bluuebunny/crossref_metadata_2025 huggingface dataset:
Inter-datacenter bulk transfers with netstitcher
Authors: Laoutaris Nikolaos , Sirivianos Michael , Yang Xiaoyuan , Rodriguez Pablo
Published: December 2011

Large datacenter operators with sites at multiple locations dimension their key resources according to the peak demand of the geographic area that each site covers. The demand of specific areas follows strong diurnal patterns with high peak to valley ratios that result in poor average utilization across a day. In this paper, we show how to rescue unutilized bandwidth across multiple datacenters and backbone networks and use it for non-real-time applications, such as backups, propagation of bulky updates, and migration of data. Achieving the above is non-trivial since leftover bandwidth appears at different times, for different durations, and at different places in the world.

For this purpose, we have designed, implemented, and validated
NetStitcher
, a system that employs a network of storage nodes to stitch together unutilized bandwidth, whenever and wherever it exists. It gathers information about leftover resources, uses a store-and-forward algorithm to schedule data transfers, and adapts to resource fluctuations.

We have compared
NetStitcher
with other bulk transfer mechanisms using both a testbed and a live deployment on a real CDN. Our testbed evaluation shows that
NetStitcher
outperforms all other mechanisms and can rescue up to five times additional datacenter bandwidth thus making it a valuable tool for datacenter providers. Our live CDN deployment demonstrates that our solution can perform large data transfers at a much lower cost than naive end-to-end or store-and-forward schemes.
Broadband internet performance
Authors: Sundaresan Srikanth , de Donato Walter , Feamster Nick , Teixeira Renata , Crawford Sam , Pescapè Antonio
Published: December 2011

We present the first study of network access link performance measured directly from home gateway devices. Policymakers, ISPs, and users are increasingly interested in studying the performance of Internet access links. Because of many confounding factors in a home network or on end hosts, however, thoroughly understanding access network performance requires deploying measurement infrastructure in users' homes as gateway devices. In conjunction with the Federal Communication Commission's study of broadband Internet access in the United States, we study the throughput and latency of network access links using longitudinal measurements from nearly 4,000 gateway devices across 8 ISPs from a deployment of over 4,200 devices. We study the performance users achieve and how various factors ranging from the user's choice of modem to the ISP's traffic shaping policies can affect performance. Our study yields many important findings about the characteristics of existing access networks. Our findings also provide insights into the ways that access network performance should be measured and presented to users, which can help inform ongoing broader efforts to benchmark the performance of access networks.
Random access heterogeneous MIMO networks
Authors: Lin Kate Ching-Ju , Gollakota Shyamnath , Katabi Dina
Published: December 2011

This paper presents the design and implementation of 802.11n+, a fully distributed random access protocol for MIMO networks. 802.11n+ allows nodes that differ in the number of antennas to contend not just for time, but also for the degrees of freedom provided by multiple antennas. We show that even when the medium is already occupied by some nodes, nodes with more antennas can transmit concurrently without harming the ongoing transmissions. Furthermore, such nodes can contend for the medium in a fully distributed way. Our testbed evaluation shows that even for a small network with three competing node pairs, the resulting system about doubles the average network throughput. It also maintains the random access nature of today's 802.11n networks.
Strider
Authors: Gudipati Aditya , Katti Sachin
Published: December 2011

This paper presents the design, implementation and evaluation of Strider, a system that automatically achieves almost the optimal rate adaptation without incurring any overhead. The key component in Strider is a novel code that has two important properties: it is
rateless and collision-resilient
. First, in time-varying wireless channels, Strider's rateless code allows a sender to effectively achieve almost the optimal bitrate, without knowing how the channel state varies. Second, Strider's collision-resilient code allows a receiver to decode both packets from collisions, and achieves the same throughput as the collision-free scheduler. We show via theoretical analysis that Strider achieves Shannon capacity for Gaussian channels, and our empirical evaluation shows that Strider outperforms SoftRate, a state of the art rate adaptation technique by 70% in mobile scenarios and by upto 2.8× in contention scenarios.
DOF
Authors: Hong Steven Siying , Katti Sachin Rajsekhar
Published: December 2011

The ability to detect what unlicensed radios are operating in a neigh borhood, their spectrum occupancies and the spatial directions their signals are traversing is a fundamental primitive needed by many applications, ranging from smart radios to coexistence to network management to security. In this paper we present DOF, a detector that in a single framework accurately estimates all three parameters. DOF builds on the insight that in most wireless protocols, there are hidden repeating patterns in the signals that can be used to construct unique signatures, and accurately estimate signal types and their spectral and spatial parameters. We show via experimental evaluation in an indoor testbed that DOF is
robust and accurate
, it achieves greater than 85% accuracy even when the SNRs of the detected signals are as low as 0 dB, and even when there are multiple interfering signals present. To demonstrate the benefits of DOF, we design and implement a preliminary prototype of a smart radio that operates on top of DOF, and show experimentally that it provides a 80% increase in throughput over Jello, the best known prior implementation, while causing less than 10% performance drop for co-existing WiFi and Zigbee radios.
Demystifying configuration challenges and trade-offs in network-based ISP services
Authors: Benson Theophilus , Akella Aditya , Shaikh Aman
Published: December 2011

