bluuebunny/crossref_metadata_2025 huggingface dataset:
Learning How and Learning What: Effects of Tacit and Codified Knowledge on Performance Improvement Following Technology Adoption
Authors: Edmondson Amy C. , Winslow Ann B. , Bohmer Richard M. J. , Pisano Gary P.
Published: September 2003

This paper examines effects of tacit and codified knowledge on performance improvement as organizations gain experience with a new technology. We draw from knowledge management and learning curve research to predict improvement rate heterogeneity across organizations. We first note that the same technology can present opportunities for improvement along more than one dimension, such as efficiency and breadth of use. We compare improvement for two dimensions: one in which the acquisition of codified knowledge leads to improvement and another in which improvement requires tacit knowledge. We hypothesize that improvement rates across organizations will be more heterogeneous for dimensions of performance that rely on tacit knowledge than for those that rely on codified knowledge (H1), and that group membership stability predicts improvement rates for dimensions relying on tacit knowledge (H2). We further hypothesize that when performance relies on codified knowledge, later adopters should improve more quickly than earlier adopters (H3). All three hypotheses are supported in a study of 15 hospitals learning to use a new surgical technology. Implications for theory and practice are discussed.
The Role of Existing Knowledge in New Product Innovativeness and Performance
Authors: Brockman Beverly K. , Morgan Robert M.
Published: September 2003

The purpose of this study is to provide a more thorough assessment of the link between existing knowledge and organizational performance than currently exists in the literature. We identify factors and processes influential in the management of existing knowledge within the areas of learning culture, knowledge building, and organizational performance. Through structural equation modeling, a more thorough examination is given of the role existing knowledge plays in new product performance and innovativeness. In completing this task, we provide insight into the subprocesses of knowledge building by evaluating the influence of shared interpretation and two aspects of information acquisition—efficiency and degree of innovativeness of newly acquired information—on new product development (NPD) outcomes. Included in the examination of these processes are organizational culture and structure characteristics believed to influence knowledge management success.
Understanding the Antecedents of Effective Knowledge Management: The Importance of a Knowledge‐Centered Culture*
Authors: Janz Brian D. , Prasarnphanich Pattarawan
Published: September 2003

Within the context of knowledge management, little research has been conducted that identifies the antecedents of a knowledge‐centered culture—those organizational qualities that encourage knowledge creation and dissemination. In this study, the existing literature on organizational climate, job characteristics, and organizational learning (in the form of cooperative learning theory) are linked with the current thinking and research findings related to knowledge management to develop a theoretical model explaining the relationships among organizational climate, the level of cooperative learning that takes place between knowledge workers, and the resulting level of knowledge created and disseminated as measured by team performance and individual satisfaction levels. The study goes on to empirically test the proposed research model by investigating the climate of organizations, and seeks to understand the linkage between a set of organizational and individual characteristics and knowledge‐related activities found in cooperative learning groups and the resulting work outcomes. The hypothesized research model is tested usingLISRELwith data collected from 203 information systems (IS) professionals engaged in systems development activities. The paper concludes with a discussion of the implications the results have for future research and managerial practice.
An Empirical Study of the Effect of Knowledge Management Processes at Individual, Group, and Organizational Levels*
Authors: Sabherwal Rajiv , Becerra‐Fernandez Irma
Published: September 2003

To enhance our understanding of knowledge management, this paper focuses on a specific question: How do knowledge management processes influence perceived knowledge management effectiveness? Prior literature is used to develop the research model, including hypotheses about the effects of four knowledge management processes (internalization, externalization, socialization, and combination) on perceived individual‐level, group‐level, and organizational‐level knowledge management effectiveness. The study was conducted at the John F. Kennedy Space Center of the National Aeronautics and Space Administration using a survey of 159 individuals and two rounds of personal interviews. Structural equation modeling was performed to test measurement and structural models using the survey data. The emergent model suggests that internalization and externalization impact perceived effectiveness of individual‐level knowledge management. Socialization and combination influence perceived effectiveness of knowledge management at group and organizational levels, respectively. The results also support the expected upward impact in perceived effectiveness of knowledge management, from individual to group level, as well as from group level to organizational level. The study's limitations and implications for practice and future research are described.
Integrating Knowledge through Information Trading: Examining the Relationship between Boundary Spanning Communication and Individual Performance*
Authors: Teigland Robin , Wasko Molly McLure
Published: September 2003

With the global penetration of Internet technologies, individuals may now cross organizational boundaries to communicate efficiently with others regardless of time and space. Thus, when looking for help in solving work tasks, knowledge workers may just as easily contact individuals in rival firms across the globe as a coworker sitting at the next desk. As a result, management faces questions such as (1) How should firms manage employees' knowledge‐sourcing activities when they span both intra‐organizational and extra‐organizational boundaries, and (2) What is the relationship between different knowledge‐sourcing activities and individual performance? Grounded in the knowledge‐based view of the firm, we investigate these questions using data from Europe's largest information technology (IT) services and management consulting company. Our results provide evidence that organizations should support boundary spanning and knowledge sourcing from both internal and external sources. Results suggest (1) apositiverelationship between boundary spanning communication and creativity and general performance, and (2) anegativerelationship between a reliance on colocated coworkers as knowledge sources and creativity.
Experiential and Informational Knowledge, Architectural Marketing Capabilities, and the Adaptive Performance of Export Ventures: A Cross‐National Study
Authors: Morgan Neil A. , Zou Shaoming , Vorhies Douglas W. , Katsikeas Constantine S.
Published: September 2003

