bluuebunny/crossref_metadata_2025 huggingface dataset:
A Generalized Definition of Unnecessary Test Vectors in Functional Test Sequences
Authors: Pomeranz Irith
Published: March 2015

A class of static test compaction procedures for functional test sequences is based on the omission of unnecessary test vectors. According to the definition used by these procedures, a test vector is unnecessary if all the target faults continue to be detected after it is omitted. This article introduces a more general definition of unnecessary test vectors that allows additional ones to be omitted. According to this definition, a test vector is unnecessary if every target fault can be detected by a sequence that is obtained after omitting the vector, and possibly other vectors. The article develops a procedure for omitting test vectors based on this definition and discusses its effects on the storage requirements and test application time.
Obstacle-Avoiding Algorithm in X-Architecture Based on Discrete Particle Swarm Optimization for VLSI Design
Authors: Huang Xing , Liu Genggeng , Guo Wenzhong , Niu Yuzhen , Chen Guolong
Published: March 2015

Obstacle-avoiding Steiner minimal tree (OASMT) construction has become a focus problem in the physical design of modern very large-scale integration (VLSI) chips. In this article, an effective algorithm is presented to construct an OASMT based on X-architecturex for a given set of pins and obstacles. First, a kind of special particle swarm optimization (PSO) algorithm is proposed that successfully combines the classic genetic algorithm (GA), and greatly improves its own search capability. Second, a pretreatment strategy is put forward to deal with obstacles and pins, which can provide a fast information inquiry for the whole algorithm by generating a precomputed lookup table. Third, we present an efficient adjustment method, which enables particles to avoid all the obstacles by introducing some corner points of obstacles. Finally, an excellent refinement method is discussed to further enhance the quality of the final routing tree, which can improve the quality of the solution by 7.93% on average. To our best knowledge, this is the first time to specially solve the single-layer obstacle-avoiding problem in X-architecture. Experimental results show that the proposed algorithm can further shorten wirelength in the presence of obstacles. And it achieves the best solution quality in a reasonable runtime among the existing algorithms.
Reconfigurable Scan Networks
Authors: Baranowski Rafal , Kochte Michael A. , Wunderlich Hans-Joachim
Published: March 2015

Efficient access to on-chip instrumentation is a key requirement for post-silicon validation, test, debug, bringup, and diagnosis. Reconfigurable scan networks, as proposed by, for example, IEEE Std 1687-2014 and IEEE Std 1149.1-2013, emerge as an effective and affordable means to cope with the increasing complexity of on-chip infrastructure.

Reconfigurable scan networks are often hierarchical and may have complex structural and functional dependencies. Common approaches for scan verification based on static structural analysis and functional simulation are not sufficient to ensure correct operation of these types of architectures. To access an instrument in a reconfigurable scan network, a scan-in bit sequence must be generated according to the current state and structure of the network. Due to sequential and combinational dependencies, the access pattern generation process (
pattern retargeting
) poses a complex decision and optimization problem.

This article presents the first generalized formal model that considers structural and functional dependencies of reconfigurable scan networks and is directly applicable to 1687-2014-based and 1149.1-2013-based scan architectures. This model enables efficient formal verification of complex scan networks, as well as automatic generation of access patterns. The proposed pattern generation method supports concurrent access to multiple target scan registers (
access merging
) and generates short scan-in sequences.
3DTI Amphitheater
Authors: Chen Shannon , Gao Zhenhuan , Nahrstedt Klara , Gupta Indranil
Published: March 2015

3DTI Amphitheater is a live broadcasting system for dissemination of 3DTI (3D Tele-immersive) content. The virtual environment constructed by the system mimics an amphitheater in the real world, where performers interact with each other in the central circular stage, and the audience is placed in virtual seats that surround the stage. Users of the Amphitheater can be geographically dispersed and the streams created by the performer sites are disseminated in a P2P network among the participants. To deal with the high bandwidth demand and strict latency bound of the service, we identify the hierarchical priority of streams in construction of the content dissemination forest. Result shows that the Amphitheater outperforms prior 3DTI systems by boosting the application QoS by a factor of 2.8 while sustaining the same hundred-scale audience group.
What Do Thirty-One Columns Say about a “Theoretical” Thirty-Second?
Authors: Buglio David Lo , Lardinois Vanessa , Luca Livio De
Published: March 2015

Over the past three decades, the introduction of digital technologies in the field of architectural documentation has profoundly changed tools and acquisition techniques. Most of the developments concern metrical and colorimetric characteristics of the objects studied. These developments, surrounding the practice of architectural survey, tend to respond primarily to the requirements of completeness. In this context, it seems necessary to assess the impact of these instruments on the cognitive value of architectural representation. With a strong technological presence, the study of the built heritage is facing a problem of “information overload.” Indeed, this strong technological presence fails to strengthen representation in its role as a vehicle of knowledge. Confronted with the intelligibility deficit, this article proposes an original approach for reading morphological features of an artifact by using a bottom-up approach: the meaning of elements (i.e., their semantic layouts) come from a statistical analysis of the major shape discontinuities of a collection of instances. The idea is to rely on data accumulation to render apparent high-level semantic structures from the comparative analysis of common low-level geometric features. The principles introduced are illustrated by the study of 31 columns of the cloister of the abbey of Saint-Michel-de-Cuxa. To summarize, the first objective is to understand how digital technologies can help us in the analysis of artistic and technical production of Romanesque columns. The second objective is to automatically identify the common semantic articulations of the entire collection to build a reference model for the future assessment of each artifact.
ASP-Based Encoding Model of Architecture Synthesis for Smart Cameras in Distributed Networks
Authors: Yonga Franck , Mefenza Michael , Bobda Christophe
Published: March 2015

