bluuebunny/crossref_metadata_2025 huggingface dataset:
Distribution of the Beijing Family Genotypes of
Mycobacterium tuberculosis
in Taiwan
Authors: Jou Ruwen , Chiang Chen-Yuan , Huang Wei-Lun
Published: January 2005

To investigate the distribution of the Beijing family genotypes of
Mycobacterium tuberculosis
in Taiwan, we collected 421
M. tuberculosis
complex clinical isolates at random from four geographic regions of Taiwan and analyzed them by spacer oligonucleotide typing (spoligotyping) in 2003. We found 113 resolved spoligotypes, among which we identified 28 (24.8%) clusters. One hundred eighty-seven (44.4%) isolates were Beijing family genotypes and consisted of 172 (40.9%) characteristic Beijing genotypes and 15 (3.6%) Beijing-like ones. We also found that substantially larger proportions of tuberculosis patients were infected with Beijing family genotypes in the northern (51.6%) and eastern (46.2%) regions of Taiwan, while 31.6 and 28.0% of the tuberculosis patients in the central and southern regions, respectively, were infected with these genotypes. The proportion of Beijing genotype isolates was the highest in patients below the age of 24 years (61.5%), the second highest in elderly patients over age 65 years (46.8%), and the lowest in middle-age patients between the ages of 45 and 54 years (34.0%). Geographic location and age were found by multivariate analysis to be associated with Beijing family genotypes. Antituberculosis drug resistance was found more often in Beijing family genotype strains (46.4%) than in non-Beijing family genotype strains (34.3%), with more Beijing family genotype strains being resistant to ethambutol and isoniazid. These findings suggest that
M. tuberculosis
Beijing family genotypes have been dominant for several decades and that they are the cause of a significant proportion of the recent transmissions of tuberculosis in Taiwan.
Risk and supervised exercise: the example of anorexia to illustrate a new ethical issue in the traditional debates of medical ethics
Authors: Giordano S
Published: January 2005

Sport and physical activityisan area that remains relatively unexplored by contemporary bioethics. It is, however, an area in which important ethical issues arise. This paper explores the case of the participation of people with anorexia nervosa in exercise. Exercise is one of the central features of anorexia. The presence of anorexics in exercise classes is becoming an increasingly sensitive issue for instructors and fitness professionals. The ethics of teaching exercise to anorexics has, however, seldom, if ever, been addressed. Codes of ethics and legislation do not offer guidelines pertinent to the case and it is left unclear whether anorexics should be allowed to participate in exercise classes. It is shown by this paper that there are strong ethical reasons to let anorexics participate in exercise classes. However, the paper also explains why, despite these apparently cogent ethical reasons, there is no moral obligation to allow a person with anorexia to take part in exercise/sports activities.
Informed consent should be obtained from patients to use products (skin substitutes) and dressings containing biological material
Authors: Enoch S , Shaaban H , Dunn K W
Published: January 2005

Background:Biological products (tissue engineered skin, allograft and xenograft, and biological dressings) are widely used in the treatment of burns, chronic wounds, and other forms of acute injury. However, the religious and ethical issues, including consent, arising from their use have never been addressed in the medical literature.

Aims:This study was aimed to ascertain the views of religious leaders about the acceptability of biological products and to evaluate awareness among healthcare professionals about their constituents.

Methods:The religious groups that make up about 75% of the United Kingdom population were identified and a questionnaire on 11 biological products was sent to its leaders. Another questionnaire concerning 17 products (11 biological and 6 synthetic dressings) was sent to 100 healthcare professionals working in seven specialist units in the UK.

Results:All religious leaders (100% response rate) replied, some after consultation with international bodies. Among them, 77% said that patients should be informed of the constituents of the biological products and consent obtained. Some leaders expressed concerns about particular products including the transmission of viral and prion diseases, cruelty to animals, and material derived from neonates. None of the healthcare professionals (73% response rate) surveyed knew the constituents of all the products correctly.

