bluuebunny/crossref_metadata_2025 huggingface dataset:
Emergence of Resistant
Klebsiella pneumoniae
in the Intestinal Tract during Successful Treatment of
Klebsiella pneumoniae
Lung Infection in Rats
Authors: Kesteman Anne-Sylvie , Perrin-Guyomard Agnès , Laurentie Michel , Sanders Pascal , Toutain Pierre-Louis , Bousquet-Mélou Alain
Published: May 2010

Antibiotic treatment of lung infections may lead to the emergence of resistance in the gut flora. Appropriate dosing regimens could mitigate this adverse effect. In gnotobiotic rats harboring intestinal
Escherichia coli
and
Enterococcus faecium
populations, a lung infection by
Klebsiella pneumoniae
was instigated with two different sizes of inoculum to represent an early or a late initiation of antibiotic treatment. The rats were treated with marbofloxacin, an expanded-spectrum fluoroquinolone, by a single-shot administration or a fractionated regimen over 4 days. Intestinal bacterial populations were monitored during and after treatment. At the infection site, bacterial cure without any selection of resistance was observed. Whatever the dosage regimen, fluoroquinolone treatment had a transient negative impact on the
E. coli
gut population but not on that of
E. faecium
. The intestinal flora was colonized by the pathogenic lung bacteria, and there was the emergence of intestine-resistant
K. pneumoniae
, occurring more often in animals treated with a single marbofloxacin dose than with the fractionated dose. Bacterial cure without resistance selection at the infection site with fluoroquinolone treatment can be linked to colonization of the digestive tract by targeted pulmonary bacteria, followed by the emergence of resistance.
Pharmacokinetics and Safety of CXA-101, a New Antipseudomonal Cephalosporin, in Healthy Adult Male and Female Subjects Receiving Single- and Multiple-Dose Intravenous Infusions
Authors: Ge Yigong , Whitehouse M. J. , Friedland Ian , Talbot George H.
Published: May 2010

CXA-101 is a novel, broad-spectrum cephalosporin with excellent antipseudomonal activity. A Phase 1 study was performed to determine the safety, tolerability, and pharmacokinetics of CXA-101 after single- and multiple-dose intravenous administration over 1 h to healthy male and female subjects. In part 1 of the study, five cohorts of eight subjects each (six receiving CXA-101 and two receiving a placebo) received single ascending doses of 250, 500, 1,000, 1,500, and 2,000 mg. In part 2, cohorts 1 and 2 received 500 mg and 1,000 mg, respectively, every 8 h, and cohort 3 received 1,500 mg every 12 h; each cohort received dosing for 10 days. Standard safety and tolerability assessments were performed. Blood and urine pharmacokinetic samples were assayed by a validated bioanalytical method and analyzed using standard noncompartmental methodology. All 64 subjects completed dosing; none withdrew from the study. Drug-related systemic adverse events were infrequent and mild. Mild, non-treatment-limiting infusion site events occurred during multiple-dose administration. No clinically significant laboratory or electrocardiographic finding or dose-limiting toxicity was observed. CXA-101 exhibited dose-linear pharmacokinetics; the mean plasma half-life was ∼2.3 h. More than 90% of the administered dose was eliminated unchanged through renal excretion. In summary, CXA-101 administered as a 1-hour infusion was generally safe and well tolerated in single doses up to 2,000 mg and in multiple doses up to 3 g daily over 10 days. The favorable safety and predictable pharmacokinetic profile of CXA-101 support its continuing clinical development for the treatment of serious bacterial infections.
Immunogenicity and Protection Induced by a
Mycobacterium tuberculosis
sigE
Mutant in a BALB/c Mouse Model of Progressive Pulmonary Tuberculosis
Authors: Pando Rogelio Hernandez , Aguilar Leon Diana , Smith Issar , Manganelli Riccardo
Published: May 2010

Tuberculosis is still one of the main challenges to human global health, leading to about two million deaths every year. One of the reasons for its success is the lack of efficacy of the widely used vaccine
Mycobacterium bovis
BCG. In this article, we analyze the potential use of an attenuated mutant of
Mycobacterium tuberculosis
H37Rv lacking the sigma factor σ
E
as a live vaccine. We have demonstrated that BALB/c mice infected by the intratracheal route with this mutant strain showed significantly higher survival rates and less tissue damage than animals infected with the parental or complemented mutant strain. Although animals infected with the
sigE
mutant had low bacillary loads, their lungs showed significantly higher production of the protective factors gamma interferon (IFN-γ), tumor necrosis factor alpha (TNF-α), inducible nitric oxide synthase (iNOS), and β-defensins than those of animals infected with the parental or complemented mutant strain. Moreover, we demonstrate that the
sigE
mutant, when inoculated subcutaneously, was more attenuated than BCG in immunodeficient nude mice, thus representing a good candidate for a novel attenuated live vaccine strain. Finally, when we used the
sigE
mutant as a subcutaneous vaccine, it was able to induce a higher level of protection than did BCG with both H37Rv and a highly virulent strain of
M. tuberculosis
(Beijing code 9501000). Taken together, our findings suggest that the
sigE
mutant is a very promising strain for the development of a new vaccine against tuberculosis.
Cholangiocyte Myosin IIB Is Required for Localized Aggregation of Sodium Glucose Cotransporter 1 to Sites ofCryptosporidium parvumCellular Invasion and Facilitates Parasite Internalization
Authors: O'Hara Steven P. , Gajdos Gabriella B. , Trussoni Christy E. , Splinter Patrick L. , LaRusso Nicholas F.
Published: May 2010

