. In this paper, retiming is performed based on nature inspired evolutionary computation method. This technique generates the database of solutions from which best solution can be picked for folding further.

As a part of this work, an efficient folded noise removal audio filter prototype is designed as an application example using evolutionary computation-based retiming and folding with register minimization. Folding technique will however increase the number of registers while multiplexing datapath adder and multiplier elements. Register minimization technique is used after folding to reduce the number of registers. After obtaining retimed, folded filter architecture, low level synthesis is performed which involves mapping of datapath adder and multiplier blocks to actual hardware. Various architectures of adders and multipliers are compared in area-power-performance space and depending on the user defined constraint, folded architecture with specific combination of data path elements is mapped on to hardware. A framework is designed in this paper to automate the entire process which reduces the design cycle time. All the designed filters are targeted for ASIC implementation. The results are compared and are provided as part of simulation results.
Anomalous buried hollows in London: development of a hazard susceptibility map
Authors: Banks V. J. , Bricker S. H. , Royse K. R. , Collins P. E. F.
Published: February 2015

Engineering works carried out in central London over many decades have revealed a number of buried hollows that exhibit curious characteristics. Some extend deep into the bedrock geology and are in-filled with disturbed superficial deposits and reworked bedrock. Others are contained within the superficial deposits. They can be up to 500 m wide and more than 60 m in depth. As the infill material often has different behavioural characteristics from the surrounding deposits failure to identify them during an initial site investigation can prove costly. This paper considers their common characteristics and describes the method used to develop a buried hollow hazard susceptibility map. This map provides planners with a broader awareness of the potential location of difficult ground conditions associated with them, thereby reducing the potential for unforeseen ground conditions through effective site investigation design. The paper continues with a discussion of some of the likely processes associated with their formation, which are attributed to cryogenic processes, and concludes with potential future research directions.
Carrara Marble: a nomination for ‘Global Heritage Stone Resource’ from Italy
Authors: Primavori P.
Published: February 2015

Carrara Marble, from Italy, probably one of the most famous dimension stones in the collective memory and in ordinary people, is here nominated as a suitable ‘Global Heritage Stone Resource’.

Quarried since pre-Roman times, the Carrara marble is the testimonial of an area/industry that was able – for a variety of reasons not easily repeatable in future stone history – from the dawn of the stone sector, to trigger a flywheel effect on a global scale. Suitable for any environment and cultural context, this versatile marble has been appreciated in almost any field of application – from building to architecture, from fine arts to urban landscape, from funerary art to modern 3D design – probably reaching its highest point in the eternal works of famous sculpturers, artists and architects such as Michelangelo, Donatello, Jacopo Della Quercia, Canova, Bernini, and many others. It is currently excavated in more than 100 quarries, processed almost everywhere and sold all over the world.
An abiotic model for the development of textures in some South Atlantic early Cretaceous lacustrine carbonates
Authors: Wright V. Paul , Barnett Andrew J.
Published: February 2015

The cyclic distribution of various types of carbonates and Mg-clays in early Cretaceous rift-sag phase lacustrine carbonates from the subsurface of the South Atlantic provides an insight into how evolving lake chemistries in highly alkaline settings control facies development. The typically subdecametre scale symmetrical and asymmetrical cyclothems exhibit three main components: mud-grade laminated carbonates, millimetre-diameter spherulites with evidence of having been in a matrix of Mg-silicates, and millimetre–centimetre calcitic shrub-like growths. The laminites contain conspicuous numbers of ostracods and vertebrate remains and were produced by short-lived pluvial events, causing expansion of shallow lakes. Later evaporation triggered Mg-silicate precipitation and calcite nucleation within gels to produce spherulitic textures. When the rate of gel precipitation decreased or ceased, calcite growth, now less inhibited, produced shrub-like calcites resembling those produced abiotically in modern travertines, although still with some evidence of the former presence of some Mg-silicates. Physical reworking of these sediments led to the dispersion of the gels and the concentration of detrital carbonate components. Despite earlier proposals, evidence of microbial processes producing carbonates in these Cretaceous lake deposits is rare and the application of facies models based on modern and ancient microbialite analogues maybe be misplaced.
EVOLUTION OF A STUDENT MODEL-BUILDING PROGRAM
Authors: Weaver Debbi A. , Kemm Robert E. , Petrovic Tom , Gilding Tony , Harris Peter J. , Delbridge Lea
Published: February 2015

