bluuebunny/crossref_metadata_2025 huggingface dataset:
Adult spinal motoneurones are not hyperexcitable in a mouse model of inherited amyotrophic lateral sclerosis
Authors: Delestrée Nicolas , Manuel Marin , Iglesias Caroline , Elbasiouny Sherif M. , Heckman C. J. , Zytnicki Daniel
Published: January 2014

Key points

Intrinsic hyperexcitability of spinal motoneurones is thought to contribute to excitotoxicity during amyotrophic lateral sclerosis (ALS), but it has never been demonstrated that adult motoneurones become hyperexcitable before disconnection from their muscle fibres.

We found an increased input conductance in motoneurones recorded in a mouse model of ALS. Yet, most cells retained normal excitability as measured by current onset for firing and input–output gain. This indicates successful regulation of excitability, compensating for the increase in conductance.

In contrast, some cells became hypoexcitable, losing their ability to fire repetitively to quasi‐stationary inputs before denervation. Hypoexcitability might therefore be an early marker of disease progression.

We thereby demonstrate that, if excitotoxicity is indeed a mechanism leading to degeneration in ALS, it is not caused by changes in the intrinsic electrical properties of the motoneurones but most probably by extrinsic factors such as excessive synaptic excitation.

In amyotrophic lateral sclerosis (ALS), an adult onset disease in which there is progressive degeneration of motoneurones, it has been suggested that an intrinsic hyperexcitability of motoneurones (i.e. an increase in their firing rates), contributes to excitotoxicity and to disease onset. Here we show that there is no such intrinsic hyperexcitability in spinal motoneurones. Our studies were carried out in an adult mouse model of ALS with a mutated form of superoxide dismutase 1 around the time of the first muscle fibre denervations. We showed that the recruitment current, the voltage threshold for spiking and the frequency–intensity gain in the primary range are all unchanged in most spinal motoneurones, despite an increased input conductance. On its own, increased input conductance would decrease excitability, but the homeostasis for excitability is maintained due to an upregulation of a depolarizing current that is activated just below the spiking threshold. However, this homeostasis failed in a substantial fraction of motoneurones, which became hypoexcitable and unable to produce sustained firing in response to ramps of current. We found similar results both in lumbar motoneurones recorded in anaesthetized mice, and in sacrocaudal motoneurones recorded in vitro, indicating that the lack of hyperexcitability is not caused by anaesthetics. Our results suggest that, if excitotoxicity is indeed a mechanism leading to degeneration in ALS, it is not caused by the intrinsic electrical properties of motoneurones but by extrinsic factors such as excessive synaptic excitation.
Deficiency of slow skeletal muscle troponin T causes atrophy of type I slow fibres and decreases tolerance to fatigue
Authors: Wei Bin , Lu Yingru , Jin J.‐P.
Published: January 2014

Key points

Loss of slow skeletal muscle troponin T (ssTnT) due to a nonsense mutation in codon Glu180 causes a lethal form of recessively inherited nemaline myopathy.

We studied the phenotypes of partial and total loss of ssTnT in the diaphragm and soleus muscles of Tnnt1 gene targeted mice.

ssTnT deficiency resulted in significant decreases in other slow fibre‐specific myofilament proteins whereas fast fibre‐specific myofilament proteins were increased correspondingly.

ssTnT deficiency produced significantly smaller type I slow fibres and compensatory growth of type II fast fibres with significantly reduced contractile force and tolerance to fatigue.

ssTnT‐deficient soleus muscle exhibited a significant numbers of small‐sized central nuclei type I fibres, indicating regeneration.

The data support the critical role of ssTnT in skeletal muscle function and the causal effect of its loss on the pathogenesis of nemaline myopathy.

The total loss of slow skeletal muscle troponin T (ssTnT encoded by TNNT1 gene) due to a nonsense mutation in codon Glu180 causes a lethal form of recessively inherited nemaline myopathy (Amish nemaline myopathy, ANM). To investigate the pathogenesis and muscle pathophysiology of ANM, we studied the phenotypes of partial and total loss of ssTnT in Tnnt1 gene targeted mice. An insertion of neomycin resistance cassette in intron 10 of Tnnt1 gene caused an approximately 60% decrease in ssTnT protein expression whereas cre‐loxP‐mediated deletion of exons 11–13 resulted in total loss of ssTnT, as seen in ANM muscles. In diaphragm and soleus muscles of the knockdown and knockout mouse models, we demonstrated that ssTnT deficiency resulted in significantly decreased levels of other slow fibre‐specific myofilament proteins whereas fast fibre‐specific myofilament proteins were increased correspondingly. Immunohistochemical studies revealed that ssTnT deficiency produced significantly smaller type I slow fibres and compensatory growth of type II fast fibres. Along with the slow fibre atrophy and the changes in myofilament protein isoform contents, ssTnT deficiency significantly reduced the tolerance to fatigue in soleus muscle. ssTnT‐deficient soleus muscle also contains significant numbers of small‐sized central nuclei type I fibres, indicating active regeneration. The data provide strong support for the essential role of ssTnT in skeletal muscle function and the causal effect of its loss in the pathology of ANM. This observation further supports the hypothesis that the function of slow fibres can be restored in ANM patients if a therapeutic supplement of ssTnT is achieved.
Purinergic signalling contributes to chemoreception in the retrotrapezoid nucleus but not the nucleus of the solitary tract or medullary raphe
Authors: Sobrinho Cleyton R. , Wenker Ian C. , Poss Erin M. , Takakura Ana C. , Moreira Thiago S. , Mulkey Daniel K.
Published: January 2014

Key points

Several brain regions are thought to sense changes in tissue CO2/H+ to regulate breathing (i.e. central chemoreceptors) including the nucleus of the solitary tract (NTS), medullary raphe and retrotrapezoid nucleus (RTN).