Internalization of the obligate intracellular apicomplexan parasite,Cryptosporidium parvum, results in the formation of a unique intramembranous yet extracytoplasmic niche on the apical surfaces of host epithelial cells, a process that depends on host cell membrane extension. We previously demonstrated that efficientC. parvuminvasion of biliary epithelial cells (cholangiocytes) requires host cell actin polymerization and localized membrane translocation/insertion of Na+/glucose cotransporter 1 (SGLT1) and of aquaporin 1 (Aqp1), a water channel, at the attachment site. The resultant localized water influx facilitates parasite cellular invasion by promoting host-cell membrane protrusion. However, the molecular mechanisms by whichC. parvuminduces membrane translocation/insertion of SGLT1/Aqp1 are obscure. We report here that cultured human cholangiocytes express several nonmuscle myosins, including myosins IIA and IIB. Moreover,C. parvuminfection of cultured cholangiocytes results in the localized selective aggregation of myosin IIB but not myosin IIA at the region of parasite attachment, as assessed by dual-label immunofluorescence confocal microscopy. Concordantly, treatment of cells with the myosin light chain kinase inhibitor ML-7 or the myosin II-specific inhibitor blebbistatin or selective RNA-mediated repression of myosin IIB significantly inhibits (P< 0.05)C. parvumcellular invasion (by 60 to 80%). Furthermore ML-7 and blebbistatin significantly decrease (P< 0.02)C. parvum-induced accumulation of SGLT1 at infection sites (by approximately 80%). Thus, localized actomyosin-dependent membrane translocation of transporters/channels initiated byC. parvumis essential for membrane extension and parasite internalization, a phenomenon that may also be relevant to the mechanisms of cell membrane protrusion in general.
Inhibitory Effect of Needle Penetration on Vibration-Induced Finger Flexion Reflex in Humans
Authors: Takakura Nobuari , Yajima Hiroyoshi , Takayama Miho , Kawase Akiko , Homma Ikuo
Published: May 2010

Background

Vibration-induced finger flexion reflex (VFR) in the upper extremity is inhibited by needle insertion acupuncture to the large intestine 4 (LI4) at the hand. This claim has a limitation because the inhibitory effect is deduced only from reduction in the maximum finger flexion (FF) force during the tonic flexion reflex by vibratory stimulation after acupuncture.

Methods

The study was a crossover design with two conditions—acupuncture and control—to which 16 healthy volunteers were subjected. VFR in the upper extremity was induced by applying vibratory stimulation on the volar side of the middle fingertip of the right hand, before and after acupuncture at the right LI4 in 16 healthy volunteers. We measured the area under the curve (AUC) of finger flexion force and surface electromyogram (EMG) in the flexor muscles, in addition to the maximum FF force during vibratory stimulation. We compared AUC, surface EMG and maximum FF force in the acupuncture condition with those in the control condition. We also estimated the correlation between AUC, surface EMG and maximum FF force.

Results

AUC, surface EMG and maximum FF force were significantly reduced (p <0.01) after acupuncture compared with those of the control group. A strong correlation was observed in maximum FF force versus AUC (r=0.98, p <0.01) and surface EMG (r=0.77, p <0.01).

Conclusions

Acupuncture at ipsilateral LI4 inhibited tonic activities in the finger flexor muscles during VFR, which suggests that afferent input with needle penetration has inhibitory effect on the motor neuronal activities in the reflex circuits of VFR.
Does Needling Sensation (de qi) Affect Treatment Outcome in Pain? Analysis of Data from a Larger Single-blind, Randomised Controlled Trial
Authors: White Peter , Prescott Philip , Lewith George
Published: May 2010

Background

Insertion of an acupuncture needle into an acupuncture point typically generates a range of sensations called ‘ de qi’. Most acupuncturists are taught that obtaining de qi is important when treating patients with pain but this can be quite uncomfortable for patients.

Objective

This study assesses the importance of the strength of de qi, on the clinical outcome in osteoarthritic pain.

Method

This study was part of a larger randomised, single-blind, multifactorial trial involving three interventions: real acupuncture (RA), Streitberger needle (SN) and mock electrical stimulation for the treatment of patients with osteoarthritis (OA) of the hip and knee. Patients were treated twice a week for 4 weeks. The two outcomes relevant to this study were pain reduction assessed by visual analogue scale and the Park needling sensation questionnaire, both measured at completion of the study. Two arms of the trial were analysed (RA and SN). Reduction in pain was correlated against strength of de qi for both RA and SN. Those who felt de qi were compared with those who did not.

Results

147 patients were recruited to the study (140 completed) with a mean pain reduction of 15.2 mm and mean de qi score of 6.2. There was no significant correlation between the strength of de qi and improvement in pain (p=0.49). There was also no significant difference in pain relief (p=0.52) between those who felt de qi and those who did not using the de qi subscale of the Park questionnaire.

