bluuebunny/crossref_metadata_2025 huggingface dataset:
A Tool for Analog/RF BIST Evaluation Using Statistical Models of Circuit Parameters
Authors: Beznia Kamel , Bounceur Ahcene , Euler Reinhardt , Mir Salvador
Published: March 2015

Testing analog integrated circuits is expensive in terms of both test equipment and time. To reduce the cost, Design-For-Test techniques (DFT) such as Built-In Self-Test (BIST) have been developed. For a given Circuit Under Test (CUT), the choice of a suitable technique should be made at the design stage as a result of the analysis of test metrics such as test escapes and yield loss. However, it is very hard to carry out this estimation for analog/RF circuits by using fault simulation techniques. Instead, the estimation of parametric test metrics is made possible by Monte Carlo circuit-level simulations and the construction of statistical models. These models represent the output parameter space of the CUT in which the test metrics are defined. In addition, models of the input parameter space may be required to accelerate the simulations and obtain higher confidence in the DFT choices. In this work, we describe a methodological flow for the selection of most adequate statistical models and several techniques that can be used for obtaining these models. Some of these techniques have been integrated into a Computer-Aided Test (CAT) tool for the automation of the process of test metrics estimation. This estimation is illustrated for the case of a BIST solution for CMOS imager pixels that requires the use of advanced statistical modeling techniques.
ePlace
Authors: Lu Jingwei , Chen Pengwen , Chang Chin-Chih , Sha Lu , Huang Dennis Jen-Hsin , Teng Chin-Chi , Cheng Chung-Kuan
Published: March 2015

We develop a flat, analytic, and nonlinear placement algorithm,
ePlace
, which is more effective, generalized, simpler, and faster than previous works. Based on the analogy between placement instance and electrostatic system, we develop a novel placement density function
eDensity
, which models every object as positive charge and the density cost as the potential energy of the electrostatic system. The electric potential and field distribution are coupled with density using a well-defined Poisson's equation, which is numerically solved by spectral methods based on fast Fourier transform (FFT). Instead of using the conjugate gradient (CG) nonlinear solver in previous placers, we propose to use Nesterov's method which achieves faster convergence. The efficiency bottleneck on line search is resolved by predicting the steplength using a closed-form equation of Lipschitz constant. The placement performance is validated through experiments on the ISPD 2005 and ISPD 2006 benchmark suites, where ePlace outperforms all state-of-the-art placers (Capo10.5, FastPlace3.0, RQL, MAPLE, ComPLx, BonnPlace, POLAR, APlace3, NTUPlace3, mPL6) with much shorter wirelength and shorter or comparable runtime. On average, of all the ISPD 2005 benchmarks, ePlace outperforms the leading placer BonnPlace with 2.83% shorter wirelength and runs 3.05× faster; and on average, of all the ISPD 2006 benchmarks, ePlace outperforms the leading placer MAPLE with 4.59% shorter wirelength and runs 2.84× faster.
Guarantee IP lookup performance with FIB explosion
Authors: Yang Tong , Xie Gaogang , Li YanBiao , Fu Qiaobin , Liu Alex X. , Li Qi , Mathy Laurent
Published: March 2015

The Forwarding Information Base (FIB) of backbone routers has been rapidly growing in size. An ideal IP lookup algorithm should achieve constant, yet small, IP lookup time and on-chip memory usage. However, no prior IP lookup algorithm achieves both requirements at the same time. In this paper, we first propose SAIL, a Splitting Approach to IP Lookup. One splitting is along the dimension of the lookup process, namely finding the prefix length and finding the next hop, and another splitting is along the dimension of prefix length, namely IP lookup on prefixes of length less than or equal to 24 and IP lookup on prefixes of length longer than 24. Second, we propose a suite of algorithms for IP lookup based on our SAIL framework. Third, we implemented our algorithms on four platforms: CPU, FPGA, GPU, and many-core. We conducted extensive experiments to evaluate our algorithms using real FIBs and real traffic from a major ISP in China. Experimental results show that our SAIL algorithms are several times or even two orders of magnitude faster than well known IP lookup algorithms.
Control-plane protocol interactions in cellular networks
Authors: Tu Guan-Hua , Li Yuanjie , Peng Chunyi , Li Chi-Yu , Wang Hongyi , Lu Songwu
Published: March 2015

Control-plane protocols are complex in cellular networks. They communicate with one another along three dimensions of cross layers, cross (circuit-switched and packet-switched) domains, and cross (3G and 4G) systems. In this work, we propose signaling diagnosis tools and uncover six instances of problematic interactions. Such control-plane issues span both design defects in the 3GPP standards and operational slips by carriers. They are more damaging than data-plane failures. In the worst-case scenario, users may be out of service in 4G, or get stuck in 3G. We deduce root causes, propose solutions, and summarize learned lessons.
Network neutrality inference
Authors: Zhang Zhiyong , Mara Ovidiu , Argyraki Katerina
Published: March 2015

When can we reason about the neutrality of a network based on external observations? We prove conditions under which it is possible to (a) detect neutrality violations and (b) localize them to specific links, based on external observations. Our insight is that, when we make external observations from different vantage points, these will most likely be inconsistent with each other if the network is not neutral. Where existing tomographic techniques try to form solvable systems of equations to infer network properties, we try to form \emph{un}solvable systems that reveal neutrality violations. We present an algorithm that relies on this idea to identify sets of non-neutral links based on external observations, and we show, through network emulation, that it achieves good accuracy for a variety of network conditions.
Decentralized task-aware scheduling for data center networks
Authors: Dogar Fahad R. , Karagiannis Thomas , Ballani Hitesh , Rowstron Antony
Published: March 2015

Many data center applications perform rich and complex tasks (e.g., executing a search query or generating a user's news-feed). From a network perspective, these tasks typically comprise multiple flows, which traverse different parts of the network at potentially different times. Most network resource allocation schemes, however, treat all these flows in isolation -- rather than as part of a task -- and therefore only optimize flow-level metrics.