We describe the design and development of a highly interactive model-building program to assist students from a diverse range of academic backgrounds to understand the baroreceptor reflex. Our approach is to have students work in small groups to construct their own simple model of such a control system. This model then provides the basis for a structural framework for students to add further complexity without losing overall perspective and allows exploration of deeper issues. Our program is suitable for many disciplines and student backgrounds and provides a visual representation of a difficult concept, providing a basis to ground further knowledge. Audit trail data have been analyzed to identify and resolve areas of student difficulty, and extensive surveys and observations on students’ use of the program over three years in several courses have been used to test and improve its effectiveness.
THE OSMOTIC GRADIENT IN KIDNEY MEDULLA: A RETOLD STORY
Authors: Kurbel S. , Dodig K. , Radić R.
Published: February 2015

This article is an attempt to simplify lecturing about the osmotic gradient in the kidney medulla. In the model presented, the kidneys are described as a limited space with a positive interstitial hydrostatic pressure. Traffic of water, sodium, and urea is described in levels (or horizons) of different osmolarity, governed by osmotic forces and positive interstitial pressure. In this way, actions of the countercurrent multiplier in nephron tubules and of the countercurrent exchanger in vasa recta are integrated in each horizon. We hope that this approach can help students to better accept conventional presentations in their textbooks.
INTEGRATING RECENT ADVANCES IN NEUROSCIENCE INTO UNDERGRADUATE NEUROSCIENCE AND PHYSIOLOGY COURSES
Authors: Cleland Corey L.
Published: February 2015

Neuroscience has enjoyed tremendous growth over the past 20 years, including a substantial increase in the number of neuroscience departments, programs, and courses at the undergraduate level. To meet the need of new neuroscience courses, there has also been growth in the number of introductory neuroscience textbooks designed for undergraduates. However, textbooks typically trail current knowledge by five to ten years, especially in neuroscience where our understanding is increasing rapidly. Consequently, it is often important to supplement neuroscience and physiology textbooks with information about recent findings in neuroscience. To design supplementary educational material, it is essential first to identify the educational objectives of the program and the characteristics of the learners, which can differ dramatically between undergraduate and graduate or professional students. Four principles that may serve the selection and design of supplementary material for undergraduate neuroscience and physiology courses are that 1) material must be interesting to the undergraduates, 2) material should reinforce previously learned concepts, 3) students must be adequately prepared, and 4) the teacher and student must have sufficient appropriate resources.
Individual variation in body temperature and energy expenditure in response to mild cold
Authors: van Marken Lichtenbelt Wouter D. , Schrauwen Patrick , van de Kerckhove Stephanie , Westerterp-Plantenga Margriet S.
Published: February 2015

We studied interindividual variation in body temperature and energy expenditure, the relation between these two, and the effect of mild decrease in environmental temperature (16 vs. 22°C) on both body temperature and energy expenditure. Nine males stayed three times for 60 h (2000–0800) in a respiration chamber, once at 22°C and twice at 16°C, in random order. Twenty-four-hour energy expenditure, thermic effect of food, sleeping metabolic rate, activity-induced energy expenditure, and rectal and skin temperatures were measured. A rank correlation test with data of 6 test days showed significant interindividual variation in both rectal and skin temperatures and energy expenditures adjusted for body composition. Short-term exposure of the subjects to 16°C caused a significant decrease in body temperature (both skin and core), an increase in temperature gradients, and an increase in energy expenditure. The change in body temperature gradients was negatively related to changes in energy expenditure. This shows that interindividual differences exist with respect to the relative contribution of metabolic and insulative adaptations to cold.
Physiological regulation of the expression of a GLUT4 homolog in fish skeletal muscle
Authors: Capilla Encarnación , Dı́az Mònica , Gutiérrez Joaquim , Planas Josep V.
Published: February 2015

We have recently cloned a glucose transporter from brown trout muscle (btGLUT) with high sequence homology to mammalian GLUT4 that is predominantly expressed in red and white skeletal muscle, the two major sites of glucose uptake in trout. To study the physiological regulation of this putative fish GLUT4, we have investigated the expression of btGLUT in red and white skeletal muscle of trout in which blood insulin levels have been altered experimentally. The expression of btGLUT in red muscle increased significantly when insulin plasma levels were elevated by either insulin or arginine treatment and decreased significantly when insulin plasma levels were reduced either by fasting or by feeding a low-protein, high-carbohydrate diet. In contrast, the expression of btGLUT in white muscle was not affected by changes in the plasma levels of insulin. These results strongly suggest that insulin could be regulating the expression of btGLUT in trout red muscle in vivo and set the ground to test the hypothesis that btGLUT may be considered a GLUT4 homolog in fish.
Meal and oral glucose tests for assessment of β-cell function: modeling analysis in normal subjects
Authors: Mari Andrea , Schmitz Ole , Gastaldelli Amalia , Oestergaard Torben , Nyholm Birgit , Ferrannini Ele
Published: February 2015