Conclusion

These data suggest that the presence and intensity of de qi has no effect on the pain relief obtained for patients with OA. This result may have implications for both acupuncture treatment and for future trial methodology.
Implementation of Acupuncture and Acupressure under Surgical Procedures in Children: A Pilot Study
Authors: Norheim Arne Johan , Liodden Ingrid , Howley Michael
Published: May 2010

Objective

To test the feasibility of research on acupuncture and acupressure for children undergoing tonsillectomy and/or adenoidectomy.

Methods

During January and February 2008, 20 patients from the ordinary waiting list at Lovisenberg Diakonale Hospital in Oslo were randomised to either acupuncture while under anaesthesia or standard care as control. The authors gave acupuncture at Pericardium 6 (P6) at a depth of approximately 0.7 cm on both forearms. The needles were removed when the patient was transferred to the recovery unit and replaced with acupressure wristbands. The outcome measure in the pilot study was to explore if acupuncture and acupressure could be implemented without extending the anaesthesia time and surgical time. This pilot study also tested the feasibility of the research protocol for future investigation in the field, with postoperative nausea, vomiting and retching as the primary end points for effect.

Results

The study showed no delay in the surgical procedure and no additional anaesthesia time attributable to the introduction of acupuncture. The protocol was found to be feasible with regard to performance of the main study. Vomiting occurred in five patients in the treatment group and 10 patients in the control group. The total numbers of vomiting events were 13 in the treatment group and 19 in the control group.

Conclusion

The results encouraged performance of the main study according to the research protocol.
CONTROLLING IDEAL TURBULENCE IN TIME-DELAYED CHUA'S CIRCUIT: STABILIZATION AND SYNCHRONIZATION
Authors: SUZUKI MASAYASU , SAKAMOTO NOBORU
Published: May 2010

We try to stabilize steady solutions of a physical model described by wave equations with nonlinear boundary conditions. This system is a distributed parameter system in which ideal turbulence, introduced by Sharkovsky et al., occurs. Although the behavior of the system is quite intricate both in time and space, by using d'Alembert's solution, the analysis of the dynamic characteristics can be reduced to that of a finite-dimensional difference equation. In this report, based on this analytical method using d'Alembert's solution, we design control laws to stabilize steady solutions (equilibrium solutions and periodic solutions) and synchronize a pair of identical systems.
DISCRETIZING BIFURCATION DIAGRAMS NEAR CODIMENSION TWO SINGULARITIES
Authors: JOSEPH PÁEZ CHÁVEZ
Published: May 2010

We consider parameter-dependent, continuous-time dynamical systems under discretizations. It is shown that fold-Hopf singularities are O(hp)-shifted and turned into fold-Neimark–Sacker points by one-step methods of order p. Then we analyze the effect of discretizations methods on the local bifurcation diagram near Bogdanov–Takens and fold-Hopf singularities. In particular, we prove that the discretized codimension one curves intersect at the singularities in a generic manner. The results are illustrated by a numerical example.
LOCALIZING BOUNDS FOR COMPACT INVARIANT SETS OF NONLINEAR SYSTEMS POSSESSING FIRST INTEGRALS WITH APPLICATIONS TO HAMILTONIAN SYSTEMS
Authors: STARKOV KONSTANTIN E.
Published: May 2010

In this paper, we study the localization problem of compact invariant sets of nonlinear systems possessing first integrals by using the first order extremum conditions and positive definite polynomials. In the case of natural polynomial Hamiltonian systems, our results include those in [Starkov, 2008] as a special case. This paper discusses the application to studies of the generalized Yang–Mills Hamiltonian system and the Hamiltonian system describing dynamics of hydrogenic atoms in external fields.
NEW CONSTRUCTION OF MIXED-MODE CHAOTIC CIRCUITS
Authors: KLOMKARN KITDAKORN , SOORAKSA PITIKHATE , CHEN GUANRONG
Published: May 2010

This paper presents a simple scheme for designing mixed-mode chaotic circuits using quadrature core oscillators. Two mixed-mode circuits are constructed by using a few operational amplifiers in suitable combination with some autonomous/nonautonomous second/third-order chaotic circuits. Simulation and experimental results have verified the simplicity and effectiveness of the new design.
SYNCHRONIZATION OF CHAOTIC OSCILLATORS BY MEANS OF GENERALIZED PROPORTIONAL INTEGRAL OBSERVERS
Authors: LUVIANO-JUÁREZ ALBERTO , CORTÉS-ROMERO JOHN , SIRA-RAMÍREZ HEBERTT
Published: May 2010

The problem of synchronization of chaotic oscillators, using state observers, is handled through the use of a simplified perturbed linear integration model of the chaotic system output dynamics. The linear simplified model of the chaotic system does not entitle approximate linearizations, nor state coordinate transformations, but, simply, a pure linear integration model with additive unknown but bounded perturbation inputs lumping all the output dynamics nonlinearities. An extended linear state observer (here addressed as Generalized Proportional Integral (GPI) observer) is proposed for the accurate estimation of the phase variables and the perturbation input of the nonlinear output dynamics. The effectiveness of the approach is tested in the synchronization of two study cases: The Genesio–Tesi chaotic system and the Rossler oscillator. As an application of the estimation process, a coding–decoding process involving encrypted messages, in transmitted phase variables, is implemented using a Rossler chaotic system.
A DEGREE-BASED STRATEGY FOR CONSTRAINED PINNING CONTROL OF COMPLEX NETWORKS
Authors: TANG WALLACE K. S. , NG KA-HO , JIA QIANG
Published: May 2010

