bluuebunny/crossref_metadata_2025 huggingface dataset:
Accurate and efficient SLA compliance monitoring
Authors: Sommers Joel , Barford Paul , Duffield Nick , Ron Amos
Published: September 2007

Service level agreements (SLAs) define performance guarantees made by service providers,
e.g
, in terms of packet loss, delay, delay variation, and network availability. In this paper, we describe a new active measurement methodology to accurately monitor whether measured network path characteristics are in compliance with performance targets specified in SLAs. Specifically, (1) we describe a new methodology for estimating packet loss rate that significantly improves accuracy over existing approaches; (2) we introduce a new methodology for measuring mean delay along a path that improves accuracy over existing methodologies, and propose a method for obtaining confidence intervals on quantiles of the empirical delay distribution without making any assumption about the true distribution of delay; (3) we introduce a new methodology for measuring delay variation that is more robust than prior techniques; and (4) we extend existing work in network performance tomography to infer lower bounds on the quantiles of a distribution of performance measures along an unmeasured path given measurements from a subset of paths. We unify active measurements for these metrics in a discrete time-based tool called SLA
M
. The unified probe stream from SLA
M
consumes lower overall bandwidth than if individual streams are used to measure path properties. We demonstrate the accuracy and convergence properties of SLA
M
in a controlled laboratory environment using a range of background traffic scenarios and in one- and two-hop settings, and examine its accuracy improvements over existing standard techniques.
Lottery trees
Authors: Douceur John R. , Moscibroda Thomas
Published: September 2007

We address a critical deployment issue for network systems, namely motivating people to install and run a distributed service. This work is aimed primarily at peer-to-peer systems, in which the decision and effort to install a service falls to individuals rather than to a central planner. This problem is relevant for bootstrapping systems that rely on the network effect, wherein the benefits are not felt until deployment reaches a significant scale, and also for deploying asymmetric systems, wherein the set of contributors is different than the set of beneficiaries. Our solution is the lottery tree (lottree), a mechanism that probabilistically encourages both participation in the system and also solicitation of new participants. We define the lottree mechanism and normally state seven properties that encourage contribution, solicitation, and fair play. We then present the Pachira lottree scheme, which satisfies five of these seven properties, and we prove this to be a maximal satisfiable subset. Using simulation, we determine optimal parameters for the Pachira lottree scheme, and we determine how to configure a lottree system for achieving various deployment scales based on expected installation effort. We also present extensive sensitivity analyses, which bolster the generality of our conclusions.
A data-oriented (and beyond) network architecture
Authors: Koponen Teemu , Chawla Mohit , Chun Byung-Gon , Ermolinskiy Andrey , Kim Kye Hyun , Shenker Scott , Stoica Ion
Published: September 2007

The Internet has evolved greatly from its original incarnation. For instance, the vast majority of current Internet usage is data retrieval and service access, whereas the architecture was designed around host-to-host applications such as telnet and ftp. Moreover, the original Internet was a purely transparent carrier of packets, but now the various network stakeholders use middleboxes to improve security and accelerate applications. To adapt to these changes, we propose the Data-Oriented Network Architecture (DONA), which involves a clean-slate redesign of Internet naming and name resolution.
An end-middle-end approach to connection establishment
Authors: Guha Saikat , Francis Paul
Published: September 2007

The current model for flow establishment in the Internet: DNS Names, IP addresses, and transport ports, is inadequate. Not all of the problem is due to the small IPv4 address space and resulting NAT boxes. Even where global addresses exist, firewalls cannot glean enough information about a flow from packet headers, and so often err, typically by being over-conservative: disallowing flows that might otherwise be allowed. This paper presents a novel architecture, protocol design, and implementation, for flow establishment in the Internet. The architecture, called NUTSS, takes into account the combined policies of endpoints and network providers. While NUTSS borrows liberally from other proposals (URI-like naming, signaling to manage ephemeral IPv4 or IPv6 data flows), NUTSS is unique in that it couples overlay signaling with data-path signaling. NUTSS requires no changes to existing protocol stacks, and combined with recent NAT traversal techniques, works with IPv4 and existing NAT/firewalls. This paper describes NUTSS and shows how it satisfies a wide range of "end-middle-end"network requirements, including access control, middlebox steering, multi-homing, mobility, and protocol negotiation.
CONMan
Authors: Ballani Hitesh , Francis Paul
Published: September 2007

Networks are hard to manage and in spite of all the so called holistic management packages, things are getting worse. We argue that the difficulty of network management can partly be attributed to a fundamental flaw in the existing architecture: protocols expose all their internal details and hence, the complexity of the ever-evolving data plane encumbers the management plane. Guided by this observation, in this paper we explore an alternative approach and propose Complexity Oblivious Network Management (CONMan), a network architecture in which the management interface of data-plane protocols includes minimal protocol-specific information. This restricts the operational complexity of protocols to their implementation and allows the management plane to achieve high level policies in a structured fashion. We built the CONMan interface of a few protocols and a management tool that can achieve high-level configuration goals based on this interface. Our preliminary experience with applying this tool to real world VPN configuration indicates the architecture's potential to alleviate the difficulty of configuration management.
Reliability as an interdomain service
Authors: Wang Hao , Yang Yang Richard , Liu Paul H. , Wang Jia , Gerber Alexandre , Greenberg Albert
Published: September 2007