ISPs are increasingly offering a variety of network-based services such as VPN, VPLS, VoIP, Virtual-Wire and DDoS protection. Although both enterprise and residential networks are rapidly adopting these services, there is little systematic work on the design challenges and trade-offs ISPs face in providing them. The goal of our paper is to understand the complexity underlying the layer-3 design of services and to highlight potential factors that hinder their introduction, evolution and management. Using daily snapshots of configuration and device metadata collected from a tier-1 ISP, we examine the logical dependencies and special cases in device configurations for five different network-based services. We find: (1) the design of the core data-plane is usually service-agnostic and simple, but the control-planes for different services become more complex as services evolve; (2) more crucially, the configuration at the service edge inevitably becomes more complex over time, potentially hindering key management issues such as service upgrades and troubleshooting; and (3) there are key service-specific issues that also contribute significantly to the overall design complexity. Thus, the high prevalent complexity could impede the adoption and growth of network-based services. We show initial evidence that some of the complexity can be mitigated systematically.
A content propagation metric for efficient content distribution
Authors: Peterson Ryan S. , Wong Bernard , Sirer Emin Gun
Published: December 2011

Efficient content distribution in large networks comprising datacenters, end hosts, and distributed in-network caches is a difficult problem. Existing systems rely on mechanisms and metrics that fail to effectively utilize all available sources of bandwidth in the network. This paper presents a novel metric, called the Content Propagation Metric (CPM), for quantitatively evaluating the marginal benefit of available bandwidth to competing consumers, enabling efficient utilization of the bandwidth resource. The metric is simple to implement, imposes only a modest overhead, and can be retrofitted easily into existing content distribution systems. We have designed and implemented a high-performance content distribution system, called V-Formation, based on the CPM. The CPM guides V-Formation toward a global allocation of bandwidth that maximizes the aggregate download bandwidth of consumers. Results from a PlanetLab deployment and extensive simulations show that V-Formation achieves high aggregate bandwidth and that the CPM enables hosts to converge quickly on a stable allocation of resources in a wide range of deployment scenarios.
Understanding network failures in data centers
Authors: Gill Phillipa , Jain Navendu , Nagappan Nachiappan
Published: December 2011

We present the first large-scale analysis of failures in a data center network. Through our analysis, we seek to answer several fundamental questions: which devices/links are most unreliable, what causes failures, how do failures impact network traffic and how effective is network redundancy? We answer these questions using multiple data sources commonly collected by network operators. The key findings of our study are that (1) data center networks show high reliability, (2) commodity switches such as ToRs and AggS are highly reliable, (3) load balancers dominate in terms of failure occurrences with many short-lived software related faults,(4) failures have potential to cause loss of many small packets such as keep alive messages and ACKs, and (5) network redundancy is only 40% effective in reducing the median impact of failure.
Automatic inference of movements from contact histories
Authors: Wang Pengcheng , Gao Zhaoyu , Xu Xinhui , Zhou Yujiao , Zhu Haojin , Zhu Kenny Q.
Published: December 2011

This paper introduces a new security problem in which individuals movement traces (in terms of accurate routes) can be inferred from just a series of mutual contact records and the map of the area in which they roam around. Such contact records may be obtained through the bluetooth communication on mobile phones.

We present an approach that solve the trace inference problem in reasonable time, and analyze some properties of the inference algorithm.
ASAP
Authors: Li Qingxi , Zhou Wenxuan , Caesar Matthew , Godfrey P. Brighten
Published: December 2011

For interactive networked applications like web browsing, every round-trip time (RTT) matters. We introduce ASAP, a new naming and transport protocol that reduces latency by shortcutting DNS requests and eliminating TCP's three-way handshake, while ensuring the key security property of verifiable provenance of client requests. ASAP eliminates between one and two RTTs, cutting the delay of small requests by up to two-thirds.
Limiting large-scale crawls of social networking sites
Authors: Mondal Mainack , Viswanath Bimal , Clement Allen , Druschel Peter , Gummadi Krishna P. , Mislove Alan , Post Ansley
Published: December 2011

Online social networking sites (OSNs) like Facebook and Orkut contain personal data of millions of users. Many OSNs view this data as a valuable asset that is at the core of their business model. Both OSN users and OSNs have strong incentives to restrict large scale crawls of this data. OSN users want to protect their privacy and OSNs their business interest. Traditional defenses against crawlers involve rate- limiting browsing activity per user account. These defense schemes, however, are vulnerable to Sybil attacks, where a crawler creates a large number of fake user accounts. In this paper, we propose Genie, a system that can be deployed by OSN operators to defend against Sybil crawlers. Genie is based on a simple yet powerful insight: the social network itself can be leveraged to defend against Sybil crawlers. We first present Genie's design and then discuss how Genie can limit crawlers while allowing browsing of user profiles by normal users.
Spider
Authors: Soroush Hamed , Gilbert Peter , Banerjee Nilanjan , Corner Mark D. , Levine Brian N. , Cox Landon
Published: December 2011

We investigate attempting concurrent connections to multiple Wi-Fi access points (APs) from highly mobile clients. Previous multi-AP solutions are limited to stationary wireless clients and do not take into account a myriad of mobile factors. We show that connection duration, AP response times, channel scheduling, available and offered bandwidth, node speed, and dhcp joins all affect performance. Building on these results, we present a system, Spider, that establishes and maintains concurrent connections to 802.11 APs in a mobile environment. While Spider can manage multiple channels, we demonstrate that it achieves maximum throughput when using multiple APs on a single channel.
Taming power peaks in mapreduce clusters
Authors: Zhu Nan , Rao Lei , Liu Xue , Liu Jie , Guan Haibin
Published: December 2011