Knowledge‐based view (KBV) theory posits that the acquisition and use of relevant knowledge is key to understanding organizational performance. However, there is relatively little empirical evidence to support or refute several important propositions underlying KBV theory explanations of organizational performance. In particular, the extant literature has focused on individual technical and scientific components of the knowledge bases of firms in dynamic industries, and largely ignored both different levels of informational and experiential knowledge relevant to the market environment, and the increasingly important context of exporting. Our study addresses these knowledge gaps by developing a framework for export venture knowledge management and empirically examining relationships between different types of individual‐level and organizational‐level knowledge relevant to the market environment, architectural marketing capabilities, and the adaptive performance of export ventures. Using primary data collected in the United Kingdom and China, our study indicates that export ventures' organizational‐level experiential and informational knowledge, and individual‐level experiential knowledge relevant to the market environment, is positively associated with export ventures' architectural marketing capabilities, which are in turn associated with the adaptive performance of export ventures.
The Role of Knowledge in Resource Allocation to Exploration versus Exploitation in Technologically Oriented Organizations*
Authors: Garcia Rosanna , Calantone Roger , Levine Ralph
Published: September 2003

Decisions regarding research and development (R&D) activities of an organization greatly affect the fiscal and market outcomes of technologically oriented firms. Yet, the resource allocation choices between these two activities are tied strongly to an organization's technology knowledge. Technological knowledge is itself a resource that the firm can manage to achieve strategic and competitive advantage. In this paper, the authors present a system dynamics view of the decomposition of R&D efforts into explorative and exploitive activities and the resultant knowledge‐specific and performance outcomes from the decision to focus on one type of activity or another. Four factors are shown to affect the relative value of innovative knowledge to the organization: resource availability, exogenous competition, aging of knowledge bases, and adaptive capacity, a firm's ability to adapt to its environment. A variety of long‐ and short‐term strategic issues are discussed in relation to these forces.
Social Networks and Entrepreneurship
Authors: Greve Arent , Salaff Janet W.
Published: September 2003

We study network activities of entrepreneurs through three phases of establishing a firm in four countries. Entrepreneurs access people in their networks to discuss aspects of establishing and running a business. We find that entrepreneurs build networks that systematically vary by the phase of entrepreneurship, analyzing number of their discussion partners, and the time spent networking. Entrepreneurs talk with more people during the planning than other phases. Family members are present in their networks in all phases, particularly among those who took over an existing firm. However, women use their kin to a larger extent than men, and even more than men when they take over an existing firm. Experienced entrepreneurs have the same networking patterns as novices. Moreover, these networking patterns are the same in all countries. However, there are country differences in size of discussion networks and time spent networking.
Organizational Absorptive Capacity and Responsiveness: An Empirical Investigation of Growth–Oriented SMEs
Authors: Liao Jianwen , Welsch Harold , Stoica Michael
Published: September 2003

This study examines the relationship between firm absorptive capacity and organizational responsiveness in the context of growth–oriented small and medium–sized enterprises (SMEs). By testing the different dimensions of absorptive capacity, external knowledge acquisition and intrafirm knowledge dissemination were found to be positively related to organizational responsiveness. In addition, the relationships between absorptive capacity and organizational responsiveness were moderated by environmental dynamism and the SMEs’ strategic orientation. Results demonstrate that the responsiveness of growth–oriented SMEs is expected to increase if (1) they have well–developed capabilities in external knowledge acquisition and intrafirm knowledge dissemination; (2) they have a well–developed external knowledge acquisition capability and adopt a more proactive strategy, such as being a prospector; (3) they face a turbulent environment and have a well developed internal knowledge dissemination capability. Implications and future research directions are provided.
Voltage‐Gated Na+ Channel Activation Induces Both Action Potentials in Utricular Hair Cells and Brain‐Derived Neurotrophic Factor Release in the Rat Utricle During a Restricted Period of Development
Authors: Chabbert Christian , Mechaly Ilana , Sieso Victor , Giraud Pierre , Brugeaud Aurore , Lehouelleur Jacques , Couraud François , Valmier Jean , Sans Alain
Published: September 2003

The mammalian utricular sensory receptors are commonly believed to be non‐spiking cells with electrical activity limited to graded membrane potential changes. Here we provide evidence that during the first post‐natal week, the sensory hair cells of the rat utricle express a tetrodotoxin (TTX)‐sensitive voltage‐gated Na+ current that displays most of the biophysical and pharmacological characteristics of neuronal Na+ current. Single‐cell RT‐PCR reveals that several α‐subunit isoforms of the Na+ channels are co‐expressed within a single hair cell, with a major expression of Nav1.2 and Nav1.6 subunits. In neonatal hair cells, 30 % of the Na+ channels are available for activation at the resting potential. Depolarizing current injections in the range of the transduction currents are able to trigger TTX‐sensitive action potentials. We also provide evidence of a TTX‐sensitive activity‐dependent brain‐derived neurotrophic factor (BDNF) release by early post‐natal utricle explants. Developmental analysis shows that Na+ currents decrease dramatically from post‐natal day 0 (P0) to P8 and become almost undetectable at P21. Concomitantly, depolarizing stimuli fail to induce both action potential and BDNF release at P20. The present findings reveal that vestibular hair cells express neuronal‐like TTX‐sensitive Na+ channels able to generate Na+‐driven action potentials only during the early post‐natal period of development. During the same period an activity‐dependent BDNF secretion by utricular explants has been demonstrated. This could be an important mechanism involved in vestibular sensory system differentiation and synaptogenesis.
Stumbling Corrective Responses During Treadmill‐Elicited Stepping in Human Infants
Authors: Lam Tania , Wolstenholme Claire , van der Linden Marleen , Pang Marco Y. C. , Yang Jaynie F.
Published: September 2003