Reliability is a critical requirement of the Internet. The availability and resilience of the Internet under failures can have significant global effects. However, in the current Internet routing architecture, achieving the high level of reliability demanded by many mission critical activities can be costly. In this paper, we first propose a novel solution framework called reliability as an interdomain service (REIN) that can be incrementally deployed in the Internet and may improve the redundancy of IP networks at low cost. We then present robust algorithms to efficiently utilize network redundancy to improve reliability. We use real IP network topologies and traffic traces to demonstrate the effectiveness of our framework and algorithms.
A light-weight distributed scheme for detecting ip prefix hijacks in real-time
Authors: Zheng Changxi , Ji Lusheng , Pei Dan , Wang Jia , Francis Paul
Published: September 2007

As more and more Internet IP prefix hijacking incidents are being reported, the value of hijacking detection services has become evident. Most of the current hijacking detection approaches monitor IP prefixes on the control plane and detect inconsistencies in route advertisements and route qualities. We propose a different approach that utilizes information collected mostly from the data plane. Our method is motivated by two key observations: when a prefix is not hijacked, 1) the hop count of the path from a source to this prefix is generally stable; and 2) the path from a source to this prefix is almost always a super-path of the path from the same source to a reference point along the previous path, as long as the reference point is topologically close to the prefix. By carefully selecting multiple vantage points and monitoring from these vantage points for any departure from these two observations, our method is able to detect prefix hijacking with high accuracy in a light-weight, distributed, and real-time fashion. Through simulations constructed based on real Internet measurement traces, we demonstrate that our scheme is accurate with both false positive and false negative ratios below 0.5%.
Observing the evolution of internet as topology
Authors: Oliveira Ricardo V. , Zhang Beichuan , Zhang Lixia
Published: September 2007

Characterizing the evolution of Internet topology is important to our understanding of the Internet architecture and its interplay with technical, economic and social forces. A major challenge in obtaining empirical data on topology evolution is to identify
real
topology changes from the
observed
topology changes, since the latter can be due to either topology changes or transient routing dynamics. In this paper, we formulate the topology
liveness problem
and propose a solution based on the analysis of BGP data. We find that the impact of transient routing dynamics on topology observation decreases exponentially over time, and that the real topology dynamics consist of a constant-rate birth process and a constant-rate death process. Our model enables us to infer real topology changes from observation data with a given confidence level. We demonstrate the usefulness of the model by applying it to three applications: providing more accurate views of the topology, evaluating theoretical evolution models, and empirically characterizing the trends of topology evolution. We find that customer networks and provider networks have distinct evolution trends, which can provide an important input to the design of future Internet routing architecture.
Emulating AQM from end hosts
Authors: Bhandarkar Sumitha , Reddy A. L. Narasimha , Zhang Yueping , Loguinov Dimitri
Published: September 2007

In this paper, we show that end-host based congestion prediction is more accurate than previously characterized. However, it may not be possible to entirely eliminate the uncertainties in congestion prediction. To address these uncertainties, we propose Probabilistic Early Response TCP (PERT). PERT emulates the behavior of AQM/ECN, in the congestion response function of end-hosts. We present fluid-flow analysis of PERT/RED and PERT/PI, versions of PERT that emulate router-based RED and PI controllers. Our analysis shows that PERT/RED has better stability behavior than router-based RED. We also present results from ns-2 simulations to show the practical feasibility of PERT. The scheme presented here is general and can be used for emulating other AQM algorithms.
DTN routing as a resource allocation problem
Authors: Balasubramanian Aruna , Levine Brian , Venkataramani Arun
Published: September 2007

Many DTN routing protocols use a variety of mechanisms, including discovering the meeting probabilities among nodes, packet replication, and network coding. The primary focus of these mechanisms is to increase the likelihood of finding a path with limited information, so these approaches have only an
incidental
effect on such routing metrics as maximum or average delivery latency. In this paper, we present
RAPID
, an
intentional
DTN routing protocol that can optimize a specific routing metric such as worst-case delivery latency or the fraction of packets that are delivered within a deadline. The key insight is to treat DTN routing as a resource allocation problem that translates the routing metric into per-packet utilities which determine how packets should be replicated in the system.

We evaluate RAPID rigorously through a prototype of
RAPID
deployed over a vehicular DTN testbed of 40 buses and simulations based on real traces. To our knowledge, this is the first paper to report on a routing protocol deployed on a real DTN at this scale. Our results suggest that
RAPID
significantly outperforms existing routing protocols for several metrics. We also show empirically that for small loads
RAPID
is within 10% of the optimal performance.
PPR
Authors: Jamieson Kyle , Balakrishnan Hari
Published: September 2007

Bit errors occur in wireless communication when interference or noise overcomes the coded and modulated transmission. Current wireless protocols may use forward error correction (FEC) to correct some small number of bit errors, but generally retransmit the whole packet if the FEC is insufficient. We observe that current wireless mesh network protocols retransmit a number of packets and that most of these retransmissions end up sending bits that have already been received multiple times, wasting network capacity. To overcome this inefficiency, we develop, implement, and evaluate a
partial packet recovery
(PPR) system.

PPR incorporates two new ideas: (1)
SoftPHY
, an expanded physical layer (PHY) interface that provides PHY-independent hints to higher layers about the PHY's confidence in each bit it decodes, and (2) a
postamble
scheme to recover data even when a packet preamble is corrupted and not decodable at the receiver.