We investigated β-cell function and its relationship to insulin sensitivity in 17 normal volunteers. For insulin secretion (derived by C-peptide deconvolution), a mathematical model was applied to 24-h triple-meal tests (MT) as well as oral glucose tolerance tests (OGTT); insulin sensitivity was assessed by the euglycemic insulin clamp technique. The β-cell model featured a glucose concentration-insulin secretion dose response (characterized by secretion at 5 mM glucose and slope), a secretion component proportional to the glucose concentration derivative, and a time-dependent potentiation factor (modulating the dose response and accounting for effects of sustained hyperglycemia and incretins). The β-cell dose-response functions estimated from the whole 24-h MT, the first 2 h of the MT, and the OGTT differed systematically, because a different potentiation factor was involved. In fact, potentiation was higher than average during meals (1.6 ± 0.1-fold during the first meal) and had a different time course in the MT and OGTT. However, if potentiation was accounted for, the 24- and 2-h MT and the OGTT yielded similar dose responses, and most β-cell function parameters were intercorrelated ( r = 0.50–0.86, P ≤ 0.05). The potentiation factor was found to be related to plasma glucose-dependent insulin-releasing polypeptide concentrations ( r = 0.49, P< 0.0001). Among β-cell function parameters, only insulin secretion at 5 mM glucose from MT correlated inversely with insulin sensitivity (24-h MT: r = −0.74, P < 0.001; 2-h MT: r = −0.52, P < 0.05), whereas the dose-response slope and the OGTT parameters did not. In nine other subjects, reproducibility of model parameters was evaluated from repeated MTs. Coefficients of variation were generally ∼20%, but the derivative component was less reproducible. We conclude that our model for the multiple MT yields useful information on β-cell function, particularly with regard to the role of potentiation. With cautious interpretation, a 2-h MT or a standard OGTT can be used as surrogates of 24-h tests in assessing spontaneous β-cell function.
Ubiquitin-conjugating enzyme E214k/HR6B is dispensable for increased protein catabolism in muscle of fasted mice
Authors: Adegoke Olasunkanmi A. J. , Bédard Nathalie , Roest Henk P. , Wing Simon S.
Published: February 2015

Activated skeletal muscle proteolysis in catabolic states has been linked to an upregulation of the ATP-ubiquitin-dependent proteolytic system. Previous studies suggested that the N-end rule pathway is primarily responsible for the bulk of skeletal muscle proteolysis. The activity of this pathway is dependent on the 14-kDa ubiquitin-conjugating enzyme E214k(HR6B) and the ubiquitin protein ligase Ubr1. To address the requirement of E214kin muscle proteolysis, we examined muscle protein metabolism in wild-type (WT) mice and mice lacking the E214kgene (KO) in fed and fasted (48 h) states. Baseline body weight, muscle mass, and protein content were similar, and these parameters decreased similarly upon fasting in the two genotypes. There were also no effects of genotype on the rate of proteolysis in soleus muscle. The fasting-induced increase in the amount of ubiquitinated proteins was the same in WT and KO mice. The absence of any significant effect of loss of E214kfunction was not due to a compensatory induction of the closely related isoform HR6A. Total intracellular concentration of E214kand HR6A in the WT mice was 290 ± 40 nM, but the level in the KO mice (reflecting the level of HR6A) was 110 ± 9 nM. This value is about threefold the apparent Michaelis-Menten constant ( Km) of E214k(∼40 nM) for stimulating conjugation in muscle extracts. Because the HR6A isoform has a Kmof 16 nM for stimulating conjugation, the HR6A levels in the muscles of KO mice appear sufficient for supporting conjugation mediated by this pathway during fasting.
Novel experimental protocol to increase specific plasma nonesterified fatty acids in humans
Authors: Beysen Carine , Belcher Abigail K. , Karpe Fredrik , Fielding Barbara A. , Herrera Emilio , Frayn Keith N.
Published: February 2015

