bluuebunny/crossref_metadata_2025 huggingface dataset:
Keynote
Authors: Varghese George
Published: March 2015

The most compelling ideas in systems are abstractions such as virtual memory, sockets, or packet scheduling. Algorithmics is the servant of abstraction, allowing system performance to approach that of the underlying hardware, sometimes by using efficient algorithms but often by simply leveraging other aspects of the system. I will survey the trajectory of network algorithmics starting with a focus on speed and scale in the 1990s to measurement and security in the 2000s. While doing so, I will reflect on my experiences in choosing problems and conducting research. I will conclude by describing my passion for the emerging field of network verification and its confluence with programming language research.

George Varghese worked at DEC designing DECNET protocols before obtaining his Ph.D. in 1992 from MIT. He worked from 1993-1999 at Washington University and from 1999 to 2012 at UCSD, both as professor of computer science. He joined Microsoft Research as a Principal Researcher in 2012. He won the ONR Young Investigator Award in 1996, and was elected to be a Fellow of the Association for Computing Machinery (ACM) in 2002. He helped design the 40 Gbps forwarding engine for Procket Networks, subsequently acquired by Cisco Systems. His book "Network Algorithmics" was published in December 2004 by Morgan-Kaufman. He co-founded NetSift Inc. in May 2004. NetSift was acquired by Cisco in 2005. He was the 2014 winner of the IEEE Koji Kobayashi Computers and Communications Award
AI3
Authors: Zhang Bo , Wang Jinfan , Wang Xinyu , Cheng Yingying , Jia Xiaohua , He Jianfei
Published: March 2015

In the current Internet architecture, application service providers (ASPs) own users' data and social groups information, which made a handful of ASP companies growing bigger and bigger and denied small and medium companies from entering this business. We propose a new architecture, called Application Independent Information Infrastructure (AI3). The design goals of AI3 are: 1) Decoupling users' data from ASPs and users' social relations from ASPs, such that ASPs become independent from users' data and social relations. 2) Open architecture, such that different ASPs can interoperate with each other. This demo is to show a prototype of AI3. The demo has four parts: 1) ASPindependent data management in AI3; 2) ASP-independent management of users' social relations in AI3; 3) inter-domain data transport and user roaming; 4) real-time communications by using AI3. The demo video can be watched at: http://www.cs.cityu.edu.hk/~jia/AI3_DemoVideo.mp4
YouSlow
Authors: Nam Hyunwoo , Kim Kyung-Hwa , Calin Doru , Schulzrinne Henning
Published: March 2015

Adaptive bitrate (ABR) technologies are being widely used in today's popular HTTP-based video streaming such as YouTube and Netflix. Such a rate-switching algorithm embedded in a video player is designed to improve video quality-of-experience (QoE) by selecting an appropriate resolution based on the analysis of network conditions while the video is playing. However, a bad viewing experience is often caused by the video player having difficulty estimating transit or client-side network conditions accurately. In order to analyze the ABR streaming performance, we developed YouSlow, a web browser plug-in that can detect and report live buffer stalling events to our analysis tool. Currently, YouSlow has collected more than 20,000 of YouTube video stalling events over 40 countries.
Extending the software-defined network boundary
Authors: Michel Oliver , Coughlin Michael , Keller Eric
Published: March 2015

Given that Software-Defined Networking is highly successful in solving many of today's manageability, flexibility, and scalability issues in large-scale networks, in this paper we argue that the concept of SDN can be extended even further. Many applications (esp. stream processing and big-data applications) rely on graph-based inter-process communication patterns that are very similar to those in computer networks. To our mind, this network abstraction spanning over different types of entities is highly suitable for and would benefit from central (SDN-inspired) control for the same reasons classical networks do. In this work, we investigate the commonalities between such intra-host networks and classical computer networking. Based on this, we study the feasibility of a central network controller that manages both network traffic and intra-host communication over a custom bus system.
ESCAPE
Authors: Csoma Attila , Sonkoly Balázs , Csikor Levente , Németh Felicián , Gulyas Andràs , Tavernier Wouter , Sahhaf Sahel
Published: March 2015

Mininet is a great prototyping tool which combines existing SDN-related software components (e.g., Open vSwitch, OpenFlow controllers, network namespaces, cgroups) into a framework, which can automatically set up and configure customized OpenFlow testbeds scaling up to hundreds of nodes. Standing on the shoulders of Mininet, we implement a similar prototyping system called ESCAPE, which can be used to develop and test various components of the service chaining architecture. Our framework incorporates Click for implementing Virtual Network Functions (VNF), NETCONF for managing Click-based VNFs and POX for taking care of traffic steering. We also add our extensible Orchestrator module, which can accommodate mapping algorithms from abstract service descriptions to deployed and running service chains.
NetAssay
Authors: Donovan Sean , Feamster Nick
Published: March 2015

Home and business network operators have limited network statistics available over which management decisions can be made. Similarly, there are few triggered behaviors, such as usage or bandwidths cap for individual users, that are available. By looking at sources of traffic, based on Domain Name System (DNS) cues for content of particular web addresses or source Autonomous System (AS) of the traffic, network operators could create new and interesting rules for their network. NetAssay is a Software-Defined Networking (SDN)-based, network-wide monitoring and reaction framework. By integrating information from Border Gateway Protocol (BGP) and the Domain Name System, NetAssay is able to integrate formerly disparate sources of control information, and use it to provide better monitoring, more useful triggered events, and security benefits for network operators.
Sampling online social networks
Authors: Gabielkov Maksym , Rao Ashwin , Legout Arnaud
Published: March 2015