In this paper, we show that task-aware network scheduling, which groups flows of a task and schedules them together, can reduce both the average as well as tail completion time for typical data center applications. To achieve these benefits in practice, we design and implement Baraat, a decentralized task-aware scheduling system. Baraat schedules tasks in a FIFO order but avoids head-of-line blocking by dynamically changing the level of multiplexing in the network. Through experiments with Memcached on a small testbed and large-scale simulations, we show that Baraat outperforms state-of-the-art decentralized schemes (e.g., pFabric) as well as centralized schedulers (e.g., Orchestra) for a wide range of workloads (e.g., search, analytics, etc).
A "hitchhiker's" guide to fast and efficient data reconstruction in erasure-coded data centers
Authors: Rashmi K.V. , Shah Nihar B. , Gu Dikang , Kuang Hairong , Borthakur Dhruba , Ramchandran Kannan
Published: March 2015

Erasure codes such as Reed-Solomon (RS) codes are being extensively deployed in data centers since they offer significantly higher reliability than data replication methods at much lower storage overheads. These codes however mandate much higher resources with respect to network bandwidth and disk IO during reconstruction of data that is missing or otherwise unavailable. Existing solutions to this problem either demand additional storage space or severely limit the choice of the system parameters. In this paper, we present "Hitchhiker", a new erasure-coded storage system that reduces both network traffic and disk IO by around 25% to 45% during reconstruction of missing or otherwise unavailable data, with no additional storage, the same fault tolerance, and arbitrary flexibility in the choice of parameters, as compared to RS-based systems. Hitchhiker 'rides' on top of RS codes, and is based on novel encoding and decoding techniques that will be presented in this paper. We have implemented Hitchhiker in the Hadoop Distributed File System (HDFS). When evaluating various metrics on the data-warehouse cluster in production at Facebook with real-time traffic and workloads, during reconstruction, we observe a 36% reduction in the computation time and a 32% reduction in the data read time, in addition to the 35% reduction in network traffic and disk IO. Hitchhiker can thus reduce the latency of degraded reads and perform faster recovery from failed or decommissioned machines.
Diagnosing missing events in distributed systems with negative provenance
Authors: Wu Yang , Zhao Mingchen , Haeberlen Andreas , Zhou Wenchao , Loo Boon Thau
Published: March 2015

When debugging a distributed system, it is sometimes necessary to explain the absence of an event - for instance, why a certain route is not available, or why a certain packet did not arrive. Existing debuggers offer some support for explaining the presence of events, usually by providing the equivalent of a backtrace in conventional debuggers, but they are not very good at answering 'Why not?' questions: there is simply no starting point for a possible backtrace.

In this paper, we show that the concept of negative provenance can be used to explain the absence of events in distributed systems. Negative provenance relies on counterfactual reasoning to identify the conditions under which the missing event could have occurred. We define a formal model of negative provenance for distributed systems, and we present the design of a system called Y! that tracks both positive and negative provenance and can use them to answer diagnostic queries. We describe how we have used Y! to debug several realistic problems in two application domains: software-defined networks and BGP interdomain routing. Results from our experimental evaluation show that the overhead of Y! is moderate.
Locating throughput bottlenecks in home networks
Authors: Sundaresan Srikanth , Feamster Nick , Teixeira Renata
Published: March 2015

We present a demonstration of WTF (Where's The Fault?), a system that localizes performance problems in home and access networks. We implement WTF as custom firmware that runs in an off-the-shelf home router. WTF uses timing and buffering information from passively monitored traffic at home routers to detect both access link and wireless network bottlenecks.
Enabling near real-time central control for live video delivery in CDNs
Authors: Mukerjee Matthew K. , Hong JungAh , Jiang Junchen , Naylor David , Han Dongsu , Seshan Srinivasan , Zhang Hui
Published: March 2015

User-created live video streaming is marking a fundamental shift in the workload of live video delivery. However, live-video-specific challenges and the viral nature of user-created content makes it difficult for current CDNs to deliver 1) high-quality, 2) highly-scalable, and 3) highly-responsive service. We present the design and implementation of VDN, a new control plane for CDNs designed to optimize the delivery of live streams within the CDN. VDN satisfies these requirements by using two approaches: 1) optimizing directly for video quality (not just throughput) and 2) combining centralized control with local control, allowing VDN to adapt to traffic dynamics and network failures at fine timescales.
SDX
Authors: Gupta Arpit , Vanbever Laurent , Shahbaz Muhammad , Donovan Sean Patrick , Schlinker Brandon , Feamster Nick , Rexford Jennifer , Shenker Scott , Clark Russ , Katz-Bassett Ethan
Published: March 2015

BGP severely constrains how networks can deliver traffic over the Internet. Today's networks can only forward traffic based on the destination IP prefix, by selecting among routes offered by their immediate neighbors. We believe Software Defined Networking (SDN) could revolutionize wide-area traffic delivery, by offering direct control over packet-processing rules that match on multiple header fields and perform a variety of actions. Internet exchange points (IXPs) are a compelling place to start, given their central role in interconnecting many networks and their growing importance in bringing popular content closer to end users. To realize a Software Defined IXP (an "SDX"), we need new programming abstractions that allow participating networks to create and run these applications and a runtime that both behaves correctly when interacting with BGP and ensures that applications do not interfere with each other. We must also ensure that the system scales, both in rule-table size and computational overhead. In this demo, we show how we tackle these challenges demonstrating the flexibility and scalability of our SDX platform. The paper also appears in the main program.
Glucagon-like peptide-1 induces a cAMP-dependent increase of [Na+]iassociated with insulin secretion in pancreatic β-cells
Authors: Miura Yoshikazu , Matsui Hisao
Published: March 2015