Mechanism(s) underlying RTN chemoreception involve direct activation of RTN neurons by H+‐mediated inhibition of a resting K+ conductance and indirect activation of RTN neurons by purinergic signalling, most likely from CO2/H+‐sensitive astrocytes.

Here, we confirm that activation of P2 receptors in the RTN stimulates cardiorespiratory activity, and we show at the cellular and systems level that purinergic signalling is not essential for CO2/H+ sensing in the NTS or medullary raphe.

These results support the possibility that purinergic signalling is a unique feature of RTN chemoreception.

Several brain regions are thought to function as important sites of chemoreception including the nucleus of the solitary tract (NTS), medullary raphe and retrotrapezoid nucleus (RTN). In the RTN, mechanisms of chemoreception involve direct H+‐mediated activation of chemosensitive neurons and indirect modulation of chemosensitive neurons by purinergic signalling. Evidence suggests that RTN astrocytes are the source of CO2‐evoked ATP release. However, it is not clear whether purinergic signalling also influences CO2/H+ responsiveness of other putative chemoreceptors. The goals of this study are to determine if CO2/H+‐sensitive neurons in the NTS and medullary raphe respond to ATP, and whether purinergic signalling in these regions influences CO2 responsiveness in vitro and in vivo. In brain slices, cell‐attached recordings of membrane potential show that CO2/H+‐sensitive NTS neurons are activated by focal ATP application; however, purinergic P2‐receptor blockade did not affect their CO2/H+ responsiveness. CO2/H+‐sensitive raphe neurons were unaffected by ATP or P2‐receptor blockade. In vivo, ATP injection into the NTS increased cardiorespiratory activity; however, injection of a P2‐receptor blocker into this region had no effect on baseline breathing or CO2/H+ responsiveness. Injections of ATP or a P2‐receptor blocker into the medullary raphe had no effect on cardiorespiratory activity or the chemoreflex. As a positive control we confirmed that ATP injection into the RTN increased breathing and blood pressure by a P2‐receptor‐dependent mechanism. These results suggest that purinergic signalling is a unique feature of RTN chemoreception.
Shank2 mutant mice display a hypersecretory response to cholera toxin
Authors: Jung Eun Suk , Park Joonhee , Gee Heon Yung , Jung Jinsei , Noh Shin Hye , Lee Jung‐Soo , Richter Wito , Namkung Wan , Lee Min Goo
Published: January 2014

Key points

Among the three Shank proteins in human (Shank1–3), Shank2 is abundantly expressed in epithelial cells. However, the in vivo physiological role of Shank2 in epithelial transport remains elusive.

The functional activity and expression of cystic fibrosis transmembrane conductance regulator (CFTR) and fluid secretion in the gastrointestinal epithelia were examined in the intestines of Shank2+/+ and Shank2−/− mice using an integrated molecular and physiological approach.

Shank2 deletion augmented the CFTR‐mediated short‐circuit current in the mouse colon and profoundly increased the cholera toxin‐induced fluid accumulation in the mouse intestine.

Shank2 appears to be a key molecule regulating epithelial fluid secretion. Modulation of Shank2‐mediated function would be helpful to treat diseases associated with hypersecretion or hyposecretion in epithelia.

Shank2 is a PDZ (PSD‐95/discs large/ZO‐1)‐based adaptor that has been suggested to regulate membrane transporting proteins in the brain and epithelial tissues. Here, we report that Shank2 mutant (Shank2−/−) mice exhibit aberrant fluid and ion transport in the intestine. Molecular characterization using epithelial tissues from Shank2+/+ and Shank2−/− mice revealed that a long spliceoform of Shank2 (Shank2E) is predominantly expressed in the pancreatic, renal and intestinal epithelia. In functional assays, deletion of Shank2 increased the cystic fibrosis transmembrane conductance regulator (CFTR)‐dependent short‐circuit currents by 84% (P < 0.05) and 101% (P < 0.05) in the mouse colon and rectum, respectively. Disruption of the CFTR–Shank2–phosphodiesterase 4D protein complex appeared to be mostly responsible for the changes in CFTR activities. Notably, Shank2 deletion profoundly increased cholera toxin‐induced fluid accumulation in the mouse intestine (∼90%, P < 0.01). Analyses with chemical inhibitors confirmed that the hyperactivation of CFTR channel function is responsible for the increased response to cholera toxin. These results suggest that Shank2 is a key molecule that participates in epithelial homeostasis, in particular to prevent overt secretory responses caused by epithelial pathogens.
A Comparison of Women With Fibromyalgia Syndrome to Criterion Fitness Standards: A Pilot Study
Authors: Jones C. Jessie , Rakovski Carter , Rutledge Dana , Gutierrez Angela
Published: January 2014

Purpose:

To compare fitness of women with fibromyalgia syndrome (FMS) aged 50+ with performance standards associated with functional independence in late life.

Methods:

Data came from a longitudinal study tracking physical and cognitive function of 93 women with FMS and included the most recent symptoms, activity levels, and fitness assessments.

Results:

Most women performed below criterion-referenced fitness standards for all measures. Nearly 90% percent of those < 70 years scored below the standard for lower body strength. Only ~20% of respondents < 70 years old met the criteria for aerobic endurance. A third of those aged over 70 met the standard in agility and dynamic balance. Physical activity was positively associated with fitness performance, while pain and depression symptoms were negatively associated.