This study examined stumbling corrective (tripping) responses to mechanical disturbances applied to the foot during stepping in healthy human infants, in whom independent walking had not yet developed. During treadmill‐elicited stepping, a foam‐padded baton instrumented with a force transducer was used to deliver light touches to either the dorsum or the side of the foot at various times of the step cycle. Disturbances to the dorsum of the foot during the swing phase resulted in a general enhancement of flexor activity, including a significant facilitation in the tibialis anterior muscle and an increase in knee flexion during swing. There was also an increase in step cycle duration. Stance phase disturbances resulted in a significant inhibitory effect in the quadriceps muscle and after early stance disturbances, a significant prolongation of the stance phase duration. Disturbances applied to the side of the foot during the swing phase of forward stepping did not result in any effect on the kinematic pattern. If the infant was stepping sideways, however, disturbances to the side of the foot resulted in an increase in flexion during the swing phase. The results show that infants have a phase‐dependent reflex response to light touches applied to the foot. Furthermore, the reflex response is location specific and task specific. Thus, much of the sophistication necessary for controlling sensory inputs in walking is present well before the onset of independent walking.
Control of upper airway muscle activity in younger versus older men during sleep onset
Authors: Fogel Robert B. , White David P. , Pierce Robert J. , Malhotra Atul , Edwards Jill K. , Dunai Judy , Kleverlaan Darci , Trinder John
Published: September 2003

Pharyngeal dilator muscles are clearly important in the pathophysiology of obstructive sleep apnoea syndrome (OSA). We have previously shown that the activity of both the genioglossus (GGEMG) and tensor palatini (TPEMG) are decreased at sleep onset, and that this decrement in muscle activity is greater in the apnoea patient than in healthy controls. We have also previously shown this decrement to be greater in older men when compared with younger ones. In order to explore the mechanisms responsible for this decrement in muscle activity nasal continuous positive airway pressure (CPAP) was applied to reduce negative pressure mediated muscle activation. We then investigated the effect of sleep onset (transition from predominantly α to predominantly θ EEG activity) on ventilation, upper airway muscle activation and upper airway resistance (UAR) in middle‐aged and younger healthy men. We found that both GGEMG and TPEMG were reduced by the application of nasal CPAP during wakefulness, but that CPAP did not alter the decrement in activity in either muscle seen in the first two breaths following an α to θ transition. However, CPAP prevented both the rise in UAR at sleep onset that occurred on the control night, and the recruitment in GGEMG seen in the third to fifth breaths following the α to θ transition. Further, GGEMG was higher in the middle‐aged men than in the younger men during wakefulness and was decreased more in the middle‐aged men with the application of nasal CPAP. No differences were seen in TPEMG between the two age groups. These data suggest that the initial sleep onset reduction in upper airway muscle activity is due to loss of a ‘wakefulness’ stimulus, rather than to loss of responsiveness to negative pressure. In addition, it suggests that in older men, higher wakeful muscle activity is due to an anatomically more collapsible upper airway with more negative pressure driven muscle activation. Sleep onset per se does not appear to have a greater effect on upper airway muscle activity as one ages.
Developmental Decrease in Synaptic Facilitation at the Mouse Hippocampal Mossy Fibre Synapse
Authors: Mori‐Kawakami Fumiko , Kobayashi Katsunori , Takahashi Tomoyuki
Published: September 2003

Transmission at the hippocampal mossy fibre (MF)‐CA3 pyramidal cell synapse is characterized by prominent activity‐dependent facilitation, which is thought to provide a wide dynamic range in hippocampal informational flow. At this synapse in mice the magnitude of paired‐pulse facilitation and frequency‐dependent facilitation markedly decreased with postnatal development from 3 weeks (3W) to 9 weeks (9W). Throughout this period the mean amplitude and variance of unitary EPSCs stayed constant. By altering extracellular Ca2+/Mg2+ concentrations the paired‐pulse ratio could be changed to a similar extent as observed during development. However, this was accompanied by an over 30‐fold change in EPSC amplitude, suggesting that the developmental change in facilitation ratio cannot simply be explained by a change in release probability. With paired‐pulse stimulation the Ca2+ transients at MF terminals, monitored using mag‐fura‐5, showed a small facilitation, but its magnitude remained similar between 3W and 9W mice. Pharmacological tests using CNQX, adenosine, LY341495, H‐7 or KN‐62 suggested that neither presynaptic receptors (kainate, adenosine and metabotropic glutamate) nor protein kinases are responsible for the developmental change in facilitation. Nevertheless, loading the membrane‐permeable form of BAPTA attenuated the paired‐pulse facilitation in 3W mice to a much greater extent than in 9W mice, resulting in a marked reduction in age difference. These results suggest that the developmental decrease in the MF synaptic facilitation arises from a change associated with residual Ca2+, a decrease in residual Ca2+ itself or a change in Ca2+‐binding sites involved in the facilitation. A developmental decline in facilitation ratio reduces the dynamic range of MF transmission, possibly contributing to the stabilization of hippocampal circuitry.
Velocity recovery cycles of C fibres innervating human skin
Authors: Bostock Hugh , Campero Mario , Serra Jordi , Ochoa José
Published: September 2003

