bluuebunny/crossref_metadata_2025 huggingface dataset:
Minimizing movement in mobile facility location problems
Authors: Friggstad Zachary , Salavatipour Mohammad R.
Published: July 2011

In the
mobile facility location
problem, which is a variant of the classical facility location, each facility and client is assigned to a start location in a metric graph and our goal is to find a destination node for each client and facility such that every client is sent to a node which is the destination of some facility. The quality of a solution can be measured either by the total distance clients and facilities travel or by the maximum distance traveled by any client or facility. As we show in this article (by an approximation-preserving reduction), the problem of minimizing the total movement of facilities and clients generalizes the classical
k
-median problem. The class of movement problems was introduced by Demaine et al. [2007] where a simple 2-approximation was proposed for the minimum maximum movement mobile facility location problem while an approximation for the minimum total movement variant and hardness results for both were left as open problems. Our main result here is an 8-approximation algorithm for the minimum total movement mobile facility location problem. Our algorithm is obtained by rounding an LP relaxation in five phases. For the minimum maximum movement mobile facility location problem, we show that we cannot have a better than a 2-approximation for the problem, unless
P
=
NP
so the simple algorithm proposed by Demaine et al. [2007] is essentially best possible.
Move to design/design to move
Authors: Wilde Danielle , Schiphorst Thecla , Klooster Sietske
Published: July 2011

The boundaries between 'the digital' and our everyday physical world are dissolving as we develop more physical ways of interacting with computing. This forum presents some of the topics discussed in the colorful multidisciplinary field of tangible and embodied interaction.

Eva Hornecker, Editor
A Theory of Synchronous Relational Interfaces
Authors: Tripakis Stavros , Lickly Ben , Henzinger Thomas A. , Lee Edward A.
Published: July 2011

Compositional theories are crucial when designing large and complex systems from smaller components. In this work we propose such a theory for synchronous concurrent systems. Our approach follows so-called interface theories, which use game-theoretic interpretations of composition and refinement. These are appropriate for systems with distinct inputs and outputs, and explicit conditions on inputs that must be enforced during composition. Our interfaces model systems that execute in an infinite sequence of synchronous rounds. At each round, a contract must be satisfied. The contract is simply a relation specifying the set of valid input/output pairs. Interfaces can be composed by parallel, serial or feedback composition. A refinement relation between interfaces is defined, and shown to have two main properties: (1) it is preserved by composition, and (2) it is equivalent to substitutability, namely, the ability to replace an interface by another one in any context. Shared refinement and abstraction operators, corresponding to greatest lower and least upper bounds with respect to refinement, are also defined. Input-complete interfaces, that impose no restrictions on inputs, and deterministic interfaces, that produce a unique output for any legal input, are discussed as special cases, and an interesting duality between the two classes is exposed. A number of illustrative examples are provided, as well as algorithms to compute compositions, check refinement, and so on, for finite-state interfaces.
Breaking the
O
(
n
2
) bit barrier
Authors: King Valerie , Saia Jared
Published: July 2011

We describe an algorithm for Byzantine agreement that is scalable in the sense that each processor sends only Õ(√
n
) bits, where
n
is the total number of processors. Our algorithm succeeds with high probability against an
adaptive adversary
, which can take over processors at any time during the protocol, up to the point of taking over arbitrarily close to a 1/3 fraction. We assume synchronous communication but a
rushing
adversary. Moreover, our algorithm works in the presence of flooding: processors controlled by the adversary can send out any number of messages. We assume the existence of private channels between all pairs of processors but make no other cryptographic assumptions. Finally, our algorithm has latency that is polylogarithmic in
n
. To the best of our knowledge, ours is the first algorithm to solve Byzantine agreement against an adaptive adversary, while requiring
o
(
n
2
) total bits of communication.
Fast construction of the HYB index
Authors: Bast Hannah , Celikik Marjan
Published: July 2011

As shown in a series of recent works, the HYB index is an alternative to the inverted index (INV) that enables very fast prefix searches, which in turn is the basis for fast processing of many other types of advanced queries, including autocompletion, faceted search, error-tolerant search, database-style select and join, and semantic search. In this work we show that HYB can be constructed at least as fast as INV, and often up to twice as fast. This is because HYB, by its nature, requires only a half-inversion of the data and allows an efficient in-place instead of the traditional merge-based index construction. We also pay particular attention to the cache efficiency of the in-memory posting accumulation, an issue that has not been addressed in previous work, and show that our simple multilevel posting accumulation scheme yields much fewer cache misses compared to related approaches. Finally, we show that HYB supports fast dynamic index updates more easily than INV.
A Comprehensive Study of Features and Algorithms for URL-Based Topic Classification
Authors: Baykan Eda , Henzinger Monika , Marian Ludmila , Weber Ingmar
Published: July 2011