Discussion:

High proportions of women with FMS do not meet fitness standards recommended for maintaining physical independence in late life, indicating a risk for disability. Regular fitness assessments and targeted exercise interventions are warranted.
Impact of Psychosocial Factors on Functional Improvement in Latino Older Adults After Tai Chi Exercise
Authors: Siu Ka-Chun , Rajaram Shireen S. , Padilla Carolina
Published: January 2014

Increasing evidence underscores the health benefits of Tai Chi (TC), although there is limited evidence of benefits among racial and ethnic minorities. This study investigated the impact of psychosocial status on balance among 23 Latino seniors after a twice-a-week, 12-week TC exercise program. Functional status was measured at baseline, immediately after, and three months following the TC exercise program, using the Timed Up and Go Test and Tinetti Falls Efficacy Scale. Psychosocial status was measured at baseline by the Center for Epidemiologic Studies Depression Scale and Norbeck Social Support Questionnaire. Both measures of functional status improved and were sustained after three months of TC. Greater improvement was significantly related to a higher level of baseline social support. More depressed seniors reported less fear of falling after TC. Depression and social support are important moderators of functional improvement after TC among Latino seniors.
Effect of Foam Rolling and Static Stretching on Passive Hip-Flexion Range of Motion
Authors: Mohr Andrew R. , Long Blaine C. , Goad Carla L.
Published: January 2014

Context:

Many athletes report that foam rollers help release tension in their muscles, thus resulting in greater range of motion (ROM) when used before stretching. To date, no investigators have examined foam rollers and static stretching.

Objective:

To determine if foam rolling before static stretching produces a significant change in passive hip-flexion ROM.

Design:

Controlled laboratory study.

Setting:

Research laboratory.

Participants:

40 subjects with less than 90° of passive hip-flexion ROM and no lower-extremity injury in the 6 mo before data collection.

Interventions:

During each of 6 sessions, subjects' passive hip-flexion ROM was measured before and immediately after static stretching, foam rolling and static stretching, foam rolling, or nothing (control). To minimize accessory movement of the hip and contralateral leg, subjects lay supine with a strap placed across their hip and another strap located over the uninvolved leg just superior to the patella. A bubble inclinometer was then aligned on the thigh of the involved leg, with which subjects then performed hip flexion.

Main Outcome Measure:

Change in passive hip-flexion ROM from the preintervention measure on day 1 to the postintervention measure on day 6.

Results:

There was a significant change in passive hip-flexion ROM regardless of treatment (F3,17 = 8.06, P = .001). Subjects receiving foam roll and static stretch had a greater change in passive hip-flexion ROM compared with the static-stretch (P = .04), foam-rolling (P = .006), and control (P = .001) groups.

Conclusions:

Our results support the use of a foam roller in combination with a static-stretching protocol. If time allows and maximal gains in hip-flexion ROM are desired, foam rolling the hamstrings muscle group before static stretching would be appropriate in noninjured subjects who have less than 90° of hamstring ROM.
The Accuracy of the Functional Movement Screen to Identify Individuals With an Elevated Risk of Musculoskeletal Injury
Authors: Krumrei Kirk , Flanagan Molly , Bruner Josh , Durall Chris
Published: January 2014

Clinical Scenario:

Injuries are somewhat commonplace in highly active populations. One strategy for reducing injuries is to identify individuals with an elevated injury risk before participation so that remediative interventions can be provided. Preparticipation screenings have traditionally entailed strength and flexibility measures thought to be indicative of inflated injury risk. Some researchers, however, have suggested that functional movements/tasks should be assessed to help identify individuals with a high risk of future injury. One assessment tool used for this purpose is the Functional Movement Screen (FMS). The FMS generates a numeric score based on performance attributes during 7 dynamic tasks; this score is purported to reflect future injury risk. Expanding interest in the FMS has led researchers to investigate how accurately it can identify individuals with an increased risk of injury.

Focused Clinical Question:

Can the Functional Movement Screen accurately identify highly active individuals with an elevated risk of injury?
The Secreted Protein ANGPTL2 Promotes Metastasis of Osteosarcoma Cells Through Integrin α
5
β
1
, p38 MAPK, and Matrix Metalloproteinases
Authors: Odagiri Haruki , Kadomatsu Tsuyoshi , Endo Motoyoshi , Masuda Tetsuro , Morioka Masaki Suimye , Fukuhara Shigetomo , Miyamoto Takeshi , Kobayashi Eisuke , Miyata Keishi , Aoi Jun , Horiguchi Haruki , Nishimura Naotaka , Terada Kazutoyo , Yakushiji Toshitake , Manabe Ichiro , Mochizuki Naoki , Mizuta Hiroshi , Oike Yuichi
Published: January 2014

Preventing signaling by ANGPTL2, which is stimulated by the tumor microenvironment, could inhibit metastasis.
Drug with a (Re)Purpose
Authors: Kiberstis Paula A.
Published: January 2014

A drug with potent activity in multiple myeloma patients acts by inducing degradation of two specific transcription factors.
Metastatic lung cancer, an interesting stroke mimic
Authors: Torrance Hew David Thomas , Tan Kai Lee , Jackson Ava
Published: January 2014