Online social networks (OSNs) are an important source of information for scientists in different fields such as computer science, sociology, economics, etc. However, it is hard to study OSNs as they are very large. For instance, Facebook has 1.28 billion active users in March 2014 and Twitter claims 255 million active users in April 2014. Also, companies take measures to prevent crawls of their OSNs and refrain from sharing their data with the research community. For these reasons, we argue that sampling techniques will be the best technique to study OSNs in the future. In this work, we take an experimental approach to study the characteristics of well-known sampling techniques on a full social graph of Twitter crawled in 2012 [2]. Our contribution is to evaluate the behavior of these techniques on a real directed graph by considering two sampling scenarios: (a) obtaining most popular users (b) obtaining an unbiased sample of users, and to find the most suitable sampling techniques for each scenario.
Vivisecting whatsapp through large-scale measurements in mobile networks
Authors: Fiadino Pierdomenico , Schiavone Mirko , Casas Pedro
Published: March 2015

WhatsApp, the new giant in instant multimedia messaging in mobile networks is rapidly increasing its popularity, taking over the traditional SMS/MMS messaging. In this paper we present the first large-scale characterization of WhatsApp, useful among others to ISPs willing to understand the impacts of this and similar applications on their networks. Through the combined analysis of passive measurements at the core of a national mobile network, worldwide geo-distributed active measurements, and traffic analysis at end devices, we show that: (i) the WhatsApp hosting architecture is highly centralized and exclusively located in the US; (ii) video sharing covers almost 40% of the total WhatsApp traffic volume; (iii) flow characteristics depend on the OS of the end device; (iv) despite the big latencies to US servers, download throughputs are as high as 1.5 Mbps; (v) users react immediately and negatively to service outages through social networks feedbacks.
VIRL
Authors: Obstfeld Joel , Knight Simon , Kern Ed , Wang Qiang Sheng , Bryan Tom , Bourque Dan
Published: March 2015

The increasing demand to provide new network services in a timely and efficient manner is driving the need to design, test and deploy networks quickly and consistently. Testing and verifying at scale is a challenge: network equipment is expensive, requires space, power and cooling, and there is never enough test equipment for everyone who wants to use it! Network virtualization technologies enable a flexible environment for educators, researchers, and operators to create functional models of current, planned, or theoretical networks. This demonstration will show VIRL --- the Virtual Internet Routing Lab --- a platform that can be used for network change validation, training, education, research, or network-aware applications development. The platform combines network virtualization technologies with virtual machines (VMs) running open-source and commercial operating systems; VM orchestration capabilities; a context-aware configuration engine; and an extensible data-collection framework. The system simplifies the process to create both simple and complex environments, run simulations, and collect measurement data.
Native actors
Authors: Vallentin Matthias , Charousset Dominik , Schmidt Thomas C. , Paxson Vern , Wählisch Matthias
Published: March 2015

When an organization detects a security breach, it undertakes a forensic analysis to figure out what happened. This investigation involves inspecting a wide range of heterogeneous data sources spanning over a long period of time. The iterative nature of the analysis procedure requires an interactive experience with the data. However, the distributed processing paradigms we find in practice today fail to provide this requirement: the batch-oriented nature of MapReduce cannot deliver sub-second round-trip times, and distributed in-memory processing cannot store the terabytes of activity logs needed to inspect during an incident.

We present the design and implementation of Visibility Across Space and Time (VAST), a distributed database to support interactive network forensics, and libcppa, its exceptionally scalable messaging core. The extended actor framework libcppa enables VAST to distribute lightweight tasks at negligible overhead. In our live demo, we showcase how VAST enables security analysts to grapple with the huge amounts of data often associated with incident investigations.
FGF23, PHEX, and MEPE regulation of phosphate homeostasis and skeletal mineralization
Authors: Quarles L. Darryl
Published: March 2015

There is evidence for a hormone/enzyme/extracellular matrix protein cascade involving fibroblastic growth factor 23 (FGF23), a phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX), and a matrix extracellular phosphoglycoprotein (MEPE) that regulates systemic phosphate homeostasis and mineralization. Genetic studies of autosomal dominant hypophosphatemic rickets (ADHR) and X-linked hypophosphatemia (XLH) identified the phosphaturic hormone FGF23 and the membrane metalloprotease PHEX, and investigations of tumor-induced osteomalacia (TIO) discovered the extracellular matrix protein MEPE. Similarities between ADHR, XLH, and TIO suggest a model to explain the common pathogenesis of renal phosphate wasting and defective mineralization in these disorders. In this model, increments in FGF23 and MEPE, respectively, cause renal phosphate wasting and intrinsic mineralization abnormalities. FGF23 elevations in ADHR are due to mutations of FGF23 that block its degradation, in XLH from indirect actions of inactivating mutations of PHEX to modify the expression and/or degradation of FGF23 and MEPE, and in TIO because of increased production of FGF23 and MEPE. Although this model is attractive, several aspects need to be validated. First, the enzymes responsible for metabolizing FGF23 and MEPE need to be established. Second, the physiologically relevant PHEX substrates and the mechanisms whereby PHEX controls FGF23 and MEPE metabolism need to be elucidated. Finally, additional studies are required to establish the molecular mechanisms of FGF23 and MEPE actions on kidney and bone, as well as to confirm the role of these and other potential “phosphatonins,” such as frizzled related protein-4, in the pathogenesis of the renal and skeletal phenotypes in XLH and TIO. Unraveling the components of this hormone/enzyme/extracellular matrix pathway will not only lead to a better understanding of phosphate homeostasis and mineralization but may also improve the diagnosis and treatment of hypo- and hyperphosphatemic disorders.
In vivo stimulation of sympathetic nervous system modulates osteoblastic activity in mouse calvaria
Authors: Kondo Ayami , Togari Akifumi
Published: March 2015