Given
only
the URL of a Web page, can we identify its topic? We study this problem in detail by exploring a large number of different feature sets and algorithms on several datasets. We also show that the inherent overlap between topics and the sparsity of the information in URLs makes this a very challenging problem. Web page classification without a page’s content is desirable when the content is not available at all, when a classification is needed before obtaining the content, or when classification speed is of utmost importance. For our experiments we used five different corpora comprising a total of about 3 million (URL, classification) pairs. We evaluated several techniques for feature generation and classification algorithms. The individual binary classifiers were then combined via boosting into metabinary classifiers. We achieve typical F-measure values between 80 and 85, and a typical precision of around 86. The precision can be pushed further over 90 while maintaining a typical level of recall between 30 and 40.
Honesty is the best policy---part 1
Authors: Denning Peter
Published: July 2011

Untrustworthy information is an increasing threat to decision making in information environments. Rick Hayes-Roth has been studying how to detect and filter away untrustworthy information and base decisions on well-grounded claims that can improve outcomes. We interviewed him to find out more about this problem and get advice for our readers. Although there are many subtleties in the shades of truth and the intentions of speakers and listeners, Hayes-Roth finds the essential core of what you can do to ward off untrustworthy information.
Honesty is the best policy---Part 2
Authors: Denning Peter
Published: July 2011

Untrustworthy information is an increasing threat to decision making in information environments. Rick Hayes-Roth has been studying how to detect and filter away untrustworthy information and base decisions on well-grounded claims that can improve outcomes. In last week's installment of this two-part interview, we focused on the problem and the principles that help ameliorate it. In this installment, we focus on the means to implement the principles in our information environments.
Virtual machine monitor-based lightweight intrusion detection
Authors: Azmandian Fatemeh , Moffie Micha , Alshawabkeh Malak , Dy Jennifer , Aslam Javed , Kaeli David
Published: July 2011

As virtualization technology gains in popularity, so do attempts to compromise the security and integrity of virtualized computing resources. Anti-virus software and firewall programs are typically deployed in the guest virtual machine to detect malicious software. These security measures are effective in detecting known malware, but do little to protect against new variants of intrusions. Intrusion detection systems (IDSs) can be used to detect malicious behavior. Most intrusion detection systems for virtual execution environments track behavior at the application or operating system level, using virtualization as a means to isolate themselves from a compromised virtual machine.

In this paper, we present a novel approach to intrusion detection of virtual server environments which utilizes only information available from the perspective of the virtual machine monitor (VMM). Such an IDS can harness the ability of the VMM to isolate and manage several virtual machines (VMs), making it possible to provide monitoring of intrusions at a common level across VMs. It also offers unique advantages over recent advances in intrusion detection for virtual machine environments. By working purely at the VMM-level, the IDS does not depend on structures or abstractions visible to the OS (e.g., file systems), which are susceptible to attacks and can be modified by malware to contain corrupted information (e.g., the Windows registry). In addition, being situated within the VMM provides ease of deployment as the IDS is not tied to a specific OS and can be deployed transparently below different operating systems.

Due to the semantic gap between the information available to the VMM and the actual application behavior, we employ the power of data mining techniques to extract useful nuggets of knowledge from the raw, low-level architectural data. We show in this paper that by working entirely at the VMM-level, we are able to capture enough information to characterize normal executions and identify the presence of abnormal malicious behavior. Our experiments on over 300 real-world malware and exploits illustrate that there is sufficient information embedded within the VMM-level data to allow accurate detection of malicious attacks, with an acceptable false alarm rate.
Gem #67
Authors: Briot Emmanuel
Published: July 2011

GPS has a multitude of views and editors, several of which may be displayed on the screen at the same time. It is based on a very flexible desktop that helps you organize these windows the way you prefer. This Gem describes some of the lesserknown aspects of the GPS desktop.
Gem #68
Authors: Moy Yannick
Published: July 2011

In this Gem and the next one, we present a simple walk-through of SPARK's capabilities and its integration with GPS. In this first Gem, we show how to set up a SPARK project and prove that your SPARK programs are free from uninitialized variable accesses and that they execute without run-time errors.
Gem #69
Authors: Moy Yannick
Published: July 2011

In this Gem and the previous one, we give you a simple walkthrough of SPARK's capabilities and its integration with GPS. In the previous Gem, we showed how to set up a SPARK project and prove that your SPARK programs are free from uninitialized variable accesses and that they execute without run-time errors. In this Gem, we show how to prove that your SPARK programs respect given contracts.
Gem #70
Authors: Rogers Pat
Published: July 2011

This Gem marks a brief break from SPARK, which will return in two weeks with the first in a series of six Gems on that topic. Encapsulating shared variables inside protected operations is not always possible. This Gem shows how to add mutual exclusion to existing sequential code using a combination of controlled and protected types, such that the resulting code is robust and minimally changed.
Gem #71
Authors: Kuo Dean , Wallenburg Angela
Published: July 2011

In previous Gems, we saw how to create a SPARK project in GPS, and how to run the Examiner and Simplifier tools to verify various properties of a simple linear search function. In this series of Gems on SPARK, we will explore SPARK capabilities in greater depth, using source code from Tokeneer, an NSA-funded, highly secure biometric software system. In this Gem, we show how to deal with improper initialization.
Gem #73
Authors: Kuo Dean , Wallenburg Angela
Published: July 2011

In the previous Gem in this series, we saw how to identify ineffective statements in SPARK, based on source code from Tokeneer. In this Gem, we show how to validate input.
Virtualization in the age of heterogeneous machines
Authors: Bacon David F.
Published: July 2011

Since their invention over 40 years ago, virtual machines have been used to virtualize one or more von Neumann processors and their associated peripherals. System virtual machines provide the illusion that the user has their own instance of a physical machine with a given instruction set architecture (ISA). Process virtual machines provide the illusion of running on a synthetic architecture independent of the underlying ISA, generally for the purpose of supporting a high-level language.

