bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of the effects of escitalopram and atorvastatin on diet-induced atherosclerosis in rats
Authors: Unis Amina , Abdelbary Amany , Hamza Manal
Published: December 2013

Atherosclerosis is one of the most common disorders among the elderly. Depression may be associated with the development of atherosclerosis. Thus, the aim of this study is to evaluate and compare the effects of escitalopram (a selective serotonin reuptake inhibitor) with atorvastatin (a well known antihyperlipidemic drug) on high fat diet induced atherosclerosis in rats. The results of this study showed that the administration of either escitalopram or atorvastatin for 6 weeks was associated with a significant decrease in serum levels of total cholesterol, triglycerides, low density lipoproteins, very low density lipoproteins, and serum malondialdehyde, and a significant increase in high density lipoproteins when compared with the atherosclerosis model group. Histopathological examination of the aortas from the test rats revealed significant regression of atherosclerotic changes, together with a significant decrease in vascular cell adhesion molecule-1 (VCAM-1) expression in the media of both the escitalopram group and the atorvastatin group when compared with the atherosclerosis model group. This study has shown that escitalopram reduced atherosclerotic changes, thus its use as an antidepressant in elderly patients should be considered.
A FIRST STAGE COMPARATIVE SURVEY ON HUMAN ACTIVITY RECOGNITION METHODOLOGIES
Authors: TSITSOULIS ATHANASIOS , BOURBAKIS NIKOLAOS
Published: December 2013

The development of vision-based human activity recognition and analysis systems has been a matter of great interest to both the research community and practitioners during the last 20 years. Traditional methods that require a human operator watching raw video streams are nowadays deemed as at least ineffective and expensive. New, smart solutions in automatic surveillance and monitoring have emerged, propelled by significant technological advances in the fields of image processing, artificial intelligence, electronics and optics, embedded computing and networking, molding the future of several applications that can benefit from them, like security and healthcare. The main motivation behind it is to exploit the highly informative visual data captured by cameras and perform high-level inference in an automatic, ubiquitous and unobtrusive manner, so as to aid human operators, or even replace them. This survey attempts to comprehensively review the current research and development on vision-based human activity recognition. Synopses from various methodologies are presented in an effort to garner the advantages and shortcomings of the most recent state-of-the-art technologies. Also a first-level self-evaluation of methodologies is also proposed, which incorporates a set of significant features that best describe the most important aspects of each methodology in terms of operation, performance and others and weighted by their importance. The purpose of this study is to serve as a reference for further research and evaluation to raise thoughts and discussions for future improvements of each methodology towards maturity and usefulness.
FAST, MULTI-MODAL AND DISCONTINUITY-PRESERVING IMAGE REGISTRATION USING MUTUAL INFORMATION
Authors: PANIN GIORGIO
Published: December 2013

In this paper, we describe a fast and efficient method for multi-modal and discontinuity-preserving image registration, implemented on graphics hardware. Multi-sensory data fusion and medical image analysis often pose the challenging task of aligning dense, non-rigid and multi-modal images. However, also optical sequences or stereo image pairs may present variable illumination conditions and noise. The above problems can be addressed by an invariant similarity measure, such as mutual information. Additionally, when using a regularized approach to deal with the ill-posedness of the problem, one has to take care of preserving discontinuities at the motion boundaries. Our approach efficiently addresses the above issues through a primal-dual convex estimation framework, using an approximated Hessian matrix that decouples pixel dependencies, while being asymptotically correct. At the same time, we achieve a high computational efficiency by means of pre-quantized kernel density estimation and differentiation, as well as a parallel implementation on the GPU. Our approach is demonstrated on ground-truth data from the Middlebury database, as well as medical and visible-infrared image pairs.
USING DETAILED INDEPENDENT 3D SUB-MODELS TO IMPROVE FACIAL FEATURE LOCALISATION AND POSE ESTIMATION
Authors: CAUNCE ANGELA , TAYLOR CHRIS , COOTES TIM
Published: December 2013

We show that the results from searching 2D images or a video sequence, with a 3D head model can be improved by using detailed sub-models. These parts are initialised with the full model result and are allowed to search independently of that model, and of each other, using the same algorithm. The final results for the sub-models can be reported exactly, or optionally fed back into the full model to be constrained by its parameter space. In the case of a video sequence this can then be used in the initialisation of the next frame. We tested various data sets, constrained and unconstrained, including a variety of lighting conditions, poses, and expressions. Our investigation showed that using the sub-models improved on the original full model result on all but one of the data sets.
A NEW ALGORITHM FOR COMPUTING RIEMANNIAN GEODESIC DISTANCE IN RECTANGULAR 2-D AND 3-D GRIDS
Authors: NILSSON OLA , REIMERS MARTIN , MUSETH KEN , BRUN ANDERS
Published: December 2013

We present a novel way to efficiently compute Riemannian geodesic distance over a two- or three-dimensional domain. It is based on a previously presented method for computation of geodesic distances on surface meshes. Our method is adapted for rectangular grids, equipped with a variable anisotropic metric tensor. Processing and visualization of such tensor fields is common in certain applications, for instance structure tensor fields in image analysis and diffusion tensor fields in medical imaging.