Previously, we demonstrated that epinephrine induced the expression of interleukin (IL)-6 mRNA via β-adrenoceptors in cultured human osteoblastic cells. IL-6 is well known to modulate bone metabolism by regulating the development and function of osteoclasts and osteoblasts. Recently, restraint stress and intracerebroventricular injection of lipopolysaccharide (LPS) have been reported to induce the expression of IL-6 mRNA in peripheral organs in mice in which expression is mediated by the activation of the sympathetic nervous system. To prove the physiological role of sympathetic nerves in bone metabolism in vivo, we examined by RT-PCR analysis the effects of restraint stress and intracerebroventricular injection of LPS on IL-6 mRNA expression in mouse calvaria. The expression of IL-6 mRNA in mouse calvaria was stimulated by either restraint stress (30 min) or intracerebroventricular injection of LPS (50 ng/mouse, 60 min). The treatment of mice with the neurotoxin 6-hydroxydopamine (6-OHDA, 100 mg · kg-1 · day-1 ip for 3 days) inhibited LPS (icv)-induced expression of IL-6 mRNA in their calvaria. The expression of IL-6 mRNA induced by the restraint stress was not influenced by 6-OHDA, which destroys noradrenergic nerve terminals. Furthermore, pretreatment with a β-blocker, propranolol (15 or 25 mg/kg ip), inhibited both stress- and LPS-induced increases in the level of IL-6 mRNA, but pretreatment with an α-blocker, phentolamine (5 mg/kg sc), did not inhibit them in mouse calvaria. In addition, treatment of calvaria with isoprenaline or norepinephrine increased IL-6 synthesis in the organ culture system. These results indicate that in vivo adrenergic stimulation modulates the osteoblastic activity in mouse calvaria via noradrenergic nerve terminals.
Molecular and functional resistance to insulin in hypothalamus of rats exposed to cold
Authors: Torsoni Márcio A. , Carvalheira José B. , Pereira-Da-Silva Márcio , de Carvalho-Filho Marco A. , Saad Mário J. A. , Velloso Lício A.
Published: March 2015

Insulin and leptin act in the hypothalamus, providing robust anorexigenic signals. The exposure of homeothermic animals to a cold environment leads to increased feeding, accompanied by sustained low levels of insulin and leptin. In the present study, the initial and intermediate steps of the insulin-signaling cascade were evaluated in the hypothalamus of cold-exposed Wistar rats. By immunohistochemistry, most insulin receptor (IR) and insulin receptor substrate-2 (IRS-2) immunoreactivity localized to the arcuate nucleus. Basal levels of tyrosine phosphorylation of IR and IRS-2 were increased in cold-exposed rats compared with rats maintained at room temperature. However, after an acute, peripheral infusion of exogenous insulin, significantly lower increases of IR and IRS-2 tyrosine phosphorylation were detected in the hypothalamus of cold-exposed rats. Insulin-induced association of p85/phosphatidylinositol 3-kinase with IRS-2, Ser473 phosphorylation of Akt, and tyrosine phosphorylation of ERK was significantly reduced in the hypothalamus of cold-exposed rats. To test the hypothesis of functional impairment of insulin signaling in the hypothalamus, intracerebroventricularly cannulated rats were acutely treated with insulin, and food ingestion was measured over a period of 12 h. Cold-exposed animals presented a significantly lower insulin-induced reduction in food consumption compared with animals maintained at room temperature. Hence, the present studies reveal that animals exposed to cold are resistant, both at the molecular and the functional level, to the actions of insulin in the hypothalamus.
Effects of hyper- and hypothyroidism on thyroid hormone concentrations in regions of the rat brain
Authors: Broedel Oliver , Eravci Murat , Fuxius Sandra , Smolarz Tina , Jeitner Andreas , Grau Hannah , Stoltenburg-Didinger Gisela , Plueckhan Hanna , Meinhold Harald , Baumgartner Andreas
Published: March 2015

The purpose of this study was to investigate the effects of hyper- and hypothyroidism on thyroid hormone concentrations and deiodinase activities in nine regions of the rat brain. Four weeks of treatment with 75 μg thyroxine (T4)/kg body wt induced a two- to threefold increase in T4levels in all of these brain regions, whereas the 3,5,3′-triiodothyronine (T3) concentrations were reduced in five brain regions and remained unchanged in four. Even after 8 wk treatment with 300 μg T4/kg, the T3concentrations remained normal in cortical areas, the hippocampus and amygdala, and were elevated only in areas in which inner-ring deiodinase activity was low or absent, and in the hypothalamus. At the subcellular level, nuclear concentrations of T3were diminished in hypothyroidism but remained unaltered in hyperthyroidism in all areas except the hypothalamus, where they were enhanced. Cortical mitochondrial succinate dehydrogenase activity was reduced in both hypo- and hyperthyroidism in spite of normal T3concentrations in hyperthyroid animals. The results show that nuclear T3concentrations fall in hypothyroidism but do not change during severe hyperthyroidism in any brain region except the hypothalamus. Further research is thus needed to clarify the mechanisms mediating the numerous biochemical and psychological effects of hyperthyroidism.
A null mutation in H-FABP only partially inhibits skeletal muscle fatty acid metabolism
Authors: Binas Bert , Han Xiao-Xia , Erol Erdal , Luiken Joost J. F. P. , Glatz Jan F. C. , Dyck David J. , Motazavi Rafat , Adihetty Peter J. , Hood David A. , Bonen Arend
Published: March 2015