Conclusion:Ignoring religious sensitivities and neglecting consent in the usage of biological products could have very serious implications, including litigation. Hospitals and manufacturers should take immediate measures to enlighten healthcare professionals of the constituents of these products so that they can obtain informed consent from patients.
Battle over NatSteel: Undervaluation or Inimitable Foresight?
Authors: Lim Ghee Soon
Published: January 2005

On June 3, 2002, Singapore's longest corporate takeover battle broke out at NatSteel Ltd when its president Ang Kong Hua, together with his senior managers, launched a management buyout offer to acquire the only steel miller in Singapore. The management buyout offer for a government-linked company was unprecedented in terms of size. In the ensuing months, numerous twists and turns related to the saga emerged, making the takeover battle one of the most memorable and reported events in Singapore's corporate history. The long and winding case can be approached from three perspectives, namely, corporate finance, law, and strategic management. Readers would gain a lot of insight by looking at the case from all three perspectives instead of only one or two of them. A rich understanding of the dynamics of this case should help students understand and appreciate the many thorny and agonizing issues which real-life decision makers in the corporate world must face and address.
Computime, Limited: Chinas Boom Times Cause Growing Pains
Authors: Chua Bee-Leng , Young Michael N. , Zou Xi
Published: January 2005

Computime Ltd, a China-based family business, was forced to restructure and rationalize its chain of command due to rapid growth. By 2003, Computime had been able to leverage the low cost and manufacturing prowess of China-based businesses to become one of the world's largest Original Equipment Manufacturers (OEM). Yet, the company was facing growing pains, as its simple organizational structure began to run into coordination and control problems. This case outlines the obstacles and decisions facing the CEO, Bernard AuYang as he attempted to navigate the organization through this turbulent time. Bernard was hoping to keep the company on its growth trajectory and he was convinced that Computime's functional organization structure must be transformed into a multidivisional structure with decentralized business units. In this manner the institutional structure within the organization would be better aligned with the more rational institutional environment that the organization was facing. This case illustrates the obstacles which the CEO must overcome to make see his goals to fruition. Specifically, it emphasizes how he drew the restructuring plan and sought support from the cautious board members and other organization members who were resisting change. It also looks at issues of leadership and human resource management during organizational change.
Integrated model of hepatic and peripheral glucose regulation for estimation of endogenous glucose production during the hot IVGTT
Authors: Krudys Kevin M. , Dodds Michael G. , Nissen Stephanie M. , Vicini Paolo
Published: January 2005

We have developed a new model to describe endogenous glucose kinetics during a labeled (hot) intravenous glucose tolerance test (IVGTT) to derive a time profile of endogenous glucose production (EGP). We reanalyzed data from a previously published study (P. Vicini, J. J. Zachwieja, K. E. Yarasheski, D. M. Bier, A. Caumo, and C. Cobelli. Am J Physiol Endocrinol Metab 276: E285–E294, 1999), in which insulin-modified [6,6-2H2]glucose-labeled IVGTTs (0.33 g/kg glucose) were performed in 10 normal subjects. In addition, a second tracer ([U-13C]glucose) was infused in a variable rate to clamp the endogenous glucose tracer-to-tracee ratio (TTR). Our new model describing endogenous glucose kinetics was incorporated into the two-compartment hot minimal-model structure. The model gave estimates of glucose effectiveness [1.54 ± 0.31 (SE) ml·kg−1·min−1], insulin sensitivity (37.74 ± 5.23 104 dl·kg−1·min−1·μU−1·ml), and a new parameter describing the sensitivity of EGP to the inhibitory effect of insulin (IC50 = 0.0195 ± 0.0046 min−1). The model additionally provided an estimate of the time course of EGP showing almost immediate inhibition, followed by a secondary inhibitory effect caused by infusion of insulin, and a large overshoot as EGP returns to its basal value. Our estimates show very good agreement with those obtained via deconvolution and the model-independent TTR clamp technique. These results suggest that the new integrated model can serve as a simple one-step approach to obtain metabolic indexes while also providing a parametric description of EGP.
Collecting duct-specific knockout of endothelin-1 alters vasopressin regulation of urine osmolality
Authors: Ge Yuqiang , Ahn Dowahn , Stricklett Peter K. , Hughes Alisa K. , Yanagisawa Masashi , Verbalis Joseph G. , Kohan Donald E.
Published: January 2005