The included benchmark study shows that our method provides significantly better results in anisotropic regions in 2-D and 3-D and is faster than current stat-of-the-art solvers in 2-D grids. Additionally, our method is straightforward to code; the test implementation is less than 150 lines of C++ code. The paper is an extension of a previously presented conference paper and includes new sections on 3-D grids in particular.
Symmetrical tetra-β″-sulfoleno-meso-aryl-porphyrins — synthesis, spectroscopy and structural characterization
Authors: Banala Srinivas , Wurst Klaus , Kräutler Bernhard
Published: December 2013

We report here the preparation (in "one-pot") of a tetra-β″-sulfoleno-meso-aryl-porphyrin in about 80% yield by using an optimized modification of Lindsey's variant of the Adler–Longo approach. The Zn ( II )-, Cu ( II )- and Ni ( II )-complexes of the symmetrical porphyrin were prepared and characterized spectroscopically. Crystal structures of the fluorescent Zn ( II )- and of the non-fluorescent Ni ( II )-tetra-β″-sulfoleno-meso-aryl-porphyrinates showed the highly substituted porphyrin ligands to be nearly perfectly planar. The Zn ( II )-complex of this porphyrin has been used as a thermal precursor of a reactive diene, and — formally — of lateral and diagonal bis-dienes, of a tris-diene and of a tetra-diene, which all underwent [4 + 2]-cycloaddition reactions in situ with a range of dienophiles. Thus, the tetra-β″-sulfoleno-meso-aryl-porphyrin and its metal complexes represent reactive building blocks, "programmed" for the syntheses of symmetrical and highly functionalized porphyrins.
TRANSFORMING THE EUROPEAN ENERGY SYSTEM: MEMBER STATES' PROSPECTS WITHIN THE EU FRAMEWORK
Authors: KNOPF BRIGITTE , BAKKEN BJØRN , CARRARA SAMUEL , KANUDIA AMIT , KEPPO ILKKA , KOLJONEN TIINA , MIMA SILVANA , SCHMID EVA , VAN VUUREN DETLEF P.
Published: December 2013

The Energy Modeling Forum 28 (EMF28) performed a large-scale model comparison exercise to illustrate different technology pathways for cutting European greenhouse gas emissions by 80% by 2050. Focusing on selected countries (France, Germany, Italy, Sweden, and UK), this paper first analyzes climate and energy policy objectives and debates in the respective countries. It then compares EMF28 model results to the short-term projections of the National Renewable Energy Action Plans (NREAPs) and the long-term transformation pathway given in the European Commission's "Energy Roadmap 2050". It concludes that there is sufficient agreement with the NREAPs and national policies to accept the model results as conceivable scenarios. The scenarios suggest that in the future a variety of different national energy mixes will continue to reflect the different resource bases and preferences of individual Member States. In order to ensure a cost-efficient transformation, it is important to improve coordination between Member State policies and those at the EU level.
THE INFRASTRUCTURE IMPLICATIONS OF THE ENERGY TRANSFORMATION IN EUROPE UNTIL 2050 — LESSONS FROM THE EMF28 MODELING EXERCISE
Authors: HOLZ FRANZISKA , VON HIRSCHHAUSEN CHRISTIAN
Published: December 2013

This paper summarizes the approaches to and the implications of bottom–up infrastructure modeling in the framework of the EMF28 model comparison "Europe 2050: The Effects of Technology Choices on EU Climate Policy". It includes models covering all the sectors currently under scrutiny by the European Infrastructure Priorities: Electricity, natural gas, and CO 2. Results suggest that some infrastructure enhancement is required to achieve the decarbonization, and that the network development needs can be attained in a reasonable timeframe. In the electricity sector, additional cross-border interconnection is required, but generation and the development of low-cost renewables is a more challenging task. For natural gas, the falling total consumption could be satisfied by the current infrastructure in place, and even in a high-gas scenario the infrastructure implications remain manageable. Model results on the future role of Carbon Capture, Transport, and Sequestration (CCTS) vary, and suggest that most of the transportation infrastructure might be required in and around the North Sea.
MARKET DRIVEN POWER PLANT INVESTMENT PERSPECTIVES IN EUROPE: CLIMATE POLICY AND TECHNOLOGY SCENARIOS UNTIL 2050 IN THE MODEL EMELIE-ESY
Authors: SCHRÖDER A. , TRABER T. , KEMFERT C.
Published: December 2013

In the framework of the Energy Modeling Forum 28, we investigate how climate policy regimes affect market developments under different technology availabilities on the European power markets. We use the partial equilibrium model EMELIE-ESY with focus on electricity markets in order to determine how private investors optimize their generation capacity investment and operation over the horizon 2010 to 2050. For the year 2050, the model projects a minor increase of power consumption of 10% under current climate policy, and a balanced pathway for consumption under ambitious climate policy compared to 2010 levels. These results contrast with findings of POLES and PRIMES models that predict strong consumption increases of 44% to 48% by 2050 and claim competitiveness of nuclear power and CCS options. Under ambitious climate policy, our findings correspond with major increases of wholesale electricity market prices and comparatively less pronounced emission price increases, which trigger no investments into Carbon Capture and Storage (CCS) and a strongly diminishing share of nuclear energy.
The mineral signature of the Anthropocene in its deep-time context
Authors: Zalasiewicz Jan , Kryza Ryszard , Williams Mark
Published: December 2013

The Earth has shown a systematic increase in mineral species through its history, with three ‘eras’ comprising ten ‘stages’ identified by Robert Hazen and his colleagues (