The low-molecular-mass, cytosolic heart-type fatty acid-binding protein (H-FABP) is thought to be required for shuttling FA through the cytosol. Therefore, we examined the effects of an H-FABP-null mutation on FA and carbohydrate metabolism in isolated soleus muscle at rest and during a period of increased metabolic demand (30-min contraction). There were lower concentrations of creatine phosphate (-41%), ATP (-22%), glycogen (-34%), and lactate (-31%) ( P < 0.05) in H-FABP-null soleus muscles, but no differences in citrate synthase and β-3-hydroxyacyl-CoA dehydrogenase activities or in the intramuscular triacylglycerol (TAG) depots. There was a 43% increase in subsarcolemmal mitochondria in H-FABP-null solei. FA transport was reduced by 30% despite normal content of sarcolemmal long-chain fatty acid transporters fatty acid translocase/CD36 and plasma membrane-associated FABP transport proteins. Compared with wild-type soleus muscles, the H-FABP-null muscles at rest hydrolyzed less TAG (-22%), esterified less TAG (-49%), and oxidized less palmitate (-71%). The H-FABP-null soleus muscles retained a substantial capacity to increase FA metabolism during contraction (TAG esterification by +72%, CO2production by +120%), although these rates remained lower (TAG esterification -26% and CO2production -64%) than in contracting wild-type soleus muscles. Glycogen utilization during 30 min of contraction did not differ, whereas glucose oxidation was lower at rest (-24%) and during contraction (-32%) in H-FABP-null solei. Although these studies demonstrate that the absence of H-FABP alters rates of FA metabolism, it is also apparent that glucose oxidation is downregulated. The substantial increase in FA metabolism in contracting H-FABP-null muscle may indicate that other FABPs are also present, a possibility that we were not able to completely eliminate.
Tissue-specific regulation of protein synthesis by insulin and free fatty acids
Authors: Crozier Stephen J. , Anthony Joshua C. , Schworer Charles M. , Reiter Ali K. , Anthony Tracy G. , Kimball Scot R. , Jefferson Leonard S.
Published: March 2015

The purpose of the study described herein was to investigate how the mammalian target of rapamycin (mTOR)-signaling pathway and eukaryotic initiation factor 2B (eIF2B) activity, both having key roles in the translational control of protein synthesis in skeletal muscle, are regulated in cardiac muscle of rats in response to two different models of altered free fatty acid (FFA) and insulin availability. Protein synthetic rates were reduced in both gastrocnemius and heart of 3-day diabetic rats. The reduction was associated with diminished mTOR-mediated signaling and eIF2B activity in the gastrocnemius but only with diminished mTOR signaling in the heart. In response to the combination of acute hypoinsulinemia and hypolipidemia induced by administration of niacin, protein synthetic rates were also diminished in both gastrocnemius and heart. The niacin-induced changes were associated with diminished mTOR signaling and eIF2B activity in the heart but only with decreased mTOR signaling in the gastrocnemius. In the heart, mTOR signaling and eIF2B activity correlated with cellular energy status and/or redox potential. Thus FFAs may contribute to the translational control of protein synthesis in the heart but not in the gastrocnemius. In contrast, insulin, but not FFAs, is required for the maintenance of protein synthesis in the gastrocnemius.
Activation of the CRF 2 receptor modulates skeletal muscle mass under physiological and pathological conditions
Authors: Hinkle Richard T. , Donnelly Elizabeth , Cody David B. , Samuelsson Steven , Lange Jana S. , Bauer Mary Beth , Tarnopolsky Mark , Sheldon Russell J. , Coste Sarah C. , Tobar Eric , Stenzel-Poore Mary P. , Isfort Robert J.
Published: March 2015

Two receptors activated by the corticotropin-releasing factor (CRF) family of peptides have been identified, the CRF 1 receptor (CRF1R) and the CRF 2 receptor (CRF2R). Of these, the CRF2R is expressed in skeletal muscle. To understand the role of the CRF2R in skeletal muscle, we utilized CRFR knockout mice and CRF2R-selective agonists to modulate nerve damage and corticosteroid- and disuse-induced skeletal muscle atrophy in mice. These analyses demonstrated that activation of the CRF2R decreased nerve damage and corticosteroid- and disuse-induced skeletal muscle mass and function loss. In addition, selective activation of the CRF2R increased nonatrophy skeletal muscle mass. Thus we describe for the first time a novel activity of the CRF2R, modulation of skeletal muscle mass.
Basal and dynamic proinsulin-insulin relationship to assess β-cell function during OGTT in metabolic disorders
Authors: Tura Andrea , Pacini Giovanni , Kautzky-Willer Alexandra , Ludvik Bernhard , Prager Rudolf , Thomaseth Karl
Published: March 2015

The fasting proinsulin-to-insulin ratio is a currently used marker of β-cell dysfunction. This ratio is calculated at the basal condition, but its behavior in dynamic conditions, i.e., during glucose stimulation, could be more informative. Given the different kinetics of the peptides, a mathematical model was necessary to analyze the oral glucose tolerance test (OGTT) data of insulin, C-peptide, and proinsulin in 55 healthy (NGT), 30 impaired glucose-tolerant (IGT), and 31 type 2 diabetic (T2DM) subjects. The model provided for secretion and disappearance of the peptides and an index of β-cell function under dynamic conditions. Total proinsulin secretion during the OGTT was not different ( P > 0.053) among NGT (0.17 ± 0.01 mmol/l in 3 h), IGT (0.22 ± 0.02), and T2DM (0.21 ± 0.02) subjects. The proinsulin-to-insulin molar ratio measured from basal samples was higher ( P < 0.0001) in T2DM (0.39 ± 0.05) than in NGT (0.14 ± 0.01) and IGT (0.13 ± 0.02) subjects, and similar results ( P < 0.003) were found by the dynamic index (0.27 ± 0.04, 0.14 ± 0.01, 0.15 ± 0.01 in T2DM, NGT, IGT subjects, respectively). The basal ratio significantly correlated with the dynamic index, and the regression line slope was lower than 1 (0.43 ± 0.08, 0.61 ± 0.10, and 0.56 ± 0.03 in NGT, IGT, and T2DM subjects, respectively, P < 0.0001). Impaired β-cell function in T2DM could then be indicated by proinsulin-to-insulin indexes at both basal and dynamic phases.
Alterations in lipid kinetics in men with HIV-dyslipidemia
Authors: Reeds D. N. , Mittendorfer B. , Patterson B. W. , Powderly W. G. , Yarasheski K. E. , Klein S.
Published: March 2015