Finally, we present
PP-ARQ
, an asynchronous link-layer ARQ protocol built on PPR that allows a receiver to compactly encode a request for retransmission of only those bits in a packet that are likely in error. Our experimental results from a 31-node Zigbee (802.15.4) testbed that includes Telos motes with 2.4 GHz Chipcon radios and GNU Radio nodes implementing the 802.15.4 standard show that PP-ARQ increases end-to-end capacity by a factor of 2x under moderate load.
Parallel computing on any desktop
Authors: Marowka Ami
Published: September 2007

Parallelization lets applications exploit the high throughput of new multicore processors, and the OpenMP parallel programming model helps developers create multithreaded applications.
Domain expert user development
Authors: Lepouras George , Vassilakis Costas , Halatsis Constantin , Georgiadis Panagiotis
Published: September 2007

The European Union's SmartGov project transforms public-sector employees into developers of the government e-services used directly by the public.
The online consumer's hierarchy of needs
Authors: Valacich Joseph S. , Parboteeah D. Veena , Wells John D.
Published: September 2007

Web site designers take heed: Not all interface characteristics are created equal.
SOX, compliance, and power relationships
Authors: Braganza Ashley , Franken Arnoud
Published: September 2007

There are several tactics CIOs can use for SOX compliance implementation. A pivotal one is understanding their relationship with the CEO, CFO, and auditors.
Shaking hands, kissing babies, and…blogging?
Authors: Shannon Meg McGinity
Published: September 2007

The Internet and technology seek to influence politics as usual.
The conservation of uncertainty
Authors: Armour Phillip G.
Published: September 2007

Exploring different units for measuring software.
Introduction
Authors: Munakata Toshinori
Published: September 2007

The meaning and implementation of the term "computing" has changed greatly since ACM was first organized 60 years ago. This special section presents overview articles collectively called "non-silicon-based new computing paradigms." Although these paradigms often differ from one another significantly, there are three common characteristics: the techniques are not based on the traditional silicon-based integrated circuit technology; the basic computing elements have been physically implemented, meaning they are not just theory; and many of them aim at miniaturization, often on the order of 1--100 nanometers. Here, the term "computing" is employed in a very broad sense.
Computing with a trillion crummy components
Authors: Robinett Warren , Snider Gregory S. , Kuekes Philip J. , Williams R. Stanley
Published: September 2007

Attempting to build nanometer-scale circuits that are both defect- and fault-tolerant.
Computation with carbon nanotube devices
Authors: Kong Jing
Published: September 2007

The remarkable properties of carbon nanotubes make them very promising candidates for future computing elements---both as a successor for silicon-basedtechnology and beyond.
Molecular, chemical, and organic computing
Authors: Stadler Robert
Published: September 2007

Evaluating computation at the level of individual molecules.
Optical computing
Authors: Abdeldayem Hossin , Frazier Donald O.
Published: September 2007

Focusing on the reality and promise of optical computing.
Micro/nanofluidic computing
Authors: Marr David W.M. , Munakata Toshinori
Published: September 2007

Fluid-based computing may smooth the transition to microscale systems.
Amoeba-based neurocomputing with chaotic dynamics
Authors: Aono Masashi , Hara Masahiko , Aihara Kazuyuki
Published: September 2007

Implementing a deadlock-breaking neural computing scheme that can flexibly search for reasonable solutions without any resource allocation program.
The online research "bubble"
Authors: Stafford Thomas F. , Gonier Dennis
Published: September 2007

Seeking to improve the commonly used online survey sampling approaches.
An intermediate language level optimization framework for dynamic binary translation
Authors: Shi Huihui , Wang Yi , Guan Haibing , Liang Alei
Published: September 2007

This paper presents an intermediate language level optimization framework for dynamic binary translation. Performance is important to a dynamic binary translation system, so there has been a growing interest in exploring new optimization algorithms. The framework proposed in this paper includes efficient profiling, hot code recognition and smart code cache management policies. Profiling is responsible for collecting runtime information, which will be used by hot code recognition and code cache management algorithms. We only focus on recognizing the hottest code, and assign priorities to basic blocks according to their hotness to facilitate code cache management.
Some investigations on deadlock freedom issues of a cyclically connected system using Dijkstra's weakest precondition calculus
Authors: Banerjee Jayasri , Bandyopadhyay Anup Kumar , Mandal Ajit Kumar
Published: September 2007

Weakest precondition calculus is used to specify a system implemented by a cyclic interconnection of sequential processes. From this specification a predicate is derived that describes the deadlock freedom property of the system. Invariance of the predicate is proved from the specification.
A small part of lattice theory
Authors: Selfridge Ralph
Published: September 2007

Lattice algebras replace + and - with max and min, but then can create many of the operations of normal algebra. In particular lattice algebras can be used in the study of neural networks and extraction of images in the presence of noise. This paper is not a full introduction but a start with some of the simple algorithms that can be used.
Xin, an actin binding protein, is expressed within muscle satellite cells and newly regenerated skeletal muscle fibers
Authors: Hawke Thomas J. , Atkinson Daniel J. , Kanatous Shane B. , Van der Ven Peter F. M. , Goetsch Sean C. , Garry Daniel J.
Published: September 2007