Hazen
et al.
2008

), the eras being associated with planetary accretion, crust and mantle reworking and the influence of life, successively. We suggest that a further level in this form of evolution has now taken place of at least ‘stage’ level, where humans have engineered a large and extensive suite of novel, albeit not formally recognized minerals, some of which will leave a geologically significant signal in strata forming today. These include the great majority of metals (that are not found natively), tungsten carbide, boron nitride, novel garnets and many others. A further stratigraphic signal is of minerals that are rare in pre-industrial geology, but are now common at the surface, including mullite (in fired bricks and ceramics), ettringite, hillebrandite and portlandite (in cement and concrete) and ‘mineraloids’ (novel in detail) such as anthropogenic glass. These have become much more common at the Earth's surface since the mid-twentieth century. However, the scale and extent of this new phase of mineral evolution, which represents part of the widespread changes associated with the proposed Anthropocene Epoch, remains uncharted. The
International Mineralogical Association (IMA)
list of officially accepted minerals explicitly excludes synthetic minerals, and no general inventory of these exists. We propose that the growing geological and societal significance of this phenomenon is now great enough for human-made minerals to be formally listed and catalogued by the IMA, perhaps in conjunction with materials science societies. Such an inventory would enable this phenomenon to be placed more effectively within the context of the 4.6 billion year history of the Earth, and would help characterize the strata of the Anthropocene.
Built-in generation of multicycle functional broadside tests with observation points
Authors: Pomeranz Irith
Published: December 2013

Functional broadside tests allow overtesting to be avoided as part of a scheme that considers both test generation and the analysis of output responses, by ensuring that delay faults are detected under functional operation conditions. Compared with two-cycle tests, multicycle tests allow more faults to be detected with each test, thus reducing the number of tests that need to be applied. They also provide an opportunity for nonfunctional electrical effects, which are caused by switching between modes of operation, to subside before the clock cycles where delay faults are detected. Built-in test generation facilitates at-speed testing and reduces the test data volume. Motivated by these observations, this article describes the modification of a built-in test generation method for two-cycle functional broadside tests so as to generate multicycle functional broadside tests. The size of the hardware is not increased by the modification. The article investigates the following issues related to this method: (1) the effect of using multicycle tests on the number of tests that need to be applied; (2) fault simulation for tailoring the test generation hardware to a circuit that takes into account, to different extents, the need to allow nonfunctional electrical effects to subside; (3) the insertion of observation points in order to increase the transition fault coverage.
A Reconfigurable Parallel Hardware Implementation of the Self-Tuning Regulator
Authors: Ananthan T. , Vaidyan M. V.
Published: December 2013

The self-tuning regulator (STR) is a popular adaptive control algorithm. A high-performance computer is required for its implementation due to the heavy online computational burden. To extend STR for more real-time applications, a parallel hardware implementation on a low-cost reconfigurable computer is presented. The hardware was incorporated with multistage matrix multiplication (MMM) and trace technique to enhance the processing speed. This design was deeply pipelined to achieve high throughput. The algorithm was prototyped on a Xilinx field-programmable gate array (FPGA) device with a maximum operating frequency of 210.436 MHz. Application-specific integrated circuit (ASIC) implementation of STR was reported.
A theory of robust omega-regular software synthesis
Authors: Majumdar Rupak , Render Elaine , Tabuada Paulo
Published: December 2013

A key property for systems subject to uncertainty in their operating environment is
robustness
: ensuring that unmodeled but bounded disturbances have only a proportionally bounded effect upon the behaviors of the system. Inspired by ideas from robust control and dissipative systems theory, we present a formal definition of robustness as well as algorithmic tools for the design of optimally robust controllers for ω-regular properties on discrete transition systems. Formally, we define
metric automata
—automata equipped with a metric on states—and strategies on metric automata which guarantee robustness for ω-regular properties. We present fixed-point algorithms to construct optimally robust strategies in polynomial time. In contrast to strategies computed by classical graph theoretic approaches, the strategies computed by our algorithm ensure that the behaviors of the controlled system gracefully degrade under the action of disturbances; the degree of degradation is parameterized by the magnitude of the disturbance. We show an application of our theory to the design of controllers that tolerate infinitely many transient errors provided they occur infrequently enough.
Register allocation for embedded systems to simultaneously reduce energy and temperature on registers
Authors: Liu Tiantian , Orailoglu Alex , Xue Chun Jason , Li Minming
Published: December 2013

Energy and thermal issues are two important concerns for embedded system design. Diminished energy dissipation leads to a longer battery life, while reduced temperature hotspots decelerate the physical failure mechanisms. The instruction fetch logic associated with register access has a significant contribution towards the total energy consumption. Meanwhile, the register file has also been previously shown to exhibit the highest temperature compared to the rest of the components in an embedded processor. Therefore, the optimization of energy and the resolution of the thermal issue for register accesses are of great significance. In this article, register allocation techniques are studied to simultaneously reduce energy consumption and heat buildup on register accesses for embedded systems. Contrary to prevailing intuition, we observe that optimizing energy and optimizing temperature on register accesses conflict with each other. We introduce a rotator hardware in the instruction decoder to facilitate a balanced solution for the two conflicting objectives. Algorithms for register allocation and refinement are proposed based on the access patterns and the effects of the rotator. Experimental results show that the proposed algorithms obtain notable improvements of energy and peak temperature for embedded applications.
An adaptive, low-cost wear-leveling algorithm for multichannel solid-state disks
Authors: Chang Li-Pin , Chou Tung-Yang , Huang Li-Chun
Published: December 2013