This study reports a novel protocol to increase plasma monounsaturated, polyunsaturated, and saturated nonesterified fatty acids (NEFA) in eight healthy volunteers (age 29–54 yr, body mass index 23–26 kg/m2). This was achieved by feeding small boluses of fat at different time points (35 g at 0 min and 8 g at 30, 60, 90, 120, 150, 180, and 210 min) in combination with a continuous low-dose heparin infusion. Olive oil, safflower oil, or palm stearin were used to increase monounsaturated, polyunsaturated, or saturated NEFAs, respectively. Plasma NEFA concentrations were increased for 2 h, when fat and heparin were given (olive oil: 745 ± 35 μmol/l; safflower oil: 609 ± 37 μmol/l, and palm stearin: 773 ± 38 μmol/l) compared with the control test (no fat and no heparin: 445 ± 41 μmol/l). During the heparin infusion, 18:1 n-9 was the most abundant fatty acid for the olive oil test compared with 18:2 n-6 for the safflower oil test and 16:0 for the palm stearin test ( P < 0.01). The method described here successfully increases several types of plasma NEFA concentrations and could be used to investigate differential effects of elevated individual NEFAs on metabolic processes.
Stimulation of insulin secretion and associated nuclear accumulation of iPLA2β in INS-1 insulinoma cells
Authors: Ma Zhongmin , Zhang Sheng , Turk John , Ramanadham Sasanka
Published: February 2015

Accumulating evidence suggests that the cytosolic calcium-independent phospholipase A2(iPLA2β) manifests a signaling role in insulin-secreting (INS-1) β-cells. Earlier, we reported that insulin-secretory responses to cAMP-elevating agents are amplified in iPLA2β-overexpressing INS-1 cells (Ma Z, Ramanadham S, Bohrer A, Wohltmann M, Zhang S, and Turk J. J Biol Chem276: 13198–13208, 2001). Here, immunofluorescence, immunoaffinity, and enzymatic activity analyses are used to examine distribution of iPLA2β in stimulated INS-1 cells in greater detail. Overexpression of iPLA2β in INS-1 cells leads to increased accumulation of iPLA2β in the nuclear fraction. Increasing glucose concentrations alone results in modest increases in insulin secretion, relative to parental cells, and in nuclear accumulation of the iPLA2β protein. In contrast, cAMP-elevating agents induce robust increases in insulin secretion and in time-dependent nuclear accumulation of iPLA2β fluorescence, which is reflected by increases in nuclear iPLA2β protein content and specific enzymatic activity. The stimulated effects are significantly attenuated in the presence of cell-permeable inhibitors of protein phosphorylation and glycosylation. These findings suggest that conditions that amplify insulin secretion promote translocation of β-cell iPLA2β to the nuclei, where it may serve a crucial signaling role.
Effects of fatty acids on exercise plus insulin-induced glucose utilization in trained and sedentary subjects
Authors: Matzinger Oscar , Schneiter Philippe , Tappy Luc
Published: February 2015

Fatty acids are known to decrease insulin-mediated glucose utilization in humans, both at rest and during exercise. To evaluate the effect of endurance training in this process, we infused lipids or saline in groups of sedentary and highly trained subjects. Whole body glucose utilization and substrate oxidation were monitored during a 2.5-h hyperinsulinemic clamp. During the last 30 min, a cycling exercise was superimposed. During hyperinsulinemia at rest, whole body glucose utilization and glucose oxidation were higher in trained subjects than in sedentary subjects. Compared with the control experiments with the antilipolytic agent acipimox, lipid infusion stimulated lipid oxidation to the same extent in trained as in sedentary subjects. It reduced whole body glucose utilization by 37% in trained and by 41% in sedentary subjects. During exercise, lipid infusion increased more lipid oxidation in trained than in sedentary subjects and reduced whole body glucose utilization by 43 ± 4% in trained and by 22 ± 4% in sedentary subjects ( P < 0.01). The present data indicate that lipid infusion has similar effects on lipid oxidation and whole body glucose utilization during hyperinsulinemia at rest in trained and sedentary subjects. During exercise, however, it increases more lipid oxidation and produces a more important reduction in glucose utilization in trained than in sedentary subjects. These results suggest that endurance training enhances the inhibitory effect of lipids on whole body glucose metabolism during exercise.
Acetyl-coenzyme A synthetase is a lipogenic enzyme controlled by SREBP-1 and energy status
Authors: Sone Hirohito , Shimano Hitoshi , Sakakura Yuki , Inoue Noriyuki , Amemiya-Kudo Michiyo , Yahagi Naoya , Osawa Mitsujiro , Suzuki Hiroaki , Yokoo Tomotaka , Takahashi Akimitsu , Iida Kaoruko , Toyoshima Hideo , Iwama Atsushi , Yamada Nobuhiro
Published: February 2015