A synthesis approach based on Answer Set Programming (ASP) for heterogeneous system-on-chips to be used in distributed camera networks is presented. In such networks, the tight resource limitations represent a major challenge for application development. Starting with a high-level description of applications, the physical constraints of the target devices, and the specification of network configuration, our goal is to produce optimal computing infrastructures made of a combination of hardware and software components for each node of the network. Optimization aims at maximizing speed while minimizing chip area and power consumption. Additionally, by performing the architecture synthesis simultaneously for all cameras in the network, we are able to minimize the overall utilization of communication resources and consequently reduce power consumption. Because of its reconfiguration capabilities, a Field Programmable Gate Array (FPGA) has been chosen as the target device, which enhances the exploration of several design alternatives. We present several realistic network scenarios to evaluate and validate the proposed synthesis approach.
Electric flora
Authors: Dauner Joanna , Karagozler Emre , Glisson Matthew
Published: March 2015

Harnessing electrostatic energy from the body to power a forest of light.
SOUP
Authors: Koll David , Li Jun , Fu Xiaoming
Published: March 2015

With increasing frequency, users raise concerns about data privacy and protection in centralized Online Social Networks (OSNs), in which providers have the unprecedented privilege to access and exploit every user's private data at will. To mitigate these concerns, researchers have suggested to decentralize OSNs and thereby enable users to control and manage access to their data themselves. However, previously proposed decentralization approaches suffer from several drawbacks. To tackle their deficiencies, we introduce the Self-Organized Universe of People (SOUP). In this demonstration, we present a prototype of SOUP and share our experiences from a real-world deployment.
Identifying traffic differentiation on cellular data networks
Authors: Molavi Kakhki Arash , Razaghpanah Abbas , Golani Rajesh , Choffnes David , Gill Phillipa , Mislove Alan
Published: March 2015

The goal of this research is to detect traffic differentiation in cellular data networks. We define service differentiation as any attempt to change the performance of network traffic traversing an ISP's boundaries. ISPs may implement differentiation policies for a number of reasons, including load balancing, bandwidth management, or business reasons. Specifically, we focus on detecting whether certain types of network traffic receive better (or worse) performance. As an example, a wireless provider might limit the performance of third-party VoIP or video calling services (or any other competing services) by introducing delays or reducing transfer rates to encourage users to use services provided by the wireless provider. Previous work explored this problem in limited environments. Glasnost focused on BitTorrent in the desktop/laptop environment, and lacked the ability to conduct controlled experiments to provide strong evidence of differentiation. NetDiff covered a wide range of passively gathered traffic from a large ISP but likewise did not support targeted, controlled experiments. We address these limitations with Mobile Replay.
Drawbridge
Authors: Li Jun , Berg Skyler , Zhang Mingwei , Reiher Peter , Wei Tao
Published: March 2015

End hosts in today's Internet have the best knowledge of the type of traffic they should receive, but they play no active role in traffic engineering. Traffic engineering is conducted by ISPs, which unfortunately are blind to specific user needs. End hosts are therefore subject to unwanted traffic, particularly from Distributed Denial of Service (DDoS) attacks. This research proposes a new system called DrawBridge to address this traffic engineering dilemma. By realizing the potential of software-defined networking (SDN), in this research we investigate a solution that enables end hosts to use their knowledge of desired traffic to improve traffic engineering during DDoS attacks.
PDZ proteins retain and regulate membrane transporters in polarized epithelial cell membranes
Authors: Brône Bert , Eggermont Jan
Published: March 2015

PDZ proteins retain and regulate membrane transporters in polarized epithelial cell membranes. Am J Physiol Cell Physiol 288: C20–C29, 2005; doi:10.1152/ajpcell.00368.2004.—The plasma membrane of epithelial cells is subdivided into two physically separated compartments known as the apical and basolateral membranes. To obtain directional transepithelial solute transport, membrane transporters (i.e., ion channels, cotransporters, exchangers, and ion pumps) need to be targeted selectively to either of these membrane domains. In addition, the transport properties of an epithelial cell will be maintained only if these membrane transporters are retained and properly regulated in their specific membrane compartments. Recent reports have indicated that PDZ domain-containing proteins play a dual role in these processes and, in addition, that different apical and basolateral PDZ proteins perform similar tasks in their respective membrane domains. First, although PDZ-based interactions are dispensable for the biosynthetic targeting to the proper membrane domain, the PDZ network ensures that the membrane proteins are efficiently retained at the cell surface. Second, the close spatial positioning of functionally related proteins (e.g., receptors, kinases, channels) into a signal transduction complex (transducisome) allows fast and efficient control of membrane transport processes.
C-peptide increases forearm blood flow in patients with type 1 diabetes via a nitric oxide-dependent mechanism
Authors: Johansson Bo-Lennart , Wahren John , Pernow John
Published: March 2015

Proinsulin C-peptide has been shown to increase muscle blood flow in type 1 diabetic patients. The underlying mechanism is not fully understood. The aim of this study was to evaluate if the vasodilator effect of C-peptide is mediated by nitric oxide (NO). Eleven type 1 diabetic patients were studied two times and randomized to administration of intravenous and intra-arterial infusion of C-peptide or saline. Forearm blood flow (FBF) was measured by venous occlusion plethysmography during infusion of C-peptide or saline before, during, and after NO synthase (NOS) blockade. Endothelium-dependent and -independent vasodilatation was evaluated by administration of acetylcholine and sodium nitroprusside, respectively. FBF increased by 35% during intravenous C-peptide ( P < 0.01) but not during saline infusion (–2%, not significant). NOS blockade resulted in a more pronounced reduction in FBF during intravenous C-peptide than during saline infusion (–41 vs. –26%, P < 0.05). Intra-arterial C-peptide failed to increase FBF during NOS blockade. However, when C-peptide was given after the recovery from NOS blockade, FBF rose by 30% ( P < 0.001). The vasodilator effects of acetylcholine and nitroprusside were not influenced by C-peptide. It is concluded that the stimulatory effect of C-peptide on FBF in type 1 diabetic patients is mediated via the NO system and that C-peptide increases basal endothelial NO levels.
Activation of the KATPchannel-independent signaling pathway by the nonhydrolyzable analog of leucine, BCH
Authors: Liu Yi-Jia , Cheng Haiying , Drought Heather , MacDonald Michael J. , Sharp Geoffrey W. G. , Straub Susanne G.
Published: March 2015