Along with the surging service demands on the cloud, the energy cost of Internet Data Centers (IDCs) is dramatically increasing. Energy management for IDCs is becoming ever more important. A large portion of applications running on data centers are data-intensive applications. MapReduce (and Hadoop) has been one of the mostly deployed frameworks for data-intensive applications. Both academia and industry have been greatly concerned with the problem of how to reduce the energy consumption of IDCs. However the critical power peak problem for MapReduce clusters has been overlooked, which is a new challenge brought by the usage of MapReduce. We elaborate the power peak problem and investigate the cause of the problem in details. Then we design an adaptive approach to regulate power peaks.
Revisiting next-hop selection in multipath networks
Authors: van der Linden Simon , Detal Gregory , Bonaventure Olivier
Published: December 2011

Multipath routing strategies such as Equal-Cost MultiPath (ECMP) are widely used in IP and data-center networks. Most current methods to balance packets over the multiple next hops toward the destination base their decision on a hash computed over selected fields of the packet headers. Because of the non-invertible nature of hash functions, it is hard to determine the values of those fields so as to make the packet follow a specific path in the network. However, several applications might benefit from being able to choose such a path. Therefore, we propose a novel next-hop selection method based on an invertible function. By encoding the selection of successive routers into common fields of packet headers, the proposed method enables end hosts to force their packets to follow a specific path.
Detecting and assessing the hybrid IPv4/IPv6 as relationships
Authors: Giotsas Vasileios , Zhou Shi
Published: December 2011

The business relationships between the Autonomous Systems (ASes) play a central role in the BGP routing. The existing relationship inference algorithms are profoundly based on the valley-free rule and generalize their inference heuristics for both the IPv4 and IPv6 planes, introducing unavoidable inference artifacts. To discover and analyze the Type-of-Relationship (ToR) properties of the IPv6 topology we mine the BGP Communities attribute which provides an unexploited wealth of reliable relationship information. We obtain the actual relationships for 72% of the IPv6 AS links that are visible in the RouteViews and RIPE RIS repositories. Our results show that as many as 13% of AS links that serve both IPv4 and IPv6 traffic have different relationships depending on the IP version. Such relationships are characterized as hybrid. We observe that links with hybrid relationships are present in a large number of IPv6 AS paths. Furthermore, an unusually large portion of IPv6 AS paths violate the valley-free rule, indicating that the global reachability in the IPv6 Internet requires the relaxation of the valley-free rule. Our work highlights the importance of correctly inferring the AS relationships and the need to appreciate the distinct characteristics of IPv6 routing policies.
A novel approach for making energy efficient PON
Authors: Newaz S.H. Shah , Cuevas Ángel , Lee Gyu Myoung , Crespi Noël , Choi JunKyun
Published: December 2011

Nowadays Passive Optical Network (PON) requires that Optical Network Units (ONUs) wake up periodically to check if the Optical Line Terminal (OLT) has any message directed to them. This implies that ONUs change from sleeping mode in which they just consume 1 W to active mode in which the consumption goes up to 10 W. In many cases, the OLT does not have any packets for the ONU and it goes to sleep again, what supposes a waste of energy. In this paper, we propose a novel Hybrid ONU that relies on a low-cost and low-energy technology, IEEE 802.15.4, to wake up those ONUs that are going to receive a packet. Our first estimations demonstrates that our solution would save around 25000$ per year and OLT.
Wide-area routing dynamics of malicious networks
Authors: Konte Maria , Feamster Nick
Published: December 2011

This paper studies the routing dynamics of malicious networks. We characterize the routing behavior of malicious networks on both short and long timescales. We find that malicious networks more consistently advertise prefixes with short durations and long inter- arrival times; over longer timescales, we find that malicious ASes connect with more upstream providers than legitimate ASes, and they also change upstream providers more frequently.
Online testing of federated and heterogeneous distributed systems
Authors: Canini Marco , Jovanović Vojin , Venzano Daniele , Novaković Dejan , Kostić Dejan
Published: December 2011

DiCE is a system for online testing of federated and heterogeneous distributed systems. We have built a prototype of DiCE and integrated it with an open-source BGP router. DiCE quickly detects three important classes of faults, resulting from configuration mistakes, policy conflicts and programming errors.

The goal of this demo is to showcase our DiCE prototype while it executes an experiment that involves exploring BGP system behavior in a topology with 27 BGP routers and Internet-like conditions (Figure 1).
PANDAA
Authors: Sun Zheng , Purohit Aveek , De Wagter Philippe , Brinster Irina , Hamm Chorom , Zhang Pei
Published: December 2011

This demo presents PANDAA, a zero-configuration automatic spatial localization technique for networked devices based on ambient sound sensing. We will demonstrate that after initial placement of the devices, ambient sounds, such as human speech, music, footsteps, finger snaps, hand claps, or coughs and sneezes, can be used to autonomously resolve the spatial relative arrangement of devices, such as mobile phones, using trigonometric bounds and successive approximation.
LifeNet
Authors: Mehendale Hrushikesh , Paranjpe Ashwin , Vempala Santosh
Published: December 2011