Multilevel flash memory cells double or even triple storage density, producing affordable solid-state disks for end users. As flash memory endures only limited program-erase cycles, solid-state disks employ wear-leveling methods to prevent any portions of flash memory from being retired prematurely. Modern solid-state disks must consider wear evenness at both block and channel levels. This study first presents a block-level wear-leveling method whose design has two new ideas. First, the proposed method reuses the intelligence available in flash-translation layers so it does not require any new data structures. Second, it adaptively tunes the threshold of block-level wear leveling according to the runtime write pattern. This study further introduces a new channel-level wear-leveling strategy, because block-level wear leveling is confined to a channel, but realistic workloads do not evenly write all channels. The proposed method swaps logical blocks among channels for achieving an eventually-even state of channel lifetimes. A series of trace-driven simulations show that our wear-leveling method outperforms existing approaches in terms of wear evenness and overhead reduction.
Ginsenoside Rb1 ameliorates lipopolysaccharide-induced albumin leakage from rat mesenteric venules by intervening in both trans- and paracellular pathway
Authors: Zhang Yu , Sun Kai , Liu Yu-Ying , Zhang Yun-Pei , Hu Bai-He , Chang Xin , Yan Li , Pan Chun-Shui , Li Quan , Fan Jing-Yu , He Ke , Mao Xiao-Wei , Tu Lei , Wang Chuan-She , Han Jing-Yan
Published: December 2013

Lipopolysaccharide (LPS) is one of the common pathogens that causes mesentery hyperpermeability- and intestinal edema-related diseases. This study evaluated whether ginsenoside Rb1 (Rb1), an ingredient of a Chinese medicine Panax ginseng, has beneficial effects on mesentery microvascular hyperpermeability induced by LPS and the underlying mechanisms. Male Wistar rats were continuously infused with LPS (5 mg·kg−1·h−1) via the left jugular vein for 90 min. In some rats, Rb1 (5 mg·kg−1·h−1) was administrated through the left jugular vein 30 min after LPS infusion. The dynamics of fluorescein isothiocynate-labeled albumin leakage from mesentery venules was assessed by intravital microscopy. Intestinal tissue edema was evaluated by hematoxylin and eosin staining. The number of caveolae in endothelial cells of microvessels was examined by electron microscopy. Confocal microscopy and Western blotting were applied to detect caveolin-1 (Cav-1) expression and phosphorylation, junction-related proteins, and concerning signaling proteins in intestinal tissues and human umbilical vein endothelial cells. LPS infusion evoked an increased albumin leakage from mesentery venules that was significantly ameliorated by Rb1 posttreatment. Mortality and intestinal edema around microvessels were also reduced by Rb1. Rb1 decreased caveolae number in endothelial cells of microvessels. Cav-1 expression and phosphorylation, VE-Cadherin phosphorylation, ZO-1 degradation, nuclear factor-κB (NF-κB) activation, and Src kinase phosphorylation were inhibited by Rb1. Rb1 ameliorated microvascular hyperpermeability after the onset of endotoxemia and improved intestinal edema through inhibiting caveolae formation and junction disruption, which was correlated to suppression of NF-κB and Src activation.
Brain-derived neurotrophic factor enhances cholinergic contraction of longitudinal muscle of rabbit intestine via activation of phospholipase C
Authors: Al-Qudah M. , Anderson C. D. , Mahavadi S. , Bradley Z. L. , Akbarali H. I. , Murthy K. S. , Grider J. R.
Published: December 2013

Brain-derived neurotrophic factor (BDNF) belongs to the neurotrophin family of proteins best known for its role in neuronal survival, differentiation, migration, and synaptic plasticity in central and peripheral neurons. BDNF is also widely expressed in nonneuronal tissues including the gastrointestinal tract. The role of BDNF in intestinal smooth muscle contractility is not well defined. The aim of this study was to identify the role of BDNF in carbachol (CCh)- and substance P (SP)-induced contraction of intestinal longitudinal smooth muscle. BDNF, selective tropomyosin-related kinase B (TrkB) receptor agonists, and pharmacological inhibitors of signaling pathways were examined for their effects on contraction of rabbit intestinal longitudinal muscle strips induced by CCh and SP. BDNF activation of intracellular signaling pathways was examined by Western blot in homogenates of muscle strips and isolated muscle cells. One-hour preincubation with BDNF enhanced intestinal muscle contraction induced by CCh but not by SP. The selective synthetic TrkB agonists LM 22A4 and 7,8-dihydroxyflavone produced similar effects to BDNF. The Trk antagonist K-252a, a TrkB antibody but not p75NTR antibody, blocked the effect of BDNF. The enhancement of CCh-induced contraction by BDNF was blocked by the phospholipase C (PLC) antagonist U73122, but not by ERK1/2 or Akt antagonists. Direct measurement in muscle strips and isolated muscle cells showed that BDNF caused phosphorylation of TrkB receptors and PLC-γ, but not ERK1/2 or Akt. We conclude that exogenous BDNF augments the CCh-induced contraction of longitudinal muscle from rabbit intestine by activating TrkB receptors and subsequent PLC activation.
Involvement of the mitochondrial permeability transition pore in chronic ethanol-mediated liver injury in mice
Authors: King Adrienne L. , Swain Telisha M. , Mao Zhengkuan , Udoh Uduak S. , Oliva Claudia R. , Betancourt Angela M. , Griguer Corrine E. , Crowe David R. , Lesort Mathieu , Bailey Shannon M.
Published: December 2013