Hypertriglyceridemia is common in individuals with human immunodeficiency (HIV) infection, but the mechanisms responsible for increased plasma triglyceride (TG) concentrations are not clear. We evaluated fatty acid and VLDL-TG kinetics during basal conditions and during a glucose infusion that resulted in typical postprandial plasma glucose and insulin concentrations in six men with HIV-dyslipidemia [body mass index (BMI): 28 ± 2 kg/m2] and six healthy men (BMI: 26 ± 2 kg/m2). VLDL-TG secretion and palmitate rate of appearance (Ra) in plasma were measured by using stable-isotope-labeled tracer techniques. Basal palmitate Raand VLDL-TG secretion rates were greater ( P < 0.01 for both) in men with HIV-dyslipidemia (1.04 ± 0.07 μmol palmitate · kg-1· min-1and 5.7 ± 0.6 μmol VLDL-TG · l plasma-1· min-1) than in healthy men (0.67 ± 0.08 μmol palmitate · kg-1· min-1and 3.0 ± 0.5 μmol VLDL-TG · l plasma-1· min-1). Basal VLDL-TG plasma clearance was lower in men with HIV-dyslipidemia (13 ± 1 ml/min) than in healthy men (19 ± 2 ml/min; P < 0.05). Glucose infusion decreased palmitate Ra(by ∼50%) and the VLDL-TG secretion rate (by ∼30%) in both groups, but the VLDL-TG secretion rate remained higher ( P < 0.05) in subjects with HIV-dyslipidemia. These findings demonstrate that increased secretion of VLDL-TG and decreased plasma VLDL-TG clearance, during both fasting and fed conditions, contribute to hypertriglyceridemia in men with HIV-dyslipidemia. Although it is likely that increased free fatty acid release from adipose tissue contributes to the increase in basal VLDL-TG concentration, other factors must be involved, because insulin-induced suppression of lipolysis and systemic fatty acid availability did not normalize the VLDL-TG secretion rate.
TNF-α acutely inhibits vascular effects of physiological but not high insulin or contraction
Authors: Zhang Lei , Wheatley Catherine M. , Richards Stephen M. , Barrett Eugene J. , Clark Michael G. , Rattigan Stephen
Published: March 2015

TNF-α is elevated in many states of insulin resistance, and acutely administered TNF-α in vivo inhibits insulin-mediated hemodynamic effects and glucose uptake in muscle. In this study, we assess whether the inhibitory effects of TNF-α are affected by insulin dose or muscle contraction. Whole body glucose infusion rate (GIR), femoral blood flow (FBF), hindleg vascular resistance, hindleg glucose uptake (HGU), 2-deoxyglucose uptake into muscles of the lower leg (R′g) and hindleg metabolism of infused 1-methylxanthine (1-MX), a measure of capillary recruitment, were determined. Three groups were studied with and without infusion of TNF-α: euglycemic insulin-clamped, one-leg field-stimulated (2 Hz, 0.1 ms at 30 V), and saline-infused control anesthetized rats. Insulin infusions were 3, 10, or 30 mU · kg-1· min-1for 2 h. 1-MX metabolism was maximally increased by all three doses of insulin. GIR, HGU, and R′g were maximal at 10 mU and FBF was maximal at 30 mU of insulin. Contraction increased FBF, HGU, and 1-MX. TNF-α (0.5 μg · kg-1· h-1) totally blocked the 3 and 10 mU insulin-mediated increases in FBF and 1-MX, and partly blocked GIR, HGU, and R′g. None of the increases due to twitch contraction was affected by TNF-α, and only the increase in FBF due to 30 mU of insulin was partly affected. We conclude that muscle capillary recruitment and glucose uptake due to high levels of insulin or muscle contraction under twitch stimuli at 2 Hz are resistant to TNF-α. These findings may have implications for ameliorating muscle insulin resistance resulting from increased plasma TNF-α and for the differing mechanisms by which contraction and insulin recruit capillary flow in muscle.
Betacellulin improves glucose metabolism by promoting conversion of intraislet precursor cells to β-cells in streptozotocin-treated mice
Authors: Li Lei , Seno Masaharu , Yamada Hidenori , Kojima Itaru
Published: March 2015