In vitro studies suggest that endothelin-1 (ET-1) inhibits vasopressin (AVP)-stimulated water permeability in the collecting duct (CD). To evaluate the role of CD-derived ET-1 in regulating renal water metabolism, the ET-1 gene was selectively disrupted in the CD (CD ET-1 KO). During normal water intake, urinary osmolality (Uosm), plasma Na concentration, urine volume, and renal aquaporin-2 (AQP2) levels were unchanged, but plasma AVP concentration was reduced in CD ET-1 KO animals. CD ET-1 KO mice had impaired ability to excrete an acute, but not a chronic, water load, and this was associated with increased CD ET-1 mRNA in control, but not CD ET-1 KO, mice. In response to continuous infusion of 1-desamino-8-d-arginine vasopressin, CD ET-1 KO mice had greater increases in Uosm, V2 and AQP2 mRNA, and phosphorylation of AQP2. CD suspensions from CD ET-1 KO mice had enhanced AVP- and forskolin-stimulated cAMP accumulation. These data indicate that CD ET-1 KO increases renal sensitivity to the urinary concentrating effects of AVP and suggest that ET-1 functions as a physiological autocrine regulator of AVP action in the CD.
Referral of Tactile Sensation to the Tips of L-Shaped Sticks
Authors: Yamamoto Shinya , Moizumi Shunjiro , Kitazawa Shigeru
Published: January 2005

When we touch something with a tool, we feel the touch at the tip of the tool rather than at the hand that holds the tool. We reported previously that judging the temporal order of two successive stimuli delivered to the tips of straight sticks held in each hand was dramatically altered by crossing the sticks without changing hand position. The results suggested that tactile signals are referred to the tip of a tool held in the hand. Here we examined temporal order judgement using L-shaped sticks instead of straight ones to determine whether the shape of a tool affects the way tactile signals are referred. Subjects reported the order of stimuli correctly in most trials when the tip of each L-shaped stick occupied the hemispace ipsilateral to the anatomical laterality of the hand holding the L-shaped stick. The subjects, however, misreported the order of stimuli presented at moderately short intervals (<300 ms) when the tip of the stick occupied the hemispace contralateral to the anatomical laterality of the hand holding it. The judgment reversal occurred irrespective of the number of physical crossings between the sticks and the arms (0, 1, and 3), as long as the tips of L-shaped tools were placed in the contralateral hemispace. Our results suggest that our brain refers tactile signals from the hand directly to the location of the tip without much accounting for the route that connects hand and tip.
Atmospheric Emitted Radiance Interferometer. Part I: Instrument Design
Authors: Knuteson R. O. , Revercomb H. E. , Best F. A. , Ciganovich N. C. , Dedecker R. G. , Dirkx T. P. , Ellington S. C. , Feltz W. F. , Garcia R. K. , Howell H. B. , Smith W. L. , Short J. F. , Tobin D. C.
Published: January 2005

A ground-based Fourier transform spectrometer has been developed to measure the atmospheric downwelling infrared radiance spectrum at the earth's surface with high absolute accuracy. The Atmospheric Emitted Radiance Interferometer (AERI) instrument was designed and fabricated by the University of Wisconsin Space Science and Engineering Center (UW-SSEC) for the Department of Energy (DOE) Atmospheric Radiation Measurement (ARM) Program. This paper emphasizes the key features of the UW-SSEC instrument design that contribute to meeting the AERI instrument requirements for the ARM Program. These features include a highly accurate radiometric calibration system, an instrument controller that provides continuous and autonomous operation, an extensive data acquisition system for monitoring calibration temperatures and instrument health, and a real-time data processing system. In particular, focus is placed on design issues crucial to meeting the ARM requirements for radiometric calibration, spectral calibration, noise performance, and operational reliability. The detailed performance characteristics of the AERI instruments built for the ARM Program are described in a companion paper.
Atmospheric Emitted Radiance Interferometer. Part II: Instrument Performance
Authors: Knuteson R. O. , Revercomb H. E. , Best F. A. , Ciganovich N. C. , Dedecker R. G. , Dirkx T. P. , Ellington S. C. , Feltz W. F. , Garcia R. K. , Howell H. B. , Smith W. L. , Short J. F. , Tobin D. C.
Published: January 2005

The Atmospheric Emitted Radiance Interferometer (AERI) instrument was developed for the Department of Energy (DOE) Atmospheric Radiation Measurement (ARM) Program by the University of Wisconsin Space Science and Engineering Center (UW-SSEC). The infrared emission spectra measured by the instrument have the sensitivity and absolute accuracy needed for atmospheric remote sensing and climate studies. The instrument design is described in a companion paper. This paper describes in detail the measured performance characteristics of the AERI instruments built for the ARM Program. In particular, the AERI systems achieve an absolute radiometric calibration of better than 1% (3σ) of ambient radiance, with a reproducibility of better than 0.2%. The knowledge of the AERI spectral calibration is better than 1.5 ppm (1σ) in the wavenumber range 400– 3000 cm−1.
Gas Exchange and Bubble-Induced Supersaturation in a Wind-Wave Tank
Authors: Bowyer Peter , Woolf David
Published: January 2005

Gas exchange and bubble-induced supersaturation were measured in a wind-wave tank using total gas saturation meters. The water in the tank was subjected to bubbling using a large number of frits at a depth of 0.6 m.