Xin is a muscle-specific actin binding protein of which its role and regulation within skeletal muscle is not well understood. Here we demonstrate that Xin mRNA is robustly upregulated (>16-fold) within 12 h of skeletal muscle injury and is localized to the muscle satellite cell population. RT-PCR confirmed the expression pattern of Xin during regeneration, as well as within primary muscle myoblast cultures, but not other known stem cell populations. Immunohistochemical staining of single myofibers demonstrate Xin expression colocalized with the satellite cell marker Syndecan-4 further supporting the mRNA expression of Xin in satellite cells. In situ hybridization of regenerating muscle 5–7 days postinjury illustrates Xin expression within newly regenerated myofibers. Promoter-reporter assays demonstrate that known myogenic transcription factors [myocyte enhancer factor-2 (MEF2), myogenic differentiation-1 (MyoD), and myogenic factor-5 (Myf-5)] transactivate Xin promoter constructs supporting the muscle-specific expression of Xin. To determine the role of Xin within muscle precursor cells, proliferation, migration, and differentiation analysis using Xin, short hairpin RNA (shRNA) were undertaken in C2C12 myoblasts. Reducing endogenous Xin expression resulted in a 26% increase ( P < 0.05) in cell proliferation and a 20% increase ( P < 0.05) in myoblast migratory capacity. Skeletal muscle myosin heavy chain protein levels were increased ( P < 0.05) with Xin shRNA administration; however, this was not accompanied by changes in myoglobin protein (another marker of differentiation) nor overt morphological differences relative to differentiating control cells. Taken together, the present findings support the hypothesis that Xin is expressed within muscle satellite cells during skeletal muscle regeneration and is involved in the regulation of myoblast function.
C/EBPβ phosphorylation rescues macrophage dysfunction and apoptosis induced by anthrax lethal toxin
Authors: Buck Martina , Chojkier Mario
Published: September 2007

Bacillus anthracis lethal toxin (LT) impairs innate and adaptive immunity. Anthrax lethal factor stimulates cleavage of MAPK kinases, which prevents the activation of antiapoptotic MAPK targets. However, these MAPK targets have not been yet identified. Here, we found that LT induces macrophage apoptosis by enhancing caspase 8 activation and by preventing the activation of ribosomal S6 kinase-2 (RSK), a MAPK target, and the phosphorylation of CCAAT/enhancer binding protein-β (C/EBPβ) on T217, a RSK target. Expression of the dominant positive, phosphorylation mimic C/EBPβ-E217 rescued macrophages from LT-induced apoptosis by blocking the activation of procaspase 8. LT inhibited macrophage phagocytosis and oxidative burst and induced apoptosis in normal mice but not in C/EBPβ-E217 transgenic mice. These findings suggest that C/EBPβ may play a critical role in anthrax pathogenesis, at least in macrophages.
Voltage-gated Ca2+ currents are necessary for slow-wave propagation in the canine gastric antrum
Authors: Bayguinov Orline , Ward Sean M. , Kenyon James L. , Sanders Kenton M.
Published: September 2007

Electrical slow waves determine the timing and force of peristaltic contractions in the stomach. Slow waves originate from a dominant pacemaker in the orad corpus and propagate actively around and down the stomach to the pylorus. The mechanism of slow-wave propagation is controversial. We tested whether Ca2+ entry via a voltage-dependent, dihydropyridine-resistant Ca2+ conductance is necessary for active propagation in canine gastric antral muscles. Muscle strips cut parallel to the circular muscle were studied with intracellular electrophysiological techniques using a partitioned-chamber apparatus. Slow-wave upstroke velocity and plateau amplitude decreased from the greater to the lesser curvature, and this corresponded to a decrease in the density of interstitial cells of Cajal in the lesser curvature. Slow-wave propagation velocity between electrodes impaling cells in two regions of muscle and slow-wave upstroke and plateau were measured in response to experimental conditions that reduce the driving force for Ca2+ entry or block voltage-dependent Ca2+ currents. Nicardipine (0.1–1 μM) did not affect slow-wave upstroke or propagation velocities. Upstroke velocity, amplitude, and propagation velocity were reduced in a concentration-dependent manner by Ni2+ (1–100 μM), mibefradil (10–30 μM), and reduced extracellular Ca2+ (0.5–1.5 mM). Depolarization (by 10–15 mM K+) or hyperpolarization (10 μM pinacidil) also reduced upstroke and propagation velocities. The higher concentrations (or lowest Ca2+) of these drugs and ionic conditions tested blocked slow-wave propagation. Treatment with cyclopiazonic acid to empty Ca2+ stores did not affect propagation. These experiments show that voltage-dependent Ca2+ entry is obligatory for the upstroke phase of slow waves and active propagation.
Levels of plasma membrane expression in progressive and benign mutations of the bile salt export pump (Bsep/Abcb11) correlate with severity of cholestatic diseases
Authors: Lam Ping , Pearson Claire L. , Soroka Carol J. , Xu Shuhua , Mennone Albert , Boyer James L.
Published: September 2007