To continue the historical trend of exponential increase in computational power in the face of limits on clock frequency scaling, we must find ways to harness the inherent parallelism of billions of transistors. I contend that multi-core chips are a fatally flawed approach - instead, maximum performance will be achieved by using heterogeneous chips and systems that combine customized and customizable computational substrates that achieve very high performance by closely matching the computational and communications structures of the application at hand.

Such chips might look like a mashup of a conventional multicore, a GPU, an FPGA, some ASICs, and a DSP. But programming them with current technologies would be nightmarishly complex, portability would be lost, and innovation between chip generations would be severely limited.

The answer (of course) is virtualization, and at both the device level and the language level.

In this talk I will illustrate some challenges and potential solutions in the context of IBM's Liquid Metal project, in which we are designing a new high-level language (Lime) and compiler/runtime technology to virtualize the underlying computational devices by providing a uniform semantic model.

I will also discuss problems (and opportunities) that this raises at the operating system and data center levels, particularly with computational elements like FPGAs for which "context switching" is currently either extremely expensive or simply impossible.
ReHype
Authors: Le Michael , Tamir Yuval
Published: July 2011

With existing virtualized systems, hypervisor failures lead to overall system failure and the loss of all the work in progress of virtual machines (VMs) running on the system. We introduce ReHype, a mechanism for recovery from hypervisor failures by booting a new instance of the hypervisor while preserving the state of running VMs. VMs are stalled during the hypervisor reboot and resume normal execution once the new hypervisor instance is running. Hypervisor failures can lead to arbitrary state corruption and inconsistencies throughout the system. ReHype deals with the challenge of protecting the recovered hypervisor instance from such corrupted state and resolving inconsistencies between different parts of hypervisor state as well as between the hypervisor and VMs and between the hypervisor and the hardware. We have implemented ReHype for the Xen hypervisor. The implementation was done incrementally, using results from fault injection experiments to identify the sources of dangerous state corruption and inconsistencies. The implementation of ReHype involved only 880 LOC added or modified in Xen. The memory space overhead of ReHype is only 2.1MB for a pristine copy of the hypervisor code and static data plus a small reserved memory area. The fault injection campaigns used to evaluate the effectiveness of ReHype involved a system with multiple VMs running I/O and hypercall-intensive benchmarks. Our experimental results show that the ReHype prototype can successfully recover from over 90% of detected hypervisor failures.
Evaluation of delta compression techniques for efficient live migration of large virtual machines
Authors: Svärd Petter , Hudzia Benoit , Tordsson Johan , Elmroth Erik
Published: July 2011

Despite the widespread support for live migration of Virtual Machines (VMs) in current hypervisors, these have significant shortcomings when it comes to migration of certain types of VMs. More specifically, with existing algorithms, there is a high risk of service interruption when migrating VMs with high workloads and/or over low-bandwidth networks. In these cases, VM memory pages are dirtied faster than they can be transferred over the network, which leads to extended migration downtime. In this contribution, we study the application of delta compression during the transfer of memory pages in order to increase migration throughput and thus reduce downtime. The delta compression live migration algorithm is implemented as a modification to the KVM hypervisor. Its performance is evaluated by migrating VMs running different type of workloads and the evaluation demonstrates a significant decrease in migration downtime in all test cases. In a benchmark scenario the downtime is reduced by a factor of 100. In another scenario a streaming video server is live migrated with no perceivable downtime to the clients while the picture is frozen for eight seconds using standard approaches. Finally, in an enterprise application scenario, the delta compression algorithm successfully live migrates a very large system that fails after migration using the standard algorithm. Finally, we discuss some general effects of delta compression on live migration and analyze when it is beneficial to use this technique.
CloudNet
Authors: Wood Timothy , Ramakrishnan K. K. , Shenoy Prashant , van der Merwe Jacobus
Published: July 2011