Betacellulin (BTC) induces differentiation of pancreatic β-cells and promotes regeneration of β-cells in experimental diabetes. The present study was conducted to determine if BTC improved glucose metabolism in severe diabetes induced by a high dose of streptozotocin (STZ) in mice. Male ICR mice were injected with 200 μg/g ip STZ, and various doses of BTC were administered daily for 14 days. The plasma glucose concentration increased to a level of >500 mg/dl in STZ-injected mice. BTC (0.2 μg/g) significantly reduced the plasma glucose concentration, but a higher concentration was ineffective. The effect of BTC was marked by day 4 but became smaller on day 6 or later. The plasma insulin concentration and the insulin content were significantly higher in mice treated with 0.1 and 0.2 μg/g BTC. BTC treatment significantly increased the number of β-cells in each islet as well as the number of insulin-positive islets. Within islets, the numbers of 5-bromo-2-deoxyuridine/somatostatin-positive cells and pancreatic duodenal homeobox-1/somatostatin-positive cells were significantly increased by BTC. These results indicate that BTC improved hyperglycemia induced by a high dose of STZ by promoting neoformation of β-cells, mainly from somatostatin-positive islet cells.
Influence of diet on the modeling of adipose tissue triglycerides during growth
Authors: Brunengraber Daniel Z. , McCabe Brendan J. , Kasumov Takhar , Alexander James C. , Chandramouli Visvanathan , Previs Stephen F.
Published: March 2015

We have studied the accretion of lipids in growing mice. We measured the rates of synthesis and degradation of triglycerides in epididymal fat pads of mice maintained for 44 days on a low-fat, high-carbohydrate diet ( I) or a high-fat, lowcarbohydrate diet ( II).2H2O was added to the drinking water for 14 days. Rates of incorporation/washout of2H to/from C1 of triglyceride-glycerol showed that triglyceride synthesis was greater than triglyceride degradation (net triglyceride balance was ∼2.5 times greater in II than in I). The data also show that the contribution of de novo lipogenesis to triglyceride-bound palmitate was ∼3 times greater in I than in II. This was consistent with a greater relative intake of carbohydrate in I vs. II. The rates of incorporation and washout of newly synthesized (2H-labeled) palmitate into and from triglycerides were also measured. Those data suggested a remodeling of triglyceride-bound fatty acids. On measuring the profile of triglyceride-bound fatty acids, we observed a decrease in the relative abundance of triglyceride-bound palmitate and stearate and an increase in triglyceride-bound oleate and linoleate. This was observed in I and II. In summary, diet substantially affects the deposition and modeling of triglycerides in adipose tissue during growth.2H2O can be used to examine the mechanisms responsible for the accumulation of triglycerides, e.g., factors that affect 1) triglyceride synthesis and degradation and 2) the source of fatty acids that are used in esterification.
O-glycosylation of Sp1 and transcriptional regulation of the calmodulin gene by insulin and glucagon
Authors: Majumdar Gipsy , Harmon Ashley , Candelaria Rosalind , Martinez-Hernandez Antonio , Raghow Rajendra , Solomon Solomon S.
Published: March 2015

Both insulin and glucagon stimulate steady-state levels of Sp1 transcription factor, but only insulin stimulates transcription of the calmodulin (CaM) gene in liver. Because O-glycosylation of Sp1 by O-linked N-acetylglucosamine ( O-GlcNAc) is thought to regulate its ability to activate transcription, we assayed the levels of Sp1 with anti-Sp1 and anti- O-GlcNAc antibodies in Western blots by use of extracts of H-411E liver cells treated with insulin (10,000 μU/ml) or glucagon (1.5 × 10-5M). We also assessed subcellular localization of the native and glycosylated Sp1 in H411E cells treated with either hormone in the presence of deoxynorleucine (DON, an indirect inhibitor of O-glycosylation) or streptozotocin (STZ, an indirect stimulator of O-glycosylation). Insulin stimulated both total and O-GlcNAc-modified Sp1 primarily in the nucleus and induced CaM gene transcription ( P < 0.0001). In contrast, glucagon promoted accumulation of Sp1 in the cytoplasm but not the nucleus, without significantly stimulating ( P = not significant) either its O-glycosylation or transcription of the CaM gene. DON inhibited O-glycosylation of Sp1 and its ability to migrate to the nucleus and transactivate CaM gene transcription. In contrast, cotreatment of cells with STZ and glucagon enhanced O-glycosylation of Sp1, promoting its migration to the nucleus and resulting in increased CaM gene transcription. Thus O-glycosylation of Sp1 by insulin, but not glucagon, apparently enhances its (Sp1) nuclear recruitment and results in activation of CaM gene transcription.
Relative importance of liver, kidney, and substrates in epinephrine-induced increased gluconeogenesis in humans
Authors: Meyer Christian , Stumvoll Michael , Welle Stephen , Woerle Hans J. , Haymond Morey , Gerich John
Published: March 2015

Splanchnic and renal net balance measurements indicate that lactate and glycerol may be important precursors for epinephrine-stimulated gluconeogenesis (GNG) in liver and kidney, but the effects of epinephrine on their renal and hepatic conversion to glucose in humans have not yet been reported. We therefore used a combination of renal balance and isotopic techniques in nine postabsorptive volunteers to measure systemic and renal GNG from these precursors before and during a 3-h infusion of epinephrine (270 pmol · kg–1· min–1) and calculated hepatic GNG as the difference between systemic and renal rates. During infusion of epinephrine, renal and hepatic GNG from lactate increased 4- to 6-fold and accounted for ∼85 and 70% of renal and hepatic glucose release, respectively, at the end of study; renal and hepatic GNG from glycerol increased ∼1.5- to 2-fold and accounted for ∼7–9% of renal and hepatic glucose release at the end of study. The increased renal GNG from lactate and glycerol was due not only to their increased renal uptake (∼3.3- and 1.4-fold, respectively) but also increased renal gluconeogenic efficiency (∼1.8- and 1.5-fold). The increased renal uptake of lactate and glycerol was wholly due to their increased arterial concentrations, since their renal fractional extraction remained unchanged and renal blood flow decreased. We conclude that 1) lactate is the predominant precursor for epinephrine-stimulated GNG in both liver and kidney, 2) hepatic and renal GNG from lactate and glycerol are similarly sensitive to stimulation by epinephrine, and 3) epinephrine increases renal GNG from lactate and glycerol by increasing substrate availability and the gluconeogenic efficiency of the kidney.
Magnitude and variation of fat-free mass density: a cellular-level body composition modeling study
Authors: Wang Zimian , Heshka Stanley , Wang Jack , Wielopolski Lucian , Heymsfield Steven B.
Published: March 2015