Human BSEP (ABCB11) mutations are the molecular basis for at least three clinical forms of liver disease, progressive familial intrahepatic cholestasis type 2 (PFIC2), benign recurrent intrahepatic cholestasis type 2 (BRIC2), and intrahepatic cholestasis of pregnancy (ICP). To better understand the pathobiology of these disease phenotypes, we hypothesized that different mutations may cause significant differences in protein defects. Therefore we compared the effect of two PFIC2 mutations (D482G, E297G) with two BRIC2 mutations (A570T and R1050C) and one ICP mutation (N591S) with regard to the subcellular localization, maturation, and function of the rat Bsep protein. Bile salt transport was retained in all but the E297G mutant. Mutant proteins were expressed at reduced levels on the plasma membrane of transfected HEK293 cells compared with wild-type (WT) Bsep in the following order: WT > N591S > R1050C ∼ A570T ∼ E297G >> D482G. Total cell protein and surface protein expression were reduced to the same extent, suggesting that trafficking of these mutants to the plasma membrane is not impaired. All Bsep mutants accumulate in perinuclear aggresome-like structures in the presence of the proteasome inhibitor MG-132, suggesting that mutations are associated with protein instability and ubiquitin-dependent degradation. Reduced temperature, sodium butyrate, and sodium 4-phenylbutyrate enhanced the expression of the mature and cell surface D482G protein in HEK293 cells. These results suggest that the clinical phenotypes of PFIC2, BRIC2, and ICP may directly correlate with the amount of mature protein that is expressed at the cell surface and that strategies to stabilize cell surface mutant protein may be therapeutic.
Mapping the dynamics of shear stress-induced structural changes in endothelial cells
Authors: Mott Rosalind E. , Helmke Brian P.
Published: September 2007

Hemodynamic shear stress regulates endothelial cell biochemical processes that govern cytoskeletal contractility, focal adhesion dynamics, and extracellular matrix (ECM) assembly. Since shear stress causes rapid strain focusing at discrete locations in the cytoskeleton, we hypothesized that shear stress coordinately alters structural dynamics in the cytoskeleton, focal adhesion sites, and ECM on a time scale of minutes. Using multiwavelength four-dimensional fluorescence microscopy, we measured the displacement of rhodamine-fibronectin and green fluorescent protein-labeled actin, vimentin, paxillin, and/or vinculin in aortic endothelial cells before and after onset of steady unidirectional shear stress. In the cytoskeleton, the onset of shear stress increased actin polymerization into lamellipodia, altered the angle of lateral displacement of actin stress fibers and vimentin filaments, and decreased centripetal remodeling of actin stress fibers in subconfluent and confluent cell layers. Shear stress induced the formation of new focal complexes and reduced the centripetal remodeling of focal adhesions in regions of new actin polymerization. The structural dynamics of focal adhesions and the fibronectin matrix varied with cell density. In subconfluent cell layers, shear stress onset decreased the displacement of focal adhesions and fibronectin fibrils. In confluent monolayers, the direction of fibronectin and focal adhesion displacement shifted significantly toward the downstream direction within 1 min after onset of shear stress. These spatially coordinated rapid changes in the structural dynamics of cytoskeleton, focal adhesions, and ECM are consistent with focusing of mechanical stress and/or strain near major sites of shear stress-mediated mechanotransduction.
Expansion of intestinal stem cells associated with long-term adaptation following ileocecal resection in mice
Authors: Dekaney Christopher M. , Fong Jerry J. , Rigby Rachael J. , Lund P. Kay , Henning Susan J. , Helmrath Michael A.
Published: September 2007

Sustained increases in mucosal surface area occur in remaining bowel following massive intestinal loss. The mechanisms responsible for expanding and perpetuating this response are not presently understood. We hypothesized that an increase in the number of intestinal stem cells (ISC) occurs following intestinal resection and is an important component of the adaptive response in mice. This was assessed in the jejunum of mice 2–3 days, 4–5 days, 6–7 days, 2 wk, 6 wk, and 16 wk following ileocecal resection (ICR) or sham operation. Changes in ISC following ICR compared with sham resulted in increased crypt fission and were assayed by 1) putative ISC population (SP) by flow cytometry, 2) Musashi-1 immunohistochemistry, and 3) bromodeoxyuridine (BrdU) label retention. Observed early increases in crypt depth and villus height were not sustained 16 wk following operation. In contrast, long-term increases in intestinal caliber and overall number of crypts per circumference appear to account for the enhanced mucosal surface area following ICR. Flow cytometry demonstrated that significant increases in SP cells occur within 2–3 days following resection. By 7 days, ICR resulted in marked increases in crypt fission and Musashi-1 immunohistochemistry staining. Separate label-retention studies confirmed a 20-fold increase in BrdU incorporation 6 wk following ICR, confirming an overall increase in the number of ISC. These studies support that expansion of ISC occurs following ICR, leading to an overall increase number of crypts through a process of fission and intestinal dilation. Understanding the mechanism expanding ISCs may provide important insight into management of intestinal failure.
Transport of butyryl-l-carnitine, a potential prodrug, via the carnitine transporter OCTN2 and the amino acid transporter ATB0,+
Authors: Srinivas Sonne R. , Prasad Puttur D. , Umapathy Nagavedi S. , Ganapathy Vadivel , Shekhawat Prem S.
Published: September 2007