A simple linear model of bubble-mediated gas exchange implies that this should force an equilibrium supersaturation of 3%. This is confirmed by experiment, but a small additional steady-state supersaturation is also forced by warming. The total steady-state supersaturation is approached asymptotically.

When the bubblers were switched off, the total gas pressure approached a new steady state at much lower supersaturation, at a rate that depended on the state of the wind and waves in the tank. The rates of approach on the various equilibria enabled the gas flux across the surface of the bubbles or across the air–water interface to be calculated.

In addition a series of experiments was conducted where the water was subjected to bubbling in the presence of wind or wind and paddle waves: in this case gas invasion from the bubbles was balanced by gas evasion near or at the surface resulting in an equilibrium at <3% and enabling the relative strength of the invasion and evasion to be estimated.

Gas concentrations could be measured in a rapid, automated manner using simple apparatus. To derive gas fluxes, corrections for changes in water temperature and fluctuations in air pressure are necessary, and these are quantified. In addition, transient fluctuations in gas concentration at the start of bubbling periods allowed mixing within the tank to be observed.
The Residual GEM Technique and Its Application to the Southwestern Japan/East Sea
Authors: Mitchell D. A. , Wimbush M. , Watts D. R. , Teague W. J.
Published: January 2005

The standard gravest empirical mode (GEM) technique for utilizing hydrography in concert with integral ocean measurements performs poorly in the southwestern Japan/East Sea (JES) because of a spatially variable seasonal signal and a shallow thermocline. This paper presents a new method that combines the U.S. Navy's Modular Ocean Data Assimilation System (MODAS) static climatology (which implicitly contains the mean seasonal signal) with historical hydrography to construct a “residual GEM” from which profiles of such parameters as temperature (T) and specific volume anomaly (δ) can be estimated from measurements of an integral quantity such as geopotential height or acoustic echo time (τ). This is called the residual GEM technique. In a further refinement, sea surface temperature (SST) measurements are included in the profile determinations. In the southwestern JES, profiles determined by the standard GEM technique capture 70% of the T variance and 64% of the δ variance, while the residual GEM technique using SST captures 89% of the T variance and 84% of the δ variance. The residual GEM technique was applied to optimally interpolated τ measurements from a two-dimensional array of pressure-gauge-equipped inverted echo sounders moored from June 1999 to July 2001 in the southwestern JES, resulting in daily 3D estimated fields of T and δ throughout the region. These estimates are compared with those from direct measurements and good agreement is found between them.
An Axial-Flow Cyclone for Aircraft-Based Cloud Water Sampling
Authors: Straub Derek J. , Collett Jeffrey L.
Published: January 2005

A new aircraft-based cloud water collection system has been developed to provide samples of cloud water for chemical analysis. The collection system makes use of centrifugal separation in an axial-flow cyclone to remove cloud drops from the airstream. An automated sample storage system allows up to seven independent samples to be obtained during a single research flight. The entire collection system is housed in a Particle Measurement Systems (PMS) canister to permit the collector to be used on a range of research aircraft without extensive modification to the collector or the aircraft structure. Computational fluid dynamics (CFD) analysis was used extensively throughout the development of the new collector for component design and to predict internal flow dynamics. CFD-based cloud drop trajectory simulations provided an estimate of collection efficiency as a function of drop size. Based on the numerical modeling, the 50% cut diameter was predicted to be 8 μm. Through a quantitative laboratory calibration using fluorescein-tagged monodisperse drops, CFD predictions of drop deposition patterns in the interior of the axial-flow cyclone were verified. The numerical and experimental evaluations were performed to ensure that the population of collected cloud drops is well characterized. Initial flight testing of the system occurred during the Dynamics and Chemistry of Marine Stratocumulus, Phase II (DYCOMS-II) field project in July 2001. Although the major components of the prototype collection system operated as expected during flight testing, sample collection rates were lower than expected because of the inefficient removal and storage of cloud water collected in the axial-flow cyclone. Actual sample collection rates ranged between 0.1 and 1.2 mL min−1.
A Laterally Averaged Nonhydrostatic Ocean Model
Authors: Bourgault Daniel , Kelley Dan E.
Published: January 2005