Chronic ethanol consumption increases sensitivity of the mitochondrial permeability transition (MPT) pore induction in liver. Ca2+promotes MPT pore opening, and genetic ablation of cyclophilin D (CypD) increases the Ca2+threshold for the MPT. We used wild-type (WT) and CypD-null (CypD−/−) mice fed a control or an ethanol-containing diet to investigate the role of the MPT in ethanol-mediated liver injury. Ca2+-mediated induction of the MPT and mitochondrial respiration were measured in isolated liver mitochondria. Steatosis was present in WT and CypD−/−mice fed ethanol and accompanied by increased terminal deoxynucleotidyl transferase dUTP-mediated nick-end label-positive nuclei. Autophagy was increased in ethanol-fed WT mice compared with ethanol-fed CypD−/−mice, as reflected by an increase in the ratio of microtubule protein 1 light chain 3B II to microtubule protein 1 light chain 3B I. Higher levels of p62 were measured in CypD−/−than WT mice. Ethanol decreased mitochondrial respiratory control ratios and select complex activities in WT and CypD−/−mice. Ethanol also increased CypD protein in liver of WT mice. Mitochondria from control- and ethanol-fed WT mice were more sensitive to Ca2+-mediated MPT pore induction than mitochondria from their CypD−/−counterparts. Mitochondria from ethanol-fed CypD−/−mice were also more sensitive to Ca2+-induced swelling than mitochondria from control-fed CypD−/−mice but were less sensitive than mitochondria from ethanol-fed WT mice. In summary, CypD deficiency was associated with impaired autophagy and did not prevent ethanol-mediated steatosis. Furthermore, increased MPT sensitivity was observed in mitochondria from ethanol-fed WT and CypD−/−mice. We conclude that chronic ethanol consumption likely lowers the threshold for CypD-regulated and -independent characteristics of the ethanol-mediated MPT pore in liver mitochondria.
Key role of endothelial importin-α in VEGF expression and gastric angiogenesis: novel insight into aging gastropathy
Authors: Ahluwalia Amrita , Jones Michael K. , Tarnawski Andrzej S.
Published: December 2013

Recent in vivo studies demonstrated that aging gastric mucosa has impaired angiogenesis and reduced expression of vascular endothelial growth factor (VEGF). Angiogenesis is triggered by hypoxia and VEGF gene activation, and the latter requires transport of transcription factor(s) into endothelial cell nuclei. We focused on gastric mucosal endothelial cells (GMEC), which are key targets and effectors of gastric angiogenesis, and determined whether and to what extent importin-α, a nuclear transport protein, regulates VEGF gene activation and gastric angiogenesis and the possible role of importin-α in aging gastropathy. GMEC were isolated from rats 3 and 24 mo of age, young (YGEC) and aging (AGEC), respectively. We examined in these cells 1) in vitro angiogenesis, 2) expression of VEGF and importin-α, 3) nuclear transport of hypoxia-inducible factor (HIF)-1α by importin-α, 4) binding of HIF-1α to the VEGF gene promoter, and 5) effects of importin-α silencing in YGEC and its upregulation in AGEC on angiogenesis and VEGF expression. AGEC exhibited significantly impaired in vitro angiogenesis by fourfold and decreased expression of VEGF, importin-α, and nuclear HIF-1α by 1.4-fold, 1.6-fold, and 2.9-fold, respectively, vs. YGEC. Upregulation of importin-α in AGEC significantly reversed all these abnormalities. In YGEC, knockdown of importins-α1 and -α3 significantly reduced in vitro angiogenesis by 93% and 73% and VEGF expression by 48% and 52%, respectively. The above findings demonstrate that importin-α is a novel and critical regulator of gastric angiogenesis. Its reduced expression in AGEC is the key mechanism for impaired angiogenesis and reduced VEGF.
Xenin-25 delays gastric emptying and reduces postprandial glucose levels in humans with and without Type 2 diabetes
Authors: Chowdhury Sara , Reeds Dominic N. , Crimmins Dan L. , Patterson Bruce W. , Laciny Erin , Wang Songyan , Tran Hung D. , Griest Terry A. , Rometo David A. , Dunai Judit , Wallendorf Michael J. , Ladenson Jack H. , Polonsky Kenneth S. , Wice Burton M.
Published: December 2013

Xenin-25 (Xen) is a neurotensin-related peptide secreted by a subset of glucose-dependent insulinotropic polypeptide (GIP)-producing enteroendocrine cells. In animals, Xen regulates gastrointestinal function and glucose homeostasis, typically by initiating neural relays. However, little is known about Xen action in humans. This study determines whether exogenously administered Xen modulates gastric emptying and/or insulin secretion rates (ISRs) following meal ingestion. Fasted subjects with normal (NGT) or impaired (IGT) glucose tolerance and Type 2 diabetes mellitus (T2DM; n = 10–14 per group) ingested a liquid mixed meal plus acetaminophen (ACM; to assess gastric emptying) at time zero. On separate occasions, a primed-constant intravenous infusion of vehicle or Xen at 4 (Lo-Xen) or 12 (Hi-Xen) pmol·kg−1·min−1was administered from zero until 300 min. Some subjects with NGT received 30- and 90-min Hi-Xen infusions. Plasma ACM, glucose, insulin, C-peptide, glucagon, Xen, GIP, and glucagon-like peptide-1 (GLP-1) levels were measured and ISRs calculated. Areas under the curves were compared for treatment effects. Infusion with Hi-Xen, but not Lo-Xen, similarly delayed gastric emptying and reduced postprandial glucose levels in all groups. Infusions for 90 or 300 min, but not 30 min, were equally effective. Hi-Xen reduced plasma GLP-1, but not GIP, levels without altering the insulin secretory response to glucose. Intense staining for Xen receptors was detected on PGP9.5-positive nerve fibers in the longitudinal muscle of the human stomach. Thus Xen reduces gastric emptying in humans with and without T2DM, probably via a neural relay. Moreover, endogenous GLP-1 may not be a major enhancer of insulin secretion in healthy humans under physiological conditions.
The effect of supine exercise on the distribution of regional pulmonary blood flow measured using proton MRI
Authors: Hall E. T. , Sá R. C. , Holverda S. , Arai T. J. , Dubowitz D. J. , Theilmann R. J. , Prisk G. K. , Hopkins S. R.
Published: December 2013