l-Carnitine is absorbed in the intestinal tract via the carnitine transporter OCTN2 and the amino acid transporter ATB0,+. Loss-of-function mutations in OCTN2 may be associated with inflammatory bowel disease (IBD), suggesting a role for carnitine in intestinal/colonic health. In contrast, ATB0,+is upregulated in bowel inflammation. Butyrate, a bacterial fermentation product, is beneficial for prevention/treatment of ulcerative colitis. Butyryl-l-carnitine (BC), a butyrate ester of carnitine, may have potential for treatment of gut inflammation, since BC would supply both butyrate and carnitine. We examined the transport of BC via ATB0,+to determine if this transporter could serve as a delivery system for BC. We also examined the transport of BC via OCTN2. Studies were done with cloned ATB0,+and OCTN2 in heterologous expression systems. BC inhibited ATB0,+-mediated glycine transport in mammalian cells (IC50, 4.6 ± 0.7 mM). In Xenopus laevis oocytes expressing human ATB0,+, BC induced Na+-dependent inward currents under voltage-clamp conditions. The currents were saturable with a K0.5of 1.4 ± 0.1 mM. Na+activation kinetics of BC-induced currents suggested involvement of two Na+per transport cycle. BC also inhibited OCTN2-mediated carnitine uptake (IC50, 1.5 ± 0.3 μM). Transport of BC via OCTN2 is electrogenic, as evidenced from BC-induced inward currents. These currents were Na+dependent and saturable ( K0.5, 0.40 ± 0.02 μM). We conclude that ATB0,+is a low-affinity/high-capacity transporter for BC, whereas OCTN2 is a high-affinity/low-capacity transporter. ATB0,+may mediate intestinal absorption of BC when OCTN2 is defective.
Transporters, enzymes, and enalapril removal in a rat (CC531-induced) liver metastatic model
Authors: Liu Lichuan , Sun Huadong , Valji Wiqas Y. , Pang K. Sandy
Published: September 2007

Temporal changes in physiological spaces, protein expression of transporters and enzymes, and enalapril removal were appraised in the metastatic liver tumor model developed from male Wag/Rij rats after the intraportal injection of CC531 colon adenocarcinoma cells; sham-operated preparations received PBS. Liver tissue spaces, investigated with multiple indicator dilution technique in liver perfusion studies, were unchanged at week 3 after tumor induction. At week 4, however, the sinusoidal blood volume and albumin Disse space in tumor-bearing livers were slightly lower compared with those of shams. Increased levels of the canalicular ATP transporters, P-glycoprotein, multidrug resistance-associated protein 2 (Mrp2), and bile salt export pump (Bsep) at week 2 ( P < 0.05), unchanged levels of Ntcp, Oatp1a1, Oatp1a4, and Mct2, but decreased levels of cytochrome P450 3a2 (Cyp3a2) and glutathione S-transferase (Gst4-4) at week 4 ( P < 0.05) were observed in peritumor vs. sham-operated liver tissues with Western blotting. The steady-state extraction ratio of enalapril, a substrate that enters the liver rapidly via Oatp1a1 and primarily undergoes metabolism by the carboxylesterases, was unaffected by liver metastasis at week 4 regardless of its delivery via the portal vein or hepatic artery into the perfused liver preparations.
Cardiovascular effects of intravenous ghrelin infusion in healthy young men
Authors: Vestergaard Esben Thyssen , Andersen Niels Holmark , Hansen Troels Krarup , Rasmussen Lars Melholt , Moller Niels , Sorensen Keld E. , Sloth Erik , Jorgensen Jens Otto Lunde
Published: September 2007

Ghrelin infusion improves cardiac function in patients suffering from cardiac failure, and bolus administration of ghrelin increases cardiac output in healthy subjects. The cardiovascular effects of more continuous intravenous ghrelin exposure remain to be studied. We therefore studied the cardiovascular effects of a constant infusion of human ghrelin at a rate of 5 pmol/kg per minute for 180 min. Fifteen healthy, young (aged 23.2 ± 0.5 yr), normal-weight (23.0 ± 0.4 kg/m2) men volunteered in a randomized double-blind, placebo-controlled crossover study. With the subjects remaining fasting, peak myocardial systolic velocity S′, tissue tracking TT, left ventricular ejection fraction EF, and endothelium-dependent flow-mediated vasodilatation were measured. Ghrelin infusion increased S′ 9% ( P = 0.002) and TT 10% ( P < 0.001), whereas EF, resting blood flow velocity, and endothelium-dependent flow-mediated vasodilatation did not change ( P = 0.13). This was associated with a peak in serum growth hormone after 60 min of infusion (37.77 ± 5.27 ng/ml, P < 0.001), a doubling of free fatty acid levels ( P = 0.001), and a 1.6-fold increase in cortisol levels ( P < 0.05), whereas glucose and catecholamine levels were constant. In conclusion, supraphysiological levels of ghrelin stimulate left ventricular function in terms of S′ and TT in healthy young normal-weight men without changing resting blood flow velocity and endothelium-dependent flow-mediated vasodilatation. The effects did not translate into detectable increments in EF.
Chaperone-dependent E3 ligase CHIP ubiquitinates and mediates proteasomal degradation of soluble guanylyl cyclase
Authors: Xia Tian , Dimitropoulou Christiana , Zeng Jingmin , Antonova Galina N. , Snead Connie , Venema Richard C. , Fulton David , Qian Shuibing , Patterson Cam , Papapetropoulos Andreas , Catravas John D.
Published: September 2007