An elderly man presented to the emergency department with symptoms of a left-sided weakness. A CT of the brain scan showed an abnormality, and he was diagnosed with a stroke and admitted to the stroke unit. The stroke consultant reviewed him the next morning; a detailed history was acquired and imaging reviewed. As a result of the history of neurological symptoms, a diagnosis of malignancy was suspected and an MRI of the brain was ordered. This did not show a stroke but suggested a mass lesion. A CT of the chest, abdomen and pelvis was ordered to rule out a primary cause. Unfortunately, this showed widespread metastatic carcinoma with a left upper lobe primary (T4 N3 M1b). This was confirmed on histology. The patient died soon after the diagnosis.
SOME FIELD-THEORETICAL ASPECTS OF TWO TYPES OF THE POINCARÉ GROUP REPRESENTATIONS
Authors: SLAD L. M.
Published: January 2014

The capabilities of some approaches to the relativistic description of hadronic states with any rest spin are analysed. The key feature in the Wigner's construction of irreducible representations of the Poincaré group, which makes this construction fruitless in particle physics, is picked out. A realization of unitary irreducible representations of the Poincaré group of the standard type, which has not yet been considered, is discussed. The viability of the description of hadrons by the Poincaré group representations of the standard type in the space of the infinite-component ISFIR-class fields is pointed out.
THIN FILM FERROELECTRIC TUNABLE ZEROTH-ORDER RESONATOR BASED ON CRLH METAMATERIALS
Authors: MANSOUR MOHAMED M. , ELMALA MOSTAFA A. , SHALABY ABDEL-AZIZ T. , EL-RABAIE EL-SAYED M.
Published: January 2014

In this paper, we propose a tunable CRLH ZOR based on the latest resurgent of ferroelectric materials. It is known that for most resonant structures, attainment of optimal performance requires some level of additional tuning through either mechanical means (i.e., with tuning screws) or other coupling mechanisms. Therefore, incorporation of electronic tuning into high temperature superconductor (HTS) material components without degradation of performance is very attractive. The result will be low-loss microwave components that could be fine-tuned for optimal performance, with the additional attribute of being tunable over a broadband frequency range. The dielectric properties of the ferroelectric thin film, and the thickness of the ferroelectric film, play a fundamental role in the frequency or phase tunability and the overall insertion loss of the circuit. The main driving force toward using the ferroelectric is the potential for substantial miniaturization of microwave components and systems and the potential for integration with microelectronic circuits due to the development of thin and thick film ferroelectric technology. The ZOR is designed, and simulated by the full-wave analysis software. The response shows a variation of electromagnetic characteristics with the applied electric field, ferroelectric thickness and the operating temperature.
The positive occupation time of Brownian motion with two-valued drift and asymptotic dynamics of sliding motion with noise
Authors: Simpson D. J. W. , Kuske R.
Published: January 2014

We derive the probability density function of the positive occupation time of one-dimensional Brownian motion with two-valued drift. Long time asymptotics of the density are also computed. We use the result to describe the transitional probability density function of a general N-dimensional system of stochastic differential equations representing stochastically perturbed sliding motion of a discontinuous, piecewise-smooth vector field on short time frames. A description of the density at larger times is obtained via an asymptotic expansion of the Fokker-Planck equation.
Improvement on "an efficient protocol for the quantum private comparison of equality with W state"
Authors: Liu Wen-Jie , Liu Chao , Chen Han-Wu , Liu Zhi-Hao , Yuan Min-Xiao , Lu Jin-Shen
Published: January 2014

A quantum private comparison (QPC) protocol based on W states [W. Liu et al., Opt. Commun.284, 3160 (2011)] has pointed out there is a flaw of information leak [Y. B. Li et al., Eur. Phys. J. D.66, 110 (2012)]. In order to solve the problem, a special kind of W-class state is introduced, and its construction framework of quantum circuits is sketched. Based on this kind of W-class states, an improvement on Liu et al.'s protocol is presented. Analysis shows the improvement can not only hold the characteristics of original protocol, but also avoid the information leak that Li et al. pointed out.
THE CONCEPTUAL DESIGN OF THE MAGDALENA RIDGE OBSERVATORY INTERFEROMETER
Authors: BUSCHER D. F. , CREECH-EAKMAN M. , FARRIS A. , HANIFF C. A. , YOUNG J. S.
Published: January 2014

We describe the scientific motivation for and conceptual design of the Magdalena Ridge Observatory Interferometer, an imaging interferometer designed to operate at visible and near-infrared wavelengths. The rationale for the major technical decisions in the interferometer design is discussed, the success of the concept is appraised, and the implications of this analysis for the design of future arrays are drawn out.
THE CLASSIC/CLIMB BEAM COMBINER AT THE CHARA ARRAY
Authors: TEN BRUMMELAAR T. A. , STURMANN J. , RIDGWAY S. T. , STURMANN L. , TURNER N. H. , MCALISTER H. A. , FARRINGTON C. D. , BECKMANN U. , WEIGELT G. , SHURE M.
Published: January 2014

In the same way that every telescope has multiple instruments and cameras, an interferometric array like the CHARA Array will have numerous beam combiners at the back end. And like the instruments of a single telescope, each of these combiners will be optimized for a particular kind of observation or scientific program. In this paper we describe the CLASSIC and CLIMB beam combiners of the CHARA Array. Both are open air, aperture plane, wide bandwidth single spectral channel instruments optimized for sensitivity. CLASSIC is the original two beam combiner used for the first science at CHARA, and it still has the faintest magnitude limit. CLIMB is a three beam expansion of CLASSIC that can also provide closure phase measurements.
PHASE-REFERENCED INTERFEROMETRY AND NARROW-ANGLE ASTROMETRY WITH SUSI
Authors: KOK Y. , IRELAND M. J. , TUTHILL P. G. , ROBERTSON J. G. , WARRINGTON B. A. , RIZZUTO A. C. , TANGO W. J.
Published: January 2014