Velocity changes following single and double conditioning impulses were studied by microneurography in single human C fibres to provide information about axonal membrane properties. C units were identified as mechano‐responsive (n= 19) or mechano‐insensitive (12) nociceptors, cold‐sensitive (8) or sympathetic fibres (9), and excited by single, double and triple electrical stimuli to the skin at mean rates of 0.25–2 Hz. The interval between single or paired (20 ms apart) conditioning stimuli and test stimulus was then varied between 500 and 2 ms, and recovery curves of velocity change against inter‐spike interval constructed, allowing for changes in these variables with distance. All fibres exhibited an initial (4–24 ms) relative refractory phase, and a long‐lasting (>500 ms) ‘H2’ phase of reduced velocity, attributed to activation of Na+/K+‐ATPase. Mechano‐responsive nociceptors exhibited an intermediate phase of either supernormality or subnormality, depending on stimulation rate. Mechano‐insensitive nociceptors behaved similarly, but all were supernormal at 1 Hz. Sympathetic units exhibited only a long‐lasting supernormality, while cold fibres exhibited a briefer supernormal and a late subnormal phase (H1), similar to A fibres. A pre‐conditioning impulse doubled H2 and increased H1, but did not augment supernormality or the subnormality of similar time course. Like A fibre supernormality, these phenomena were explained by a passive cable model, so that they provide an estimate of membrane time constant. Nociceptor membrane time constants (median 110 ms, n= 17) were rather insensitive to membrane potential, indicating few active voltage‐dependent potassium channels, whereas sympathetic time constants were longer and reduced by activity‐dependent hyperpolarisation.
Ileitis modulates potassium and sodium currents in guinea pig dorsal root ganglia sensory neurons
Authors: Stewart Timothy , Beyak Michael J. , Vanner Stephen
Published: September 2003

Intestinal inflammation induces hyperexcitability of dorsal root ganglia sensory neurons, which has been implicated in increased pain sensation. This study examined whether alteration of sodium (Na+) and/ or potassium (K+) currents underlies this hyperexcitability. Ileitis was induced in guinea pig ileum with trinitrobenzene sulphonic acid (TBNS) and dorsal root ganglion neurons innervating the site of inflammation were identified by Fast Blue or DiI fluorescence labelling. Whole cell recordings were made from acutely dissociated small‐sized neurons at 7–10 days. Neurons exhibited transient A‐type and sustained outward rectifier K+ currents. Compared to control, both A‐type and sustained K+ current densities were significantly reduced (42 and 34 %, respectively; P < 0.05) in labelled neurons from the inflamed intestine but not in non‐labelled neurons. A‐type current voltage dependence of inactivation was negatively shifted in labelled inflamed intestine neurons. Neurons also exhibited tetrodotoxin‐sensitive and resistant Na+ currents. Tetrodotoxin‐resistant sodium currents were increased by 37 % in labelled neurons from the inflamed intestine compared to control (P < 0.01), whereas unlabelled neurons were unaffected. The activation and inactivation curves of these currents were unchanged by inflammation. These data suggest ileitis increases excitability of intestinal sensory neurons by modulating multiple ionic channels. The lack of effect in non‐labelled neurons suggests signalling originated at the nerve terminal rather than through circulating mediators and, given that Na+ currents are enhanced whereas K+ currents are suppressed, one or more signalling pathways may be involved.
Expression profiling identifies dysregulation of myosin heavy chains IIb and IIx during limb immobilization in the soleus muscles of old rats
Authors: Pattison J. Scott , Folk Lillian C. , Madsen Richard W. , Childs Thomas E. , Spangenburg Espen E. , Booth Frank W.
Published: September 2003

Aged individuals suffer from multiple dysfunctions during skeletal muscle atrophy. The purpose of this study was to determine differential changes in gene expression in atrophied soleus muscle induced by hindlimb immobilization in young (3–4 months) and old (30–31 months) rats. The hypothesis was that differentially expressed mRNAs with age‐atrophy interactions would reveal candidates that induce loss of function responses in aged animals. Each muscle was applied to an independent set of Affymetrix micoarrays, with 385 differentially expressed mRNAs with atrophy and 354 age‐atrophy interactions detected by two‐factor ANOVA (α of 0.05 with a Bonferroni adjustment). Functional trends were observed for 23 and 15 probe sets involved in electron transport and the extracellular matrix, respectively, decreasing more in the young than in the old. Other functional categories with atrophy in both ages included chaperones, glutathione‐S‐transferases, the tricarboxylic acid cycle, reductions in Z‐line‐associated proteins and increases in probe sets for protein degradation. Surprisingly, myosin heavy chain IIb and IIx mRNAs were suppressed in the atrophied soleus muscle of old rats as opposed to the large increases in the young animals (16‐ and 25‐fold, respectively, with microarrays, and 61‐ and 68‐fold, respectively, with real‐time PCR). No significant changes were observed in myosin heavy chain IIb and IIx mRNA with micoarrays in the atrophied soleus muscles of old rats, but they were found to increase six‐ and fivefold, respectively, with real‐time PCR. Therefore, deficiencies in pre‐translational signals that normally upregulate myosin heavy chain IIb and IIx mRNAs during atrophy may exist in the soleus muscle of old animals.
Preservation of Motor Neuron Ca2+ Channel Sensitivity to Insulin‐Like Growth Factor‐1 in Brain Motor Cortex from Senescent Rat
Authors: Shan Hongqu , Messi María Laura , Zheng Zhenlin , Wang Zhong‐Min , Delbono Osvaldo
Published: September 2003