Leucine and glutamine were used to elicit biphasic insulin release in rat pancreatic islets. Leucine did not mimic the full biphasic response of glucose. Glutamine was without effect. However, the combination of the two did mimic the biphasic response. When the ATP-sensitive K+(KATP) channel-independent pathway was studied in the presence of diazoxide and KCl, leucine and its nonmetabolizable analog 2-aminobicyclo[2,2,1]heptane-2-carboxylic acid (BCH) both stimulated insulin secretion to a greater extent than glucose. Glutamine and dimethyl glutamate had no effect. Because the only known action of BCH is stimulation of glutamate dehydrogenase, this is sufficient to develop the full effect of the KATPchannel-independent pathway. Glucose, leucine, and BCH had no effect on intracellular citrate levels. Leucine and BCH both decreased glutamate levels, whereas glucose was without effect. Glucose and leucine decreased palmitate oxidation and increased esterification. Strikingly, BCH had no effect on palmitate oxidation or esterification. Thus BCH activates the KATPchannel-independent pathway of glucose signaling without raising citrate levels, without decreasing fatty acid oxidation, and without mimicking the effects of glucose and leucine on esterification. The results indicate that increased flux through the TCA cycle is sufficient to activate the KATPchannel-independent pathway.
Pheromone-induced anorexia in male Syrian hamsters
Authors: Morgan Caurnel , Urbanski Henryk F. , Fan Wei , Akil Huda , Cone Roger D.
Published: March 2015

Transition from long days (LDs) to short days (SDs) triggers seasonal obesity in Syrian hamsters. We report here that SD-exposed males housed near females exhibit obesity resistance, episodic weight loss, and reduced adiposity. Negative energy balance is achieved by reduced eating, elevated motor activity, and increased caloric efficiency without metabolic compensation. Circulating leptin, insulin, testosterone, corticosterone, and cortisol are normal or reduced in obesity-resistant hamsters. When males are housed in chambers that block physical, visual, and auditory, but not pheromonal, signals from females, resistance to seasonal obesity persists. Moreover, inhalation of extracts from pheromone-releasing flank glands of females suppresses eating and weight gain in SD-exposed males. This novel phenomenon, pheromone-induced anorexia, shows that female pheromones play a critical role in the seasonal energy balance of male hamsters. These findings provide a model to study neural and endocrine mechanisms that underlie eating disorders.
Suppression of glucose production by GLP-1 independent of islet hormones: a novel extrapancreatic effect
Authors: Prigeon Ronald L. , Quddusi Shaista , Paty Breay , D'Alessio David A.
Published: March 2015

Glucagon-like peptide-1 (GLP-1) is an intestinal hormone that stimulates insulin secretion and decreases glucagon release. It has been hypothesized that GLP-1 also reduces glycemia independent of its effect on islet hormones. Based on preliminary evidence that GLP-1 has independent actions on endogenous glucose production, we undertook a series of experiments that were optimized to address this question. The effect of GLP-1 on glucose appearance (Ra) and glucose disposal (Rd) was measured in eight men during a pancreatic clamp that was performed by infusing octreotide to suppress secretion of islet hormones, while insulin and glucagon were infused at rates adjusted to maintain blood glucose near fasting levels. After stabilization of plasma glucose and equilibration of [3H]glucose tracer, GLP-1 was given intravenously for 60 min. Concentrations of insulin, C-peptide, and glucagon were similar before and during the GLP-1 infusion (115 ± 14 vs. 113 ± 11 pM; 0.153 ± 0.029 vs. 0.156 ± 0.026 nM; and 64.7 ± 11.5 vs. 65.8 ± 13.8 ng/l, respectively). With the initiation of GLP-1, plasma glucose decreased in all eight subjects from steady-state levels of 4.8 ± 0.2 to a nadir of 4.1 ± 0.2 mM. This decrease in plasma glucose was accounted for by a significant 17% decrease in Ra, from 22.6 ± 2.8 to 19.1 ± 2.8 μmol · kg–1 · min–1 ( P < 0.04), with no significant change in Rd. These findings indicate that, under fasting conditions, GLP-1 decreases endogenous glucose production independent of its actions on islet hormone secretion.
Estrogen promotes microvascular pathology in female stroke-prone spontaneously hypertensive rats
Authors: Stier Charles T. , Chander Praveen N. , Rosenfeld Louis , Powers C. Andrew
Published: March 2015