The Sydney University Stellar Interferometer (SUSI) now incorporates a new beam combiner, called the Microarc-second University of Sydney Companion Astrometry instrument (MUSCA), for the purpose of high precision differential astrometry of bright binary stars. Operating in the visible wavelength regime where photon-counting and post-processing fringe tracking is possible, MUSCA will be used in tandem with SUSI's primary beam combiner, Precision Astronomical Visible Observations (PAVO), to record high spatial resolution fringes and thereby measure the separation of fringe packets of binary stars. In its current phase of development, the dual beam combiner configuration has successfully demonstrated for the first time a dual-star phase-referencing operation in visible wavelengths. This paper describes the beam combiner optics and hardware, the network of metrology systems employed to measure every non-common path between the two beam combiners and also reports on a recent narrow-angle astrometric observation of δ Orionis A (HR 1852) as the project enters its on-sky testing phase.
Complex activity recognition using context-driven activity theory and activity signatures
Authors: Saguna Saguna , Zaslavsky Arkady , Chakraborty Dipanjan
Published: January 2014

In pervasive and ubiquitous computing systems, human activity recognition has immense potential in a large number of application domains. Current activity recognition techniques (i) do not handle variations in sequence, concurrency and interleaving of complex activities; (ii) do not incorporate context; and (iii) require large amounts of training data. There is a lack of a unifying theoretical framework which exploits both domain knowledge and data-driven observations to infer complex activities. In this article, we propose, develop and validate a novel Context-Driven Activity Theory (CDAT) for recognizing complex activities. We develop a mechanism using probabilistic and Markov chain analysis to discover complex activity signatures and generate complex activity definitions. We also develop a Complex Activity Recognition (CAR) algorithm. It achieves an overall accuracy of 95.73% using extensive experimentation with real-life test data. CDAT utilizes context and links complex activities to situations, which reduces inference time by 32.5% and also reduces training data by 66%.
Integrated online localization and navigation for people with visual impairments using smart phones
Authors: Apostolopoulos Ilias , Fallah Navid , Folmer Eelke , Bekris Kostas E.
Published: January 2014

Indoor localization and navigation systems for individuals with Visual Impairments (VIs) typically rely upon extensive augmentation of the physical space, significant computational resources, or heavy and expensive sensors; thus, few systems have been implemented on a large scale. This work describes a system able to guide people with VIs through indoor environments using inexpensive sensors, such as accelerometers and compasses, which are available in portable devices like smart phones. The method takes advantage of feedback from the human user, who confirms the presence of landmarks, something that users with VIs already do when navigating in a building. The system calculates the user's location in real time and uses it to provide audio instructions on how to reach the desired destination. Initial early experiments suggested that the accuracy of the localization depends on the type of directions and the availability of an appropriate transition model for the user. A critical parameter for the transition model is the user's step length. Consequently, this work also investigates different schemes for automatically computing the user's step length and reducing the dependence of the approach on the definition of an accurate transition model. In this way, the direction provision method is able to use the localization estimate and adapt to failed executions of paths by the users. Experiments are presented that evaluate the accuracy of the overall integrated system, which is executed online on a smart phone. Both people with VIs and blindfolded sighted people participated in the experiments, which included paths along multiple floors that required the use of stairs and elevators.
Triggering effective social support for online groups
Authors: Kumar Rohit , Rosé Carolyn P.
Published: January 2014

Conversational agent technology is an emerging paradigm for creating a social environment in online groups that is conducive to effective teamwork. Prior work has demonstrated advantages in terms of learning gains and satisfaction scores when groups learning together online have been supported by conversational agents that employ Balesian social strategies. This prior work raises two important questions that are addressed in this article. The first question is one of generality. Specifically, are the positive effects of the designed support specific to learning contexts? Or are they in evidence in other collaborative task domains as well? We present a study conducted within a collaborative decision-making task where we see that the positive effects of the Balesian social strategies extend to this new context. The second question is whether it is possible to increase the effectiveness of the Balesian social strategies by increasing the context sensitivity with which the social strategies are triggered. To this end, we present technical work that increases the sensitivity of the triggering. Next, we present a user study that demonstrates an improvement in performance of the support agent with the new, more sensitive triggering policy over the baseline approach from prior work.

The technical contribution of this article is that we extend prior work where such support agents were modeled using a composition of conversational behaviors integrated within an event-driven framework. Within the present approach, conversation is orchestrated through context-sensitive triggering of the composed behaviors. The core effort involved in applying this approach involves building a set of triggering policies that achieve this orchestration in a time-sensitive and coherent manner. In line with recent developments in data-driven approaches for building dialog systems, we present a novel technique for learning behavior-specific triggering policies, deploying it as part of our efforts to improve a socially capable conversational tutor agent that supports collaborative learning.
Towards software performance engineering for multicore and manycore systems
Authors: Koziolek Heiko , Becker Steffen , Happe Jens , Tuma Petr , de Gooijer Thijmen
Published: January 2014

In the era of multicore and manycore processors, a systematic engineering approach for software performance becomes more and more crucial to the success of modern software systems. This article argues for more software performance engineering research specifically for multicore and manycore systems, which will have a profound impact on software engineering practices.
Random access in wireless networks
Authors: Ghaderi Javad , Borst Sem , Whiting Phil
Published: January 2014