Despite the multiple effects on mammals during development, the effectiveness of the insulin‐like growth factor‐1 (IGF‐1) to sustain cell function and structure in the brain of senescent mammals is almost completely unknown. To address this issue, we investigated whether the effects of IGF‐1 on specific targets are preserved at later stages of life. Voltage‐gated Ca2+ channels (VGCC) are well‐characterized targets of IGF‐1. VGCC regulate membrane excitability and gene transcription along with other functions that have been found to be impaired in the brain of senescent rodents. As the voluntary control of movement has been reported to be altered in the elderly, we investigated the expression, function and responsiveness of high (HVA)‐ and low‐voltage‐activated (LVA) Ca2+ channels to IGF‐1, using the whole‐cell configuration of the patch‐clamp and RT‐PCR in the specific region of the rat motor cortex that controls hindlimb muscle movement. We detected the expression of α1A, α1B and α1E genes encoding the HVA Ca2+ channels P/Q, N and R, respectively, but not α1C, α1D, α1S encoding the L‐type Ca2+ channel in this region of the brain cortex. IGF‐1 enhanced Ca2+ channel currents through P/Q‐ and N‐type channels but not significantly through the R‐type or LVA channels. IGF‐1 enhanced the amplitude but did not modify the voltage dependence of Ca2+ channel currents in young (2‐ to 4‐week‐old), young adult (7‐month‐old) and senescent (28‐ to 29‐month‐old) rats. These results support the concept that despite the reported decrease in circulating (liver) and local (central nervous system) production of IGF‐1 with ageing, key neuronal targets such as the VGCC remain responsive to the growth factor throughout life.
Impaired Arterial Pressure Regulation During Exercise Due to Enhanced Muscular Vasodilatation in Calponin Knockout Mice
Authors: Masuki Shizue , Takeoka Michiko , Taniguchi Shun'ichiro , Yokoyama Minesuke , Nose Hiroshi
Published: September 2003

Calponin is known to be an actin binding protein in smooth muscle, inhibiting actomyosin ATPase activity in vitro. We previously reported that α‐adrenergic vasoconstriction in calponin knockout (KO) mice was reduced compared with that in wild‐type C57BL/6J (WT) mice and, as a compensation, arterial baroreflex sensitivity in KO mice was enhanced at rest. In the present study, we assessed arterial pressure regulation in WT and KO mice during graded treadmill exercise at 5, 10, and 15 m min‐1. Mean arterial pressure (MAP) in KO mice fluctuated more than that in WT mice at every speed of exercise with two‐fold higher variances (P < 0.001). The baroreflex sensitivity (ΔHR/ΔMAP) in WT mice (n= 6), determined from the heart rate response (δHR) to spontaneous change in MAP (δMAP), was ‐5.1 ± 0.6 beats min‐1 mmHg‐1 (mean ±s.e.m.) at rest and remained unchanged at ‐5.0 ± 0.9 beats min‐1 mmHg‐1 during exercise (P < 0.01), while that in KO mice (n= 6) was ‐9.9 ± 1.7 beats min‐1 mmHg‐1 at rest, significantly higher than that in WT mice (P < 0.001), and was reduced to ‐4.7 ± 0.4 beats min‐1 mmHg‐1 during exercise (P < 0.01), not significantly different from that in WT mice. In another experiment, we measured muscle blood flow (MBF) in the thigh by laser‐Doppler flowmetry, electromyogram (EMG), and MAP during voluntary locomotion in KO (n= 7) and WT (n= 7) mice. Muscle vascular conductance, MBF/MAP, started to increase immediately after locomotion, judged from EMG, and reached 50 % of the maximum after the time of 2.3 ± 0.2 s in KO mice, shorter than 5.8 ± 0.6 s in WT mice (P < 0.001). Prior administration of α‐adrenergic blockade (phentolamine) shortened the time in WT mice to that in KO mice (P < 0.001), but did not shorten the time in KO mice. Thus, impaired MAP regulation in KO mice during exercise was caused by a blunted muscle vascular α‐adrenergic contractile response and by the attenuated HR response to spontaneous change in MAP due to reduced baroreflex sensitivity.
Polyamine Flux in Xenopus Oocytes Through Hemi‐Gap Junctional Channels
Authors: Enkvetchakul D. , Ebihara L. , Nichols C. G.
Published: September 2003