Virtual machine technology and the ease with which VMs can be migrated within the LAN, has changed the scope of resource management from allocating resources on a single server to manipulating pools of resources within a data center. We expect WAN migration of virtual machines to likewise transform the scope of provisioning compute resources from a single data center to multiple data centers spread across the country or around the world. In this paper we present the CloudNet architecure as a cloud framework consisting of cloud computing platforms linked with a VPN based network infrastructure to provide seamless and secure connectivity between enterprise and cloud data center sites. To realize our vision of efficiently pooling geographically distributed data center resources, CloudNet provides optimized support for live WAN migration of virtual machines. Specifically, we present a set of optimizations that minimize the cost of transferring storage and virtual machine memory during migrations over low bandwidth and high latency Internet links. We evaluate our system on an operational cloud platform distributed across the continental US. During simultaneous migrations of four VMs between data centers in Texas and Illinois, CloudNet's optimizations reduce memory migration time by 65% and lower bandwidth consumption for the storage and memory transfer by 19GB, a 50% reduction.
Virtual WiFi
Authors: Xia Lei , Kumar Sanjay , Yang Xue , Gopalakrishnan Praveen , Liu York , Schoenberg Sebastian , Guo Xingang
Published: July 2011

As virtualization trend is moving towards "client virtualization", wireless virtualization remains to be one of the technology gaps that haven't been addressed satisfactorily. Today's approaches are mainly developed for wired network, and are not suitable for virtualizing wireless network interface due to the fundamental differences between wireless and wired LAN devices that we will elaborate in this paper. We propose a wireless LAN virtualization approach named virtual WiFi that addresses the technology gap. With our proposed solution, the full wireless LAN functionalities are supported inside virtual machines; each virtual machine can establish its own connection with self-supplied credentials; and multiple separate wireless LAN connections are supported through one physical wireless LAN network interface. We designed and implemented a prototype for our proposed virtual WiFi approach, and conducted detailed performance study. Our results show that with conventional virtualization overhead mitigation mechanisms, our proposed approach can support fully functional wireless functions inside VM, and achieve close to native performance of Wireless LAN with moderately increased CPU utilization.
The short-chain fatty acid butyrate is a substrate of breast cancer resistance protein
Authors: Gonçalves Pedro , Gregório Inês , Martel Fátima
Published: July 2011

Colorectal cancer is one of the most common cancers worldwide. Butyrate (BT) plays a key role in colonic epithelium homeostasis. The aim of this work was to investigate the possibility of BT being transported by P-glycoprotein (MDR1), multidrug resistance proteins (MRPs), or breast cancer resistance protein (BCRP). Uptake and efflux of 14C-BT and 3H-folic acid were measured in Caco-2, IEC-6, and MDA-MB-231 cell lines. mRNA expression of BCRP was detected by RT-PCR. Cell viability, proliferation, and differentiation were quantified with the lactate dehydrogenase, sulforhodamine B, and alkaline phosphatase activity assays, respectively. In both IEC-6 cells and Caco-2 cells, no evidence was found for the involvement of either MDR1 or MRPs in 14C-BT efflux from the cells. In contrast, several lines of evidence support the conclusion that BT is a substrate of both rat and human BCRP. Indeed, BCRP inhibitors reduced 14C-BT efflux in IEC-6 cells, both BT and BCRP inhibitors significantly decreased the efflux of the known BCRP substrate 3H-folic acid in IEC-6 cells, and BCRP inhibitors reduced 14C-BT efflux in the BCRP-expressing MDA-MB-231 cell line. In IEC-6 cells, combination of BT with a BCRP inhibitor significantly potentiated the effect of BT on cell proliferation. The results of this study, showing for the first time that BT is a BCRP substrate, are very important in the context of the high levels of BCRP expression in the human colon and the anticarcinogenic and anti-inflammatory role of BT at that level. So, interaction of BT with BCRP and with other BCRP substrates/inhibitors is clearly of major importance.
Low glucose sensitivity and polymodal chemosensing in neonatal rat adrenomedullary chromaffin cells
Authors: Livermore S. , Piskuric N. A. , Buttigieg J. , Zhang M. , Nurse C. A.
Published: July 2011

Glucose is the primary metabolic fuel in mammalian fetuses, yet mammals are incapable of endogenous glucose production until several hours after birth. Thus, when the maternal supply of glucose ceases at birth there is a transient hypoglycemia that elicits a counterregulatory surge in circulating catecholamines. Because the innervation of adrenomedullary chromaffin cells (AMCs) is immature at birth, we hypothesized that neonatal AMCs act as direct glucosensors, a property that could complement their previously established roles as hypoxia and acid hypercapnia sensors. During perforated-patch, whole cell recordings, low glucose depolarized and/or excited a subpopulation of neonatal AMCs; in addition, aglycemia (0 mM glucose) caused inhibition of outward K+ current, blunted by the simultaneous activation of glibenclamide-sensitive KATP channels. Some cells were excited by each of the three metabolic stimuli, i.e., aglycemia, hypoxia (Po2 ∼30 mmHg), and isohydric hypercapnia (10% CO2; pH = 7.4). Using carbon fiber amperometry, aglycemia and hypoglycemia (3 mM glucose) induced robust catecholamine secretion that was sensitive to nickel (50 μM and 2 mM) and the L-type Ca2+ channel blocker nifedipine (10 μM), suggesting involvement of both T-type and L-type voltage-gated Ca2+ channels. Fura-2 measurements of intracellular Ca2+ ([Ca2+] i) revealed that ∼42% of neonatal AMCs responded to aglycemia with a significant rise in [Ca2+] i. Approximately 40% of these cells responded to hypoxia, whereas ∼25% cells responded to both aglycemia and hypoxia. These data suggest that together with hypoxia and acid hypercapnia, low glucose is another important metabolic stimulus that contributes to the vital asphyxia-induced catecholamine surge from AMCs at birth.
Endotoxin transiently inhibits protein synthesis through Akt and MAPK mediating pathways in C2C12 myotubes
Authors: Tarabees R. , Hill D. , Rauch C. , Barrow P. A. , Loughna P. T.
Published: July 2011