DNA microarray analysis on upregulated genes in the livers from transgenic mice overexpressing nuclear sterol regulatory element-binding protein (SREBP)-1a, identified an espressed sequence tag (EST) encoding a part of murine cytosolic acetyl-coenzyme A synthetase (ACAS). Northern blot analysis of the livers from transgenic mice demonstrated that this gene was highly induced by SREBP-1a, SREBP-1c, and SREBP-2. DNA sequencing of the 5′ flanking region of the murine ACAS gene identified a sterol regulatory element with an adjacent Sp1 site. This region was shown to be responsible for SREBP binding and activation of the ACAS gene by gel shift and luciferase reporter gene assays. Hepatic and adipose tissue ACAS mRNA levels in normal mice were suppressed at fasting and markedly induced by refeeding, and this dietary regulation was nearly abolished in SREBP-1 knockout mice, suggesting that the nutritional regulation of the ACAS gene is controlled by SREBP-1. The ACAS gene was downregulated in streptozotocin-induced diabetic mice and was restored after insulin replacement, suggesting that diabetic status and insulin also regulate this gene. When acetate was administered, hepatic ACAS mRNA was negatively regulated. These data on dietary regulation and SREBP-1 control of ACAS gene expression demonstrate that ACAS is a novel hepatic lipogenic enzyme, providing further evidence that SREBP-1 and insulin control the supply of acetyl-CoA directly from cellular acetate for lipogenesis. However, its high conservation among different species and the wide range of its tissue distribution suggest that this enzyme might also play an important role in basic cellular energy metabolism.
Adiponectin is stimulated by adrenalectomy inob/ob mice and is highly correlated with resistin mRNA
Authors: Makimura Hideo , Mizuno Tooru M. , Bergen Hugo , Mobbs Charles V.
Published: February 2015

Plasma levels of the adipocyte product adiponectin, a putative insulin-sensitizing agent, are reduced in obesity, whereas plasma levels of resistin, an agent that some believe to confer insulin resistance, are thought to increase with obesity. Because adrenalectomy can increase insulin sensitivity, we hypothesized that adrenalectomy would increase expression of adiponectin and decrease expression of resistin. Therefore, we measured adiponectin mRNA, adiponectin peptide, and resistin mRNA in adrenalectomized ob/ob mice. Adrenalectomy restored adiponectin expression in ob/ob mice to wild-type levels and stimulated adiponectin peptide to above wild-type levels. Surprisingly, expression of adiponectin and resistin was highly positively correlated even after statistical removal of effects of insulin, glucose, and adiposity. In addition, adiponectin and resistin expression were also highly correlated in diet-induced obese mice. The data support a role for adiponectin in mediating some effects of adrenalectomy on insulin sensitivity.
SG, SI, and EGP of exercise-trained middle-aged men estimated by a two-compartment labeled minimal model
Authors: Nishida Yuichiro , Tokuyama Kumpei , Nagasaka Shoichiro , Higaki Yasuki , Fujimi Kanta , Kiyonaga Akira , Shindo Munehiro , Kusaka Ikuyo , Nakamura Tomoatsu , Ishikawa San-E , Saito Toshikazu , Nakamura Orie , Sato Yuzo , Tanaka Hiroaki
Published: February 2015

To examine the effects of physical training on glucose effectiveness (SG), insulin sensitivity (SI), and endogenous glucose production (EGP) in middle-aged men, stable-labeled frequently sampled intravenous glucose tolerance tests (FSIGTT) were performed on 11 exercise-trained middle-aged men and 12 age-matched sedentary men. The time course of EGP during the FSIGTT was estimated by nonparametric stochastic deconvolution. Glucose uptake-specific indexes of glucose effectiveness (S[Formula: see text]*× 102: 0.81 ± 0.08 vs. 0.60 ± 0.05 dl · min−1· kg−1, P < 0.05) and insulin sensitivity [S[Formula: see text]*  × 104: 24.59 ± 2.98 vs. 11.89 ± 2.36 dl · min−1· (μU/ml)−1· kg−1, P < 0.01], which were analyzed using the two-compartment minimal model, were significantly greater in the trained group than in the sedentary group. Plasma clearance rate (PCR) of glucose was consistently greater in the trained men than in sedentary men throughout FSIGTT. Compared with sedentary controls, EGP of trained middle-aged men was higher before glucose load. The EGP of the two groups was similarly suppressed by ∼70% within 10 min, followed by an additional suppression after insulin infusion. EGP returned to basal level at ∼60 min in the trained men and at 100 min in the controls, followed by its overshoot, which was significantly greater in the trained men than in the controls. In addition, basal EGP was positively correlated with S[Formula: see text]*. The higher basal EGP and greater EGP overshoot in trained middle-aged men appear to compensate for the increased insulin-independent (S[Formula: see text]*) and -dependent (S[Formula: see text]*) glucose uptake to maintain glucose homeostasis.
Analyte flux through chronically implanted subcutaneous polyamide membranes differs in humans and rats
Authors: Wisniewski N. , Rajamand N. , Adamsson U. , Lins P. E. , Reichert W. M. , Klitzman B. , Ungerstedt U.
Published: February 2015