A laterally averaged nonhydrostatic model for stratified flow in dynamically narrow domains is presented. Averaging laterally yields the computational efficiency of a two-dimensional model, while retaining some effects associated with variable domain width, such as flow acceleration through contracting channels. The model may be run in both hydrostatic and nonhydrostatic modes, and in the latter case it converges rapidly if the flow is approximately hydrostatic. The model's strengths and weaknesses are illustrated with a series of test cases of increasing complexity. Side-by-side comparisons with laboratory observations show the ability of the model to simulate the structures of nonhydrostatic flows, including shear instabilities and overturning internal waves, with discrepancies becoming apparent mainly for transition to three-dimensional turbulence. Similar results are demonstrated in an application to the stratified sill flow in Knight Inlet, British Columbia. The model reproduces nonhydrostatic features thought to be dynamically important to this system, including the generation of large-amplitude lee waves and shear instabilities.
Evaluation of Wind Vectors Measured by a Bistatic Doppler Radar Network
Authors: Friedrich Katja , Hagen Martin
Published: January 2005

By installing and linking additional receivers to a monostatic Doppler radar, several wind components can be measured and combined into a wind vector field. Such a bistatic Doppler radar network was developed in 1993 by the National Center for Atmospheric Research and has been in operation at different research departments. Since then, the accuracy of wind vectors has been investigated mainly based on theoretical examinations. Observational analysis of the accuracy has been limited to comparisons of dual-Doppler-derived wind vectors always including the monostatic Doppler radar. Intercomparisons to independent wind measurements have not yet been accomplished. In order to become an alternative to monostatic multiple–Doppler applications, the reliability of wind vector fields has to be also proven by observational analysis. In this paper wind vectors measured by a bistatic Doppler radar network are evaluated by 1) internally comparing results of bistatic receivers; 2) comparing with independent wind measurements observed by a second Doppler radar; and 3) comparing with in situ flight measurements achieved with a research aircraft during stratiform precipitation events. Investigations show how reliable bistatically measured wind fields are and how they can contribute highly to research studies, weather surveillance, and forecasting. As a result of the intercomparison, the instrumentation error of the bistatic receivers can be assumed to be within 1 m s−1. Differences between bistatic Doppler radar and independent measurements range mainly between 2 and 3 m s−1.
Hedonic Price Models and Sun-and-Beach Package Tours: The Norwegian Case
Authors: Thrane Christer
Published: January 2005

With the research on hedonic price theory serving as background, this study examined how the overall price of a sun-and-beach package tour was determined by choice of tour operator, choice of destination, hotel star rating, and a number of different attributes characterizing the package tour. In addition, the study drew attention to a particular problem in previous price hedonic tourism research: the possible endogeneity of the hotel star rating variable. To address this issue, a hierarchical regression procedure was adopted. This procedure permitted the tracing of the attributes’ possible indirect effects on overall package tour prices through the hotel star rating variable. The results help consumers identify those package tour attributes that they have to pay extra for as opposed to those that they do not, and at the same time provide tour operators with a useful instrument for strategic pricing.
A Choice Modeling Application for Greek Heritage Attractions
Authors: Apostolakis Alexandros , Jaffry Shabbar
Published: January 2005

The article adopts a discrete choice modeling methodology with a focus on capturing systematic heterogeneity to evaluate tourists’ preferences for two Greek heritage attractions. This methodology provides useful insights on the preferences of tourists belonging in different demand segments while also providing direction for future policy making in this area. The article presents empirical justification for the frequently cited argument for adopting a more customer-oriented rationale for the optimal use of heritage resources. Overall, the article supports the claim that tourists value positively the introduction of services and amenities that improve the quality of customer service. Thus, policy makers and heritage managers should pay more attention to visitors’ needs and their particular requirements.
Rational Choice, Structural Context, and Increasing Returns
Authors: Pedriana Nicholas
Published: January 2005