In this paper, a modified degree-based strategy is proposed for pinning control of complex networks under constrained control capacity. Limited by the total control strength, the pinning strategy design problem is reconsidered as a constrained optimization problem. To provide a fast and effective solution, a decrease-and-conquer approach has been designed to assign the best control strengths to the pinned highest-degree nodes. Simulation results have demonstrated that the obtained strategy provides an outperformed control effect on various kinds of complex networks, as compared with strategies derived from degree, betweenness or closeness using evenly-distributed control strength.
ADDITIVE RISK ANALYSIS OF MICROARRAY GENE EXPRESSION DATA VIA CORRELATION PRINCIPAL COMPONENT REGRESSION
Authors: ZHAO YICHUAN , WANG GUOSHEN
Published: May 2010

In order to predict future patients' survival time based on their microarray gene expression data, one interesting question is how to relate genes to survival outcomes. In this paper, by applying a semi-parametric additive risk model in survival analysis, we propose a new approach to conduct a careful analysis of gene expression data with the focus on the model's predictive ability. In the proposed method, we apply the correlation principal component regression to deal with right censoring survival data under the semi-parametric additive risk model frame with high-dimensional covariates. We also employ the time-dependent area under the receiver operating characteristic curve and root mean squared error for prediction to assess how well the model can predict the survival time. Furthermore, the proposed method is able to identify significant genes, which are significantly related to the disease. Finally, the proposed useful approach is illustrated by the diffuse large B-cell lymphoma data set and breast cancer data set. The results show that the model fits the data sets very well.
A NON-PARAMETRIC BAYESIAN APPROACH FOR PREDICTING RNA SECONDARY STRUCTURES
Authors: SATO KENGO , HAMADA MICHIAKI , MITUYAMA TOUTAI , ASAI KIYOSHI , SAKAKIBARA YASUBUMI
Published: May 2010

Since many functional RNAs form stable secondary structures which are related to their functions, RNA secondary structure prediction is a crucial problem in bioinformatics. We propose a novel model for generating RNA secondary structures based on a non-parametric Bayesian approach, called hierarchical Dirichlet processes for stochastic context-free grammars (HDP-SCFGs). Here non-parametric means that some meta-parameters, such as the number of non-terminal symbols and production rules, do not have to be fixed. Instead their distributions are inferred in order to be adapted (in the Bayesian sense) to the training sequences provided. The results of our RNA secondary structure predictions show that HDP-SCFGs are more accurate than the MFE-based and other generative models.
CONSERVATION AREA START-UPS: COMBINING THEORY AND PRACTICE
Authors: WRIGHT NORMAN S. , CANEEN JEFF , ALEXANDER NATHAN , GOMEZ ANDREW
Published: May 2010

Business start-ups by indigenous people in wildlife conservation areas are prone to failure. Funding issues have been identified as a contributing cause of the disappointing results. A great deal has been written about capital structure both in the start-up literature and the corporate literature, but the applicability of this research to small, indigenous start-ups in and around conservation areas is lacking. Although current practice dictates a reliance on equity, we apply the relevant corporate and start-up research to the conservation area context in an attempt to better understand the capital funding question. The results argue that equity funding is appropriate in the early stages for control and liquidity reasons. However, it also shows that greater attention could be paid to some degree of early debt financing to create debt discipline and later debt funding for motivational and financial discipline purposes.
The end of the information system life
Authors: Furneaux Brent , Wade Michael
Published: May 2010

Considerable information systems (IS) research has sought to understand the adoption, implementation, and use of information systems. In contrast, the literature offers only limited insight into end-of-life issues such as those surrounding the nature of, and basis for, organizational IS discontinuance. This situation, in conjunction with the dramatic impact that discontinuance can have on organizational performance and measures of system success, suggests a strong need for further research. Since the absence of sound theoretical frameworks can impede such research, this paper offers a theoretical model of IS discontinuance that seeks to account for organizational intention to discontinue the use of an information system. The model is based on the premise that forces contributing to the formation of discontinuance intentions are opposed by inertial tendencies in favor of the status quo. Environmental change and organizational initiative are posited to be the two broad forces driving an information system toward the end of its useful life. Organizational investments in the system, system embeddedness within the organization, and mimetic isomorphism are then seen to constrain the extent to which change forces lead to the emergence of organizational discontinuance intentions. A series of propositions are offered and related guidance is provided for those interested in pursuing further research. An exploration of how the proposed model can be generalized to other discontinuance decisions such as the decision to terminate the use of an IS standard or management practice is also offered for interested readers.
Capturing user readiness to interact with information systems
Authors: Sun Jun , Poole Marshall Scott
Published: May 2010

Drawing on an understanding of user experiences in interacting with information systems grounded in Activity Theory, this study posits a new psychological construct, information system interaction readiness (ISIR), to capture how ready an individual is to interact with each of the systems available for a task. This construct reflects the affective, cognitive and behavioral components of user situated attitude toward taking mediated actions involving input interface, output interface and communication rules in a user-system interaction activity. Two versions (long and short) of a measurement instrument were developed, and validation studies were conducted. The results showed that the two versions had similar psychometric properties and provided supporting evidence for various aspects of measurement validity. Theoretical and practical implications were discussed.
The role of task characteristics and organizational culture in non-work-related computing
Authors: Bock Gee-Woo , Shin Yuhyung , Liu Ping , Sun Hua
Published: May 2010