Random access schemes are simple and inherently distributed, yet capable of matching the optimal throughput performance of centralized scheduling algorithms. The throughput optimality however has been established for activation rules that are relatively sluggish, and may yield excessive queues and delays. More aggressive/persistent access schemes have the potential to improve the delay performance, but it is not clear if they can offer any universal throughput optimality guarantees. In this paper, we identify a limit on the aggressiveness of nodes, beyond which instability is bound to occur in a broad class of networks.
A martingale-envelope and applications
Authors: Poloczek Felix , Ciucu Florin
Published: January 2014

In the framework of stochastic network calculus we present a new envelope-based approach which uses martingales to characterize a queueing system. We show that this setting allows a simple handling of multiplexing and scheduling: whereas multiplexing of several sources results in multiplication of the corresponding martingales, per-flow analysis in a scheduled system can be done by shifting the martingales to a certain point in time. Applying this calculus to Markov Arrival Processes, it is shown that the performance bounds can become reasonably tight.
Monotonic marginal pricing
Authors: Temple William G. , Ma Richard T.B.
Published: January 2014

In this paper we develop a general dynamic pricing scheme based on consumer-indexed marginal cost, and demonstrate its properties in a simulated electricity market derived from New York ISO data. We show that monotonic marginal (MM) pricing provides price certainty, ensuring that every consumer's instantaneous price is non-increasing for a constant consumption level. Additionally, we show that MM pricing ensures budget balance for energy suppliers, allowing them to recover any operating costs and a profit margin. Using a Summer 2012 peak load day as a case study, we simulate a population of over 25000 electricity users and evaluate the performance of an example MM pricing plan versus historical real-time prices under various demand elasticities. The results demonstrate that MM pricing can provide system-level demand response and cost savings comparable with real-time pricing, while protecting consumers from price volatility.
Harvesting heat in an urban greenhouse
Authors: Pervilä Mikko , Remes Lassi , Kangasharju Jussi
Published: January 2014

This extended abstract summarizes the key technical results from the authors' previous article [9]. It describes the first eight months of operation of a prototype rooftop greenhouse located in Helsinki, Finland. This version adds experiences from another five months, including the past winter. The greenhouse is heated by exhaust heat harvested from a rack of computer servers, while the servers are cooled by unconditioned outside air only.
Switch sizing for energy-efficient datacenter networks
Authors: Widjaja Indra , Walid Anwar , Luo Yanbin , Xu Yang , Chao H. Jonathan
Published: January 2014

Saving power in datacenter networks has become a pressing issue. ElasticTree and CARPO fat-tree networks have recently been proposed to reduce power consumption by using sleep mode during the operation stage of the network. In this paper, we address the design stage where the right switch size is evaluated to maximize power saving during the expected operation of the network. Our findings reveal that deploying a large number of small switches is more power-efficient than a small number of large switches when the traffic demand is relatively moderate or when servers exchanging traffic are in close proximity. We also discuss the impact of sleep mode on performance such as packet delay and loss.
A first implementation and evaluation of the IEEE 802.11aa group addressed transmission service
Authors: Salvador Pablo , Cominardi Luca , Gringoli Francesco , Serrano Pablo
Published: January 2014

The IEEE 802.11aa Task Group has recently standardized a set of mechanisms to efficiently support video multicasting, namely, the Group Addressed Transmission Service (GATS). In this article, we report the implementation of these mechanisms over commodity hardware, which we make publicly available, and conduct a study to assess their performance under a variety of real-life scenarios. To the best of our knowledge, this is the first experimental assessment of GATS, which is performed along three axes: we report their complexity in terms of lines of code, their effectiveness when delivering video traffic, and their efficiency when utilizing wireless resources. Our results provide key insights on the resulting trade-offs when using each mechanism, and paves the way for new enhancements to deliver video over 802.11 Wireless LANs.
Helping a future internet architecture mature
Authors: Partridge Craig
Published: January 2014

Some of the challenges of developing and maturing a future internet architecture (FIA) are described. Based on a talk given at the Conference on Future Internet Technologies 2013.
Bridging the gap between internet standardization and networking research
Authors: Ding Aaron Yi , Korhonen Jouni , Savolainen Teemu , Kojo Markku , Ott Joerg , Tarkoma Sasu , Crowcroft Jon
Published: January 2014

The participation of the network research community in the Internet Standards Development Organizations (SDOs) has been relatively low over the recent years, and this has drawn attention from both academics and industry due to its possible negative impact. The reasons for this gap are complex and extend beyond the purely technical. In this editorial we share our views on this challenge, based on the experience we have obtained from joint projects with universities and companies. We highlight the lessons learned, covering both successful and under-performing cases, and suggest viable approaches to bridge the gap between networking research and Internet standardization, aiming to promote and maximize the outcome of such collaborative endeavours.
Gene Silencing Associated with SWI/SNF Complex Loss during NSCLC Development
Authors: Song Shujie , Walter Vonn , Karaca Mehmet , Li Ying , Bartlett Christopher S. , Smiraglia Dominic J. , Serber Daniel , Sproul Christopher D. , Plass Christoph , Zhang Jiren , Hayes D. Neil , Zheng Yanfang , Weissman Bernard E.
Published: January 2014

The SWI/SNF chromatin-remodeling complex regulates gene expression and alters chromatin structures in an ATP-dependent manner. Recent sequencing efforts have shown mutations in BRG1 (SMARCA4), one of two mutually exclusive ATPase subunits in the complex, in a significant number of human lung tumor cell lines and primary non–small cell lung carcinoma (NSCLC) clinical specimens. To determine how BRG1 loss fuels tumor progression in NSCLC, molecular profiling was performed after restoration of BRG1 expression or treatment with a histone deacetylase inhibitor or a DNA methyltransferase (DNMT) inhibitor in a BRG1-deficient NSCLC cells. Importantly, validation studies from multiple cell lines revealed that BRG1 reexpression led to substantial changes in the expression of CDH1, CDH3, EHF, and RRAD that commonly undergo silencing by other epigenetic mechanisms during NSCLC development. Furthermore, treatment with DNMT inhibitors did not restore expression of these transcripts, indicating that this common mechanism of gene silencing did not account for their loss of expression. Collectively, BRG1 loss is an important mechanism for the epigenetic silencing of target genes during NSCLC development.