This article considers one way to construct “analytic” narratives in historical sociology. The author grounds his approach in ongoing methodological debates over temporality and sequence in historical processes and the assumed trade-off between historical particularity and causal generality. He promotes narratives that exploit both the sequential/ eventful and contextual properties of analytic time, with an approach that combines and builds on two emerging developments in narrative methodology: the use of rational choice theory and the idea of “increasing returns” in path-dependent historical processes. While doing narrative in this way will not be appropriate for analyzing all historical processes, it can be a useful methodological strategy for many of the questions, events, and outcomes that interest historical sociologists. The author draws on his own research program on early equal employment law in the mid-to late 1960s to illustrate how this method can work in practice.
Meta-Analysis of Randomized Response Research
Authors: Lensvelt-Mulders Gerty J. L. M. , Hox Joop J. , van der Heijden Peter G. M. , Maas Cora J. M.
Published: January 2005

This article discusses two meta-analyses on randomized response technique (RRT) studies, the first on 6 individual validation studies and the second on 32 comparative studies. The meta-analyses focus on the performance of RRTs compared to conventional question-and-answer methods. The authors use the percentage of incorrect answers as effect size for the individual validation studies and the standardized difference score (d-probit) as effect size for the comparative studies. Results indicate that compared to other methods, randomized response designs result in more valid data. For the individual validation studies, the mean percentage of incorrect answers for the RRT condition is .38; for the other conditions, it is .49. The more sensitive the topic under investigation, the higher the validity of RRT results. However, both meta-analyses have unexplained residual variances across studies, which indicates that RRTs are not completely under the control of the researcher.
Conditions for the Equivalence of the Autoregressive Latent Trajectory Model and a Latent Growth Curve Model With Autoregressive Disturbances
Authors: Hamaker Ellen L.
Published: January 2005

Curran and Bollen combined two models for longitudinal panel data: the latent growth curve model and the autoregressive model. In their model, the autoregressive relationships are modeled between the observed variables. This is a different model than a latent growth curve model with autoregressive relationships between the disturbances. However, when the autoregressive parameter is invariant over time and lies between-1 and 1, it can be shown that these models are algebraically equivalent. This result can be shown to generalize to the multivariate case. When the autoregressive parameters in the autoregressive latent trajectory model vary over time, the equivalence between the autoregressive latent trajectory model and a latent growth curve model with autoregressive disturbances no longer holds. However, a latent growth curve model with time-varying autoregressive parameters for the disturbances could be considered an interesting alternative to the autoregressive latent trajectory model with time-varying autoregressive parameters.
The Internet and Public Participation: State Legislature Web Sites and the Many Definitions of Interactivity
Authors: Ferber Paul , Foltz Franz , Pugliese Rudy
Published: January 2005

The interactive nature of the Internet is seen by some as a technological innovation that might boost participation in politics and civic affairs. That potential, however, is clouded by imprecise definitions of interactivity found among scholars and practitioners alike. Evaluation of state legislature Web sites found them to not be very interactive under most definitions of the term. Chief technology officers of the legislatures appear to differ as to which site features promote interactivity. The current state of these sites may do more to encourage civic engagement than to promote interactivity.
“Whose Barrio Is It?”
Authors: Oguss Greg
Published: January 2005

The popular 1970s sitcom Chico and the Mandepicted whites and Chicanos living side by side in the East L.A. barrio. As a prime-time network series, Chico presented a mediated fantasy space that appealed to utopian possibilities and offered multiple sorts of pleasure and displeasure to a multiracial audience, providing the opportunity to interrogate cultural signs of Otherness or Chicano-ness in comparison to whiteness, which traditionally “never has to acknowledge its role as an organizing principle,” as George Lipsitz states. Although the paternalistic relationship between an older white figure and a young Chicano at the show’s core invokes the racial power dynamics of other 1970s integrated ghetto shows, Chico offers brief disruptive moments that escape this strategy of ideological containment. These highlight the contradictory nature of the show (and TV itself), which often succeeds in quelling minoritized voices but can still be mobilized by them as an instrument for enjoyment/self-affirmation.
Rap1GAP2 is a new GTPase-activating protein of Rap1 expressed in human platelets
Authors: Schultess Jan , Danielewski Oliver , Smolenski Albert P.
Published: January 2005