Glucagon-like peptide-1 (GLP-1) elevates the intracellular free calcium concentration ([Ca2+]i) and insulin secretion in a Na+-dependent manner. To investigate a possible role of Na ion in the action of GLP-1 on pancreatic islet cells, we measured the glucose-and GLP-1-induced intracellular Na+concentration ([Na+]i), [Ca2+]i, and insulin secretion in hamster islet cells in various concentrations of Na+. The [Na+]iand [Ca2+]iwere monitored in islet cells loaded with sodium-binding benzofuran isophthalate and fura 2, respectively. In the presence of 135 mM Na+and 8 mM glucose, GLP-1 (10 nM) strongly increased the [Na+]i, [Ca2+]i, and insulin secretion. In the presence of 13.5 mM Na+, both glucose and GLP-1 increased neither the [Na+]inor the [Ca2+]i. In a Na+-free medium, GLP-1 and glucose did not increase the [Na+]i. SQ-22536, an inhibitor of adenylate cyclase, and H-89, an inhibitor of PKA, incompletely inhibited the response. In the presence of both 8 mM glucose and H-89, 8-pCPT-2′-O-Me-cAMP, a PKA-independent cAMP analog, increased the insulin secretion and the [Na+]i. Therefore, we conclude that GLP-1 increases the cAMP level via activation of adenylate cyclase, which augments the membrane Na+permeability through PKA-dependent and PKA-independent mechanisms, thereby increasing the [Ca2+]iand promoting insulin secretion from hamster islet cells.
Pyruvate shuttle in muscle cells: high-affinity pyruvate transport sites insensitive totrans-lactate efflux
Authors: Mengual Raymond , el Abida Kaoukib , Mouaffak Nassima , Rieu Michel , Beaudry Michele
Published: March 2015

The specificity of the transport mechanisms for pyruvate and lactate and their sensitivity to inhibitors were studied in L6 skeletal muscle cells. Trans- and cis-lactate effects on pyruvate transport kinetic parameters were examined. Pyruvate and lactate were transported by a multisite carrier system, i.e., by two families of sites, one with low affinity and high capacity (type I sites) and the other with high affinity and low capacity (type II). The multisite character of transport kinetics was not modified by either hydroxycinnamic acid (CIN) or p-chloromercuribenzylsulfonic acid (PCMBS), which exert different types of inhibition. The transport efficiency (TE) ratios of maximal velocity to the trans-activation dissociation constant ( Kt) showed that lactate and pyruvate were preferentially transported by types I and II sites, respectively. The cis-lactate effect was observed with high Kivalues for both sites. The trans-lactate effect on pyruvate transport occurred only on type I sites and exhibited an asymmetric interaction pattern ( Ktof inward lactate > Ktof outward lactate). The inability of lactate to trans-stimulate type II sites suggests that intracellular lactate cannot recruit these sites. The high-affinity type II sites act as a specific pyruvate shuttle and constitute an essential relay for the intracellular lactate shuttle.
Infection impairs insulin-dependent hepatic glucose uptake during total parenteral nutrition
Authors: Donmoyer Christine M. , Chen Sheng-Song , Lacy D. Brooks , Pearson David A. , Poole Adrian , Zhang Yiqun , McGuinness Owen P.
Published: March 2015

Total parenteral nutrition (TPN) markedly augments net hepatic glucose uptake (NHGU) and hepatic glycolysis in the presence of mild hyperglycemia and hyperinsulinemia. This increase is impaired by an infection. We determined whether the adaptation to TPN alters the responsiveness of the liver to insulin and whether infection impairs that response. Chronically catheterized dogs received TPN for 5 days. On day 3 of TPN, either a nonlethal hypermetabolic infection was induced (INF, n = 5) or a sham surgery was performed (SHAM, n = 5). Forty-two hours after clot implantation, somatostatin and glucagon (34 ± 3 vs. 84 ± 11 pg/ml in artery, SHAM vs. INF) were infused, and a three-step (120 min each) isoglycemic (∼120 mg/dl) hyperinsulinemic (∼12, 25, and 50 μU/ml) clamp was performed to simulate levels seen in normal, infected, and exogenous insulin treatment states. In SHAM, NHGU (3.5 ± 0.2 to 4.2 ± 0.4 to 4.6 ± 0.5 mg · kg−1· min−1) modestly increased. In INF, NHGU was consistently lower at each insulin step (1.1 ± 0.5 to 2.6 ± 0.5 to 2.8 ± 0.7 mg · kg−1· min−1). Although NHGU increased from the first to the second step in INF, it did not increase further with the highest dose of insulin. Despite increases in NHGU, net hepatic lactate release did not increase in SHAM and fell in INF. In summary, in the TPN-adapted state, liver glucose uptake is unresponsive to increases in insulin above the basal level. Although the infection-induced increase in insulin sustains NHGU, further increments in insulin enhance neither NHGU nor glycolysis.
Increased glucose uptake promotes oxidative stress and PKC-δ activation in adipocytes of obese, insulin-resistant mice
Authors: Talior Ilana , Yarkoni Merav , Bashan Nava , Eldar-Finkelman Hagit
Published: March 2015