The Zone model of pulmonary perfusion predicts that exercise reduces perfusion heterogeneity because increased vascular pressure redistributes flow to gravitationally nondependent lung, and causes dilation and recruitment of blood vessels. However, during exercise in animals, perfusion heterogeneity as measured by the relative dispersion (RD, SD/mean) is not significantly decreased. We evaluated the effect of exercise on pulmonary perfusion in six healthy supine humans using magnetic resonance imaging (MRI). Data were acquired at rest, while exercising (∼27% of maximal oxygen consumption) using a MRI-compatible ergometer, and in recovery. Images were acquired in most of the right lung in the sagittal plane at functional residual capacity, using a 1.5-T MR scanner equipped with a torso coil. Perfusion was measured using arterial spin labeling (ASL-FAIRER) and regional proton density using a fast multiecho gradient-echo sequence. Perfusion images were corrected for coil-based signal heterogeneity, large conduit vessels removed and quantified (in ml·min−1·ml−1) (perfusion), and also normalized for density and quantified (in ml·min−1·g−1) (density-normalized perfusion, DNP) accounting for tissue redistribution. DNP increased during exercise (11.1 ± 3.5 rest, 18.8 ± 2.3 exercise, 13.2 ± 2.2 recovery, ml·min−1·g−1, P < 0.0001), and the increase was largest in nondependent lung (110 ± 61% increase in nondependent, 63 ± 35% in mid, 70 ± 33% in dependent, P < 0.005). The RD of perfusion decreased with exercise (0.93 ± 0.21 rest, 0.73 ± 0.13 exercise, 0.94 ± 0.18 recovery, P < 0.005). The RD of DNP showed a similar trend (0.82 ± 0.14 rest, 0.75 ± 0.09 exercise, 0.81 ± 0.10 recovery, P = 0.13). In conclusion, in contrast to animal studies, in supine humans, mild exercise decreased perfusion heterogeneity, consistent with Zone model predictions.
AltitudeOmics: enhanced cerebrovascular reactivity and ventilatory response to CO2 with high-altitude acclimatization and reexposure
Authors: Fan Jui-Lin , Subudhi Andrew W. , Evero Oghenero , Bourdillon Nicolas , Kayser Bengt , Lovering Andrew T. , Roach Robert C.
Published: December 2013

The present study is the first to examine the effect of high-altitude acclimatization and reexposure on the responses of cerebral blood flow and ventilation to CO2. We also compared the steady-state estimates of these parameters during acclimatization with the modified rebreathing method. We assessed changes in steady-state responses of middle cerebral artery velocity (MCAv), cerebrovascular conductance index (CVCi), and ventilation (V̇e) to varied levels of CO2 in 21 lowlanders (9 women; 21 ± 1 years of age) at sea level (SL), during initial exposure to 5,260 m (ALT1), after 16 days of acclimatization (ALT16), and upon reexposure to altitude following either 7 (POST7) or 21 days (POST21) at low altitude (1,525 m). In the nonacclimatized state (ALT1), MCAv and V̇e responses to CO2 were elevated compared with those at SL (by 79 ± 75% and 14.8 ± 12.3 l/min, respectively; P = 0.004 and P = 0.011). Acclimatization at ALT16 further elevated both MCAv and V̇e responses to CO2 compared with ALT1 (by 89 ± 70% and 48.3 ± 32.0 l/min, respectively; P < 0.001). The acclimatization gained for V̇e responses to CO2 at ALT16 was retained by 38% upon reexposure to altitude at POST7 ( P = 0.004 vs. ALT1), whereas no retention was observed for the MCAv responses ( P > 0.05). We found good agreement between steady-state and modified rebreathing estimates of MCAv and V̇e responses to CO2 across all three time points ( P < 0.001, pooled data). Regardless of the method of assessment, altitude acclimatization elevates both the cerebrovascular and ventilatory responsiveness to CO2. Our data further demonstrate that this enhanced ventilatory CO2 response is partly retained after 7 days at low altitude.
Physiological mechanisms of dyspnea during exercise with external thoracic restriction: Role of increased neural respiratory drive
Authors: Mendonca Cassandra T. , Schaeffer Michele R. , Riley Patrick , Jensen Dennis
Published: December 2013

We tested the hypothesis that neuromechanical uncoupling of the respiratory system forms the mechanistic basis of dyspnea during exercise in the setting of “abnormal” restrictive constraints on ventilation (VE). To this end, we examined the effect of chest wall strapping (CWS) sufficient to mimic a “mild” restrictive lung deficit on the interrelationships between VE, breathing pattern, dynamic operating lung volumes, esophageal electrode-balloon catheter-derived measures of the diaphragm electromyogram (EMGdi) and the transdiaphragmatic pressure time product (PTPdi), and sensory intensity and unpleasantness ratings of dyspnea during exercise. Twenty healthy men aged 25.7 ± 1.1 years (means ± SE) completed symptom-limited incremental cycle exercise tests under two randomized conditions: unrestricted control and CWS to reduce vital capacity (VC) by 21.6 ± 0.5%. Compared with control, exercise with CWS was associated with 1) an exaggerated EMGdi and PTPdi response; 2) no change in the relationship between EMGdi and each of tidal volume (expressed as a percentage of VC), inspiratory reserve volume, and PTPdi, thus indicating relative preservation of neuromechanical coupling; 3) increased sensory intensity and unpleasantness ratings of dyspnea; and 4) no change in the relationship between increasing EMGdi and each of the intensity and unpleasantness of dyspnea. In conclusion, the increased intensity and unpleasantness of dyspnea during exercise with CWS could not be readily explained by increased neuromechanical uncoupling but likely reflected the awareness of increased neural respiratory drive (EMGdi) needed to achieve any given VEduring exercise in the setting of “abnormal” restrictive constraints on tidal volume expansion.
Right ventricular dysfunction in chronic thromboembolic obstruction of the pulmonary artery: a pressure-volume study using the conductance catheter
Authors: McCabe Colm , White Paul A. , Hoole Stephen P. , Axell Richard G. , Priest Andrew N. , Gopalan Deepa , Taboada Dolores , MacKenzie Ross Robert , Morrell Nicholas W. , Shapiro Leonard M. , Pepke-Zaba Joanna
Published: December 2013