Many organizations have created control mechanisms and discipline systems to prevent employees from engaging in non-work-related computing (NWRC). Since such control mechanisms and discipline systems often fail to reduce NWRC, it is necessary to delineate task characteristics and organizational cultures that can enhance the effectiveness of NWRC management. Based on a fit perspective, we examined the effects of task characteristic-control mechanism fit and organizational culture-discipline system fit on employees' NWRC behaviors and attitudes toward NWRC discipline systems. Two separate studies on full-time employees in Asian organizations revealed three important findings. First, when task non-routineness was high, NWRC control mechanisms were less effective in reducing NWRC behavior. Second, progressive (punitive) discipline systems were associated with greater satisfaction with the discipline system in bureaucratic cultures, whereas positive discipline systems were related to higher satisfaction in innovative and supportive cultures. Finally, positive discipline systems were also associated with reduced NWRC behavior in innovative cultures.
Involvement of CaV3.1 T-type calcium channels in cell proliferation in mouse preadipocytes
Authors: Oguri Atsushi , Tanaka Tomofumi , Iida Haruko , Meguro Kentarou , Takano Haruhito , Oonuma Hitoshi , Nishimura Satoshi , Morita Toshihiro , Yamasoba Tatsuya , Nagai Ryozo , Nakajima Toshiaki
Published: May 2010

Voltage-gated Ca2+ channels (CaV) are ubiquitously expressed in various cell types and play vital roles in regulation of cellular functions including proliferation. However, the molecular identities and function of CaV remained unexplored in preadipocytes. Therefore, whole cell voltage-clamp technique, conventional/quantitative real-time RT-PCR, Western blot, small interfering RNA (siRNA) experiments, and immunohistochemical analysis were applied in mouse primary cultured preadipocytes as well as mouse 3T3-L1 preadipocytes. The effects of CaV blockers on cell proliferation and cell cycle were also investigated. Whole cell recordings of 3T3-L1 preadipocytes showed low-threshold CaV, which could be inhibited by mibefradil, Ni2+ (IC50 of 200 μM), and NNC55-0396. Dominant expression of α1G mRNA was detected among CaV transcripts (α1A–α1I), supported by expression of CaV3.1 protein encoded by α1G gene, with immunohistochemical studies and Western blot analysis. siRNA targeted for α1G markedly inhibited CaV. Dominant expression of α1G mRNA and expression of CaV3.1 protein were also observed in mouse primary cultured preadipocytes. Expression level of α1G mRNA and CaV3.1 protein significantly decreased in differentiated adipocytes. Mibefradil, NNC55-0396, a selective T-type CaV blocker, but not diltiazem, inhibited cell proliferation in response to serum. NNC55-0396 and siRNA targeted for α1G also prevented cell cycle entry/progression. The present study demonstrates that the CaV3.1 T-type Ca2+ channel encoded by α1G subtype is the dominant CaV in mouse preadipocytes and may play a role in regulating preadipocyte proliferation, a key step in adipose tissue development.
Dynamic changes in the TRPA1 selectivity filter lead to progressive but reversible pore dilation
Authors: Banke T. G. , Chaplan S. R. , Wickenden A. D.
Published: May 2010

TRPA1 is a nonselective cation channel belonging to the transient receptor potential (TRP) family that is expressed in peripheral sensory neurons and may play important roles in pain perception and inflammation. We found that agonist stimulation of TRPA1, along with other members of the TRP family (TRPV1–4 and TRPM8), can induce the appearance of a large pore permeable to large organic cations such as Yo-Pro (YP) and N-methyl-d-glucamine, in an agonist and divalent cation-dependent manner. YP uptake was not inhibited by a panel of putative gap junction/pannexin blockers, suggesting that gap junction proteins are not required in this process. Our data suggest that changes in the TRP channel selectivity filter itself result in a progressive but reversible pore dilation process, a process that is under strong regulation by external calcium ions. Our data suggest that calcium plays a novel role in setting the amount of time TRPA1 channels spend in a dilated state providing a mechanism that may limit sensory neuron activation by painful or irritating substances.
Functional characterization of the central hydrophilic linker region of the urea transporter UT-A1: cAMP activation and snapin binding
Authors: Mistry Abinash C. , Mallick Rickta , Klein Janet D. , Sands Jeff M. , Fröhlich Otto
Published: May 2010