Increased oxidative stress is believed to be one of the mechanisms responsible for hyperglycemia-induced tissue damage and diabetic complications. In these studies, we undertook to characterize glucose uptake and oxidative stress in adipocytes of type 2 diabetic animals and to determine whether these promote the activation of PKC-δ. The adipocytes used were isolated either from C57Bl/6J mice that were raised on a high-fat diet (HF) and developed obesity and insulin resistance or from control animals. Basal glucose uptake significantly increased (8-fold) in HF adipocytes, and this was accompanied with upregulation of GLUT1 expression levels. Insulin-induced glucose uptake was inhibited in HF adipocytes and GLUT4 content reduced by 20% in these adipocytes. Reactive oxygen species (ROS) increased twofold in HF adipocytes compared with control adipocytes and were largely reduced with decreased glucose concentrations. At zero glucose, ROS levels were reduced to the normal levels seen in control adipocytes. The activity of PKC-δ increased twofold in HF adipocytes compared with control adipocytes and was further activated by H2O2. Moreover, PKC-δ activity was inhibited in HF adipocytes either by glucose deprivation or by treatment with the antioxidant N-acetyl-l-cysteine. In summary, we propose that increased glucose intake in HF adipocytes increases oxidative stress, which in turn promotes the activation of PKC-δ. These consequential events may be responsible, at least in part, for development of HF diet-induced insulin resistance in the fat tissue.
Enteral infusion of glucose at rates approximating EGP enhances glucose disposal but does not cause hypoglycemia
Authors: Zangeneh Farhad , Basu Rita , Shah Pankaj , Arora Puneet , Camilleri Michael , Rizza Robert A.
Published: March 2015

Portal infusion of glucose at rates approximating endogenous glucose production (EGP) causes paradoxical hypoglycemia in wild-type but not GLUT2 null mice, implying activation of a specific portal glucose sensor. To determine whether this occurs in humans, glucose containing [3-3H]glucose was infused intraduodenally at rates of 3.1 mg · kg-1 · min-1 ( n = 5), 1.55 mg · kg-1 · min-1 ( n = 9), or 0/0.1 mg · kg-1 · min-1 ( n = 9) for 7 h in healthy nondiabetic subjects. [6,6-2H2]glucose was infused intravenously to enable simultaneous measurement of EGP, glucose disappearance, and the rate of appearance of the intraduodenally infused glucose. Plasma glucose concentrations fell ( P < 0.01) from 90 ± 1 to 84 ± 2 mg/dl during the 0/0.1 mg · kg-1 · min-1 id infusions but increased ( P < 0.001) to 104 ± 5 and 107 ± 3 mg/dl, respectively, during the 1.55 and 3.1 mg · kg-1 · min-1 id infusions. In contrast, insulin increased ( P < 0.05) during the 1.55 and 3.0 mg · kg-1 · min-1 infusions, reaching a peak of 10 ± 2 and 18 ± 5 μU/ml, respectively, by 2 h. Insulin concentrations then fell back to concentrations that no longer differed by study end (7 ± 1 vs. 8 ± 1 μU/ml). This resulted in comparable suppression of EGP by study end (0.84 ± 0.2 and 0.63 ± 0.1 mg · kg-1 · min-1). Glucose disappearance was higher ( P < 0.01) during the final hour of the 3.1 than 1.55 mg · kg-1 · min-1 id infusion (4.47 ± 0.2 vs. 2.6 ± 0.1 mg · kg-1 · min-1), likely because of the slightly, but not significantly, higher glucose and insulin concentrations. We conclude that, in contrast to mice, selective portal glucose delivery at rates approximating EGP does not cause hypoglycemia in humans.
BMPs and BMPRs in chicken ovary and effects of BMP-4 and -7 on granulosa cell proliferation and progesterone production in vitro
Authors: Onagbesan O. M. , Bruggeman V. , Van As P. , Tona K. , Williams J. , Decuypere E.
Published: March 2015

Bone morphogenetic proteins (BMPs) and their receptors (BMPRs) are now known to have important roles in mammalian ovarian folliculogenesis. This study determined the expression of the mRNA encoding for BMPs and their receptors in the chicken ovary and explored possible roles for them. The expression of the mRNA for BMP-2, -4, -6, -7, and BMPR-IA, -IB, and -II was determined and quantified by a semiquantitative RT-PCR. The mRNAs for all the BMPs and receptors determined were present in both the granulosa (G) and theca (T) cells of the F1, F2, and F3 follicles. All BMP mRNAs increased in G cells with follicular development, whereas only BMP-7 mRNA had this trend in the T cells. BMP-2, -4, and -6 mRNAs in T were similar between follicles. BMPR-IA mRNA was similar in F2G and F3G but lower in F1G. BMPR-IB mRNA was similar in G of all follicles, and BMPR-II mRNA increased with development. In the T, each receptor subtype showed equal distribution between follicles. mRNA levels for BMPR-IB and -II were higher in G than in T, suggesting that the G is a major target for BMPs. BMP-4 and -7 stimulated basal, IGF-I-, and gonadotropin-stimulated progesterone production by cultured G cells, with differential responses between cells from the F1 and F3/4. This suggests involvement in follicular differentiation. BMP-4 and -7 reversed the inhibitory effects of transforming growth factor (TGF)-α on basal and gonadotropin-stimulated G cell progesterone production, with greater effect in the F1 than in the F3/4. This effect suggests an important role for BMPs interacting with TGF-α in modulating the effects of gonadotropins and IGF-I on follicular differentiation. Finally, BMP-7 stimulated G cell proliferation, but BMP-4 inhibited TGF-α+ IGF-I- and/or FSH-stimulated G cell proliferation, suggesting a role in the control of follicular growth during development. These effects of BMP-4 and -7 on the G cell function showed relationships with the expression levels of the BMPs and the BMPR-II.
Familiality of metabolic abnormalities is dependent on age at onset and phenotype of the type 2 diabetic proband
Authors: Tripathy D. , Lindholm E. , Isomaa B. , Saloranta C. , Tuomi T. , Groop L.
Published: March 2015