Pressure-volume loops describe dynamic ventricular performance, relevant to patients with and at risk of pulmonary hypertension. We used conductance catheter-derived pressure-volume loops to measure right ventricular (RV) mechanics in patients with chronic thromboembolic pulmonary arterial obstruction at different stages of pathological adaptation. Resting conductance catheterization was performed in 24 patients: 10 with chronic thromboembolic pulmonary hypertension (CTEPH), 7 with chronic thromboembolic disease without pulmonary hypertension (CTED), and 7 controls. To assess the validity of conductance measurements, RV volumes were compared in a subset of 8 patients with contemporaneous cardiac magnetic resonance (CMR). Control, CTED, and CTEPH groups showed different pressure-volume loop morphology, most notable during systolic ejection. Prolonged diastolic relaxation was seen in patients with CTED and CTEPH [tau = 56.2 ± 6.7 (controls) vs. 69.7 ± 10.0 (CTED) vs. 67.9 ± 6.2 ms (CTEPH), P = 0.02]. Control and CTED groups had lower afterload (Ea) and contractility (Ees) compared with the CTEPH group (Ea = 0.30 ± 0.10 vs. 0.52 ± 0.24 vs. 1.92 ± 0.70 mmHg/ml, respectively, P < 0.001) (Ees = 0.44 ± 0.20 vs. 0.59 ± 0.15 vs. 1.13 ± 0.43 mmHg/ml, P < 0.01) with more efficient ventriculoarterial coupling (Ees/Ea = 1.46 ± 0.30 vs. 1.27 ± 0.36 vs. 0.60 ± 0.18, respectively, P < 0.001). Stroke volume assessed by CMR and conductance showed closest agreement (mean bias +9 ml, 95% CI −1 to +19 ml) compared with end-diastolic volume (+48 ml, −16 to 111 ml) and end-systolic volume (+37 ml, −21 to 94 ml). RV conductance catheterization detects novel alteration in pressure-volume loop morphology and delayed RV relaxation in CTED, which distinguish this group from controls. The observed agreement in stroke volume assessed by CMR and conductance suggests RV mechanics are usefully measured by conductance catheter in chronic thromboembolic obstruction.
Characterization of LY2228820 Dimesylate, a Potent and Selective Inhibitor of p38 MAPK with Antitumor Activity
Authors: Campbell Robert M. , Anderson Bryan D. , Brooks Nathan A. , Brooks Harold B. , Chan Edward M. , De Dios Alfonso , Gilmour Raymond , Graff Jeremy R. , Jambrina Enrique , Mader Mary , McCann Denis , Na Songqing , Parsons Stephen H. , Pratt Susan E. , Shih Chuan , Stancato Louis F. , Starling James J. , Tate Courtney , Velasco Juan A. , Wang Yong , Ye Xiang S.
Published: December 2013

p38α mitogen-activated protein kinase (MAPK) is activated in cancer cells in response to environmental factors, oncogenic stress, radiation, and chemotherapy. p38α MAPK phosphorylates a number of substrates, including MAPKAP-K2 (MK2), and regulates the production of cytokines in the tumor microenvironment, such as TNF-α, interleukin-1β (IL-1β), IL-6, and CXCL8 (IL-8). p38α MAPK is highly expressed in human cancers and may play a role in tumor growth, invasion, metastasis, and drug resistance. LY2228820 dimesylate (hereafter LY2228820), a trisubstituted imidazole derivative, is a potent and selective, ATP-competitive inhibitor of the α- and β-isoforms of p38 MAPK in vitro (IC50 = 5.3 and 3.2 nmol/L, respectively). In cell-based assays, LY2228820 potently and selectively inhibited phosphorylation of MK2 (Thr334) in anisomycin-stimulated HeLa cells (at 9.8 nmol/L by Western blot analysis) and anisomycin-induced mouse RAW264.7 macrophages (IC50 = 35.3 nmol/L) with no changes in phosphorylation of p38α MAPK, JNK, ERK1/2, c-Jun, ATF2, or c-Myc ≤ 10 μmol/L. LY2228820 also reduced TNF-α secretion by lipopolysaccharide/IFN-γ–stimulated macrophages (IC50 = 6.3 nmol/L). In mice transplanted with B16-F10 melanoma, tumor phospho-MK2 (p-MK2) was inhibited by LY2228820 in a dose-dependent manner [threshold effective dose (TED)70 = 11.2 mg/kg]. Significant target inhibition (>40% reduction in p-MK2) was maintained for 4 to 8 hours following a single 10 mg/kg oral dose. LY2228820 produced significant tumor growth delay in multiple in vivo cancer models (melanoma, non–small cell lung cancer, ovarian, glioma, myeloma, breast). In summary, LY2228820 is a p38 MAPK inhibitor, which has been optimized for potency, selectivity, drug-like properties (such as oral bioavailability), and efficacy in animal models of human cancer. Mol Cancer Ther; 13(2); 364–74. ©2013 AACR.
Cancer-Associated CD43 Glycoforms as Target of Immunotherapy
Authors: Tuccillo Franca Maria , Palmieri Camillo , Fiume Giuseppe , de Laurentiis Annamaria , Schiavone Marco , Falcone Cristina , Iaccino Enrico , Galandrini Ricciarda , Capuano Cristina , Santoni Angela , D'Armiento Francesco Paolo , Arra Claudio , Barbieri Antonio , Dal Piaz Fabrizio , Venzon David , Bonelli Patrizia , Buonaguro Franco Maria , Scala Iris , Mallardo Massimo , Quinto Ileana , Scala Giuseppe
Published: December 2013