We demonstrate a new ad hoc routing method that can handle transience such as node-mobility, obstructions and node failures. It has controlled management overhead, and is platform-independent (our demo includes phones, routers, and laptops running different operating systems). It achieves reliability and flexibility at the expense of throughput. It is ideal for scenarios where the reliability of connectivity is critical and bandwidth requirements are low. For e.g., disaster relief operations and sensor networks. Along with applications, we exhibit measurements to illustrate the advantages of our approach in dealing with transience.
Supporting novel home network management interfaces with openflow and NOX
Authors: Mortier Richard , Bedwell Ben , Glover Kevin , Lodge Tom , Rodden Tom , Rotsos Charalampos , Moore Andrew W. , Koliousis Alexandros , Sventek Joseph
Published: December 2011

The Homework project has examined redesign of existing home network infrastructures to better support the needs and requirements of actual home users. Integrating results from several ethnographic studies, we have designed and built a home networking platform providing detailed per-flow measurement and management capabilities supporting several novel management interfaces. This demo specifically shows these new visualization and control interfaces (1), and describes the broader benefits of taking an integrated view of the networking infrastructure, realised through our router's augmented measurement and control APIs (2).

Aspects of this work have been published: the Homework Database in Internet Management (IM) 2011 [3] and implications of the ethnographic results are to appear at the SIGCOMM W-MUST workshop 2011 [2]. Separate, more detailed expositions of the interface elements and system performance and implications are currently under submission at other venues. A partial code release is already available and we anticipate fuller public beta release by Q4 2011.
OSPF failure reconvergence through SRG inference and prediction of link state advertisements
Authors: Puype Bart , Papadimitriou Dimitri , Das Goutam , Colle Didier , Pickavet Mario , Demeester Piet
Published: December 2011

We demonstrate machine learning augmented Open Shortest Path First (OSPF) routing which infers Shared Risk Groups (SRG) from link failure history. For an initial link failure matching an SRG, it predicts subsequent link state advertisements corresponding with that SRG, improving convergence and recovery times during multiple network failures.
Communicating with caps
Authors: Kim Hyojoon , Sundaresan Srikanth , Chetty Marshini , Feamster Nick , Edwards W. Keith
Published: December 2011

As Internet service providers increasingly implement and impose "usage caps", consumers need better ways to help them understand and control how devices in the home use up the available network resources or available capacity. Towards this goal, we will demonstrate a system that allows users to monitor and manage their usage caps. The system uses the BISMark firmware running on network gateways to collect usage statistics and report them to a logically centralized controller, which displays usage information. The controller allows users to specify policies about how different people, devices, and applications should consume the usage cap; it implements and enforces these policies via a secure OpenFlow control channel to each gateway device. The demonstration will show various use cases, such as limiting the usage of a particular application, visualizing usage statistics, and allowing users within a single household to "trade" caps with one another.
Better medicine through machine learning
Authors: Savage Neil
Published: December 2011

Computers that tease out patterns from clinical data could improve patient diagnosis and care.
The IBM PC
Authors: Haigh Thomas
Published: December 2011

Looking back at three decades of PC platform evolution.
An interview with Stephen A. Cook
Authors: Frana Philip L.
Published: December 2011

Stephen A. Cook, winner of the 1982 A.M. Turing Award, reflects on his career.
Long-term confidentiality of PKI
Authors: Laih Chi-Sung , Jen Shang-Ming , Lu Chia-Yu
Published: December 2011

How to guarantee files encrypted and transmitted today stay confidential for years to come.
Networking named content
Authors: Jacobson Van , Smetters Diana K. , Thornton James D. , Plass Michael , Briggs Nick , Braynard Rebecca
Published: December 2011

Current network use is dominated by content distribution and retrieval yet current networking protocols are designed for conversations between hosts. Accessing content and services requires mapping from the what that users care about to the network's where. We present Content-Centric Networking (CCN) which uses content chunks as a primitive---decoupling location from identity, security and access, and retrieving chunks of content by name. Using new approaches to routing named content, derived from IP, CCN simultaneously achieves scalability, security, and performance. We describe our implementation of the architecture's basic features and demonstrate its performance and resilience with secure file downloads and VoIP calls.
Metabolism of [13C5]hydroxyproline in vitro and in vivo: implications for primary hyperoxaluria
Authors: Jiang Juquan , Johnson Lynnette C. , Knight John , Callahan Michael F. , Riedel Travis J. , Holmes Ross P. , Lowther W. Todd
Published: December 2011

Hydroxyproline (Hyp) metabolism is a key source of glyoxylate production in the body and may be a major contributor to excessive oxalate production in the primary hyperoxalurias where glyoxylate metabolism is impaired. Important gaps in our knowledge include identification of the tissues with the capacity to degrade Hyp and the development of model systems to study this metabolism and how to suppress it. The expression of mRNA for enzymes in the pathway was examined in 15 different human tissues. Expression of the complete pathway was identified in liver, kidney, pancreas, and small intestine. HepG2 cells also expressed these mRNAs and enzymes and were shown to metabolize Hyp in the culture medium to glycolate, glycine, and oxalate. [18O]- and [13C5]Hyp were synthesized and evaluated for their use with in vitro and in vivo models. [18O]Hyp was not suitable because of an apparent tautomerism of [18O]glyoxylate between enol and hydrated forms, which resulted in a loss of isotope. [13C5]Hyp, however, was metabolized to [13C2]glycolate, [13C2]glycine, and [13C2]oxalate in vitro in HepG2 cells and in vivo in mice infused with [13C5]Hyp. These model systems should be valuable tools for exploring various aspects of Hyp metabolism and will be useful in determining whether blocking Hyp catabolism is an effective therapy in the treatment of primary hyperoxaluria.
Angiotensin II-induced reduction in exercise capacity is associated with increased oxidative stress in skeletal muscle
Authors: Inoue Naoki , Kinugawa Shintaro , Suga Tadashi , Yokota Takashi , Hirabayashi Kagami , Kuroda Satoshi , Okita Koichi , Tsutsui Hiroyuki
Published: December 2011