The rat is commonly used to evaluate physiological responses of subcutaneous tissue to implanted devices. In vivo longevity of various devices and the biocompatibility of biomaterials depend on how adjacent tissue interacts. How closely the rat model predicts the human response has not been well characterized. The objective of this study was to compare rat and human subcutaneous foreign body responses by monitoring the biochemical environment at a polymer-tissue interface over 8 days using microdialysis. Polyamide microdialysis probes were implanted subcutaneously in humans and rats ( n = 12). Daily microdialysis samples were analyzed for glucose, lactate, pyruvate, glycerol, and urea. Blood glucose was also monitored. Analyte concentrations differed significantly between rats and humans at the implant-tissue interface. There were also qualitative differences in the 8-day trends. For example, over 8 days, microdialysate glucose increased two- to fourfold in humans but decreased in rats ( P < 0.001). This study reveals profound physiological differences at material-tissue interfaces in rats and humans and highlights the need for caution when extrapolating subcutaneous rat biocompatibility data to humans.
Hyperleptinemia in Ay/a mice upregulates arcuate cocaine- and amphetamine-regulated transcript expression
Authors: Tsuruta Yoshio , Yoshimatsu Hironobu , Hidaka Shuji , Kondou Seiya , Okamoto Kenjiro , Sakata Toshiie
Published: February 2015

The effects of leptin on cocaine- and amphetamine-regulated transcript (CART) and agouti-related protein (AGRP) expression in the hypothalamic arcuate nucleus of obese Ay/a mice were investigated. CART mRNA expression was upregulated by 41% and AGRP mRNA downregulated by 78% in hyperleptinemic Ay/a mice relative to levels in lean a/a mice. The mRNA expression of these neuropeptides in either young nonobese Ay/a mice or rats treated with SHU-9119, a synthetic melanocortin-4 receptor (MC4R) antagonist, did not differ significantly from that in the corresponding controls. After a 72-h fast, which decreased the concentration of serum leptin, CART and AGRP mRNA expression decreased and increased, respectively, in Ay/a mice. The expression levels of these neuropeptides in leptin-deficient Ay/a ob/ob double mutants were comparable to those in a/a ob/ob mice. Leptin thus modulates both CART and AGRP mRNA expression in obese Ay/amice, whereas leptin signals are blocked at the MCR4R level. Taken together, the present findings indicate that differential expression of these neuropeptides in Ay/a and ob/obmice results in dissimilar progression toward obesity.
RXR receptor agonist suppression of thyroid function: central effects in the absence of thyroid hormone receptor
Authors: Macchia Paolo E. , Jiang Ping , Yuan Yan-Dar , Chandarardna Roshantha A. S. , Weiss Roy E. , Chassande Olivier , Samarut Jacques , Refetoff Samuel , Burant Charles F.
Published: February 2015

High-affinity agonists for the retinoic acid X receptors (RXR) have pleotropic effects when administered to humans. These include induction of hypertriglyceridemia and hypothyroidism. We determined the effect of a novel high-affinity RXR agonist with potent antihyperglycemic effects on thyroid function of female Zucker diabetic rats and nondiabetic littermates and in db/ db mice. In both nondiabetic and ZFF rats, AGN194204 causes a 70–80% decrease in thyrotropin (TSH), 3,3′,5-triiodothyronine, and thyroxine (T4) concentrations. In the db/ db mouse, AGN194204 causes a time-dependent decrease in thyroid hormone levels with the fall in TSH that was significant after 1 day of treatment preceding the fall in T4levels that was significant at 3 days of treatment. Treatment with AGN194204 caused an initial increase in hepatic 5′-deiodinase mRNA levels which then fell to undetectable levels by 3 days of treatment and continued to be low at 7 days of treatment. After treatment for 5 days with AGN194204, both wild-type and thyroid hormone receptor β (TRβ−/−)-deficient mice demonstrated a nearly 50% decrease in serum TSH and T4concentrations. The results suggest that a high-affinity RXR agonist with antihyperglycemic activity can cause central hypothyroidism independently of TRβ, the main mediator of hormone-induced TSH suppression.
Transgenic mice with green fluorescent protein-labeled pancreatic β-cells
Authors: Hara Manami , Wang Xiaoyu , Kawamura Toshihiko , Bindokas Vytas P. , Dizon Restituto F. , Alcoser Sergio Y. , Magnuson Mark A. , Bell Graeme I.
Published: February 2015