To determine the impact of a family history of the common form of type 2 diabetes and the phenotype of the proband on anthropometric and metabolic variables in normoglycemic first-degree relatives, we studied 2,100 first-degree relatives of patients with the common form of type 2 diabetes (FH+) and 388 subjects without a family history of diabetes (FH–). All subjects participated in an oral glucose tolerance test to allow measurement of insulin secretion [30-min incremental insulin/glucose (I/G 30)] and insulin sensitivity [homeostasis model assessment (HOMA) of insulin resistance (IR)]. A subset participated in a euglycemic clamp ( n = 75) and an intravenous glucose tolerance test ( n = 300). To study the effect of a particular phenotype of the proband, insulin secretion and sensitivity were also compared between first-degree relatives of diabetic probands with high and low waist-to-hip ratio (WHR) and probands with early and late onset of diabetes. FH+ subjects were more insulin resistant, as seen from a higher HOMA-IR index ( P = 0.006) and a lower rate of insulin-stimulated glucose uptake ( P = 0.001) and had more features of the metabolic syndrome ( P = 0.02, P = 0.0002) compared with FH– subjects. Insulin secretion adjusted for insulin resistance (disposition index, DI) was also lower in the FH+ vs. FH– subjects ( P = 0.04). Relatives of diabetic probands with a high WHR had reduced insulin-mediated glucose uptake compared with relatives of probands with a low WHR ( P = 0.04). Relatives of diabetic patients with age at onset <44 yr had higher HOMA IR ( P < 0.005) and lower DI ( P < 0.005) than relatives of patients with age at onset >65 yr (highest quartile). We conclude that early age at onset of type 2 diabetes and abdominal obesity have a significant influence on the metabolic phenotype in the nondiabetic first-degree relative.
Hepatosplanchnic clearance of interleukin-6 in humans during exercise
Authors: Febbraio Mark A. , Ott Peter , Nielsen Henning Bay , Steensberg Adam , Keller Charlotte , Krustrup Peter , Secher Niels H. , Pedersen Bente Klarlund
Published: March 2015

The cytokine interleukin (IL)-6 can increase markedly in the circulation during exercise, but whether the liver is a source of this increase is unknown. The aim of this study was to measure IL-6 flux across the hepatosplanchnic tissues in humans. To elevate systemic concentrations of IL-6, six healthy male subjects performed 120 min of semirecumbent cycling, and blood samples were simultaneously obtained from a brachial artery and the hepatic vein before and during exercise for the analysis of IL-6. Hepatosplanchnic blood flow (HBF) was measured using the indocyanine green infusion technique. Net hepatosplanchnic IL-6 balance was calculated from these measures. HBF was 1.3 ± 0.1 l/min at rest and was not reduced throughout exercise, averaging 1.1 ± 0.2 l/min. Arterial plasma IL-6 markedly increased ( P < 0.05) from 1.8 ± 0.6 ng/l at rest to 14.3 ± 3.2 ng/l after 120 min of exercise. The hepatosplanchnic viscera did not contribute to this increase, since there was a net hepatosplanchnic IL-6 uptake (0.8 ± 0.3 vs. 5.5 ± 1.9 ng/min, rest vs. 120 min; P < 0.05). These data demonstrate that the hepatosplanchnic viscera remove IL-6 from the circulation in humans. This removal may constitute a mechanism limiting the negative chronic metabolic action of chronically elevated circulating IL-6.
Impaired glucagon response to sympathetic nerve stimulation in the BB diabetic rat: effect of early sympathetic islet neuropathy
Authors: Mundinger Thomas O. , Mei Qi , Figlewicz Dianne P. , Lernmark Åke , Taborsky Gerald J.
Published: March 2015

We investigated the functional impact of a recently described islet-specific loss of sympathetic nerves that occurs soon after the autoimmune destruction of β-cells in the BB diabetic rat ( 35 ). We found that the portal venous (PV) glucagon response to sympathetic nerve stimulation (SNS) was markedly impaired in newly diabetic BB rats (BB D). We next found a normal glucagon response to intravenous epinephrine in BB D, eliminating the possibility of a generalized secretory defect of the BB D α-cell as the mediator of the impaired glucagon response to SNS. We then sought to determine whether the glucagon impairment to SNS in BB D was due solely to their loss of islet sympathetic nerve terminals or whether other effects of autoimmune diabetes contributed. We therefore reproduced, in nondiabetic Wistar rats, an islet nerve terminal loss similar to that in BB D with systemic administration of the sympathetic neurotoxin 6-hydroxydopamine. The impairment of the glucagon response to SNS in these chemically denervated, nondiabetic rats was similar to that in the spontaneously denervated BB D. We conclude that the early sympathetic islet neuropathy of BB D causes a functional defect of the sympathetic pathway to the α-cell that can, by itself, account for the impaired glucagon response to postganglionic SNS.
Nonnutritive flow impairs uptake of fatty acid by white muscles of the perfused rat hindlimb
Authors: Clerk L. H. , Smith M. E. , Rattigan S. , Clark M. G.
Published: March 2015

Triglyceride hydrolysis by the perfused rat hindlimb is enhanced with serotonin-induced nonnutritive flow (NNF) and may be due to the presence of nonnutritive route-associated connective tissue fat cells. Here, we assess whether NNF influences muscle uptake of 0.55 mM palmitate in the perfused hindlimb. Comparisons were made with insulin-mediated glucose uptake. NNF induced during 60 nM insulin infusion inhibited hindlimb oxygen uptake from 22.0 ± 0.5 to 9.7 ± 0.8 μmol · g−1· h−1( P < 0.001), 1-methylxanthine metabolism (indicator of nutritive flow) from 5.8 ± 0.4 to 3.8 ± 0.4 nmol · min−1· g−1( P = 0.004), glucose uptake from 29.2 ± 1.7 to 23.1 ± 1.8 μmol · g−1· h−1( P = 0.005) and muscle 2-deoxyglucose uptake from 82.1 ± 4.6 to 41.6 ± 6.7 μmol · g−1· h−1( P < 0.001). Palmitate uptake, unaffected by insulin alone, was inhibited by NNF in extensor digitorum longus, white gastrocnemius, and tibialis anterior muscles; average inhibition was from 13.9 ± 1.2 to 6.9 ± 1.4 μmol · g−1· h−1( P = 0.02). Thus NNF impairs both fatty acid and glucose uptake by muscle by restricting flow to myocytes but, as shown previously, favors triglyceride hydrolysis and uptake into nearby connective tissue fat cells. The findings have implications for lipid partitioning in limb muscles between myocytes and attendant adipocytes.
Potential role of leucine metabolism in the leucine-signaling pathway involving mTOR
Authors: Lynch Christopher J. , Halle Beth , Fujii Hisao , Vary Thomas C. , Wallin Reidar , Damuni Zahi , Hutson Susan M.
Published: March 2015