Estrogen produces both beneficial and adverse effects on cardiovascular health via mechanisms that remain unclear. Stroke-prone spontaneously hypertensive rats (SHRSP) maintained on Stroke-Prone Rodent Diet and 1% NaCl drinking water (starting at 8 wk of age) rapidly develop stroke and malignant nephrosclerosis that can be prevented, despite continued hypertension, by drugs targeting angiotensin II and aldosterone actions. This study evaluated estrogen's effects in the SHRSP model. Female SHRSP that were sham operated (SHAM), ovariectomized (OVX) at 4 wk of age, or OVX and treated with estradiol benzoate (E2,30 μg·kg-1·wk-1) were studied. In a survival protocol, OVX rats lived significantly longer (15.1 ± 0.3 wk) compared with SHAM (13.6 ± 0.2 wk) or OVX+E2rats (12.4 ± 0.2 wk). In a protocol in which animals were matched for age, at 11.5 wk, terminal systolic blood pressure and urine protein excretion were elevated in SHAM and OVX+E2rats compared with OVX rats; blood urea nitrogen, renal microvascular and glomerular lesions, and plasma renin concentration were elevated in OVX+E2relative to SHAM or OVX rats. In a survival protocol using intact female SHRSP, treatment with an antiestrogen (tamoxifen, 7 mg·kg-1·wk-1) prolonged survival by >2 wk compared with controls ( P < 0.01). The data indicate that estrogen promotes microangiopathy in the kidney and stroke in saline-drinking SHRSP.
Isocaloric maternal low-protein diet alters IGF-I, IGFBPs, and hepatocyte proliferation in the fetal rat
Authors: El Khattabi Ilham , Grégoire Francine , Remacle Claude , Reusens Brigitte
Published: March 2015

We investigated the effect of an isocaloric maternal low-protein diet during pregnancy in rats on the proliferative capacity of cultured fetal hepatocytes. The potential roles of these changes on the IGF-IGF-binding protein (IGFBP) axis, and the role of insulin and glucocorticoids in liver growth retardation, were also evaluated. Pregnant Wistar rats were fed a control (C) diet (20% protein) or a low-protein (LP) diet (8%) throughout gestation. In primary culture, the DNA synthesis of hepatocytes derived from LP fetuses was decreased by ∼30% compared with control hepatocytes ( P < 0.05). In parallel, in vivo moderate protein restriction in the dam reduced the fetal liver weight and IGF-I level in fetal plasma ( P < 0.01) and augmented the abundance of 29- to 32-kDa IGFBPs in fetal plasma ( P < 0.01) and fetal liver ( P < 0.01). By contrast, the abundance of IGF-II mRNA in liver of LP fetuses was unaffected by the LP diet. In vitro, the LP-derived hepatocytes produced less IGF-I ( P < 0.01) and more 29- to 32-kDa IGFBPs ( P < 0.01) than hepatocytes derived from control fetuses. These alterations still appeared after 3–4 days of culture, indicating some persistence in programming. Dexamethasone treatment of control-derived hepatocytes decreased cell proliferation (54 ± 2.3%, P < 0.01) and stimulated 29- to 32-kDa IGFBPs, whereas insulin promoted fetal hepatocyte growth (127 ± 5.5%, P < 0.01) and inhibited 29- to 32-kDa IGFBPs. These results show that liver growth and cell proliferation in association with IGF-I and IGFBP levels are affected in utero by fetal undernutrition. It also suggests that glucocorticoids and insulin may modulate these effects.
Expression of somatostatin, cortistatin, and somatostatin receptors in human monocytes, macrophages, and dendritic cells
Authors: Dalm Virgil A. S. H. , van Hagen P. Martin , van Koetsveld Peter M. , Achilefu Sam , Houtsmuller Adriaan B. , Pols David H. J. , van der Lely Aart-Jan , Lamberts Steven W. J. , Hofland Leo J.
Published: March 2015

Increasing evidence suggests that neuropeptides play a role in the regulatory mechanisms between the neuroendocrine and immune systems. A differential expression of the five known somatostatin (SS) receptors (sst1–5) has been demonstrated in human immune cells and tissues. However, little is known concerning regulation and expression of sst1–5and the peptide SS. Therefore, we investigated the expression and the time-dependent regulation of sst1–5, SS, and cortistatin (CST), a novel SS-like peptide, in human monocytes (MO), monocyte-derived macrophages (MP), and dendritic cells (DC) in the basal and lipopolysaccharide (LPS)-activated state. MO, MP, and DC selectively expressed sst2mRNA. SS mRNA was not detectable, whereas all samples expressed CST mRNA. Expression levels of sst2and CST mRNA showed marked differences and were in the rank order of MP>>DC>>>MO. LPS stimulation did not induce expression of SS or sst1,3,4,5. However, sst2mRNA expression was upregulated significantly by stimulation with LPS. CST mRNA was upregulated as well. During differentiation of MO in MP or DC, time-dependent, significantly increasing sst2and CST mRNA levels were found. By confocal microscopy, the presence of sst2receptors was demonstrated on MP, but not on DC. This study demonstrates for the first time a selective and inducible expression of the recently discovered CST, as well as sst2, in human monocyte-derived cells, suggesting a role for a CST-sst2system rather than a SS-sst2system in these immune cell types.
Regulation of leptin secretion from white adipocytes by free fatty acids
Authors: Cammisotto Philippe G. , Gélinas Yves , Deshaies Yves , Bukowiecki Ludwik J.
Published: March 2015