Diverse polyamine transport systems have been described in different cells, but the molecular entities that mediate polyamine influx and efflux remain incompletely defined. We have previously demonstrated that spermidine efflux from oocytes is a simple electrodiffusive process, inhibitable by external Ca2+, consistent with permeation through a membrane cation channel. Hemi‐gap junctional channels in Xenopus oocytes are formed from connexin 38 (Cx38), and produce a calcium‐sensitive (Ic) current that is inhibited by external Ca2+. Spermidine efflux is also calcium sensitive, and removal of external calcium increases both Ic currents and spermidine efflux in Xenopus oocytes. Injection of Cx38 cRNA or Cx38 antisense oligonucleotides (to increase or decrease, respectively, Cx38 expression) also increases or decreases spermidine efflux in parallel. Spermidine efflux has a large voltage‐dependent component, which is abolished with injection of Cx38 antisense oligonucleotides. In addition, spermidine uptake is significantly increased in Cx38 cRNA‐injected oocytes in the absence of external calcium. The data indicate that hemi‐gap junctional channels provide the Ca2+‐inhibited pathway for electrodiffusive efflux of polyamines from oocytes, and it is likely that hemi‐gap junctional channels provide Ca2+ and metabolism‐sensitive polyamine permeation pathways in other cells.
Adenosine A1 receptor‐mediated presynaptic inhibition at the calyx of Held of immature rats
Authors: Kimura Masahiro , Saitoh Naoto , Takahashi Tomoyuki
Published: September 2003

At the calyx of Held synapse in brainstem slices of 5‐ to 7‐day‐old (P5–7) rats, adenosine, or the type 1 adenosine (A1) receptor agonist N6‐cyclopentyladenosine (CPA), inhibited excitatory postsynaptic currents (EPSCs) without affecting the amplitude of miniature EPSCs. The A1 receptor antagonist 8‐cyclopentyltheophylline (CPT) had no effect on the amplitude of EPSCs evoked at a low frequency, but significantly reduced the magnitude of synaptic depression caused by repetitive stimulation at 10 Hz, suggesting that endogenous adenosine is involved in the regulation of transmitter release. Adenosine inhibited presynaptic Ca2+ currents (IpCa) recorded directly from calyceal terminals, but had no effect on presynaptic K+ currents. When EPSCs were evoked by IpCa during simultaneous pre‐ and postsynaptic recordings, the magnitude of the adenosine‐induced inhibition of IpCa fully explained that of EPSCs, suggesting that the presynaptic Ca2+ channel is the main target of A1 receptors. Whereas the N‐type Ca2+ channel blocker ω‐conotoxin attenuated EPSCs, it had no effect on the magnitude of adenosine‐induced inhibition of EPSCs. During postnatal development, in parallel with a decrease in the A1 receptor immunoreactivity at the calyceal terminal, the inhibitory effect of adenosine became weaker. We conclude that presynaptic A1 receptors at the immature calyx of Held synapse play a regulatory role in transmitter release during high frequency transmission, by inhibiting multiple types of presynaptic Ca2+ channels.
GABAB Receptor‐ and Metabotropic Glutamate Receptor‐Dependent Cooperative Long‐Term Potentiation of Rat Hippocampal GABAA Synaptic Transmission
Authors: Patenaude Christian , Chapman C. Andrew , Bertrand Sandrine , Congar Patrice , Lacaille Jean‐Claude
Published: September 2003

Repetitive stimulation of Schaffer collaterals induces activity‐dependent changes in the strength of polysynaptic inhibitory postsynaptic potentials (IPSPs) in hippocampal CA1 pyramidal neurons that are dependent on stimulation parameters. In the present study, we investigated the effects of two stimulation patterns, theta‐burst stimulation (TBS) and 100 Hz tetani, on pharmacologically isolated monosynaptic GABAergic responses in adult CA1 pyramidal cells. Tetanization with 100 Hz trains transiently depressed both early and late IPSPs, whereas TBS induced long‐term potentiation (LTP) of early IPSPs that lasted at least 30 min. Mechanisms mediating this TBS‐induced potentiation were examined using whole‐cell recordings. The paired‐pulse ratio of monosynaptic inhibitory postsynaptic currents (IPSCs) was not affected during LTP, suggesting that presynaptic changes in GABA release are not involved in the potentiation. Bath application of the GABAB receptor antagonist CGP55845 or the group I/II metabotropic glutamate receptor antagonist E4‐CPG inhibited IPSC potentiation. Preventing postsynaptic G‐protein activation or Ca2+ rise by postsynaptic injection of GDP‐β‐S or BAPTA, respectively, abolished LTP, indicating a G‐protein‐ and Ca2+‐dependent induction in this LTP. Finally during paired‐recordings, activation of individual interneurons by intracellular TBS elicited solely short‐term increases in average unitary IPSCs in pyramidal cells. These results indicate that a stimulation paradigm mimicking the endogenous theta rhythm activates cooperative postsynaptic mechanisms dependent on GABABR, mGluR, G‐proteins and intracellular Ca2+, which lead to a sustained potentiation of GABAA synaptic transmission in pyramidal cells. GABAergic synapses may therefore contribute to functional synaptic plasticity in adult hippocampus.
Endocytosis at the synaptic terminal
Authors: Royle Stephen J. , Lagnado Leon
Published: September 2003