Implications: Inactivation of the SWI/SNF complex provides a novel mechanism to induce gene silencing during NSCLC development. Mol Cancer Res; 12(4); 560–70. ©2014 AACR.
RapidCaP, a Novel GEM Model for Metastatic Prostate Cancer Analysis and Therapy, Reveals Myc as a Driver of Pten-Mutant Metastasis
Authors: Cho Hyejin , Herzka Tali , Zheng Wu , Qi Jun , Wilkinson John E. , Bradner James E. , Robinson Brian D. , Castillo-Martin Mireia , Cordon-Cardo Carlos , Trotman Lloyd C.
Published: January 2014

Genetically engineered mouse (GEM) models are a pillar of functional cancer research. Here, we developed RapidCaP, a GEM modeling system that uses surgical injection for viral gene delivery to the prostate. We show that in Pten deficiency, loss of p53 suffices to trigger metastasis to distant sites at greater than 50% penetrance by four months, consistent with results from human prostate cancer genome analysis. Live bioluminescence tracking showed that endogenous primary and metastatic disease responds to castration before developing lethal castration resistance. To our surprise, the resulting lesions showed no activation of Akt but activation of the Myc oncogene. Using RapidCaP, we find that Myc drives local prostate metastasis and is critical for maintenance of metastasis, as shown by using the Brd4 inhibitor JQ1. Taken together, our data suggest that a “MYC-switch” away from AKT forms a critical and druggable event in PTEN-mutant prostate cancer metastasis and castration resistance.

Significance: The RapidCaP system introduces fast and flexible genetics for functional analysis and therapy for endogenous metastatic prostate cancer. The approach introduces targeting of MYC as a critical strategy against PTEN-deficient lethal prostate cancer. Cancer Discov; 4(3); 318–33. ©2014 AACR.

This article is highlighted in the In This Issue feature, p. 259
Inhibition of KRAS-Driven Tumorigenicity by Interruption of an Autocrine Cytokine Circuit
Authors: Zhu Zehua , Aref Amir R. , Cohoon Travis J. , Barbie Thanh U. , Imamura Yu , Yang Shenghong , Moody Susan E. , Shen Rhine R. , Schinzel Anna C. , Thai Tran C. , Reibel Jacob B. , Tamayo Pablo , Godfrey Jason T. , Qian Zhi Rong , Page Asher N. , Maciag Karolina , Chan Edmond M. , Silkworth Whitney , Labowsky Mary T. , Rozhansky Lior , Mesirov Jill P. , Gillanders William E. , Ogino Shuji , Hacohen Nir , Gaudet Suzanne , Eck Michael J. , Engelman Jeffrey A. , Corcoran Ryan B. , Wong Kwok-Kin , Hahn William C. , Barbie David A.
Published: January 2014

Although the roles of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signaling in KRAS-driven tumorigenesis are well established, KRAS activates additional pathways required for tumor maintenance, the inhibition of which are likely to be necessary for effective KRAS-directed therapy. Here, we show that the IκB kinase (IKK)–related kinases Tank-binding kinase-1 (TBK1) and IKKϵ promote KRAS-driven tumorigenesis by regulating autocrine CCL5 and interleukin (IL)-6 and identify CYT387 as a potent JAK/TBK1/IKKϵ inhibitor. CYT387 treatment ablates RAS-associated cytokine signaling and impairs Kras-driven murine lung cancer growth. Combined CYT387 treatment and MAPK pathway inhibition induces regression of aggressive murine lung adenocarcinomas driven by Kras mutation and p53 loss. These observations reveal that TBK1/IKKϵ promote tumor survival by activating CCL5 and IL-6 and identify concurrent inhibition of TBK1/IKKϵ, Janus-activated kinase (JAK), and MEK signaling as an effective approach to inhibit the actions of oncogenic KRAS.

Significance: In addition to activating MAPK and PI3K, oncogenic KRAS engages cytokine signaling to promote tumorigenesis. CYT387, originally described as a selective JAK inhibitor, is also a potent TBK/IKKϵ inhibitor that uniquely disrupts a cytokine circuit involving CCL5, IL-6, and STAT3. The efficacy of CYT387-based treatment in murine Kras-driven lung cancer models uncovers a novel therapeutic approach for these refractory tumors with immediate translational implications. Cancer Discov; 4(4); 452–65. ©2014 AACR.

This article is highlighted in the In This Issue feature, p. 377
Effect of Radiofrequency Catheter Ablation for Atrial Fibrillation on Morbidity and Mortality
Authors: Chang Chia-Hsuin , Lin Jou-Wei , Chiu Fu-Chun , Caffrey James L. , Wu Li-Chiu , Lai Mei-Shu
Published: January 2014

Background—

This study examined the effect of radiofrequency catheter ablation (RFA) on reducing morbidity and mortality among patients with atrial fibrillation (AF).