In this study, the effect of lipopolysaccharide (LPS) on protein synthesis (PS) and intracellular signaling factors that regulate it have been investigated in C2C12 murine-derived myotubes. In particular, the role of Akt/mammalian target of rapamycin (mTOR) and the mitogen-activated protein kinases (MAPKs) [p38 and extracelluar regulated protein kinase (ERK1/2)] have been examined. The direct effect of LPS on PS was measured at 3 and 18 h. LPS significantly decreased PS at 3 h but not at the 18-h time point. This effect was preceded by decreased Akt phosphorylation at 5 and 30 min after LPS administration. The mTOR phosphorylation exhibited a long time dose-dependent increase at all the time points. Similarly, the activity-related phosphorylation of p38 and ERK1/2 significantly increased in a time- and dose-dependent manner at all the time points. Polymyxin B abolished the LPS-induced decrease in PS rate. The phosphatidylinositol 3-kinase inhibitor LY-0294002 in combination with LPS significantly decreased the rate of PS by 81% and alone by 66%, respectively, for the 3- and 18-h time points, whereas p38 and ERK inhibitors in combination with LPS significantly decreased the rate PS rate at the 18-h time point by 41% and 59%, respectively, compared with control cells. In conclusion, LPS alone transiently decreased the rate of PS by 50% at 3 h; this effect is most likely mediated via the Toll-like receptor 4 (TLR4)-Akt/mTOR pathway, and both p38 and ERK when inhibited in the presence of LPS at 3 h have a similar effect in preventing the LPS-induced reduction in PS.
Molecular and structural antioxidant defenses against oxidative stress in animals
Authors: Pamplona Reinald , Costantini David
Published: July 2011

In this review, it is our aim 1) to describe the high diversity in molecular and structural antioxidant defenses against oxidative stress in animals, 2) to extend the traditional concept of antioxidant to other structural and functional factors affecting the “whole” organism, 3) to incorporate, when supportable by evidence, mechanisms into models of life-history trade-offs and maternal/epigenetic inheritance, 4) to highlight the importance of studying the biochemical integration of redox systems, and 5) to discuss the link between maximum life span and antioxidant defenses. The traditional concept of antioxidant defenses emphasizes the importance of the chemical nature of molecules with antioxidant properties. Research in the past 20 years shows that animals have also evolved a high diversity in structural defenses that should be incorporated in research on antioxidant responses to reactive species. Although there is a high diversity in antioxidant defenses, many of them are evolutionary conserved across animal taxa. In particular, enzymatic defenses and heat shock response mediated by proteins show a low degree of variation. Importantly, activation of an antioxidant response may be also energetically and nutrient demanding. So knowledge of antioxidant mechanisms could allow us to identify and to quantify any underlying costs, which can help explain life-history trade-offs. Moreover, the study of inheritance mechanisms of antioxidant mechanisms has clear potential to evaluate the contribution of epigenetic mechanisms to stress response phenotype variation.
Hydrogel-embedded endothelial progenitor cells evade LPS and mitigate endotoxemia
Authors: Ghaly Tammer , Rabadi May M. , Weber Mia , Rabadi Seham M. , Bank Michael , Grom John M. , Fallon John T. , Goligorsky Michael S. , Ratliff Brian B.
Published: July 2011

Sepsis and its complications are associated with poor clinical outcomes. The circulatory system is a well-known target of lipopolysaccharide (LPS). Recently, several clinical studies documented mobilization of endothelial progenitor cells (EPCs) during endotoxemia, with the probability of patients' survival correlating with the rise in circulating EPCs. This fact combined with endotoxemia-induced vascular injury led us to hypothesize that the developing functional EPC incompetence could impede vascular repair and that adoptive transfer of EPCs could improve hemodynamics in endotoxemia. We used LPS injection to model endotoxemia. EPCs isolated from endotoxemic mice exhibited impaired clonogenic potential and LPS exerted Toll-like receptor 4-mediated cytotoxic effects toward EPCs, which was mitigated by embedding them in hyaluronic acid (HA) hydrogels. Therefore, intact EPCs were either delivered intravenously or embedded within pronectin-coated HA hydrogels. Adoptive transfer of EPCs in LPS-injected mice improved control of blood pressure and reduced hepatocellular and renal dysfunction. Specifically, EPC treatment was associated with the restoration of renal microcirculation and improved renal function. EPC therapy was most efficient when cells were delivered embedded in HA hydrogel. These findings establish major therapeutic benefits of adoptive transfer of EPCs, especially when embedded in HA hydrogels, in mice with LPS-induced endotoxemia, and they argue that hemodynamic and renal abnormalities of endotoxemia are in significant part due to developing incompetence of endogenous EPCs.
Acute laminar shear stress reversibly increases human glomerular endothelial cell permeability via activation of endothelial nitric oxide synthase
Authors: Bevan Heather S. , Slater Sadie C. , Clarke Hayley , Cahill Paul A. , Mathieson Peter W. , Welsh Gavin I. , Satchell Simon C.
Published: July 2011