Angiotensin II (ANG II)-induced oxidative stress has been known to be involved in the pathogenesis of cardiovascular diseases. We have reported that the oxidative stress in skeletal muscle can limit exercise capacity in mice ( 16 ). We thus hypothesized that ANG II could impair the skeletal muscle energy metabolism and limit exercise capacity via enhancing oxidative stress. ANG II (50 ng·kg−1·min−1) or vehicle was infused into male C57BL/6J mice for 7 days via subcutaneously implanted osmotic minipumps. ANG II did not alter body weight, skeletal muscle weight, blood pressure, cardiac structure, or function. Mice were treadmill tested, and expired gases were analyzed. The work to exhaustion (vertical distance × body weight) and peak oxygen uptake were significantly decreased in ANG II compared with vehicle. In mitochondria isolated from skeletal muscle, ADP-dependent respiration was comparable between ANG II and vehicle, but ADP-independent respiration was significantly increased in ANG II. Furthermore, complex I and III activities were decreased in ANG II. NAD(P)H oxidase activity and superoxide production by lucigenin chemiluminescence were significantly increased in skeletal muscle from ANG II mice. Treatment of ANG II mice with apocynin (10 mmol/l in drinking water), an inhibitor of NAD(P)H oxidase activation, completely inhibited NAD(P)H oxidase activity and improved exercise capacity, mitochondrial respiration, and complex activities in skeletal muscle. ANG II-induced oxidative stress can impair mitochondrial respiration in skeletal muscle and limit exercise capacity.
EXPO2011: A new package for powder crystallography
Authors: Altomare Angela , Cuocci Corrado , Giacovazzo Carmelo , Moliterni Anna , Rizzi Rosanna
Published: December 2011

EXPO2011 is a new package for phasing crystal structures from powder diffraction diagrams. It is able to carry out all the steps necessary for crystal structure solution, from pattern indexation up to Rietveld method for structure refinement: for each step, the basic algorithm is described. Phasing is performedviaab initio(e.g., Direct Methods, integrated by real space refinement) and nonab initiotechniques (e.g., simulated annealing algorithm, when molecular geometry isa prioriknown). Some emphasis is given to running procedures: the main commands and directives are described, to allow the user to run default and non-default phasing attempts.
Development, Characterization, and In Vitro Evaluation of Tamoxifen Microemulsions
Authors: Monteagudo E. , Gándola Y. , González L. , Bregni C. , Carlucci A. M.
Published: January 2012

Microemulsions (MEs) were designed by an innovative rational development, characterized, and used to load up to 20 mM of Tamoxifen citrate (TMX). They were made with acceptable and well-characterized excipients for all the routes of administration. Some of their properties, such as nanometric mean size and long stability shelf life, make them interesting drug delivery systems. The results obtained after the in vitro inhibition of estradiol-induced proliferation in MCF-7 breast cancer cells demonstrated a significant effect in cell growth. A decreasing of at least 90% in viable cells was shown after the incubation with MEs containing 20 mM of TMX. Besides, two compositions which loaded 10 mM of drug showed a cytotoxic effect higher than 70%. These results encourage the evaluation of alternative protocols for this drug administration, not only for estrogen receptor (ER) positive tumors, but also for ER negative.
Hyperpolarized 13C Spectroscopy Detects Early Changes in Tumor Vasculature and Metabolism after VEGF Neutralization
Authors: Bohndiek Sarah E. , Kettunen Mikko I. , Hu De-en , Brindle Kevin M.
Published: January 2012

No clinically validated biomarkers exist to image tumor responses to antiangiogenic therapy. Here, we report the utility of hyperpolarized 13C magnetic resonance spectroscopy (MRS) to detect the early effects of anti-VEGF therapy. In two colorectal cancer xenograft models, displaying differential sensitivity to VEGF blockade, we compared hyperpolarized MRS with measurements of tumor perfusion using dynamic contrast agent–enhanced (DCE)-MRI and tumor cellularity using diffusion-weighted MRI of the apparent diffusion coefficient (ADC) of tissue water. In tumors sensitive to anti-VEGF therapy, 13C flux between hyperpolarized [1-13C]pyruvate and [1-13C]lactate decreased after anti-VEGF therapy and correlated with reduced perfusion. Production of [1,4-13C2]malate from hyperpolarized [1,4-13C2]fumarate increased in parallel with tumor cell necrosis, preceding any change in tumor ADC. In contrast, tumors that were less sensitive to anti-VEGF therapy showed an increase in 13C flux from hyperpolarized [1-13C]pyruvate and an increase in uptake of a gadolinium contrast agent, whereas tumor ADC decreased. Increased label flux could be explained by vascular normalization after VEGF blockade, increasing delivery of hyperpolarized [1-13C]pyruvate as observed. Despite the minimal response of these tumors to treatment, with only a minor increase in necrosis observed histologically, production of [1,4-13C2]malate from hyperpolarized [1,4-13C2]fumarate in therapy-resistant tumors also increased. Together, our findings show that hyperpolarized 13C MRS detects early responses to anti-VEGF therapy, including vascular normalization or vascular destruction and cell death. Cancer Res; 72(4); 854–64. ©2012 AACR.
Proximal Tubular Secretion of Creatinine by Organic Cation Transporter OCT2 in Cancer Patients
Authors: Ciarimboli Giuliano , Lancaster Cynthia S. , Schlatter Eberhard , Franke Ryan M. , Sprowl Jason A. , Pavenstädt Hermann , Massmann Vivian , Guckel Denise , Mathijssen Ron H. J. , Yang Wenjian , Pui Ching-Hon , Relling Mary V. , Herrmann Edwin , Sparreboom Alex
Published: January 2012