Leucine has been shown to stimulate adipose tissue protein synthesis in vivo as well as leptin secretion, protein synthesis, hyper-plastic growth, and tissue morphogenesis in in vitro experiments using freshly isolated adipocytes. Recently, others have proposed that leucine oxidation in the mitochondria may be required to activate the mammalian target of rapamycin (mTOR), the cytosolic Ser/Thr protein kinase that appears to mediate some of these effects. The first irreversible and rate-limiting step in leucine oxidation is catalyzed by the branched-chain α-keto acid dehydrogenase (BCKD) complex. The activity of this complex is regulated acutely by phosphorylation of the E1α-subunit at Ser293(S293), which inactivates the complex. Because the α-keto acid of leucine regulates the activity of BCKD kinase, it has been suggested as a potential target for leucine regulation of mTOR. To study the regulation of BCKD phosphorylation and its potential link to mTOR activation, a phosphopeptide-specific antibody recognizing this site was developed and characterized. Phospho-S293 (pS293) immunoreactivity in liver corresponded closely to diet-induced changes in BCKD activity state. Immunoreactivity was also increased in TREMK-4 cells after the induction of BCKD kinase by a drug-inducible promoter. BCKD S293 phosphorylations in adipose tissue and gastrocnemius (which is mostly inactive in vivo) were similar. This suggests that BCKD complex in epididymal adipose tissue from food-deprived rats is mostly inactive (unable to oxidize leucine), as is the case in muscle. To begin to test the leucine oxidation hypothesis of mTOR activation, the dose-dependent effects of orally administered leucine on acute activation of S6K1 (an mTOR substrate) and BCKD were compared using the pS293 antibodies. Increasing doses of leucine directly correlated with increases in plasma leucine concentration. Phosphorylation of S6K1 (Thr389, the phosphorylation site leading to activation) in adipose tissue was maximal at a dose of leucine that increased plasma leucine approximately threefold. Changes in BCKD phosphorylation state required higher plasma leucine concentrations. The results seem more consistent with a role for BCKD and BCKD kinase in the activation of leucine metabolism/oxidation than in the activation of the leucine signal to mTOR.
Endothelin-1-stimulated glucose uptake is desensitized by tumor necrosis factor-α in 3T3-L1 adipocytes
Authors: Rachdaoui Nadia , Nagy Laura E.
Published: March 2015

Tumor necrosis factor-α (TNF-α) is a potent inducer of insulin resistance, and increased TNF-α expression is associated with impaired glucose disposal. Although insulin is the primary regulator of glucose transport in adipose, endothelin-1, a vasoconstrictor peptide that signals through the heterotrimeric G proteins Gαq/11, potently stimulates glucose uptake in 3T3-L1 adipocytes by a mechanism independent of phosphatidylinositol (PI) 3-kinase. Here, we report that exposure of 3T3-L1 adipocytes to TNF-α for 48 h dose-dependently decreased endothelin-1-stimulated glucose uptake and translocation of GLUT4 to the plasma membrane. TNF-α exposure had no effect on endothelin-1 receptor number at the cell surface. In contrast, TNF-α treatment reduced the quantity of Gαq/11and proline-rich tyrosine kinase 2 (PYK2) and decreased endothelin-1-stimulated PYK2-Tyr402tyrosine phosphorylation. Taken together, these results suggest that TNF-α-induced desensitization of endothelin-1-stimulated GLUT4 translocation and glucose uptake in 3T3-L1 adipocytes is due, at least in part, to a decreased expression of Gαq/11, leading to a suppression in tyrosine phosphorylation of PYK2.
Responsiveness of insulin-induced cardiac sympathetic nerve activation associates with blood pressure regulation in diabetics
Authors: Takagi Miki , Tanaka Yasushi , Yamasaki Yoshimitsu , Yamamoto Masahiko , Hori Masatsugu , Nakaniwa Tomiko , Niwa Masataka , Uchino Hiroshi , Tamura Yoshifumi , Nomiyama Takashi , Watada Hirotaka , Kawamori Ryuzo
Published: March 2015

To quantitatively evaluate the effect of insulin on cardiac sympathetic nerve activity (SNA) and analyze clinical factors associated with insulin sensitivity for the regulation of SNA in diabetics, 29 Japanese type 2 diabetics without neuropathy were recruited. A 2-h control study and a 2-h hyperinsulinemic euglycemic glucose clamp study were performed. From the power spectral analysis of R-R intervals on ECG during both studies, two major components, the low-frequency (LF) and the high-frequency component (HF), were obtained. Then %LF was calculated as LF/(LF +HF), and the ratio of the average %LF during the last 30 min of the clamp or the control to the average %LF for the entire time for clamp or control (R-%LF) was used as a marker of changes in SNA. R-%LF was significantly higher during the clamp than in the control (1.07 ± 0.04 vs. 1.03 ± 0.03, P < 0.05). High responders (individual R-%LF during clamp ≥ mean + 2SD in control) showed a higher basal mean blood pressure (BP) before the clamp (89 ± 3 vs. 82 ± 2, P < 0.03) but not a higher glucose infusion rate (GIR) compared with low responders (<mean + 2SD). Furthermore, R-%LF showed a positive correlation with basal mean BP ( P < 0.02) but not with GIR. These data demonstrate that an acute insulin load stimulates cardiac SNA, and insulin sensitivity in the regulation of SNA may be associated with BP regulation independently of peripheral insulin sensitivity.
Phosphorylation of eukaryotic initiation factor eIF2Bε in skeletal muscle during sepsis
Authors: Vary Thomas C. , Deiter Gina , Kimball Scot R.
Published: March 2015