Methods and Results—

A retrospective cohort of patients with AF without prior stroke or heart failure (HF) who underwent RFA between 2003 and 2009 was identified using Taiwan’s National Health Insurance claims database. Outpatients with AF who met the same enrollment criteria but did not receive RFA were matched (≤1:20) by hospitals and dates to serve as controls. Outcomes of interest were death, stroke, or hospitalization for HF. A proportional hazard Cox regression model adjusted by propensity scores (based on age, sex, hypertension, diabetes mellitus, comorbidities, medications, and medical resource utilization) was applied to estimate the hazard ratio and 95% confidence interval. A total of 846 patients with AF who received RFA and 11 324 matched AF controls were included, with a mean follow-up of 3.74 and 3.96 years, respectively. RFA was associated with a lower hazard for stroke (hazard ratio, 0.57; 95% confidence interval, 0.35–0.94;
P
=0.026). The reduction in the hazard for death and HF did not reach statistical significance (hazard ratio, 0.88; 95% confidence interval, 0.62–1.23;
P
=0.451 and hazard ratio, 0.78; 95% confidence interval, 0.55–1.12;
P
=0.185, respectively). Additional analysis using death as a competing risk showed similar results for stroke and HF.

Conclusions—

RFA did not reduce mortality or hospitalization for HF during the immediate 3.5-year follow-up. Although a beneficial effect on stroke prevention associated with RFA was suggested, residual confounding attributable to unmeasured factors remains a concern.
Time Course of Inflammation, Myocardial Injury, and Prothrombotic Response After Radiofrequency Catheter Ablation for Atrial Fibrillation
Authors: Lim Han S. , Schultz Carlee , Dang Jerry , Alasady Muayad , Lau Dennis H. , Brooks Anthony G. , Wong Christopher X. , Roberts-Thomson Kurt C. , Young Glenn D. , Worthley Matthew I. , Sanders Prashanthan , Willoughby Scott R.
Published: January 2014

Background—

Inflammation has been linked to the genesis of stroke in atrial fibrillation (AF) and is implicated in early recurrent arrhythmia after AF ablation. We aimed to define the time course of inflammation, myocardial injury, and prothrombotic markers after radiofrequency ablation for AF and its relation to AF recurrence.

Methods and Results—

Ninety consecutive AF patients (53% paroxysmal) undergoing radiofrequency ablation were recruited. High-sensitivity C-reactive protein (hs-CRP), Troponin-T, creatine kinase-MB, fibrinogen, and D-Dimer concentrations were measured at baseline, at 1, 2, 3, 7 days, and at 1 month after ablation. AF recurrence was documented at 3 days and at 1, 3, and 6 months follow-up. Troponin-T and creatine kinase-MB peaked at day 1 after procedure (both
P
<0.05). Hs-CRP peaked at day 3 after procedure (
P
<0.05). Fibrinogen (
P
<0.05) and D-Dimer (
P
<0.05) concentrations were significantly elevated at 1 week after procedure. Ln hs-CRP elevation correlated with Ln Troponin-T and fibrinogen elevation. The extent of Ln hs-CRP, Ln Troponin-T, and fibrinogen elevation predicted early AF recurrence within 3 days after procedure (
P
<0.05, respectively), but not at 3 and 6 months.

Conclusions—

Patients undergoing radiofrequency ablation for AF exhibit an inflammatory response within 3 days. The extent of inflammatory response predicts early AF recurrence but not late recurrence. Prothrombotic markers are elevated at 1 week after ablation and may contribute to increased risk of early thrombotic events after AF ablation.
Efficacy and Safety of LCZ696, a First-in-Class Angiotensin Receptor Neprilysin Inhibitor, in Asian Patients With Hypertension
Authors: Kario Kazuomi , Sun Ningling , Chiang Fu-Tien , Supasyndh Ouppatham , Baek Sang Hong , Inubushi-Molessa Akiko , Zhang Ying , Gotou Hiromi , Lefkowitz Martin , Zhang Jack
Published: January 2014

Abstract—

LCZ696 (Japanese adopted name: sucabitril valsartan sodium hydrate), a first-in-class angiotensin receptor neprilysin inhibitor, concomitantly inhibits neprilysin and blocks angiotensin type 1 receptor. This randomized, double-blind, placebo-controlled study, the first in Asia for this drug, evaluated the dose-related efficacy and safety of LCZ696 in patients with hypertension using 24-hour ambulatory blood pressure (BP) monitoring. Asian patients aged ≥18 years (n=389) with hypertension were randomized to receive LCZ696 100 mg (n=100), 200 mg (n=101), 400 mg (n=96), or placebo (n=92) for
8 weeks
. The primary end point was mean difference across the 3 single-dose pairwise comparisons of LCZ696 versus placebo in clinic diastolic BP after 8-week treatment. Key secondary efficacy variables included changes in clinic systolic BP and pulse pressure and changes in 24-hour, daytime, and nighttime ambulatory BPs and pulse pressure. Safety assessments included recording all adverse events and serious adverse events. A total of 362 patients completed the study. Reductions in clinic systolic BP, diastolic BP (
P
<0.0001), and pulse pressure (
P
<0.001) were significantly greater with all doses of LCZ696 than with placebo. There were also significant reductions in 24-hour, daytime, and nighttime ambulatory systolic BP, diastolic BP, and pulse pressure for all doses of LCZ696 compared with placebo (
P
<0.0001). LCZ696 was well tolerated, and no cases of angioedema were reported. In conclusion, LCZ696 is effective for the treatment of hypertension in Asian population and, in general, is safe and well tolerated.

Clinical Trial Information—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01193101.