The mean density of fat-free mass (FFM) is remarkably stable at 1.10 g/cm3in healthy adult humans, and this stability is a cornerstone of the widely applied densitometry-based two-compartment model for estimating total body fat. At present, the usual means of exploring FFM density is by in vitro or in vivo experimental studies. The purpose of the present investigation was to develop a cellular-level body composition model that includes seven factors that determine FFM density. The model, when applied with available empirical coefficients, predicted an FFM density similar to that observed in vivo. An analysis of the seven model components indicates that the ratio of extracellular solids to total body water is a major determinant of individual variation in FFM density. The difference in FFM density across sex, race, and age groups was examined with the developed model. The present study thus provides a conceptual framework for the systematic study of FFM density in humans.
Aerobic training improves exercise-induced lipolysis in SCAT and lipid utilization in overweight men
Authors: de Glisezinski I. , Moro C. , Pillard F. , Marion-Latard F. , Harant I. , Meste M. , Berlan M. , Crampes F. , Rivière D.
Published: March 2015

The aim of this study was to investigate whether endurance training improves lipid mobilization and oxidation in overweight subjects. Eleven young men (25.6 ± 1.4 yr and body mass index 27.7 ± 0.2) performed a 4-mo training program consisting of practicing aerobic exercise 5 days/wk. Before and after the training period, lipid oxidation was explored during a 60-min exercise at 50% of peak O2consumption by use of indirect calorimetry. Lipid mobilization and antilipolytic α2-adrenoceptor effect were also studied using the microdialysis method in abdominal subcutaneous adipose tissue (SCAT). After training, plasma nonesterified fatty acid (NEFA) levels, at rest and during exercise, were significantly lower than before ( P < 0.001). Lipolysis in SCAT was significantly higher after than before training. An antilipolytic α2-adrenoceptor effect in SCAT was underlined during exercise before training and disappeared after. The respiratory exchange ratio was lower after training, i.e., the percentage of lipid oxidation was higher only at rest. The amount of lipid oxidized was higher after training, at rest, and during exercise. Although exercise power was higher after training, the relative intensity was equivalent, as suggested by a similar increase in plasma catecholamine concentrations before and after training. In conclusion, 4-mo training in overweight men improved lipid mobilization through a decrease of antilipolytic α2-adrenoceptor effect in SCAT and lipid oxidation during moderate exercise. Training induced a decrease of blood NEFA, predicting better prevention of obesity.
MCT1 and its accessory protein CD147 are differentially regulated by TSH in rat thyroid cells
Authors: Fanelli Albertina , Grollman Evelyn F. , Wang Dian , Philp Nancy J.
Published: March 2015

In thyroid cells, basal and TSH-stimulated glycolysis is associated with lactic acid efflux. In this report, we address whether monocarboxylate transporters (MCTs) are present in thyroid tissue for exporting excess lactic acid generated by aerobic glycolysis. Using immunostaining techniques, we show that MCT4 localizes with its accessory protein CD147 in the basolateral membrane of rat thyroid follicular cells. In cultured rat thyroid (FRTL-5) cells, MCT1 rather than MCT4 is expressed. CD147 colocalizes and coimmunoprecipitates with MCT1. TSH upregulates MCT1/CD147 expression as a function of time through a cAMP-dependent mechanism as forskolin reproduces the effect of TSH. TSH enhances protein expression of both MCT1 and CD147 in FRTL-5 cells. Whereas MCT1 protein expression is controlled at the level of transcription, CD147 protein expression is regulated by a posttranscriptional mechanism. Results of these studies suggest that hormone stimulation of lactate transport is mediated by regulating MCT1 transcription.
Effect of treatment of diabetic rats with dehydroepiandrosterone on vascular and neural function
Authors: Yorek Mark A. , Coppey Lawrence J. , Gellett Jill S. , Davidson Eric P. , Bing Xinyu , Lund Donald D. , Dillon Joseph S.
Published: March 2015

Nutritional supplementation with dehydroepiandrosterone (DHEA) may be a candidate for treating diabetes-induced vascular and neural dysfunction. DHEA is a naturally occurring adrenal androgen that has antioxidant properties and is reportedly reduced in diabetes. Using a prevention protocol, we found that dietary supplementation of streptozotocin-induced diabetic rats with 0.1, 0.25, or 0.5% DHEA caused a concentration-dependent prevention in the development of motor nerve conduction velocity and endoneurial blood flow impairment, which are decreased in diabetes. At 0.25%, DHEA significantly prevented the diabetes-induced increase in serum thiobarbituric acid-reactive substances and sciatic nerve conjugated diene levels. This treatment also reduced the production of superoxide by epineurial arterioles of the sciatic nerve. DHEA treatment (0.25%) significantly improved vascular relaxation mediated by acetylcholine in epineurial vessels of diabetic rats. Sciatic nerve Na+-K+-ATPase activity and myoinositol content was also improved by DHEA treatment, whereas sorbitol and fructose content remained elevated. These studies suggest that DHEA, by preventing oxidative stress and perhaps improving sciatic nerve Na+-K+-ATPase activity, may improve vascular and neural dysfunction in diabetes.
Effect of β1- and β2-adrenergic stimulation on energy expenditure, substrate oxidation, and UCP3 expression in humans
Authors: Hoeks Joris , van Baak Marleen A. , Hesselink Matthijs K. C. , Hul Gabby B. , Vidal Hubert , Saris Wim H. M. , Schrauwen Patrick
Published: March 2015