The nitric oxide receptor soluble guanylyl cyclase (sGC) exists in multimeric protein complexes, including heat shock protein (HSP) 90 and endothelial nitric oxide synthase. Inhibition of HSP90 by geldanamycin causes proteasomal degradation of sGC protein. In this study, we have investigated whether COOH terminus of heat shock protein 70-interacting protein (CHIP), a co-chaperone molecule that is involved in protein folding but is also a chaperone-dependent ubiquitin E3 ligase, could play a role in the process of degradation of sGC. Transient overexpression of CHIP in COS-7 cells degraded heterologous sGC in a concentration-related manner; this downregulation of sGC was abrogated by the proteasome inhibitor MG-132. Transfection of tetratricopeptide repeats and U-box domain CHIP mutants attenuated sGC degradation, suggesting that both domains are indispensable for CHIP function. Results from immunoprecipitation and indirect immunofluorescent microscopy experiments demonstrated that CHIP is associated with sGC, HSP90, and HSP70 in COS-7 cells. Furthermore, CHIP increased the association of HSP70 with sGC. In in vitro ubiquitination assays using purified proteins and ubiquitin enzymes, E3 ligase CHIP directly ubiquitinated sGC; this ubiquitination was potentiated by geldanamycin in COS-7 cells, followed by proteasomal degradation. In rat aortic smooth muscle cells, endogenous sGC was also degraded by adenovirus-infected wild-type CHIP but not by the chaperone interaction-deficient K30A CHIP, whereas CHIP, but not K30A, attenuated sGC expression in, and nitric oxide donor-induced relaxation of, rat aortic rings, suggesting that CHIP plays a regulatory role under physiological conditions. This study reveals a new mechanism for the regulation of sGC, an important mediator of cellular and vascular function.
Baroreceptor reflex modulation by circulating angiotensin II is mediated by AT1receptors in the nucleus tractus solitarius
Authors: Tan Peter S. P. , Killinger Suzanne , Horiuchi Jouji , Dampney Roger A. L.
Published: September 2007

Circulating ANG II modulates the baroreceptor reflex control of heart rate (HR), at least partly via activation of ANG II type 1 (AT1) receptors on neurons in the area postrema. In this study, we tested the hypothesis that the effects of circulating ANG II on the baroreflex also depend on AT1receptors within the nucleus tractus solitarius (NTS). In confirmation of previous studies in other species, increases in arterial pressure induced by intravenous infusion of ANG II had little effect on HR in urethane-anesthetized rats, in contrast to the marked bradycardia evoked by equipressor infusion of phenylephrine. In the presence of a continuous background infusion of ANG II, the baroreflex control of HR was shifted to higher levels of HR but had little effect on the baroreflex control of renal sympathetic activity. The modulatory effects of circulating ANG II on the cardiac baroreflex were significantly reduced by microinjection of candesartan, an AT1receptor antagonist, into the area postrema and virtually abolished by microinjections of candesartan into the medial NTS. After acute ablation of the area postrema, a background infusion of ANG II still caused an upward shift of the cardiac baroreflex curve, which was reversed by subsequent microinjection of candesartan into the medial NTS. The results indicate that AT1receptors in the medial NTS play a critical role in modulation of the cardiac baroreflex by circulating ANG II via mechanisms that are at least partly independent of AT1receptors in the area postrema.
Pharmacological actions of the peptide hormone amylin in the long-term regulation of food intake, food preference, and body weight
Authors: Mack Christine , Wilson Julie , Athanacio Jennifer , Reynolds James , Laugero Kevin , Guss Stacy , Vu Calvin , Roth Jonathan , Parkes David
Published: September 2007

The ability of amylin to reduce acute food intake in rodents is well established. Longer-term administration in rats (up to 24 days) shows a concomitant reduction in body weight, suggesting energy intake plays a significant role in mediating amylin-induced weight loss. The current set of experiments further explores the long-term effects of amylin (4–11 wk) on food preference, energy expenditure, and body weight and composition. Furthermore, we describe the acute effect of amylin on locomotor activity and kaolin consumption to test for possible nonhomeostatic mechanisms that could affect food intake. Four-week subcutaneous amylin infusion of high-fat fed rats (3–300 μg·kg−1·day−1) dose dependently reduced food intake and body weight gain (ED50for body weight gain = 16.5 μg·kg−1·day−1). The effect of amylin on body weight gain was durable for up to 11 wks and was associated with a specific loss of fat mass and increased metabolic rate. The body weight of rats withdrawn from amylin (100 μg·kg−1·day−1) after 4 wks of infusion returned to control levels 2 wks after treatment cessation, but did not rebound above control levels. When self-selecting calories from a low- or high-fat diet during 11 wks of infusion, amylin-treated rats (300 μg·kg−1·day−1) consistently chose a larger percentage of calories from the low-fat diet vs. controls. Amylin acutely had no effect on locomotor activity or kaolin consumption at doses that decreased food intake. These results demonstrate pharmacological actions of amylin in long-term body weight regulation in part through appetitive-related mechanisms and possibly via changes in food preference and energy expenditure.
Oxidative stress response and gene expression with acute copper exposure in zebrafish (Danio rerio)
Authors: Craig Paul M. , Wood Chris M. , McClelland Grant B.
Published: September 2007