Of the three major protein variants produced by the UT-A gene (UT-A1, UT-A2, and UT-A3) UT-A1 is the largest. It contains UT-A3 as its NH2-terminal half and UT-A2 as its COOH-terminal half. When being part of UT-A1, UT-A3 and UT-A2 are joined by a segment, Lp, whose central part, Lc, is not part of UT-A3 or UT-A2 but is present only in UT-A1. Lc contains the phosphorylation sites S486 and S499 that are involved in protein kinase A-dependent activation, as well as the binding site for snapin, a protein involved in soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor (SNARE)-mediated vesicle trafficking and fusion to the plasma membrane. We attached Lc to UT-A2 and UT-A3 to test how these phosphorylation sites influenced their urea transport activity. Adding Lc to UT-A2 conferred stimulation by cAMP to the cAMP-unresponsive UT-A2, and adding Lc to UT-A3 did not further enhance its already existing cAMP response. These findings suggest that the responsiveness to vasopressin that is observed with UT-A1 can be introduced into the unresponsive UT-A2 variant through the Lc segment that is unique to UT-A1. In UT-A3, however, the Lc segment plays no significant role in its activation by cAMP. In addition, the Lc segment also gave UT-A2 the ability to bind snapin and, in Xenopus oocytes, to be stimulated in its urea transport activity by snapin and syntaxins 3 and 4, in the same way as UT-A1.
Pak1 regulates branching morphogenesis in 3D MDCK cell culture by a PIX and β1-integrin-dependent mechanism
Authors: Hunter Michael P. , Zegers Mirjam M.
Published: May 2010

Branching morphogenesis is a fundamental process in the development of the kidney. This process gives rise to a network of ducts, which form the collecting system. Defective branching can lead to a multitude of kidney disorders including agenesis and reduced nephron number. The formation of branching tubules involves changes in cell shape, cell motility, and reorganization of the cytoskeleton. However, the exact intracellular mechanisms involved are far from understood. We have used the three-dimensional (3D) Madin-Darby canine kidney (MDCK) cell culture system to study how p21-activated kinase 1 (Pak1), which is an important regulator of the cytoskeleton, modulates branching. Our data reveal that Pak1 plays a crucial role in regulating branching morphogenesis. Expression of a dominant-negative Pak1 mutant (DN-Pak1) in MDCK cysts resulted in the spontaneous formation of extensions and branching tubules. Cellular contractility and levels of phosphorylated myosin light chain (pMLC) were increased in DN-Pak1 cells in collagen. Expression of a DN-Pak1 mutant that does not bind to PIX (DN-Pak1-ΔPIX) failed to form extensions in collagen and did not have increased contractility. This shows that the DN-Pak1 mutant requires PIX binding to generate extensions and increased contractility in 3D culture. Furthermore, a β1-integrin function-blocking antibody (AIIB2) inhibited the formation of branches and blocked the increased contractility in DN-Pak1 cysts. Taken together, our work shows that DN-Pak1-induced branching morphogenesis requires PIX binding and β1-integrin signaling.
Diversification of Intrinsic Motoneuron Electrical Properties During Normal Development and Botulinum Toxin–Induced Muscle Paralysis in Early Postnatal Mice
Authors: Nakanishi S. T. , Whelan P. J.
Published: May 2010

During early postnatal development, between birth and postnatal days 8–11, mice start to achieve weight-bearing locomotion. In association with the progression of weight-bearing locomotion there are presumed developmental changes in the intrinsic electrical properties of spinal α-motoneurons. However, these developmental changes in the properties of α-motoneuron properties have not been systematically explored in mice. Here, data are presented documenting the developmental changes of selected intrinsic motoneuron electrical properties, including statistically significant changes in action potential half-width, intrinsic excitability and diversity (quantified as coefficient of variation) of rheobase current, afterhyperpolarization half-decay time, and input resistance. In various adult mammalian preparations, the maintenance of intrinsic motoneuron electrical properties is dependent on activity and/or transmission-sensitive motoneuron–muscle interactions. In this study, we show that botulinum toxin–induced muscle paralysis led to statistically significant changes in the normal development of intrinsic motoneuron electrical properties in the postnatal mouse. This suggests that muscle activity during early neonatal life contributes to the development of normal motoneuron electrical properties.
Carving the Clock at Its Component Joints: Neural Bases for Interval Timing
Authors: Wencil Elaine B. , Coslett H. Branch , Aguirre Geoffrey K. , Chatterjee Anjan
Published: May 2010

Models of time perception often describe an “internal clock” that involves at least two components: an accumulator and a comparator. We used functional magnetic resonance imaging to test the hypothesis that distinct distributed neural networks mediate these components of time perception. Subjects performed a temporal discrimination task that began with a visual stimulus (S1) that varied parametrically in duration of presentation. A varying interstimulus interval was followed by a second visual stimulus (S2). After the S2 offset, the subject indicated whether S2 was longer or shorter than S1. We reasoned that neural activity that correlated with S1 duration would represent accumulator networks. We also reasoned that neural activity that correlated with the difficulty of comparisons for each paired-judgment would represent comparator networks. Using anatomically defined regions of interest, we found duration of S1 significantly correlated with left inferior frontal, supplementary motor area (SMA) and superior temporal regions. Furthermore, task difficulty correlated with activity within bilateral inferior frontal gyri. Therefore accumulator and comparator functioning of the internal clock are mediated by distinct as well as partially overlapping neural regions.
Comparing Tactile Pattern and Vibrotactile Frequency Discrimination: A Human fMRI Study
Authors: Li Hegner Yiwen , Lee Ying , Grodd Wolfgang , Braun Christoph
Published: May 2010