Laminar shear stress is a key determinant of systemic vascular behavior, including through activation of endothelial nitric oxide synthase (eNOS), but little is known of its role in the glomerulus. We confirmed eNOS expression by glomerular endothelial cells (GEnC) in tissue sections and examined effects of acute exposure (up to 24 h) to physiologically relevant levels of laminar shear stress (10–20 dyn/cm2) in conditionally immortalized human GEnC. Laminar shear stress caused an orientation of GEnC and stress fibers parallel to the direction of flow and induced Akt and eNOS phosphorylation along with NO production. Inhibition of the phophatidylinositol (PI)3-kinase/Akt pathway attenuated laminar shear stress-induced eNOS phosphorylation and NO production. Laminar shear stress of 10 dyn/cm2 had a dramatic effect on GEnC permeability, reversibly decreasing the electrical resistance across GEnC monolayers. Finally, the laminar shear stress-induced reduction in electrical resistance was attenuated by the NOS inhibitors l- NG-monomethyl arginine (l-NMMA) and l- NG-nitroarginine methyl ester (l-NAME) and also by inhibition of the PI3-kinase/Akt pathway. Hence we have shown for GEnC in vitro that acute permeability responses to laminar shear stress are dependent on NO, produced via activation of the PI3-kinase/Akt pathway and increased eNOS phosphorylation. These results suggest the importance of laminar shear stress and NO in regulating the contribution of GEnC to the permeability properties of the glomerular capillary wall.
Effect of twitch interval duration on the contractile function of subsequent twitches in isolated rat, rabbit, and dog myocardium under physiological conditions
Authors: Xu Ying , Monasky Michelle M. , Hiranandani Nitisha , Haizlip Kaylan M. , Billman George E. , Janssen Paul M. L.
Published: July 2011

Many studies have shown that a change in stimulation frequency leads to altered contractility of the myocardium. However, it remains unclear what changes occur directly after a change in frequency and which ones are a result of the slow processes that lead to the altered homeostasis, which develops after a change in stimulation frequency. To distinguish the immediate from the slow responses, we assessed contractile function in two species that have distinctively different calcium (Ca2+)-handling properties using a recently developed, randomized pacing protocol. In isolated dog and rat right ventricular trabeculae, twitch contractions at five different cycle lengths within the physiologic range of each species were randomized around a steady-state frequency. We found, in both species, that the duration of the cycle length just prior to the analyzed twitch (primary) positively correlated with the increased force of the analyzed twitch. In sharp contrast, the cycle lengths, one and two more removed from the analyzed twitch (“secondary” and “tertiary”), displayed a negative correlation with force of the analyzed twitch. In additional experiments, assessment of intracellular Ca2+ transients in rabbit trabeculae revealed that diastolic Ca2+ levels were closely correlated to contractile function outcome. The relative contribution of the primary cycle length was different between dog (51%) and rat (71%), whereas in neither species was a significant effect on relaxation time observed. With the use of randomized cycle lengths, we have distinguished the intrinsic response from the signaling-mediated effects of frequency-dependent activation on myofilament properties and Ca2+ handling.
Skilled throwers use physics to time ball release to the nearest millisecond
Authors: Hore Jon , Watts Sherry
Published: July 2011

Skilled throwers achieve accuracy in overarm throwing by releasing the ball on the handpath with a timing precision as low as 1 ms. It is generally believed that this remarkable ability results from a precisely timed command from the brain that opens the fingers. Alternatively, precise timing of ball release could result from a backforce from the ball that pushes the fingers open. The objective was to test these hypotheses in skilled throwers. Angular positions of the hand and phalanges of the middle finger were recorded with the search-coil technique. In support of the backforce hypothesis, we found that when subjects made a throwing motion without a ball in the hand (i.e., without a backforce), they could not open the fingers rapidly, and they had lost the ability to time finger opening in the 1- to 2-ms range. In addition, relationships were found between the magnitude and timing of hand angular acceleration and finger (joint) extension acceleration. The results indicate that although a central command produced initial hand opening, precise timing of ball release came from a mechanism involving Newtonian mechanics, i.e., hand acceleration produced a backforce from the ball on the fingers that pushed the fingers open. In this mechanism, given the appropriate finger force/stiffness, correction for errors in hand acceleration occurs automatically because hand motion causes finger motion. We propose that skilled throwers achieve ball accuracy by computing finger force/stiffness based on state estimation of hand acceleration and that ball inaccuracy occurs when this computation is imprecise.
Role of mutual inhibition in binocular rivalry
Authors: Seely Jeffrey , Chow Carson C.
Published: July 2011