In fish, environmental pollution is one factor that induces oxidative stress, and this can disturb the natural antioxidant defense system. Oxidative stress has been well characterized in vitro, yet the in vivo effects of metal-induced oxidative stress have not been extensively studied. In two experiments we examined the impacts of copper (Cu) on gene expression, oxidative damage, and cell oxidative capacity in liver and gill of zebrafish. In the first experiment, soft water-acclimated zebrafish were exposed to 8 and 15 μg/l Cu for 48 h. This exposure resulted in significant increases in gene expression of cytochrome c oxidase subunit 17 (COX-17) and catalase, associated with both increased Cu load and protein carbonyl concentrations in the gill and liver after 48 h. In addition, we examined the potential protective effects of increased waterborne Ca2+(3.3 mM) and Na+(10 mM) on acute Cu toxicity. While both treatments were effective at reducing liver and/or gill Cu loads and attenuating oxidative damage at 48 h, 10 mM Na+was more protective than 3.3 mM Ca2+. There were variable changes in the maximal activities of COX and citrate synthase (CS), indicating possible alterations in cell oxidative capacity. Moreover, Cu affected COX-to-CS ratios in both gill and liver, suggesting that Cu alters normal mitochondrial biogenic processes, possibly though metallochaperones like COX-17. Overall, this study provides important steps in determining the transcriptional and physiological endpoints of acute Cu toxicity in a model tropical species.
Increased expression of cyclooxygenase 2 contributes to aberrant renin production in connexin 40-deficient kidneys
Authors: Wagner Charlotte , de Wit Cor , Gerl Melanie , Kurtz Armin , Höcherl Klaus
Published: September 2007

We previously found that deletion of connexin 40 (Cx40) causes a misdirection of renin-expressing cells from the media layer of afferent arterioles to the perivascular tissue, extraglomerular mesangium, and periglomerular and peritubular interstitium. The mechanisms underlying this aberrant renin expression are unknown. Here, we questioned the relevance of cyclooxygenase-2 (COX-2) activity for aberrant renin expression in Cx40-deficient kidneys. We found that COX-2 mRNA levels were increased three-fold in the renal cortex of Cx40-deficient kidneys relative to wild-type (wt) kidneys. In wt kidneys, COX-2 immunoreactivity was minimally detected in the juxtaglomerular region, but renin expression was frequently associated with COX-2 immunoreactivity in Cx40-deficient kidneys. Treatment with COX-2 inhibitors for 1 wk lowered renin mRNA levels in wt kidneys by about 40%. In Cx40-deficient kidneys, basal renin mRNA levels were increased two-fold relative to wt kidneys, and these elevated mRNA levels were reduced to levels of untreated wt mice by COX-2 inhibitors. In parallel, renin immunoreactive areas were clearly reduced by COX-2 inhibitors such that renin expression vanished and decreased significantly in the periglomerular and peritubular extensions. Notably, COX-2 inhibitor treatment lowered plasma renin concentration (PRC) in wt kidneys by about 40% but did not affect the highly elevated PRC levels in Cx40-deficient mice. These findings suggest that aberrant renin-producing cells in Cx40-deficient kidneys express significant amounts of COX-2, which contribute to renin expression in these cells, in particular, those in the periglomerular and peritubular position. Apparently, these disseminated cells do not contribute to the enhanced renin secretion rates of Cx40-deficient kidneys.
Fractional urinary excretion of endothelin-1 is reduced by acute ETB receptor blockade
Authors: Goddard Jane , Johnston Neil R. , Cumming Allan D. , Webb David J.
Published: September 2007

Evidence suggests that urinary excretion of endothelin-1 (ET-1) reflects renal ET-1 production and is independent of systemic ET-1 activity. The influence of ET receptors on urinary ET-1 excretion has not been studied in humans, yet peritubular ETB receptors are abundant within the kidney. We have studied the effects of acute ETA and ETB receptor blockade with BQ-123 and BQ-788, respectively, on urinary ET-1 excretion in a randomized, placebo-controlled, double-blind study in 16 subjects with a wide range of GFRs (15–152 ml/min). Plasma ET-1 concentrations (pET-1) and urinary ET-1 excretion rate (uET-1) at baseline correlated inversely with GFR ( R2= 0.18 and 0.36, respectively, P < 0.01). However, changes in pET-1 after ET receptor antagonism were not related to changes in uET-1 ( R2= 0.007, P = 0.18). pET-1 increased only after BQ-788, alone or in combination with BQ-123, consistent with ETB receptor-mediated clearance of ET-1 from the circulation. uET-1 was reduced only after BQ-788 alone [−4.7 pg/min (SD 5.5), P < 0.01]. Because BQ-788 also reduced GFR, fractional excretion of ET-1 (FeET-1) was calculated. FeET-1 fell after BQ-788 alone [−41% (SD 26%), P < 0.01] or in combination with BQ-123 [−40% (SD 29%), P < 0.01]. FeET-1 was not altered by placebo or BQ-123 alone. In conclusion, urinary ET-1 excretion does not appear to relate to the pool of plasma ET-1. Because of the short duration of this study, it is unlikely that ET receptor blockade had significant effects on renal ET-1 production. Therefore, the reduction in FeET-1 after ETB blockade appears to indicate that renal excretion of ET-1 is at least partly facilitated by ETB receptor activation.