Norepinephrine stimulates lipolysis and concurrently inhibits insulin-stimulated leptin secretion from white adipocytes. To assess whether there is a cause-effect relationship between these two metabolic events, the effects of fatty acids were investigated in isolated rat adipocytes incubated in buffer containing low (0.1%) and high (4%) albumin concentrations. Palmitic acid (1 mM) mimicked the inhibitory effects of norepinephrine (1 μM) on insulin (10 nM)-stimulated leptin secretion, but only at low albumin concentrations. Studies investigating the effects of the chain length of saturated fatty acids [from butyric (C4) to stearic (C18) acids] revealed that only fatty acids with a chain length superior or equal to eight carbons effectively inhibited insulin-stimulated leptin secretion. Long-chain mono- and polyunsaturated fatty acids constitutively present in adipocyte triglyceride stores (oleic, linoleic, γ-linolenic, palmitoleic, eicosapentanoic, and docosahexanoic acids) also completely suppressed leptin secretion. Saturated and unsaturated fatty acids inhibited insulin-stimulated leptin secretion with the same potency and without any significant effect on basal secretion. On the other hand, inhibitors of mitochondrial fatty acid oxidation (palmoxirate, 2-bromopalmitate, 2-bromocaproate) attenuated the stimulatory effects of insulin on leptin release without reversing the effects of fatty acids or norepinephrine, suggesting that fatty acids do not need to be oxidized by the mitochondria to inhibit leptin release. These results demonstrate that long-chain fatty acids mimic the effects of norepinephrine on leptin secretion and suggest that they may play a regulatory role as messengers between stimulation of lipolysis by norepinephrine and inhibition of leptin secretion.
AMP kinase activation ameliorates insulin resistance induced by free fatty acids in rat skeletal muscle
Authors: Olsen Grith S. , Hansen Bo F.
Published: March 2015

We examined whether acute activation of 5′-AMP-activated protein kinase (AMPK) by 5′-aminoimidazole-4-carboxamide-1-β-d-ribonucleoside (AICAR) ameliorates insulin resistance in isolated rat skeletal muscle. Insulin resistance was induced in extensor digitorum longus (EDL) muscles by prolonged exposure to 1.6 mM palmitate, which inhibited insulin-stimulated glycogen synthesis to 51% of control after 5 h of incubation. Insulin-stimulated glucose transport was less affected (22% of control). The decrease in glycogen synthesis was accompanied by decreased glycogen synthase (GS) activity and increased GS phosphorylation. When including 2 mM AICAR in the last hour of the 5-h incubation with palmitate, the inhibitory effect of palmitate on insulin-stimulated glycogen synthesis and glucose transport was eliminated. This effect of AICAR was accompanied by activation of AMPK. Importantly, AMPK inhibition was able to prevent this effect. Neither treatment affected total glycogen content. However, glucose 6-phosphate was increased after inclusion of AICAR, indicating increased influx of glucose. No effect of AICAR on the inhibited insulin-stimulated GS activity or increased GS phosphorylation by palmitate could be detected. Thus the mechanism by which AMPK activation ameliorates the lipid-induced insulin resistance probably involves induction of compensatory mechanisms overriding the insulin resistance. Our results emphasize AMPK as a promising molecular target for treatment of insulin resistance.
Defective protein histidine phosphorylation in islets from the Goto-Kakizaki diabetic rat
Authors: Kowluru Anjaneyulu
Published: March 2015

We recently described novel regulatory roles for protein histidine phosphorylation of key islet proteins (e.g., nucleoside diphosphate kinase and succinyl thiokinase) in insulin secretion from the islet β-cell (Kowluru A. Diabetologia 44: 89-94, 2001; Kowluru A, Tannous M, and Chen HQ. Arch Biochem Biophys 398: 160-169, 2002). In this context, we also characterized a novel, ATP- and GTP-sensitive protein histidine kinase in isolated β-cells that catalyzed the histidine phosphorylation of islet (endogenous) proteins as well as exogenously added histone 4, and we implicated this kinase in the activation of islet endogenous G proteins (Kowluru A. Biochem Pharmacol 63: 2091-2100, 2002). In the present study, we describe abnormalities in ATP- or GTP-mediated histidine phosphorylation of nucleoside diphosphate kinase in islets derived from the Goto-Kakizaki (GK) rat, a model for non-insulin-dependent diabetes. Furthermore, we provide evidence for a marked reduction in the activities of ATP- or GTP-sensitive histidine kinases in GK rat islets. On the basis of these observations, we propose that alterations in protein histidine phosphorylation could contribute toward insulin-secretory abnormalities demonstrable in the diabetic islet.
Differential regional metabolism of glucagon in anesthetized pigs
Authors: Deacon Carolyn F. , Kelstrup Mette , Trebbien Ramona , Klarskov Letty , Olesen Mette , Holst Jens J.
Published: March 2015

Glucagon metabolism under basal (endogenous) conditions and during intravenous glucagon infusion was studied in anesthetized pigs by use of midregion (M), COOH-terminal (C), and NH2-terminal (N)-RIAs. Arteriovenous concentration differences revealed a negative extraction of endogenous glucagon immunoreactivity across the portal bed (-35.4 ± 11.0, -40.3 ± 9.6, -35.6 ± 16.9%, M-, C-, N-RIA, respectively), reflecting net secretion of pancreatic glucagon and intestinal glicentin and oxyntomodulin, but under exogenous conditions, a net extraction occurred (11.6 ± 3.6 and 18.6 ± 5.7%, C- and N-RIA, respectively). Hindlimb extraction of endogenous (17.4 ± 3.7%, C-RIA) and exogenous (29.1 ± 4.8 and 19.8 ± 5.1%, C- and M-RIA) glucagon was detected, indicating M and C cleavage of the molecule. Renal extraction of glucagon was detected by all assays under endogenous (19.4 ± 6.7, 33.9 ± 7.1, 29.5 ± 6.7%, M-, C-, N-RIA) and exogenous conditions (46.9 ± 4.8, 46.4 ± 6.0, 47.0 ± 7.7%; M-, C-, N-RIA), indicating substantial elimination of the peptide. Hepatic glucagon extraction was undetectable under basal conditions and detected only by M-RIA (10.0 ± 3.8%) during glucagon infusion, indicating limited midregional cleavage of the molecule. The plasma half-life determined by C- and N-RIAs (2.7 ± 0.2 and 2.3 ± 0.2 min) were similar, but both were shorter than when determined by M-RIA (3.2 ± 0.2 min, P < 0.02). Metabolic clearance rates were similar regardless of assay (14.4 ± 1.1, 13.6 ± 1.7, 17.0 ± 1.7 ml·kg-1·min-1, M-, C-, N-RIA). Porcine plasma degraded glucagon, but this was not significantly affected by the dipeptidyl peptidase IV (DPP IV) inhibitor valine-pyrrolidide, and in anesthetized pigs, glucagon's metabolic stability was unchanged by DPP IV inhibition. We conclude that tissue-specific metabolism of glucagon occurs, with the kidney being the main site of removal and the liver playing little, if any, role. Furthermore, valine-pyrrolidide has no effect on glucagon stability, suggesting that DPP IV is unimportant in glucagon metabolism in vivo, in contrast to its significant role in the metabolism of the other proglucagon-derived peptides and glucose-dependent insulinotropic polypeptide.
Chronic hepatic artery ligation does not prevent liver from differentiating portal vs. peripheral glucose delivery
Authors: Moore Mary Courtney , Burish Mark J. , Farmer Ben , Neal Doss W. , Pan Catherine , Cherrington Alan D.
Published: March 2015