The Ras-like guanine-nucleotide–binding protein Rap1 controls integrin αIIbβ3 activity and platelet aggregation. Recently, we have found that Rap1 activation can be blocked by the nitric oxide/cyclic guanosine monophosphate (NO/cGMP) signaling pathway by type 1 cGMP-dependent protein kinase (cGKI). In search of possible targets of NO/cGMP/cGKI, we studied the expression of Rap1-specific GTPase-activating proteins (GAPs) and guanine nucleotide exchange factors (GEFs) in platelets. We could detect mRNAs for a new protein most closely related to Rap1GAP and for postsynaptic density-95 discs-large and zona occludens protein 1 (PDZ)–GEF1 and CalDAG-GEFs I and III. Using 5′–rapid amplification of cDNA ends (RACE), we isolated the complete cDNA of the new GAP encoding a 715-amino acid protein, which we have termed Rap1GAP2. Rap1GAP2 is expressed in at least 3 splice variants, 2 of which are detectable in platelets. Endogenous Rap1GAP2 protein partially colocalizes with Rap1 in human platelets. In transfected cells, we show that Rap1GAP2 exhibits strong GTPase-stimulating activity toward Rap1. Rap1GAP2 is highly phosphorylated, and we have identified cGKI as a Rap1GAP2 kinase. cGKI phosphorylates Rap1GAP2 exclusively on serine 7, a residue present only in the platelet splice variants of Rap1GAP2. Phosphorylation of Rap1GAP2 by cGKI might mediate inhibitory effects of NO/cGMP on Rap1. Rap1GAP2 is the first GTPase-activating protein of Rap1 found in platelets and is likely to have an important regulatory role in platelet aggregation.
Rapid detection of intracellular SH2D1A protein in cytotoxic lymphocytes from patients with X-linked lymphoproliferative disease and their family members
Authors: Tabata Yasuhiro , Villanueva Joyce , Lee Susan Molleran , Zhang Kejian , Kanegane Hirokazu , Miyawaki Toshio , Sumegi Janos , Filipovich Alexandra H.
Published: January 2005

Mutations in the SH2D1A gene have been described in most patients with the clinical syndrome of X-linked lymphoproliferative disease (XLP). The diagnosis of XLP is still difficult given its clinical heterogeneity and the lack of a readily available rapid diagnostic laboratory test, particularly in patients without a family history of XLP. XLP should always be a consideration in males with Epstein-Barr virus–associated hemophagocytic lymphohistiocytosis (EBV-HLH). Four-color flow cytometric analysis was used to establish normal patterns of SH2D1A protein expression in lymphocyte subsets for healthy subjects. Three of 4 patients with XLP, as confirmed by the detection of mutations in the SH2D1A gene, had minimal intracellular SH2D1A protein in all cytotoxic cell types. The remaining patient lacked intracellular SH2D1A protein in CD56+ natural killer (NK) and T lymphocytes and had an abnormal bimodal pattern in CD8+ T cells. Carriers of SH2D1A mutations had decreased SH2D1A protein staining patterns compared with healthy controls. Eleven males with clinical syndromes consistent with XLP, predominantly EBV-HLH, had patterns of SH2D1A protein expression similar to those of healthy controls. Four-color flow cytometry provides diagnostic information that may speed the identification of this fatal disease, differentiating it from other causes of EBV-HLH.
Rituximab Plus Short-Duration Chemotherapy As First-Line Treatment for Follicular Non-Hodgkin’s Lymphoma: A Phase II Trial of the Minnie Pearl Cancer Research Network
Authors: Hainsworth John D. , Litchy Sharlene , Morrissey Lisa H. , Andrews Michael B. , Grimaldi Manuel , McCarty Matthew , Greco F. Anthony
Published: January 2005

Purpose

To evaluate the feasibility and efficacy of rituximab with short-duration chemotherapy in the first-line treatment of patients with follicular non-Hodgkin’s lymphoma (NHL).

Patients and Methods

Patients with previously untreated stage II-IV follicular NHL, grade 1 or 2, were eligible for this multicenter phase II trial. All patients received four weekly doses of rituximab (375 mg/m2 intravenous), followed by three courses of combination chemotherapy (either cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP], or cyclophosphamide, vincristine, and prednisone [CVP]) plus rituximab. Patients were evaluated for response after completing treatment, and were then followed up at 3-month intervals.

Results

Between January 2000 and July 2001, 86 patients were treated. Eight-two patients (95%) completed treatment; no patient was withdrawn due to toxicity. The overall response rate was 93%, with 55% complete responses. After a median follow-up of 42 months, the 3- and 4-year actuarial progression-free survivals were 71% and 62%, respectively. Five patients (6%) died from lymphoma; the overall actuarial survival at 3 years was 95%. Grade 3/4 leukopenia occurred in 53% of patients, but only six patients (7%) had neutropenia or fever. Grade 3/4 nonhematologic toxicities were uncommon.