Purpose: Knowledge of transporters responsible for the renal secretion of creatinine is key to a proper interpretation of serum creatinine and/or creatinine clearance as markers of renal function in cancer patients receiving chemotherapeutic agents.

Experimental Design: Creatinine transport was studied in transfected HEK293 cells in vitro and in wild-type mice and age-matched organic cation transporter 1 and 2–deficient [Oct1/2(−/−)] mice ex vivo and in vivo. Clinical pharmacogenetic and transport inhibition studies were done in two separate cohorts of cancer patients.

Results: Compared with wild-type mice, creatinine clearance was significantly impaired in Oct1/2(−/−) mice. Furthermore, creatinine inhibited organic cation transport in freshly isolated proximal tubules from wild-type mice and humans, but not in those from Oct1/2(−/−) mice. In a genetic association analysis (n = 590), several polymorphisms around the OCT2/SLC22A2 gene locus, including rs2504954 (P = 0.000873), were significantly associated with age-adjusted creatinine levels. Furthermore, in cancer patients (n = 68), the OCT2 substrate cisplatin caused an acute elevation of serum creatinine (P = 0.0083), consistent with inhibition of an elimination pathway.

Conclusions: Collectively, this study shows that OCT2 plays a decisive role in the renal secretion of creatinine. This process can be inhibited by OCT2 substrates, which impair the usefulness of creatinine as a marker of renal function. Clin Cancer Res; 18(4); 1101–8. ©2012 AACR.
Performance of Genotype Imputations Using Data from the 1000 Genomes Project
Authors: Sung Yun Ju , Wang Lihua , Rankinen Tuomo , Bouchard Claude , Rao D.C.
Published: December 2011

Genotype imputations based on 1000 Genomes (1KG) Project data have the advantage of imputing many more SNPs than imputations based on HapMap data. It also provides an opportunity to discover associations with relatively rare variants. Recent investigations are increasingly using 1KG data for genotype imputations, but only limited evaluations of the performance of this approach are available. In this paper, we empirically evaluated imputation performance using 1KG data by comparing imputation results to those using the HapMap Phase II data that have been widely used. We used three reference panels: the CEU panel consisting of 120 haplotypes from HapMap II and 1KG data (June 2010 release) and the EUR panel consisting of 566 haplotypes also from 1KG data (August 2010 release). We used Illumina 324,607 autosomal SNPs genotyped in 501 individuals of European ancestry. Our most important finding was that both 1KG reference panels provided much higher imputation yield than the HapMap II panel. There were more than twice as many successfully imputed SNPs as there were using the HapMap II panel (6.7 million vs. 2.5 million). Our second most important finding was that accuracy using both 1KG panels was high and almost identical to accuracy using the HapMap II panel. Furthermore, after removing SNPs with MACH Rsq <0.3, accuracy for both rare and low frequency SNPs was very high and almost identical to accuracy for common SNPs. We found that imputation using the 1KG-EUR panel had advantages in successfully imputing rare, low frequency and common variants. Our findings suggest that 1KG-based imputation can increase the opportunity to discover significant associations for SNPs across the allele frequency spectrum. Because the 1KG Project is still underway, we expect that later versions will provide even better imputation performance.
Comparison of Preserved Vascular Allografts Using Glycerol and University of Wisconsin Solution in a Goat Carotid Artery Transplantation Model
Authors: Fahner P.J. , Legemate D.A. , van der Wal A.C. , van Marle J. , Peters S.L.M. , van Eck C.F. , van Gulik T.M. , Idu M.M.
Published: December 2011

Background: Prosthetic grafts have poor patency rates in peripheral arterial reconstructions. Glycerol (GL)-preserved grafts are an alternative. The aim of this study was to examine patency, graft morphology and function of GL-preserved allografts in a goat carotid artery animal model. Methods: The first group (n = 7) underwent bilateral replacement of the carotid artery by a carotid allograft that was preserved in GL for 1 week. In the second group (n = 5), a carotid artery allograft that was preserved in University of Wisconsin solution (UW) for 48 h was used. In the third group (n = 5), the jugular vein (autologous vein, AU) was used. The follow-up was 3 months. Results: One UW graft and 1 GL graft occluded in the first 24 h postoperatively. Three-month primary patency rates for GL, UW and AU grafts were 93, 100 and 80%, respectively (p = 0.39). Graft diameter was increased in UW allografts (p < 0.005), whereas GL allografts remained unchanged. After explantation, GL allografts demonstrated contraction and relaxation capacity and lower intimal thickness (p < 0.001). Conclusion: GL preservation has proven to be a feasible method for arterial allograft transplantation in a large animal model with decreased intimal hyperplasia and renewed functional capability.
Clinical Correlates of Apathy in Patients Recently Diagnosed with Parkinson’s Disease: The ANIMO Study
Authors: Cubo Esther , Benito-León Julián , Coronell Carlos , Armesto Diana ,   on behalf of the ANIMO Study Group
Published: January 2012