Infusion of glucose into the hepatic artery blocks the stimulatory effect of the “portal signal” on net hepatic glucose uptake (NHGU) during portal glucose delivery. We hypothesized that hepatic artery ligation (HAL) would result in enhanced NHGU during peripheral glucose infusion because the arterial glucose concentration would be perceived as lower than that in the portal vein. Fourteen dogs underwent HAL ∼16 days before study. Conscious 42-h-fasted dogs received somatostatin, intraportal insulin, and glucagon infusions at fourfold basal and at basal rates, respectively, and peripheral glucose infusion to create hyperglycemia. After 90 min ( period 1), seven dogs (HALpo) received intraportal glucose (3.8 mg · kg–1 · min–1) and seven (HALpe) continued to receive only peripheral glucose for 90 min ( period 2). These two groups were compared with nine non-HAL control dogs (control) treated as were HALpe. During period 2, the arterial plasma insulin concentrations (24 ± 3, 20 ± 1, and 24 ± 2 μU/ml) and hepatic glucose loads (39.1 ± 2.5, 43.8 ± 2.9, and 37.7 ± 3.7 mg · kg–1 · min–1) were not different in HALpe, HALpo, and control, respectively. HALpo exhibited greater ( P < 0.05) NHGU than HALpe and control (3.1 ± 0.3, 2.0 ± 0.4, and 2.0 ± 0.1 mg · kg–1 · min–1, respectively). Net hepatic carbon retention was approximately twofold greater ( P < 0.05) in HALpo than in HALpe and control. NHGU and net hepatic glycogen synthesis during peripheral glucose infusion were not enhanced by HAL. Even though there exists an intrahepatic arterial reference site for the portal vein glucose concentration, the failure of HAL to result in enhanced NHGU during peripheral glucose infusion suggests the existence of one or more comparison sites outside the liver.
Mechanisms underlying increases in SR Ca2+-ATPase activity after exercise in rat skeletal muscle
Authors: Schertzer J. D. , Green H. J. , Duhamel T. A. , Tupling A. R.
Published: March 2015

Prolonged exercise followed by a brief period of reduced activity has been shown to result in an overshoot in maximal sarcoplasmic reticulum (SR) Ca2+-ATPase activity [maximal velocity ( Vmax)] in rat locomoter muscles (Ferrington DA, Reijneveld JC, Bär PR, and Bigelow DJ. Biochim Biophys Acta 1279: 203–213, 1996). To investigate the functional significance and underlying mechanisms for the increase in Vmax, we analyzed Ca2+-ATPase activity and Ca2+uptake in SR vesicles from the fast rat gastrocnemius muscles after prolonged running (RUN) and after prolonged running plus 45 min of low-intensity activity (RUN+) or no activity (REC45) and compared them with controls (Con). Although no differences were observed between RUN and Con, both Vmaxand Ca2+uptake were higher ( P < 0.05) by 43 and 63%, respectively, in RUN+ and by 35 and 34%, respectively, in REC45. The increase in Vmaxwas accompanied by increases ( P < 0.05) in the phosphorylated enzyme intermediate measured by [γ-32P]ATP. No differences between groups for each condition were found for the fluorescent probes FITC and ( N-cyclohexyl- N1-dimethylamino-α-naphthyl)carbodiimide, competitive inhibitors of the nucleotide-binding and Ca2+-binding sites on the enzyme, respectively. Similarly, no differences for the Ca2+-ATPase were observed between groups in nitrotyrosine and phosphoserine residues, a measure of nitrosylation and phosphorylation states, respectively. Western blots indicated no changes in relative isoform content of sarcoendoplasmic reticulum (SERCA)1 and SERCA2a. It is concluded that the increase in Vmaxof the Ca2+-ATPase observed in recovery is not the result of changes in enzyme nitroslyation or phosphorylation, changes in ATP and Ca2+-binding affinity, or changes in protein content of the Ca2+-ATPase.
Na+-dependent transport of large neutral amino acids occurs at the abluminal membrane of the blood-brain barrier
Authors: O'Kane Robyn L. , Hawkins Richard A.
Published: March 2015