Exocytosis of neurotransmitter from a synaptic vesicle is followed by efficient retrieval of its constituent membrane and proteins. Real‐time measurements indicate that fast and slow modes of retrieval operate in parallel at a number of presynaptic terminals. Two mechanisms can be distinguished by electron microscopy: clathrin‐mediated retrieval of small vesicles and bulk retrieval of large cisternae. Methods that investigate the behaviour of individual vesicles have recently demonstrated a third route of retrieval: the rapid reversal of a pore‐like connection between the vesicle and surface (‘kiss‐and‐run’). Key aims for the future are to identify the molecules underlying different mechanisms of endocytosis at the synapse and the signals that select between them.
Titin Isoform Variance and Length Dependence of Activation in Skinned Bovine Cardiac Muscle
Authors: Fukuda Norio , Wu Yiming , Farman Gerrie , Irving Thomas C. , Granzier Henk
Published: September 2003

We have explored the role of the giant elastic protein titin in the Frank‐Starling mechanism of the heart by measuring the sarcomere length (SL) dependence of activation in skinned cardiac muscles with different titin‐based passive stiffness characteristics. We studied muscle from the bovine left ventricle (BLV), which expresses a high level of a stiff titin isoform, and muscle from the bovine left atrium (BLA), which expresses more compliant titin isoforms. Passive tension was also varied in each muscle type by manipulating the pre‐history of stretch prior to activation. We found that the SL‐dependent increases in Ca2+ sensitivity and maximal Ca2+‐activated tension were markedly more pronounced when titin‐based passive tension was high. Small‐angle X‐ray diffraction experiments revealed that the SL dependence of reduction of interfilament lattice spacing is greater in BLV than in BLA and that the lattice spacing is coupled with titin‐based passive tension. These results support the notion that titin‐based passive tension promotes actomyosin interaction by reducing the lattice spacing. This work indicates that titin may be a factor involved in the Frank‐Starling mechanism of the heart by promoting actomyosin interaction in response to stretch.
Spontaneous Voltage Oscillations in Striatal Projection Neurons in a Rat Corticostriatal Slice
Authors: Vergara R. , Rick C. , Hernández‐López S. , Laville J. A. , Guzman J. N. , Galarraga E. , Surmeier D. J. , Bargas J.
Published: September 2003

In a rat corticostriatal slice, brief, suprathreshold, repetitive cortical stimulation evoked long‐lasting plateau potentials in neostriatal neurons. Plateau potentials were often followed by spontaneous voltage transitions between two preferred membrane potentials. While the induction of plateau potentials was disrupted by non‐NMDA and NMDA glutamate receptor antagonists, the maintenance of spontaneous voltage transitions was only blocked by NMDA receptor and L‐type Ca2+ channel antagonists. The frequency and duration of depolarized events, resembling up‐states described in vivo, were increased by NMDA and L‐type Ca2+ channel agonists as well as by GABAA receptor and K+ channel antagonists. NMDA created a region of negative slope conductance and a positive slope crossing indicative of membrane bistability in the current‐voltage relationship. NMDA‐induced bistability was partially blocked by L‐type Ca2+ channel antagonists. Although evoked by synaptic stimulation, plateau potentials and voltage oscillations could not be evoked by somatic current injection – suggesting a dendritic origin. These data show that NMDA and L‐type Ca2+ conductances of spiny neurons are capable of rendering them bistable. This may help to support prolonged depolarizations and voltage oscillations under certain conditions.
Contraction‐mediated glycogenolysis in mouse skeletal muscle lacking creatine kinase: the role of phosphorylase b activation
Authors: Katz Abram , Andersson Daniel C. , Yu Josephine , Norman Barbara , Sandström Marie E. , Wieringa Bé , Westerblad Häkan
Published: September 2003

Skeletal muscle that is deficient in creatine kinase (CK−/−) exhibits accelerated glycogenolysis during contraction. Understanding this phenomenon could provide insight into the control of glycogenolysis during contraction. Therefore, glycogen breakdown was investigated in isolated extensor digitorum longus CK−/− muscle. Muscles were stimulated to produce repeated tetani for 20 s in the presence of sodium cyanide to block mitochondrial respiration. Accumulation of lactate after stimulation was similar in wild‐type (WT) and CK−/− muscles, whereas accumulation of glucose‐6‐phosphate was twofold higher in CK−/− muscles, indicating greater glycogenolysis in CK−/− muscles. Total phosphorylase activity was decreased by almost 30 % in CK−/− muscle (P < 0.001). Phosphorylase fractional activity (−/+ 3.3 mm AMP) was similar in both groups in the basal state (about 10 %), but increased to a smaller extent in CK−/− muscles after stimulation (39 ± 4 % vs. 52 ± 4 % in WT, P < 0.05). Inorganic phosphate, the substrate for phosphorylase, increased marginally in CK−/− muscles after stimulation (basal = 25.3 ± 2.2 µmol (g dry muscle)−1; stimulated = 33.9 ± 2.3 µmol (g dry muscle)−1), but substantially in WT muscles (basal = 11.4 ± 0.7 µmol (g dry muscle)−1; stimulated = 54.2 ± 4.5 µmol (g dry muscle)−1). Kinetic studies of phosphorylase b (dephosphorylated enzyme) from muscle extracts in vitro demonstrated higher relative activities in CK−/− muscles (60–135 %) in response to low AMP concentrations (up to 50 µm) in both the basal state and after stimulation (P < 0.05), whereas no differences in activity between CK−/− and WT muscles were observed at high AMP concentrations (> 100 µm). These data indicate that allosteric activation of phosphorylase b accounts for the accelerated glycogenolysis in CK−/− muscle during contraction.
The Effects of Spermine on the Accessibility of Residues in the M2 Segment of Kir2.1 Channels Expressed in Xenopus Oocytes
Authors: Chang Hsueh‐Kai , Yeh Shih‐Hao , Shieh Ru‐Chi
Published: September 2003