In humans, β-adrenergic stimulation increases energy and fat metabolism. In the case of β1-adrenergic stimulation, it is fueled by an increased lipolysis. We examined the effect of β2-adrenergic stimulation, with and without a blocker of lipolysis, on thermogenesis and substrate oxidation. Furthermore, the effect of β1-and β2-adrenergic stimulation on uncoupling protein 3 (UCP3) mRNA expression was studied. Nine lean males received a 3-h infusion of dobutamine (DOB, β1) or salbutamol (SAL, β2). Also, we combined SAL with acipimox to block lipolysis (SAL+ACI). Energy and substrate metabolism were measured continuously, blood was sampled every 30 min, and muscle biopsies were taken before and after infusion. Energy expenditure significantly increased ∼13% in all conditions. Fat oxidation increased 47 ± 7% in the DOB group and 19 ± 7% in the SAL group but remained unchanged in the SAL+ACI condition. Glucose oxidation decreased 40 ± 9% upon DOB, remained unchanged during SAL, and increased 27 ± 11% upon SAL+ACI. Plasma free fatty acid (FFA) levels were increased by SAL (57 ± 11%) and DOB (47 ± 16%), whereas SAL+ACI caused about fourfold lower FFA levels compared with basal levels. No change in UCP3 was found after DOB or SAL, whereas SAL+ACI downregulated skeletal muscle UCP3 mRNA levels 38 ± 13%. In conclusion, β2-adrenergic stimulation directly increased energy expenditure independently of plasma FFA levels. Furthermore, this is the first study to demonstrate a downregulation of skeletal muscle UCP3 mRNA expression after the lowering of plasma FFA concentrations in humans, despite an increase in energy expenditure upon β2-adrenergic stimulation.
Alcohol impairs leucine-mediated phosphorylation of 4E-BP1, S6K1, eIF4G, and mTOR in skeletal muscle
Authors: Lang Charles H. , Frost Robert A. , Deshpande Nobuko , Kumar Vinayshree , Vary Thomas C. , Jefferson Leonard S. , Kimball Scot R.
Published: March 2015

Acute alcohol (EtOH) intoxication impairs skeletal muscle protein synthesis. Although this impairment is not associated with a decrease in the total plasma amino acid concentration, EtOH may blunt the anabolic response to amino acids. To examine this hypothesis, rats were administered EtOH or saline (Sal) and 2.5 h thereafter were orally administered either leucine (Leu) or Sal. The gastrocnemius was removed 20 min later to assess protein synthesis and signaling components important in translational control of protein synthesis. Oral Leu increased muscle protein synthesis by the same magnitude in Sal- and EtOH-treated rats. However, the increase in the latter group was insufficient to overcome the suppressive effect of EtOH, and the rate of synthesis remained lower than that observed in rats from the Sal-Sal group. Leu markedly increased phosphorylation of Thr residues 36, 47, and 70 on 4E-binding protein (BP)1 in muscle from rats not receiving EtOH, and this response was associated with a redistribution of eukaryotic initiation factor (eIF) 4E from the inactive eIF4E · 4E-BP1 to the active eIF4E · eIF4G complex. In EtOH-treated rats, the Leu-induced phosphorylation of 4E-BP1 and changes in eIF4E availability were partially abrogated. EtOH also prevented the Leu-induced increase in phosphorylation of eIF4G, the serine/threonine protein kinase S6K1, and the ribosomal protein S6. Moreover, EtOH attenuated the Leu-induced phosphorylation of the mammalian target of rapamycin (mTOR). The ability of EtOH to blunt the anabolic effects of Leu could not be attributed to differences in the plasma concentrations of insulin, insulin-like growth factor I, or Leu. Finally, although EtOH increased the plasma corticosterone concentration, inhibition of glucocorticoid action by RU-486 was unable to prevent EtOH-induced defects in the ability of Leu to stimulate 4E-BP1, S6K1, and mTOR phosphorylation. Hence, ethanol produces a leucine resistance in skeletal muscle, as evidenced by the impaired phosphorylation of 4E-BP1, eIF4G, S6K1, and mTOR, that is independent of elevations in endogenous glucocorticoids.
Expression of FAS within hypothalamic neurons: a model for decreased food intake after C75 treatment
Authors: Kim Eun-Kyoung , Miller Ian , Landree Leslie E. , Borisy-Rudin Felice F. , Brown Pierre , Tihan Tarik , Townsend Craig A. , Witters Lee A. , Moran Timothy H. , Kuhajda Francis P. , Ronnett Gabriele V.
Published: March 2015

We previously demonstrated that C75, a specific and potent inhibitor of fatty acid synthase (FAS), reduced food intake and decreased body weight in mice. In the present study, we determined that these effects were not due to conditioned taste aversion. To investigate the mechanism of C75 action, we examined FAS brain expression. FAS was expressed in a number of brain regions, including arcuate and paraventricular nuclei (PVN) within regions that comprise the arcuate-PVN pathway in mouse and human. Although C75 and fasting significantly downregulated liver FAS, FAS levels remained high in hypothalamus, indicating that FAS levels were regulated differently in brain from those in liver. Double fluorescence in situ for FAS and neuropeptide Y (NPY) showed that FAS co-localized with NPY in neurons in the arcuate nucleus. NPY immnuoreactivity after C75 treatment was decreased in axon terminals that innervate the PVN and lateral hypothalamus. Collectively, these results demonstrate that FAS is present and active in neurons and suggests that C75 may alter food intake via interactions within the arcuate-PVN pathway mediated by NPY.