Several Na+-dependent carriers of amino acids exist on the abluminal membrane of the blood-brain barrier (BBB). These Na+-dependent carriers are in a position to transfer amino acids from the extracellular fluid of brain to the endothelial cells and thence to the circulation. To date, carriers have been found that may remove nonessential, nitrogen-rich, or acidic (excitatory) amino acids, all of which may be detrimental to brain function. We describe here Na+-dependent transport of large neutral amino acids across the abluminal membrane of the BBB that cannot be ascribed to currently known systems. Fresh brains, from cows killed for food, were used. Microvessels were isolated, and contaminating fragments of basement membranes, astrocyte fragments, and pericytes were removed. Abluminal-enriched membrane fractions from these microvessels were prepared. Transport was Na+dependent, voltage sensitive, and inhibited by 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid, a particular inhibitor of the facilitative large neutral amino acid transporter 1 (LAT1) system. The carrier has a high affinity for leucine ( Km21 ± 7 μM) and is inhibited by other neutral amino acids, including glutamine, histidine, methionine, phenylalanine, serine, threonine, tryptophan, and tyrosine. Other established neutral amino acids may enter the brain by way of LAT1-type facilitative transport. The presence of a Na+-dependent carrier on the abluminal membrane capable of removing large neutral amino acids, most of which are essential, from brain indicates a more complex situation that has implications for the control of essential amino acid content of brain.
Increased expression of TNF-α, IL-6, and IL-8 in HALS: implications for reduced adiponectin expression and plasma levels
Authors: Lihn Aina S. , Richelsen Bjørn , Pedersen Steen B. , Haugaard Steen B. , Rathje Gulla Søby , Madsbad Sten , Andersen Ove
Published: March 2015

Human immunodeficiency virus (HIV)-associated lipodystrophy syndrome (HALS) is a side effect of highly active antiretroviral therapy of HIV-infected patients; however, the mechanism of the lipodystrophy and insulin resistance seen in this syndrome remains elusive. Adiponectin, an adipocyte-specific protein, is thought to play an important role in regulating insulin sensitivity. We investigated circulating levels and gene expression of adiponectin in subcutaneous abdominal adipose tissue (AT) from 18 HIV-infected patients with HALS compared with 18 HIV-infected patients without HALS. Implications of cytokines for adiponectin levels were investigated by determining circulating levels of TNF-α, IL-6, and IL-8 as well as gene expression of these cytokines in AT. HALS patients exhibited 40% reduced plasma adiponectin levels ( P < 0.05) compared with non-HALS subjects. Correspondingly, adiponectin mRNA levels in AT were reduced by >50% ( P = 0.06). HALS patients were insulin resistant, and a positive correlation was found between plasma adiponectin and insulin sensitivity ( r = 0.55, P < 0.01) and percent limb fat ( r = 0.61, P < 0.01). AT mRNA of TNF-α, IL-6, and IL-8 was increased in AT of HALS subjects ( P < 0.05), and both AT TNF-α mRNA and plasma TNF-α were negatively correlated to plasma adiponectin ( P < 0.05). Finally, TNF-α was found in vitro to inhibit human AT adiponectin mRNA by 80% ( P < 0.05). In conclusion, HALS patients have reduced levels of plasma adiponectin and adiponectin mRNA in AT. Increased cytokine mRNA in AT is hypothesized to exert an inhibitory effect on adiponectin gene expression and, consequently, to play a role in the reduced plasma adiponectin levels found in HALS patients.
Role of hypothalamic inputs in maintaining pituitary-adrenal responsiveness in repeated restraint
Authors: Zelena D. , Mergl Z. , Földes A. , Kovács K. J. , Tóth Z. , Makara G. B.
Published: March 2015

The role of hypothalamic structures in the regulation of chronic stress responses was studied by lesioning the mediobasal hypothalamus or the paraventricular nucleus of hypothalamus (PVH). Rats were acutely (60 min) and/or repeatedly (for 7 days) restrained. In controls, a single restraint elevated the plasma adrenocorticotropin (ACTH), corticosterone, and prolactin levels. Repeated restraint produced all signs of chronic stress, including decreased body and thymus weights, increased adrenal weight, basal corticosterone levels, and proopiomelanocortin (POMC) mRNA expression in the anterior pituitary. Some adaptation to repeated restraint of the ACTH response, but not of other hormonal responses, was seen. Lesioning of the mediobasal hypothalamus abolished the hormonal response and POMC mRNA activation to acute and/or repeated restraint, suggesting that the hypothalamo-pituitary-adrenal axis activation during repeated restraint is centrally driven. PVH lesion inhibited the ACTH and corticosterone rise to the first restraint by ∼50%. In repeatedly restrained rats with PVH lesion, the ACTH response to the last restraint was reduced almost to basal control levels, and the elevation of POMC mRNA level was prevented. PVH seems to be important for the repeated restraint-induced ACTH and POMC mRNA stimulation, but it appears to partially mediate other restraint-induced hormonal changes.
Ethnic differences in in vitro glyceride synthesis in subcutaneous and omental adipose tissue
Authors: Bower J. F. , Vadlamudi S. , Barakat H. A.
Published: March 2015

Considerable evidence suggests that there are ethnic differences in lipid metabolism between African American and Caucasian women, which may result in increased synthesis of fat in adipose tissue. The purpose of this study was to measure the in vitro rates of [14C]glucose incorporation into the glyceride-glycerol backbone of triglycerides (TG) and diglycerides (DG) in abdominal subcutaneous (SAT) and omental adipose tissue (OAT). Morbidly obese [African American ( n = 15): body mass index (BMI) = 45 ± 2.3; Caucasian ( n = 18): BMI = 51 ± 2.3] and preobese [African American ( n = 7): BMI = 27 ± 1.0; Caucasian ( n = 7): BMI = 25 ± 1.0] women were examined in this study. There were no significant differences in the rates of synthesis of either TG or DG in SAT of either preobese or obese women. On the other hand, both preobese and obese African American women had higher rates of synthesis of TG in OAT compared with their Caucasian counterparts. This increase in TG synthesis in OAT was not due to differences in cell size or rates of reesterification. Thus African American woman have an increased capacity to synthesize TG in OAT compared with Caucasian women, which may contribute to the higher prevalence of obesity in African American women.
Creatine transporter activity and content in the rat heart supplemented by and depleted of creatine
Authors: Boehm Ernest , Chan Sharon , Monfared Mina , Wallimann Theo , Clarke Kieran , Neubauer Stefan
Published: March 2015