We examined the effects of spermine binding to aspartate at site 172 on the accessibility of internal trimethylammonioethylmethane thiosulphonate (MTSET) to substituted cysteines within the pore of a Kir2.1 channel. Spermine prevented MTSET modification in Q164C and G168C mutants, indicating that sites 164 and 168 are located externally to the spermine binding site. The rates of MTSET modification were significantly reduced by spermine in I176C mutants, indicating that site 176 is located internally to D172 and that the bound spermine hinders the reaction of MTSET with cysteine at site 176. Spermidine, putrescine and Mg2+ also decreased MTSET modification at site 176. The order of effect is putrescine > spermidine ∼ spermine ≈ Mg2+. To account for the electrostatic and physical repulsion between MTSET and polyamines, possible locations of polyamines in the pore are discussed. In D172C mutants, the spermine that bound to sites 224 and 299 completely inhibited channels at +40 mV, yet MTSET remained accessible to site 172. In addition, in the D172C mutant, spermine did not affect the exit rate of Ba2+ bound to the threonine at the site 141. These results indicate that spermine bound at the cytoplasmic pore induces channel closure at positions 141‐172. The effects of spermine on the accessibility of amino acids in the pore may shed light on the structural and functional relationships of the Kir2.1 channels during inward rectification.
Isolation and Characterization of Viruses Related to the SARS Coronavirus from Animals in Southern China
Authors: Guan Y. , Zheng B. J. , He Y. Q. , Liu X. L. , Zhuang Z. X. , Cheung C. L. , Luo S. W. , Li P. H. , Zhang L. J. , Guan Y. J. , Butt K. M. , Wong K. L. , Chan K. W. , Lim W. , Shortridge K. F. , Yuen K. Y. , Peiris J. S. M. , Poon L. L. M.
Published: September 2003

A novel coronavirus (SCoV) is the etiological agent of severe acute respiratory syndrome (SARS). SCoV-like viruses were isolated from Himalayan palm civets found in a live-animal market in Guangdong, China. Evidence of virus infection was also detected in other animals (including a raccoon dog,
Nyctereutes procyonoides
) and in humans working at the same market. All the animal isolates retain a 29-nucleotide sequence that is not found in most human isolates. The detection of SCoV-like viruses in small, live wild mammals in a retail market indicates a route of interspecies transmission, although the natural reservoir is not known.
Transcriptional Repression of Atherogenic Inflammation: Modulation by PPARδ
Authors: Lee Chih-Hao , Chawla Ajay , Urbiztondo Ned , Liao Debbie , Boisvert William A. , Evans Ronald M.
Published: September 2003

The formation of an atherosclerotic lesion is mediated by lipid-laden macrophages (foam cells), which also establish chronic inflammation associated with lesion progression. The peroxisome proliferator-activated receptor (PPAR) γ promotes lipid uptake and efflux in these atherogenic cells. In contrast, we found that the closely related receptor PPARδ controls the inflammatory status of the macrophage. Deletion of PPARδ from foam cells increased the availability of inflammatory suppressors, which in turn reduced atherosclerotic lesion area by more than 50%. We propose an unconventional ligand-dependent transcriptional pathway in which PPARδ controls an inflammatory switch through its association and disassociation with transcriptional repressors. PPARδ and its ligands may thus serve as therapeutic targets to attenuate inflammation and slow the progression of atherosclerosis.
Essential Roles for Ecdysone Signaling During
Drosophila
Mid-Embryonic Development
Authors: Kozlova Tatiana , Thummel Carl S.
Published: September 2003

Although functions for the steroid hormone ecdysone during
Drosophila
metamorphosis have been well established, roles for the embryonic ecdysone pulse remain poorly understood. We show that the EcR-USP ecdysone receptor is first activated in the extraembryonic amnioserosa, implicating this tissue as a source of active ecdysteroids in the early embryo. Ecdysone signaling is required for germ band retraction and head involution, morphogenetic movements that shape the first instar larva. This mechanism for coordinating morphogenesis during
Drosophila
embryonic development parallels the role of ecdysone during metamorphosis. It also provides an intriguing parallel with the role of mammalian extraembryonic tissues as a critical source of steroid hormones during embryonic development.
High Levels of Interleukin-1 in Patients with Endemic Pemphigus Foliaceus
Authors: Rocha-Rodrigues Denise Bertulucci , Paschoini Giovana , Pereira Sanivia Aparecida Lima , Reis Marlene Antonia dos , Teixeira Vicente de Paula Antunes , Rodrigues Virmondes
Published: September 2003

Endemic pemphigus foliaceus (EPF) is an autoimmune disease characterized by blister formation with a loss of cohesion and infiltration of inflammatory cells. We observed that supernatants of peripheral blood mononuclear cells from patients produced significantly more interleukin-1β (IL-1β) than those from stimulated healthy controls. Furthermore, a Th2 bias was observed in EPF patients when the IL-5/gamma interferon ratio was analyzed. These results indicate that cells from pemphigus patients react with a vigorous proinflammatory response.