We reported that the inhibition of protein synthesis in skeletal muscle during sepsis correlated with reduced eukaryotic initiation factor eIF2B activity. The present studies define changes in eIF2Bε phosphorylation in gastrocnemius of septic animals. eIF2B kinase activity was significantly elevated 175% by sepsis compared with sterile inflammation, whereas eIF2B phosphatase activity was unaffected. Phosphorylation of eIF2Bε-Ser535was significantly augmented over 2-fold and 2.5-fold after 3 and 5 days and returned to control values after 10 days of sepsis. Phosphorylation of glycogen synthase kinase-3 (GSK-3), a potential upstream kinase responsible for the elevated phosphorylation of eIF2Bε, was significantly reduced over 36 and 41% after 3 and 5 days and returned to control values after 10 days of sepsis. The phosphorylation of PKB, a kinase thought to directly phosphorylate and inactivate GSK-3, was significantly reduced ∼50% on day 3, but not on days 5 or 10, postinfection compared with controls. Treatment of septic rats with TNF-binding protein prevented the sepsis-induced changes in eIF2Bε and GSK-3 phosphorylation, implicating TNF in mediating the effects of sepsis. Thus increased phosphorylation of eIF2Bε via activation of GSK-3 is an important mechanism to account for the inhibition of skeletal muscle protein synthesis during sepsis. Furthermore, the study presents the first demonstration of changes in eIF2Bε phosphorylation in vivo.
Abnormalities of leptin and ghrelin regulation in obesity-prone juvenile rats
Authors: Levin Barry E. , Dunn-Meynell Ambrose A. , Ricci Matt R. , Cummings David E.
Published: March 2015

Rats selectively bred to develop diet-induced obesity (DIO) spontaneously gain more body weight between 5 and 7 wk of age than do those bred to be diet resistant (DR). Here, chow-fed DIO rats ate 9% more and gained 19% more body weight from 5 to 6 wk of age than did DR rats but had comparable leptin and insulin levels. However, 6-wk-old DIO rats had 29% lower plasma ghrelin levels at dark onset but equivalent levels 6 h later compared with DR rats. When subsequently fed a high-energy (HE; 31% fat) diet for 10 days, DIO rats ate 70% more, gained more body and adipose depot weight, had higher leptin and insulin levels, and had 22% lower feed efficiency than DR rats fed HE diet. In DIO rats on HE diet, leptin levels increased significantly at 3 days followed by increased insulin levels at 7 days. These altered DIO leptin and ghrelin responses were associated with 10% lower leptin receptor mRNA expression in the arcuate (ARC), dorsomedial (DMN), and ventromedial hypothalamic nuclei and 13 and 15% lower ghrelin receptor (GHS-R) mRNA expression in the ARC and DMN than in the DR rats. These data suggest that increased ghrelin signaling is not a proximate cause of DIO, whereas reduced leptin sensitivity might play a causal role.
No effect of creatine supplementation on human myofibrillar and sarcoplasmic protein synthesis after resistance exercise
Authors: Louis Magali , Poortmans Jacques R. , Francaux Marc , Berré Jacques , Boisseau Nathalie , Brassine Eric , Cuthbertson Daniel J. R. , Smith Kenneth , Babraj John A. , Waddell Tom , Rennie Michael J.
Published: March 2015

Muscle hypertrophy during resistance training is reportedly increased by creatine supplementation. Having previously failed to find an anabolic effect on muscle protein turnover at rest, either fed or fasted, we have now examined the possibility of a stimulatory effect of creatine in conjunction with acute resistance exercise. Seven healthy men (body mass index, 23 ± 2 kg/m2, 21 ± 1 yr, means ± SE) performed 20 × 10 repetitions of leg extension-flexion at 75% one-repetition maximum in one leg, on two occasions, 4 wk apart, before and after ingesting 21 g/day creatine for 5 days. The subjects ate ∼21 g maltodextrin + 6 g protein/h for 3 h postexercise. We measured incorporation of [1-13C]leucine into quadriceps muscle proteins in the rested and exercised legs. Leg protein breakdown (as dilution of [2H5]phenylalanine) was also assessed in the exercised and rested leg postexercise. Creatine supplementation increased muscle total creatine by ∼21% ( P < 0.01). Exercise increased the synthetic rates of myofibrillar and sarcoplasmic proteins by two- to threefold ( P < 0.05), and leg phenylalanine balance became more positive, but creatine was without any anabolic effect.
Acute alcohol administration inhibits the refeeding response after starvation in rat skeletal muscle
Authors: Sneddon A. A. , Koll M. , Wallace M. C. , Jones J. , Miell J. P. , Garlick P. J. , Preedy V. R.
Published: March 2015