We have generated transgenic mice that express green fluorescent protein (GFP) under the control of the mouse insulin I gene promoter (MIP). The MIP-GFP mice develop normally and are indistinguishable from control animals with respect to glucose tolerance and pancreatic insulin content. Histological studies showed that the MIP-GFP mice had normal islet architecture with coexpression of insulin and GFP in the β-cells of all islets. We observed GFP expression in islets from embryonic day E13.5 through adulthood. Studies of β-cell function revealed no difference in glucose-induced intracellular calcium mobilization between islets from transgenic and control animals. We prepared single-cell suspensions from both isolated islets and whole pancreas from MIP-GFP-transgenic mice and sorted the β-cells by fluorescence-activated cell sorting based on their green fluorescence. These studies showed that 2.4 ± 0.2% ( n = 6) of the cells in the pancreas of newborn (P1) and 0.9 ± 0.1% ( n = 5) of 8-wk-old mice were β-cells. The MIP-GFP-transgenic mouse may be a useful tool for studying β-cell biology in normal and diabetic animals.
Increased synthesis rate of fibrinogen as a basis for its elevated plasma levels in obese female adolescents
Authors: Balagopal Prabhakaran , Sweeten Shawn , Mauras Nelly
Published: February 2015

Increased concentrations of plasma fibrinogen, an independent risk factor for cardiovascular disease (CVD), in obese children have been reported. The underlying mechanism for this, however, remains to be defined. In the current study, we measured the fractional synthesis rates (FSR) of plasma fibrinogen in six healthy postpubertal obese girls [body mass index (BMI) 36.6 ± 1.8 kg/m2; age 16.6 ± 0.5 yr] and six age-matched lean normal control girls (BMI 20.8 ± 0.7 kg/m2; age 16.4 ± 0.4 yr) during a primed, continuous infusion of l-[1-13C]leucine in the postabsorptive state. The method involved purification of plasma fibrinogen by use of immunoaffinity chromatography followed by measurement of [13C]leucine enrichment using gas chromatography-combustion-isotope ratio mass spectrometry. The FSR of fibrinogen in obese girls (35.06 ± 2.61%/day) was almost double that in lean girls (17.02 ± 1.43%/day), and this increase was associated with a relative increase in plasma concentration of fibrinogen as well as BMI in the subjects studied. Obese subjects had high fasting insulin levels (138 ± 47 pmol/l) compared with lean subjects (54 ± 11 pmol/l), whereas their glucose concentrations were similar (4.5 ± 0.3 mmol/l in obese and 4.4 ± 0.4 mmol/l in lean subjects), suggesting insulin resistance. The doubling of the FSR of fibrinogen provides novel insight into the mechanism of elevated levels of plasma fibrinogen and suggests a primary role for increased synthesis in producing the hyperfibrinogenemia associated with obesity. This finding may have important implications in the design of therapies for modulating plasma fibrinogen levels in obesity and/or CVD in childhood.
Plasma glucose kinetics during prolonged exercise in trained humans when fed carbohydrate
Authors: Angus Damien J. , Febbraio Mark A. , Hargreaves Mark
Published: February 2015

Nine endurance-trained men exercised on a cycle ergometer at ∼68% peak O2 uptake to the point of volitional fatigue [232 ± 14 (SE) min] while ingesting an 8% carbohydrate solution to determine how high glucose disposal could increase under physiological conditions. Plasma glucose kinetics were measured using a primed, continuous infusion of [6,6-2H]glucose and the appearance of ingested glucose, assessed from [3-3H]glucose that had been added to the carbohydrate drink. Plasma glucose was increased ( P < 0.05) after 30 min of exercise but thereafter remained at the preexercise level. Glucose appearance rate (Ra) increased throughout exercise, reaching its peak value of 118 ± 7 μmol · kg−1 · min−1 at fatigue, whereas gut Ra increased continuously during exercise, peaking at 105 ± 10 μmol · kg−1 · min−1 at the point of fatigue. In contrast, liver glucose output never rose above resting levels at any time during exercise. Glucose disposal (Rd) increased throughout exercise, reaching a peak value of 118 ± 7 μmol · kg−1 · min−1 at fatigue. If we assume 95% oxidation of glucose Rd, estimated exogenous glucose oxidation at fatigue was 1.36 ± 0.08 g/min. The results of this study demonstrate that glucose uptake increases continuously during prolonged, strenuous exercise when carbohydrate is ingested and does not appear to limit exercise performance.
Amelioration of high fructose-induced metabolic derangements by activation of PPARα
Authors: Nagai Yoshio , Nishio Yoshihiko , Nakamura Takaaki , Maegawa Hiroshi , Kikkawa Ryuichi , Kashiwagi Atsunori
Published: February 2015