Objective: Little is known about apathy in the early stages of Parkinson’s disease (PD). We determined the clinical correlates of apathy in a large representative sample of patients recently diagnosed with PD (ANIMO study). Methods: PD patients, diagnosed within 2 years of inclusion, were recruited in 102 outpatient clinics situated in 82 populations throughout Spain. Apathy was quantified using the Lille Apathy Rating Scale (LARS). Clinical comparisons and correlations were performed using nonparametric tests. Regression analyses were used to test the association of clinical variables with apathy. Results: We recruited 557 PD patients (60.3% men) with a mean age of 68.8 ± 9.7 years, and UPDRS motor score of 21.1 ± 10.8. Apathy only was diagnosed in 186 (33.4%), and apathy and depression in 215 patients (38.6%). Patients with higher comorbidity (OR = 1.10, 95% CI 1.01–1.20, p = 0.001), motor impairment (OR = 1.07, 95% CI 1.03–1.10, p < 0.0001), and lower education (OR = 2.16, 95% CI 1.21–3.85, p = 0.009) had higher odds of having apathy, in contrast to patients living in a rural environment (OR = 0.35, 95% CI 0.32–0.85, p = 0.01), and left predominant PD motor laterality (OR = 0.34, 95% CI 0.13–0.88, p = 0.01). LARS scores were significantly correlated with UPDRS motor scores (rs = 0.44, p < 0.001), predominantly with axial score (rs = 0.43, p < 0.001). Conclusions: In PD, apathy is a very common and disabling nonmotor symptom separable from depression. Patients living in a rural environment, with lower comorbidity and motor impairment, higher education background, and left predominant PD motor laterality are at lower risk of suffering from apathy.
Clinical Performance Targets and Quality of Life in Hemodialysis Patients
Authors: Mazairac Albert H.A. , de Wit G. Ardine , Grooteman Muriel P.C. , Penne E. Lars , van der Weerd Neelke C. , den Hoedt Claire H. , Lévesque Renée , van den Dorpel Marinus A. , Nubé Menso J. , ter Wee Piet M. , Blankestijn Peter J. , Bots Michiel L. ,   on behalf of the CONTRAST investigators
Published: December 2011

Background/Aims: Patients value health-related quality of life (HRQOL) over survival. It was our aim to study the relation between attainment of widely accepted performance targets and HRQOL in hemodialysis patients. Methods: This study included baseline data from 715 hemodialysis patients from 29 dialysis centers. Six clinical performance targets, as recommended by the Kidney Disease Outcomes Quality Initiative (KDOQI), were evaluated: single-pool Kt/V (≧1.2), hemoglobin (11–13 g/dl), vascular access (fistula), phosphorus (2.3–4.5 mg/dl), parathyroid hormone (150–300 pg/ml), and blood pressure (predialysis <140/90 and postdialysis <130/ 80 mm Hg). Results: After correction for case-mix and multiple comparisons, no association was found between the 6 KDOQI clinical performance targets and the 14 HRQOL domains, or between the number of performance targets reached and HRQOL. Conclusion: Attainment with widely accepted clinical performance targets was not related to the HRQOL of hemodialysis patients. Hence, in clinical guidelines, HRQOL should be adopted as an explicit treatment goal for these individuals.
The Primary Brain Vesicles Revisited: Are the Three Primary Vesicles (Forebrain/Midbrain/Hindbrain) Universal in Vertebrates
Authors: Ishikawa Yuji , Yamamoto Naoyuki , Yoshimoto Masami , Ito Hironobu
Published: January 2012

It is widely held that three primary brain vesicles (forebrain, midbrain, and hindbrain vesicles) develop into five secondary brain vesicles in all vertebrates (von Baer’s scheme). We reviewed previous studies in various vertebrates to see if this currently accepted scheme of brain morphogenesis is a rule applicable to vertebrates in general. Classical morphological studies on lamprey, shark, zebrafish, frog, chick, Chinese hamster, and human embryos provide only partial evidence to support the existence of von Baer’s primary vesicles at early stages. Rather, they suggest that early brain morphogenesis is diverse among vertebrates. Gene expression and fate map studies on medaka, chick, and mouse embryos show that the fates of initial brain vesicles do not accord with von Baer’s scheme, at least in medaka and chick brains. The currently accepted von Baer’s scheme of brain morphogenesis, therefore, is not a universal rule throughout vertebrates. We propose here a developmental hourglass model as an alternative general rule: Brain morphogenesis is highly conserved at the five-brain vesicle stage but diverges more extensively at earlier and later stages. This hypothesis does not preclude the existence of deep similarities in molecular prepatterns at early stages.
Inhibition of Bone Morphogenetic Protein Signaling Reduces Vascular Calcification and Atherosclerosis
Authors: Derwall Matthias , Malhotra Rajeev , Lai Carol S. , Beppu Yuko , Aikawa Elena , Seehra Jasbir S. , Zapol Warren M. , Bloch Kenneth D. , Yu Paul B.
Published: January 2012

Objective—

The expression of bone morphogenetic proteins (BMPs) is enhanced in human atherosclerotic and calcific vascular lesions. Although genetic gain- and loss-of-function experiments in mice have supported a causal role of BMP signaling in atherosclerosis and vascular calcification, it remains uncertain whether BMP signaling might be targeted pharmacologically to ameliorate both of these processes.