Binocular rivalry is a phenomenon that occurs when a different image is presented to each eye. The observer generally perceives just one image at a time, with perceptual switches occurring every few seconds. A natural assumption is that this perceptual mutual exclusivity is achieved via mutual inhibition between populations of neurons that encode for either percept. Theoretical models that incorporate mutual inhibition have been largely successful at capturing experimental features of rivalry, including Levelt's propositions, which characterize perceptual dominance durations as a function of image contrasts. However, basic mutual inhibition models do not fully comply with Levelt's fourth proposition, which states that percepts alternate faster as the stimulus contrasts to both eyes are increased simultaneously. This theory-experiment discrepancy has been taken as evidence against the role of mutual inhibition for binocular rivalry. Here, we show how various biophysically plausible modifications to mutual inhibition models can resolve this problem.
Population spatiotemporal dynamics of spinal intermediate zone interneurons during air-stepping in adult spinal cats
Authors: AuYong Nicholas , Ollivier-Lanvin Karen , Lemay Michel A.
Published: July 2011

The lumbar spinal cord circuitry can autonomously generate locomotion, but it remains to be determined which types of neurons constitute the locomotor generator and how their population activity is organized spatially in the mammalian spinal cord. In this study, we investigated the spatiotemporal dynamics of the spinal interneuronal population activity in the intermediate zone of the adult mammalian cord. Segmental interneuronal population activity was examined via multiunit activity (MUA) during air-stepping initiated by perineal stimulation in subchronic spinal cats. In contrast to single-unit activity, MUA provides a continuous measure of neuronal activity within a ∼100-μm volume around the recording electrode. MUA was recorded during air-stepping, along with hindlimb muscle activity, from segments L3 to L7 with two multichannel electrode arrays placed into the left and right hemicord intermediate zones (lamina V–VII). The phasic modulation and spatial organization of MUA dynamics were examined in relation to the locomotor cycle. Our results show that segmental population activity is modulated with respect to the ipsilateral step cycle during air-stepping, with maximal activity occurring near the ipsilateral swing to stance transition period. The phase difference between the population activity within the left and right hemicords was also found to correlate to the left-right alternation of the step cycle. Furthermore, examination of MUA throughout the rostrocaudal extent showed no differences in population dynamics between segmental levels, suggesting that the spinal interneurons targeted in this study may operate as part of a distributed “clock” mechanism rather than a rostrocaudal oscillation as seen with motoneuronal activity.
Modulation of inhibitory strength and kinetics facilitates regulation of persistent inward currents and motoneuron excitability following spinal cord injury
Authors: Venugopal Sharmila , Hamm Thomas M. , Crook Sharon M. , Jung Ranu
Published: July 2011

Spasticity is commonly observed after chronic spinal cord injury (SCI) and many other central nervous system disorders (e.g., multiple sclerosis, stroke). SCI-induced spasticity has been associated with motoneuron hyperexcitability partly due to enhanced activation of intrinsic persistent inward currents (PICs). Disrupted spinal inhibitory mechanisms also have been implicated. Altered inhibition can result from complex changes in the strength, kinetics, and reversal potential ( ECl−) of γ-aminobutyric acid A (GABAA) and glycine receptor currents. Development of optimal therapeutic strategies requires an understanding of the impact of these interacting factors on motoneuron excitability. We employed computational methods to study the effects of conductance, kinetics, and ECl− of a dendritic inhibition on PIC activation and motoneuron discharge. A two-compartment motoneuron with enhanced PICs characteristic of SCI and receiving recurrent inhibition from Renshaw cells was utilized in these simulations. This dendritic inhibition regulated PIC onset and offset and exerted its strongest effects at motoneuron recruitment and in the secondary range of the current-frequency relationship during PIC activation. Increasing inhibitory conductance compensated for moderate depolarizing shifts in ECl− by limiting PIC activation and self-sustained firing. Furthermore, GABAA currents exerted greater control on PIC activation than glycinergic currents, an effect attributable to their slower kinetics. These results suggest that modulation of the strength and kinetics of GABAA currents could provide treatment strategies for uncontrollable spasms.
Topological basis of epileptogenesis in a model of severe cortical trauma
Authors: Volman Vladislav , Sejnowski Terrence J. , Bazhenov Maxim
Published: July 2011

Epileptic activity often arises after a latent period following traumatic brain injury. Several factors contribute to the emergence of post-traumatic epilepsy, including disturbances to ionic homeostasis, pathological action of intrinsic and synaptic homeostatic plasticity, and remodeling of anatomical network synaptic connectivity. We simulated a large-scale, biophysically realistic computational model of cortical tissue to study the mechanisms underlying the genesis of post-traumatic paroxysmal epileptic-like activity in the deafferentation model of a severely traumatized cortical network. Post-traumatic generation of paroxysmal events did not require changes of the structural connectivity. Rather, network bursts were induced following the action of homeostatic synaptic plasticity, which selectively influenced functionally dominant groups of intact neurons with preserved inputs. This effect critically depended on the spatial density of intact neurons. Thus in the deafferentation model of post-traumatic epilepsy, a trauma-induced change in functional (rather than anatomical) connectivity might be sufficient for epileptogenesis.
Bringing up the rear: new premotor interneurons add regional complexity to a segmentally distributed motor pattern
Authors: Wenning Angela , Norris Brian J. , Doloc-Mihu Anca , Calabrese Ronald L.
Published: July 2011