To elucidate molecular mechanisms of high fructose-induced metabolic derangements and the influence of peroxisome proliferator-activated receptor-α (PPARα) activation on them, we examined the expression of sterol regulatory element binding protein-1 (SREBP-1) and PPARα as well as its nuclear activation and target gene expressions in the liver of high fructose-fed rats with or without treatment of fenofibrate. After 8-wk feeding of a diet high in fructose, the mRNA contents of PPARα protein and its activity and gene expressions of fatty acid oxidation enzymes were reduced. In contrast, the gene expressions of SREBP-1 and lipogenic enzymes in the liver were increased by high fructose feeding. Similar high fructose effects were also found in isolated hepatocytes exposed to 20 mM fructose in the media. The treatment of fenofibrate (30 mg · kg−1· day−1) significantly improved high fructose-induced metabolic derangements such as insulin resistance, hypertension, hyperlipidemia, and fat accumulation in the liver. Consistently, the decreased PPARα protein content, its activity, and its target gene expressions found in high fructose-fed rats were all improved by fenofibrate treatment. Furthermore, we also found that the copy number of mitochondrial DNA, the expressions of mitochondrial transcription factor A, ATPase-6 subunit, and uncoupling protein-3 were increased by fenofibrate treatment. These findings suggest that the metabolic syndrome in high fructose-fed rats is reversed by fenofibrate treatment, which is associated with the induction of enzyme expression related to β-oxidation and the enhancement of mitochondrial gene expression.
Middle-aged C57BL/6 mice have impaired responses to leptin that are not improved by calorie restriction
Authors: Jacobson Lauren
Published: February 2015

Midlife weight gain occurs in many species, suggesting that leptin signaling is impaired at middle age. To test this hypothesis, we measured changes in food intake and body composition in young (Y) and middle-aged (MA) C57BL/6 male mice infused subcutaneously with phosphate-buffered saline or leptin. Leptin-induced decreases in food intake and body fat were delayed in MA mice and associated with catabolism after longer treatment periods. Endogenous plasma leptin levels did not correlate with body fat in MA mice. Calorie restriction (CR) reduced body fat, plasma leptin, and insulin in MA mice to levels in Y mice but did not upregulate leptin sensitivity. CR mice did not respond to leptin doses that inhibited food intake in MA mice and reduced food intake and body fat in Y mice significantly below levels in CR mice. Plasma corticosterone was significantly higher in leptin-treated CR vs. MA mice. We conclude that MA C57BL/6 mice exhibit impaired leptin signaling and that CR, possibly by elevating glucocorticoids, impairs appetite control without improving the metabolic actions of leptin.
Pancreatic β-cell dysfunction in polycystic ovary syndrome: role of hyperglycemia-induced nuclear factor-κB activation and systemic inflammation
Authors: Malin Steven K. , Kirwan John P. , Sia Chang Ling , González Frank
Published: February 2015

In polycystic ovary syndrome (PCOS), oxidative stress is implicated in the development of β-cell dysfunction. However, the role of mononuclear cell (MNC)-derived inflammation in this process is unclear. We determined the relationship between β-cell function and MNC-derived nuclear factor-κB (NF-κB) activation and tumor necrosis factor-α (TNF-α) secretion in response to a 2-h 75-g oral glucose tolerance test (OGTT) in normoglycemic women with PCOS (15 lean, 15 obese) and controls (16 lean, 14 obese). First- and second-phase β-cell function was calculated as glucose-stimulated insulin secretion (insulin/glucose area under the curve for 0–30 and 60–120 min, respectively) × insulin sensitivity (Matsuda Index derived from the OGTT). Glucose-stimulated NF-κB activation and TNF-α secretion from MNC, and fasting plasma thiobarbituric acid-reactive substances (TBARS) and high-sensitivity C-reactive protein (hs-CRP) were also assessed. In obese women with PCOS, first- and second-phase β-cell function was lower compared with lean and obese controls. Compared with lean controls, women with PCOS had greater change from baseline in NF-κB activation and TNF-α secretion, and higher plasma TBARS. β-Cell function was inversely related to NF-κB activation (1st and 2nd) and TNF-α secretion (1st), and plasma TBARS and hs-CRP (1st and 2nd). First- and second-phase β-cell function also remained independently linked to NF-κB activation after adjustment for body fat percentage and TBARS. In conclusion, β-cell dysfunction in PCOS is linked to hyperglycemia-induced NF-κB activation from MNC and systemic inflammation. These data suggest that in PCOS, inflammation may play a role in impairing insulin secretion before the development of overt hyperglycemia.