The intracellular creatine concentration is an important bioenergetic parameter in cardiac muscle. Although creatine uptake is known to be via a NaCl-dependent creatine transporter (CrT), its localization and regulation are poorly understood. We investigated CrT kinetics in isolated perfused hearts and, by using cardiomyocytes, measured CrT content at the plasma membrane or in total lysates. Rats were fed control diet or diet supplemented with creatine or the creatine analog β-guanidinopropionic acid (β-GPA). Creatine transport in control hearts followed saturation kinetics with a Kmof 70 ± 13 mM and a Vmaxof 3.7 ± 0.07 nmol · min−1· g wet wt−1. Creatine supplementation significantly decreased the Vmaxof the CrT (2.7 ± 0.17 nmol · min−1· g wet wt−1). This was matched by an ∼35% decrease in the plasma membrane CrT; the total CrT pool was unchanged. Rats fed β-GPA exhibited a >80% decrease in tissue creatine and increase in β-GPAtotal. The Vmaxof the CrT was increased (6.0 ± 0.25 nmol · min−1· g wet wt−1) and the Kmdecreased (39.8 ± 3.0 mM). The plasma membrane CrT increased about fivefold, whereas the total CrT pool remained unchanged. We conclude that, in heart, creatine transport is determined by the content of a plasma membrane isoform of the CrT but not by the total cellular CrT pool.
Interaction between growth hormone and insulin in the regulation of lipoprotein metabolism in the rat
Authors: Frick Fredrik , Lindén Daniel , Améen Caroline , Edén Staffan , Mode Agneta , Oscarsson Jan
Published: March 2015

The importance of insulin for the in vivo effects of growth hormone (GH) on lipid and lipoprotein metabolism was investigated by examining the effects of GH treatment of hypophysectomized (Hx) female rats with and without concomitant insulin treatment. Hypophysectomy-induced changes of HDL, apolipoprotein (apo)E, LDL, and apoB levels were normalized by GH treatment but not affected by insulin treatment. The hepatic triglyceride secretion rate was lower in Hx rats than in normal rats and increased by GH treatment. This effect of GH was blunted by insulin treatment. The triglyceride content in the liver changed in parallel with the changes in triglyceride secretion rate, indicating that the effect of the hormones on triglyceride secretion was dependent on changed availability of triglycerides for VLDL assembly. GH and insulin independently increased editing of apoB mRNA, but the effects were not additive. The expression of fatty-acid synthase (FAS), stearoyl-CoA desaturase-1 (SCD-1), and sterol regulatory element-binding protein-1c (SREBP-1c) was increased by GH treatment. Insulin and GH had no additive effects on these genes; instead, insulin blunted the effect of GH on SREBP-1c mRNA. In contrast to the liver, adipose tissue expression of SREBP-1c, FAS, or SCD-1 mRNA was not influenced by GH. In conclusion, the increased hepatic expression of lipogenic enzymes after GH treatment may be explained by increased expression of SREBP-1c. Insulin does not mediate the effects of GH but inhibits the stimulatory effect of GH on hepatic SREBP-1c expression and triglyceride secretion rate.
p38 MAP kinase regulates BMP-4-stimulated VEGF synthesis via p70 S6 kinase in osteoblasts
Authors: Tokuda Haruhiko , Hatakeyama Daijiro , Shibata Toshiyuki , Akamatsu Shigeru , Oiso Yutaka , Kozawa Osamu
Published: March 2015

We previously reported that p70 S6 kinase takes part in bone morphogenetic protein-4 (BMP-4)-stimulated vascular endothelial growth factor (VEGF) synthesis in osteoblast-like MC3T3-E1 cells. Recently, we showed that BMP-4-induced osteocalcin synthesis is regulated by p44/p42 MAP kinase and p38 MAP kinase in these cells. In the present study, we investigated whether the MAP kinases are involved in the BMP-4-stimulated synthesis of VEGF in MC3T3-E1 cells. PD-98059 and U-0126, inhibitors of the upstream kinase of p44/p42 MAP kinase, failed to affect BMP-4-stimulated VEGF synthesis. SB-203580 and PD-169316, inhibitors of p38 MAP kinase, significantly reduced VEGF synthesis, whereas SB-202474, a negative control for p38 MAP kinase inhibitor, had little effect on VEGF synthesis. The BMP-4-stimulated phosphorylation of p38 MAP kinase was not affected by rapamycin, an inhibitor of p70 S6 kinase. On the contrary, SB-203580 and PD-169316 reduced the BMP-4-stimulated phosphorylation of p70 S6 kinase. In addition, anisomycin, an activator of p38 MAP kinase, phosphorylates p70 S6 kinase, and the phosphorylation was suppressed by SB-203580. LY-294002, an inhibitor of phosphatidylinositol 3-kinase, failed to suppress the phosphorylation of p38 MAP kinase induced by BMP-4. Not BMP-4 but anisomycin weakly induced the phosphorylation of phosphoinositide-dependent kinase-1. However, anisomycin had little effect on phosphorylation of either Akt or the mammalian target of rapamycin. Taken together, our results suggest that p38 MAP kinase functions in BMP-4-stimulated VEGF synthesis as a positive regulator at a point upstream from p70 S6 kinase in osteoblasts.