Central pattern generators (CPGs) pace and pattern many rhythmic activities. We have uncovered a new module in the heartbeat CPG of leeches that creates a regional difference in this segmentally distributed motor pattern. The core CPG consists of seven identified pairs and one unidentified pair of heart interneurons of which 5 pairs are premotor and inhibit 16 pairs of heart motor neurons. The heartbeat CPG produces a side-to-side asymmetric pattern of activity of the premotor heart interneurons corresponding to an asymmetric fictive motor pattern and an asymmetric constriction pattern of the hearts with regular switches between the two sides. The premotor pattern progresses from rear to front on one side and nearly synchronously on the other; the motor pattern shows corresponding intersegmental coordination, but only from segment 15 forward. In the rearmost segments the fictive motor pattern and the constriction pattern progress from front to rear on both sides and converge in phase. Modeling studies suggested that the known inhibitory inputs to the rearmost heart motor neurons were insufficient to account for this activity. We therefore reexamined the constriction pattern of intact leeches. We also identified electrophysiologically two additional pairs of heart interneurons in the rear. These new heart interneurons make inhibitory connections with the rear heart motor neurons, are coordinated with the core heartbeat CPG, and are dye-coupled to their contralateral homologs. Their strong inhibitory connections with the rearmost heart motor neurons and the small side-to-side phase difference of their bursting contribute to the different motor and beating pattern observed in the animal's rear.
Cross-orientation suppression in human visual cortex
Authors: Brouwer Gijs Joost , Heeger David J.
Published: July 2011

Cross-orientation suppression was measured in human primary visual cortex (V1) to test the normalization model. Subjects viewed vertical target gratings (of varying contrasts) with or without a superimposed horizontal mask grating (fixed contrast). We used functional magnetic resonance imaging (fMRI) to measure the activity in each of several hypothetical channels (corresponding to subpopulations of neurons) with different orientation tunings and fit these orientation-selective responses with the normalization model. For the V1 channel maximally tuned to the target orientation, responses increased with target contrast but were suppressed when the horizontal mask was added, evident as a shift in the contrast gain of this channel's responses. For the channel maximally tuned to the mask orientation, a constant baseline response was evoked for all target contrasts when the mask was absent; responses decreased with increasing target contrast when the mask was present. The normalization model provided a good fit to the contrast-response functions with and without the mask. In a control experiment, the target and mask presentations were temporally interleaved, and we found no shift in contrast gain, i.e., no evidence for suppression. We conclude that the normalization model can explain cross-orientation suppression in human visual cortex. The approach adopted here can be applied broadly to infer, simultaneously, the responses of several subpopulations of neurons in the human brain that span particular stimulus or feature spaces, and characterize their interactions. In addition, it allows us to investigate how stimuli are represented by the inferred activity of entire neural populations.
Differential roles of GABAergic and glycinergic input on FM selectivity in the inferior colliculus of the pallid bat
Authors: Williams Anthony J. , Fuzessery Zoltan M.
Published: July 2011

Multiple mechanisms have been shown to shape frequency-modulated (FM) selectivity within the central nucleus of the inferior colliculus (IC) in the pallid bat. In this study we focus on the mechanisms associated with sideband inhibition. The relative arrival time of inhibition compared with excitation can be used to predict FM responses as measured with a two-tone inhibition paradigm. An early-arriving low-frequency inhibition (LFI) prevents responses to upward sweeps and thus shapes direction selectivity. A late-arriving high-frequency inhibition (HFI) suppresses slow FM sweeps and thus shapes rate selectivity for downward sweeps. Iontophoretic application of gabazine (GBZ) to block GABAA receptors or strychnine (Strych) to block glycine receptors was used to assess the effects of removal of inhibition on each form of FM selectivity. GBZ and Strych had a similar effect on FM direction selectivity, reducing selectivity in up to 86% of neurons when both drugs were coapplied. FM rate selectivity was more resistant to drug application with less than 38% of neurons affected. In addition, only Strych could eliminate FM rate selectivity, whereas GBZ alone was ineffective. The loss of FM selectivity was directly correlated to a loss of the respective inhibitory sideband that shapes that form of selectivity. The elimination of LFI correlated to a loss of FM direction selectivity, whereas elimination of HFI correlated to a loss of FM rate selectivity. Results indicate that 1) although the majority of FM direction selectivity is created within the IC, the majority of rate selectivity is inherited from lower levels of the auditory system, 2) a loss of LFI corresponds to a loss of FM direction selectivity and is created through either GABAergic or glycinergic input, and 3) a loss of HFI corresponds to a loss of FM rate selectivity and is created mainly through glycinergic input.