We investigated to which extent the discrimination of tactile patterns and vibrotactile frequencies share common cortical areas. An adaptation paradigm has been used to identify cortical areas specific for processing particular features of tactile stimuli. Healthy right-handed subjects performed a delayed-match-to-sample (DMTS) task discriminating between pairs of tactile patterns or vibrotactile frequencies in separate functional MRI sessions. The tactile stimuli were presented to the right middle fingertip sequentially with a 5.5 s delay. Regions of interest (ROIs) were defined by cortical areas commonly activated in both tasks and those that showed differential activation between both tasks. Results showed recruitment of many common brain regions along the sensory motor pathway (such as bilateral somatosensory, premotor areas, and anterior insula) in both tasks. Three cortical areas, the right intraparietal sulcus (IPS), supramarginal gyrus (SMG)/parietal operculum (PO), and PO, were significantly more activated during the pattern than in the frequency task. Further BOLD time course analysis was performed in the ROIs. Significant BOLD adaptation was found in bilateral IPS, right anterior insula, and SMG/PO in the pattern task, whereas there was no significant BOLD adaptation found in the frequency task. In addition, the right hemisphere was found to be more dominant in the pattern than in the frequency task, which could be attributed to the differences between spatial (pattern) and temporal (frequency) processing. From the different spatio-temporal characteristics of BOLD activation in the pattern and frequency tasks, we concluded that different neuronal mechanisms are underlying the tactile spatial and temporal processing.
Retinal Synaptic Pathways Underlying the Response of the Rabbit Local Edge Detector
Authors: Russell Thomas L. , Werblin Frank S.
Published: May 2010

We studied the circuitry that underlies the behavior of the local edge detector (LED) retinal ganglion cell in rabbit by measuring the spatial and temporal properties of excitatory and inhibitory currents under whole cell voltage clamp. Previous work showed that LED excitation is suppressed by activity in the surround. However, the contributions of outer and inner retina to this characteristic and the neurotransmitters used are currently unknown. Blockage of retinal inhibitory pathways (GABAA, GABAC, and glycine) eliminated edge selectivity. Inverting gratings in the surround with 50-μm stripe sizes did not stimulate horizontal cells, but suppressed on and off excitation by roughly 60%, indicating inhibition of bipolar terminals (feedback inhibition). On pharmacologic blockage, we showed that feedback inhibition used both GABAA and GABAC receptors, but not glycine. Glycinergic inhibition suppressed GABAergic feedback inhibition in the center, enabling larger excitatory currents in response to luminance changes. Excitation, feedback inhibition, and direct (feedforward) inhibition responded to luminance-neutral flipping gratings of 20- to 50-μm widths, showing they are driven by independent subunits within their receptive fields, which confers sensitivity to borders between areas of texture and nontexture. Feedforward inhibition was glycinergic, its rise time was faster than decay time, and did not function to delay spiking at the onset of a stimulus. Both the on and off phases could be triggered by luminance shifts as short in duration as 33 ms and could be triggered during scenes that already produced a high baseline level of feedforward inhibition. Our results show how LED circuitry can use subreceptive field sensitivity to detect visual edges via the interaction between excitation and feedback inhibition and also respond to rapid luminance shifts within a rapidly changing scene by producing feedforward inhibition.
Cue Reliability and a Landmark Stability Heuristic Determine Relative Weighting Between Egocentric and Allocentric Visual Information in Memory-Guided Reach
Authors: Byrne Patrick A. , Crawford J. Douglas
Published: May 2010

It is not known how egocentric visual information (location of a target relative to the self) and allocentric visual information (location of a target relative to external landmarks) are integrated to form reach plans. Based on behavioral data from rodents and humans we hypothesized that the degree of stability in visual landmarks would influence the relative weighting. Furthermore, based on numerous cue-combination studies we hypothesized that the reach system would act like a maximum-likelihood estimator (MLE), where the reliability of both cues determines their relative weighting. To predict how these factors might interact we developed an MLE model that weighs egocentric and allocentric information based on their respective reliabilities, and also on an additional stability heuristic. We tested the predictions of this model in 10 human subjects by manipulating landmark stability and reliability (via variable amplitude vibration of the landmarks and variable amplitude gaze shifts) in three reach-to-touch tasks: an egocentric control (reaching without landmarks), an allocentric control (reaching relative to landmarks), and a cue-conflict task (involving a subtle landmark “shift” during the memory interval). Variability from all three experiments was used to derive parameters for the MLE model, which was then used to simulate egocentric–allocentric weighting in the cue-conflict experiment. As predicted by the model, landmark vibration—despite its lack of influence on pointing variability (and thus allocentric reliability) in the control experiment—had a strong influence on egocentric–allocentric weighting. A reduced model without the stability heuristic was unable to reproduce this effect. These results suggest heuristics for extrinsic cue stability are at least as important as reliability for determining cue weighting in memory-guided reaching.
Investigation of Linear Coupling Between Single-Event Blood Flow Responses and Interictal Discharges in a Model of Experimental Epilepsy
Authors: Vanzetta Ivo , Flynn Corey , Ivanov Anton I. , Bernard Christophe , Bénar Christian G.
Published: May 2010