Methods and Results—

We tested the impact of pharmacological BMP inhibition on atherosclerosis and calcification in LDL receptor-deficient (LDLR
−/−
) mice. LDLR
−/−
mice fed a high-fat diet developed abundant vascular calcification within 20 weeks. Prolonged treatment of LDLR
−/−
mice with the small molecule BMP inhibitor LDN-193189 was well-tolerated and potently inhibited development of atheroma, as well as associated vascular inflammation, osteogenic activity, and calcification. Administration of recombinant BMP antagonist ALK3-Fc replicated the antiatherosclerotic and anti-inflammatory effects of LDN-193189. Treatment of human aortic endothelial cells with LDN-193189 or ALK3-Fc abrogated the production of reactive oxygen species induced by oxidized LDL, a known early event in atherogenesis. Unexpectedly, treatment of mice with LDN-193189 lowered LDL serum cholesterol by 35% and markedly decreased hepatosteatosis without inhibiting HMG-CoA reductase activity. Treatment with BMP2 increased, whereas LDN-193189 or ALK3-Fc inhibited apolipoprotein B100 secretion in HepG2 cells, suggesting that BMP signaling contributes to the regulation of cholesterol biosynthesis.

Conclusion—

These results definitively implicate BMP signaling in atherosclerosis and calcification, while uncovering a previously unidentified role for BMP signaling in LDL cholesterol metabolism. BMP inhibition may be helpful in the treatment of atherosclerosis and associated vascular calcification.
Figure–Ground Representation and Its Decay in Primary Visual Cortex
Authors: Strother Lars , Lavell Cheryl , Vilis Tutis
Published: January 2012

We used fMRI to study figure–ground representation and its decay in primary visual cortex (V1). Human observers viewed a motion-defined figure that gradually became camouflaged by a cluttered background after it stopped moving. V1 showed positive fMRI responses corresponding to the moving figure and negative fMRI responses corresponding to the static background. This positive–negative delineation of V1 “figure” and “background” fMRI responses defined a retinotopically organized figure–ground representation that persisted after the figure stopped moving but eventually decayed. The temporal dynamics of V1 “figure” and “background” fMRI responses differed substantially. Positive “figure” responses continued to increase for several seconds after the figure stopped moving and remained elevated after the figure had disappeared. We propose that the sustained positive V1 “figure” fMRI responses reflected both persistent figure–ground representation and sustained attention to the location of the figure after its disappearance, as did subjects' reports of persistence. The decreasing “background” fMRI responses were relatively shorter-lived and less biased by spatial attention. Our results show that the transition from a vivid figure–ground percept to its disappearance corresponds to the concurrent decay of figure enhancement and background suppression in V1, both of which play a role in form-based perceptual memory.
Multa curiosa Vallisneri's Early Studies on Earth Sciences
Authors: Luzzini Francesco
Published: December 2011

In 1687, after he graduated in Medicine, young Antonio Vallisneri (1661-1730) returned in the Duchy of Modena and Reggio. In those years he mainly served as general practitioner; nevertheless, he also devoted many studies to various aspects of the natural sciences. He performed many observations, accurately reporting them in seven Quaderni, which were compiled between 1694 and 1701.Though the Earth sciences occupy only a small part of these diaries, the accuracy of the notes makes them a precious token of the scientific praxis adopted by the author in this field of study. This paper deals with the analysis of these early geological reports, pointing out the main criteria of Vallisneri's experimental method and paying attention to the great significance which these documents had in the elaboration of some of his published works.
OSCE field activities: verbal encouragement, factual cutback
Authors: Evers Frank
Published: December 2011

The OSCE reality reveals an ambiguous picture of the Organization's field activities. There is significant verbal encouragement, but also hesitation about further field engagements and an alarming actual cutback of existing field missions. During the Corfu Process in 2009-10, the participating States shared with each other opinions on these processes in a friendly tone which was as such a positive signal. At the OSCE Summit in Astana in December 2010, the Heads of State or Government of the 56 OSCE participating States collectively emphasized the value of the OSCE field missions. Beyond the declarations however, the picture is quite disappointing, the reduction of OSCE field activities that started about a decade ago continues on. Reasons include the marginalisation of the OSCE in general and emphasis put on other international organisations, fundamental mistrust and divergences between participating States, the perception of OSCE field operations as vehicles for interfering into internal affairs and traditional zones of interest, budgetary constraints of many participating States, shifts of regional interests and the takeover of various activities and responsibilities by the European Union, especially in South-eastern Europe. Apart from this, it is particularly disquieting that the OSCE is clearly about to lose its position as leading conflict manager. The second Kyrgyz crisis in June 2010 demonstrated once again the deep uncertainties in various participating States about OSCE conflict mediation. Aside from diverse brainstorming activities hosted by the Lithuanian OSCE Chairmanship in 2011, there is currently no fundamental discussion on preventing the Organization's field activities from slowly, but surely losing profile and standing.