This study determined whether an acute alcohol dose could inhibit the refeeding response in starved muscle. Rats starved for 24 h were pretreated with alcohol or saline before refeeding by intragastric or intravenous infusion of enteral diet (ENT), total parenteral nutrition (TPN), or saline. Refeeding by TPN or ENT stimulated increases in the fractional rate of protein synthesis ( k s) in skeletal muscle. Alcohol prevented the increase in k s when refeeding occurred intragastrically (TPN or ENT) ( P < 0.001) but not intravenously (TPN). Upon intragastric refeeding, alcohol inhibited the increase in both eukaryotic initiation factor 4E-binding protein-1 (4E-BP1) and p70 S6 kinase (p70S6K) phosphorylation in plantaris but caused only partial inhibition in soleus muscle (ENT only). When rats were refed intravenously, alcohol had no effect on the increased 4E-BP1 or p70S6Kphosphorylation in either muscle. Plasma insulin levels were augmented by alcohol. Alcohol-related changes in plasma amino acid concentrations were similar irrespective of the route of feeding, whereas IGF-I levels showed differential changes. This is the first study to demonstrate that acute alcohol ingestion impedes the starved-to-fed response in skeletal muscle.
Regional uptake of meal fatty acids in humans
Authors: Jensen Michael D. , Sarr Michael G. , Dumesic Daniel A. , Southorn Peter A. , Levine James A.
Published: March 2015

Two protocols were performed to study meal fatty acid metabolism. In protocol 1, 14 patients scheduled for elective intra-abdominal surgery (11 undergoing bariatric surgery for severe obesity) consumed a meal containing [3H]triolein in the evening before surgery. This allowed us to measure adipose tissue lipid specific activity (SA) in mesenteric and omental, deep and superficial abdominal subcutaneous adipose tissue. Intra-abdominal adipose tissue lipid SA was greater than subcutaneous lipid SA. There were no significant differences between mesenteric and omental or between deep and superficial abdominal subcutaneous adipose tissue. In protocol 2, meal fatty acid oxidation and uptake into subcutaneous and omental adipose tissue ([3H]triolein) were measured in six normal, healthy volunteers. Meal fatty acid oxidation (3H2O generation) plus that remaining in plasma (∼1%) plus uptake into upper body subcutaneous, lower body subcutaneous, and visceral fat allowed us to account for 98 ± 6% of meal fatty acids 24 h after meal ingestion. We conclude that omental fat is a good surrogate for visceral fat and that abdominal subcutaneous fat depots are comparable with regard to meal fatty acid metabolic studies. Using [3H]triolein, we were able to account for virtually 100% of meal fatty acids 24 h after meal ingestion. These results support the meal fatty acid tracer model as a way to study the metabolic fate of dietary fat.
Brief calorie restriction increases Akt2 phosphorylation in insulin-stimulated rat skeletal muscle
Authors: McCurdy Carrie E. , Davidson Robert T. , Cartee Gregory D.
Published: March 2015

Skeletal muscle insulin sensitivity improves with short-term reduction in calorie intake. The goal of this study was to evaluate changes in the abundance and phosphorylation of Akt1 and Akt2 as potential mechanisms for enhanced insulin action after 20 days of moderate calorie restriction [CR; 60% of ad libitum (AL) intake] in rat skeletal muscle. We also assessed changes in the abundance of SH2 domain-containing inositol phosphatase (SHIP2), a negative regulator of insulin signaling. Fisher 344 × Brown Norway rats were assigned to an AL control group or a CR treatment group for 20 days. Epitrochlearis muscles were dissected and incubated with or without insulin (500 μU/ml). Total Akt serine and threonine phosphorylation was significantly increased by 32 ( P < 0.01) and 30% ( P < 0.005) in insulin-stimulated muscles from CR vs. AL. Despite an increase in total Akt phosphorylation, there was no difference in Akt1 serine or Akt1 threonine phosphorylation between CR and AL insulin-treated muscles. However, there was a 30% decrease ( P < 0.05) in Akt1 abundance for CR vs. AL. In contrast, there was no change in Akt2 protein abundance, and there was a 94% increase ( P < 0.05) in Akt2 serine phosphorylation and an increase of 75% ( P < 0.05) in Akt2 threonine phosphorylation of insulin-stimulated CR muscles compared with AL. There was no diet effect on SHIP2 abundance in skeletal muscle. These results suggest that, with brief CR, enhanced Akt2 phosphorylation may play a role in increasing insulin sensitivity in rat skeletal muscles.
Nutrient-sensing mTOR-mediated pathway regulates leptin production in isolated rat adipocytes
Authors: Roh Cecilia , Han Jianrong , Tzatsos Alexandros , Kandror Konstantin V.
Published: March 2015

Leptin biosynthesis in adipose cells in vivo is increased by food intake and decreased by food deprivation. However, the mechanism that couples leptin production to food intake remains unknown. We found that addition of leucine to isolated rat adipocytes significantly increased leptin production by these cells, suggesting that postprandial leptin levels may be directly regulated by dietary leucine. The effect of leucine was inhibited by rapamycin and not by actinomycin D. Besides, leucine administration did not increase the amount of leptin mRNA in adipocytes. Therefore, we concluded that leucine activates leptin expression in adipose cells at the level of translation via a mammalian target of rapamycin (mTOR)-mediated pathway. Because leptin is a secreted protein, its biosynthesis is compartmentalized on the endoplasmic reticulum. To analyze mTOR signaling in this subcellular fraction, we separated adipose cells by centrifugation into a heavy membrane fraction that includes virtually all endoplasmic reticulum and the cytosolic extract. Phosphorylation of the major mTOR targets, the ribosomal protein S6 and the translational inhibitor 4E-binding protein (BP)/phosphorylated heat- and acid-stable protein (PHAS)-1, was stimulated by leucine in the cytosolic extract, whereas, in the heavy fraction, S6 was constitutively phosphorylated and leucine only induced phosphorylation of 4E-BP/PHAS-1. We also found that 60–70% of leptin mRNA was stably associated with the heavy fraction, and leucine administration did not change the ratio between compartmentalized and free cytoplasmic leptin mRNA. We suggest that, in adipose cells, a predominant part of leptin mRNA is compartmentalized on the endoplasmic reticulum, and leucine activates translation of these messages via the mTOR/4E-BP/PHAS-1-mediated signaling pathway.