A successful outcome of epilepsy neurosurgery relies on an accurate delineation of the epileptogenic region to be resected. Functional magnetic resonance imaging (fMRI) would allow doing this noninvasively at high spatial resolution. However, a clear, quantitative description of the relationship between hemodynamic changes and the underlying epileptiform neuronal activity is still missing, thereby preventing the systematic use of fMRI for routine epilepsy surgery planning. To this aim, we used a local epilepsy model to record simultaneously cerebral blood flow (CBF) with laser Doppler (LD) and local field potentials (LFP) in rat frontal cortex. CBF responses to individual interictal-like spikes were large and robust. Their amplitude correlated linearly with spike amplitude. Moreover, the CBF response added linearly in time over a large range of spiking rates. CBF responses could thus be predicted by a linear model of the kind currently used for the interpretation of fMRI data, but including also the spikes’ amplitudes as additional information. Predicted and measured CBF responses matched accurately. For high spiking frequencies (above ∼0.2 Hz), the responses saturated but could eventually recover, indicating the presence of multiple neurovascular coupling mechanisms, which might act at different spatiotemporal scales. Spatially, CBF responses peaked at the center of epileptic activity and displayed a spatial specificity at least as good as the millimeter. These results suggest that simultaneous electroencephalographic and blood flow-based fMRI recordings should be suitable for the noninvasive precise localization of hyperexcitable regions in epileptic patients candidate for neurosurgery.
Receptive Field Dynamics Underlying MST Neuronal Optic Flow Selectivity
Authors: Yu Chen Ping , Page William K. , Gaborski Roger , Duffy Charles J.
Published: May 2010

Optic flow informs moving observers about their heading direction. Neurons in monkey medial superior temporal (MST) cortex show heading selective responses to optic flow and planar direction selective responses to patches of local motion. We recorded MST neuronal responses to a 90 × 90° optic flow display and to a 3 × 3 array of local motion patches covering the same area. Our goal was to test the hypothesis that the optic flow responses reflect the sum of the local motion responses. The local motion responses of each neuron were modeled as mixtures of Gaussians, combining the effects of two Gaussian response functions derived using a genetic algorithm, and then used to predict that neuron's optic flow responses. Some neurons showed good correspondence between local motion models and optic flow responses, others showed substantial differences. We used the genetic algorithm to modulate the relative strength of each local motion segment's responses to accommodate interactions between segments that might modulate their relative efficacy during co-activation by global patterns of optic flow. These gain modulated models showed uniformly better fits to the optic flow responses, suggesting that coactivation of receptive field segments alters neuronal response properties. We tested this hypothesis by simultaneously presenting local motion stimuli at two different sites. These two-segment stimuli revealed that interactions between response segments have direction and location specific effects that can account for aspects of optic flow selectivity. We conclude that MST's optic flow selectivity reflects dynamic interactions between spatially distributed local planar motion response mechanisms.
The Neural Mechanisms of the Effects of Transcranial Magnetic Stimulation on Perception
Authors: Ruzzoli Manuela , Marzi Carlo A. , Miniussi Carlo
Published: May 2010

Transcranial magnetic stimulation (TMS) is a technique used to study perceptual, motor, and cognitive functions in the human brain. Its effects have been likened to a “virtual brain lesion,” but a direct test of this assumption is lacking. To verify this hypothesis, we measured psychophysically the interaction between the neural activity induced by a visual motion-direction discrimination task and that induced by TMS. The visual stimulus featured two elements: a visual signal (dots that moved coherently in one direction) and visual noise (dots that moved randomly in many directions). Three hypotheses were tested to explain the impairment in performance as a result of TMS: 1) a decrease in signal strength; 2) an induction of randomly distributed neural noise with an accompanying decrement in system sensitivity; and 3) a suppression of relevant information processing and addition of neural noise. We provide evidence in favor of the second hypothesis by showing that TMS basically acts by adding neural noise to the perceptual process.
Long-Latency and Voluntary Responses to an Arm Displacement Can Be Rapidly Attenuated By Perturbation Offset
Authors: Kurtzer Isaac , Pruszynski J. Andrew , Scott Stephen H.
Published: May 2010

Feedback control of our limbs must account for the unexpected offset of mechanical perturbations. Here we examine the evoked activity of elbow flexor and extensor muscles to torque pulses lasting 22–152 ms and how torque offset impacts activity in the long-latency (45–100 ms) and voluntary epochs (120–180 ms). For each pulse width, we found a significant attenuation of muscle activity ∼30 ms after the offset of torque compared with when the torque was sustained. The brief time between the offset of torque and the attenuation of muscle activity implicates group I afferents acting through a spinal pathway, because this route is the only one fast enough and short enough to be responsible. Moreover, elbow muscle activity in the subsequent 20–45 ms following torque-offset was ∼35% smaller than when the torque was sustained. These results show that a fast spinal process can powerfully attenuate corrective responses of the arm to a torque perturbation.
Adaptive Pinning Synchronization of Complex Networks with Stochastic Perturbations
Authors: Yang Xinsong , Cao Jinde
Published: May 2010

The adaptive pinning
synchronization is investigated for complex networks with
nondelayed and delayed couplings and vector‐form stochastic
perturbations. Two kinds of adaptive pinning controllers are
designed. Based on an Lyapunov‐Krasovskii functional and the
stochastic stability analysis theory, several sufficient
conditions are developed to guarantee the synchronization of the
proposed complex networks even if partial states of the nodes are
coupled. Furthermore, three examples with their numerical
simulations are employed to show the effectiveness of the
theoretical results.