CD43 is a sialoglycosylated membrane protein that is involved in cell proliferation and differentiation. CD43 glycoforms that are recognized by the UN1 monoclonal antibody (mAb) were expressed in lymphoblastoid T-cell lines and solid tumors, such as breast, colon, gastric, and squamous cell lung carcinomas, while unexpressed in the normal counterparts. The cancer association of UN1/CD43 epitope suggested the possibility to use the UN1 mAb for tumor diagnosis and therapy. In this study, we show that the UN1 mAb was endowed with antitumor activity in vivo because its passive transfer inhibited the growth of UN1-positive HPB-ALL lymphoblastoid T cells in mice. Furthermore, we demonstrate that tumor inhibition was due to UN1 mAb-dependent natural killer–mediated cytotoxicity. By screening a phage-displayed random peptide library, we identified the phagotope 2/165 as a mimotope of the UN1 antigen, as it harbored a peptide sequence that was specifically recognized by the UN1 mAb and inhibited the binding of the UN1 mAb to UN1-positive tumor cells. On the basis of sequence homology with the extracellular region of CD43 (amino acids 64 to 83), the 2/165 peptide sequence was likely mimicking the protein core of the UN1/CD43 epitope. When used as vaccine in mice, the 2/165 phagotope raised antibodies against the UN1/CD43 antigen, indicating that the 2/165 phagotope mimicked the UN1 antigen structure, and could represent a novel immunogen for cancer immunotherapy. These findings support the feasibility of using monoclonal antibodies to identify cancer-associated mimotopes for immunotherapy. Mol Cancer Ther; 13(3); 752–62. ©2013 AACR.
Glioblastoma Cells Containing Mutations in the Cohesin Component STAG2 Are Sensitive to PARP Inhibition
Authors: Bailey Melanie L. , O'Neil Nigel J. , van Pel Derek M. , Solomon David A. , Waldman Todd , Hieter Philip
Published: December 2013

Recent data have identified STAG2, a core subunit of the multifunctional cohesin complex, as a highly recurrently mutated gene in several types of cancer. We sought to identify a therapeutic strategy to selectively target cancer cells harboring inactivating mutations of STAG2 using two independent pairs of isogenic glioblastoma cell lines containing either an endogenous mutant STAG2 allele or a wild-type STAG2 allele restored by homologous recombination. We find that mutations in STAG2 are associated with significantly increased sensitivity to inhibitors of the DNA repair enzyme PARP. STAG2-mutated, PARP-inhibited cells accumulated in G2 phase and had a higher percentage of micronuclei, fragmented nuclei, and chromatin bridges compared with wild-type STAG2 cells. We also observed more 53BP1 foci in STAG2-mutated glioblastoma cells, suggesting that these cells have defects in DNA repair. Furthermore, cells with mutations in STAG2 were more sensitive than cells with wild-type STAG2 when PARP inhibitors were used in combination with DNA-damaging agents. These data suggest that PARP is a potential target for tumors harboring inactivating mutations in STAG2, and strongly recommend that STAG2 status be determined and correlated with therapeutic response to PARP inhibitors, both prospectively and retrospectively, in clinical trials. Mol Cancer Ther; 13(3); 724–32. ©2013 AACR.
Low Integrated DNA Repair Score and Lung Cancer Risk
Authors: Sevilya Ziv , Leitner-Dagan Yael , Pinchev Mila , Kremer Ran , Elinger Dalia , Rennert Hedy S. , Schechtman Edna , Freedman Laurence S. , Rennert Gad , Paz-Elizur Tamar , Livneh Zvi
Published: December 2013

DNA repair is a prime mechanism for preventing DNA damage, mutation, and cancers. Adopting a functional approach, we examined the association with lung cancer risk of an integrated DNA repair score, measured by a panel of three enzymatic DNA repair activities in peripheral blood mononuclear cells. The panel included assays for AP endonuclease 1 (APE1), 8-oxoguanine DNA glycosylase (OGG1), and methylpurine DNA glycosylase (MPG), all of which repair oxidative DNA damage as part of the base excision repair pathways. A blinded population-based case–control study was conducted with 96 patients with lung cancer and 96 control subjects matched by gender, age (±1 year), place of residence, and ethnic group (Jews/non-Jews). The three DNA repair activities were measured, and an integrated DNA repair OMA (OGG1, MPG, and APE1) score was calculated for each individual. Conditional logistic regression analysis revealed that individuals in the lowest tertile of the integrated DNA repair OMA score had an increased risk of lung cancer compared with the highest tertile, with OR = 9.7; 95% confidence interval (CI), 3.1–29.8; P < 0.001, or OR = 5.6; 95% CI, 2.1–15.1; P < 0.001 after cross-validation. These results suggest that pending validation, this DNA repair panel of risk factors may be useful for lung cancer risk assessment, assisting prevention and referral to early detection by technologies such as low-dose computed tomography scanning. Cancer Prev Res; 7(4); 398–406. ©2013 AACR.