Conclusion

Rituximab plus short-course chemotherapy is well tolerated as first-line treatment for patients with follicular NHL. The overall and complete response rates are similar to those reported with chemotherapy/rituximab combinations of longer duration. The actuarial progression-free survival of 62% at 4 years is encouraging, but further follow-up is necessary. Rituximab plus short-course chemotherapy may prove to be as effective as longer-duration chemotherapy and currently provides an attractive option for first-line treatment of elderly patients and others who tolerate chemotherapy poorly.
Cyclic changes in keratocyte speed and traction stress arise from Ca2+-dependent regulation of cell adhesiveness
Authors: Doyle Andrew D. , Lee Juliet
Published: January 2005

The activation of stretch-activated calcium channels (SACs) in keratocytes can induce spatially coordinated increases in traction stress that promote protrusion at the cell front, while simultaneously inducing retraction at the rear. To investigate how this occurs, we correlated calcium-induced changes in traction stress with alterations in cell speed and shape. Cyclic changes in these parameters were associated with each calcium transient. In addition, an inverse relationship was found between traction stress and cell speed, suggesting that alternating changes in adhesiveness were occurring at the rear. We investigated this further by inhibiting or inducing calcium transients and observing the effects on traction stress, cell speed and shape. Inhibition of calcium transients prevented retraction and led to a slow increase in traction stress. In addition, large aggregates of vinculin developed at the lateral rear edges of treated keratocytes, consistent with an increase in adhesiveness. Induction of a calcium transient resulted in a rapid retraction, involving both increased traction stress and adhesion disassembly at the rear. We also found that keratocytes exhibiting frequent transients generated larger traction stress and moved significantly faster than other cells. Together, these data suggest that calcium transients coordinate changes in adhesiveness with SAC-mediated cycles of mechano-chemical feedback.
Live imaging of bidirectional traffic from the ERGIC
Authors: Ben-Tekaya Houchaima , Miura Kota , Pepperkok Rainer , Hauri Hans-Peter
Published: January 2005

The endoplasmic reticulum-Golgi intermediate compartment (ERGIC) defined by the cycling lectin ERGIC-53 consists of tubulovesicular clusters, but it is unknown if these membranes are transport vehicles or stationary entities. Here, we show by live imaging that GFP-ERGIC-53 mainly localizes to long-lived stationary and some short-lived highly mobile elements. Unlike the anterograde marker VSV-G-GFP, GFP-ERGIC-53 does not vectorially move to the Golgi upon exit from the ERGIC, as assessed by a novel quantitative vector field method. Dual-color imaging of GFP-ERGIC-53 and a secretory protein (signal-sequence-tagged dsRed) reveals that the stationary elements are sites of repeated sorting of retrograde and anterograde cargo, and are interconnected by highly mobile elements. These results suggest that the ERGIC is stationary and not simply a collection of mobile carriers that mediate protein traffic from endoplasmic reticulum to Golgi.
SH3 domain of spectrin participates in the activation of Rac in specialized calpain-induced integrin signaling complexes
Authors: Bialkowska Katarzyna , Saido Takaomi C. , Fox Joan E. B.
Published: January 2005

In this study, we used cultured cells spreading on β3 integrin substrates to examine the possibility that spectrin is involved in signal transduction. Spectrin clustered with specialized calpain-induced β3 integrin signaling complexes that mediate the initial attachment of cells and initiate Rac activation and lamellipodia extension. It was absent from focal complexes and focal adhesions, the integrin complexes that mediate adhesion in lamellipodia and fully spread cells. Spectrin contains a Src homology (SH3) domain of unknown function. Cells overexpressing this domain adhered and calpain-induced integrin signaling complexes formed. However, Rac activation, lamellipodia extension and cell spreading were inhibited. Spreading was restored by overexpression of constitutively active Rac. These studies point to a previously unrecognized role for spectrin and its SH3 domain in initiating Rac activation in the specialized integrin clusters that initiate cell adhesion and spreading. Thus, spectrin may have a pivotal role in initiating integrin-induced physiological and pathological events such as development, proliferation, cell survival, wound healing, metastasis and atherosclerosis.
Evidence that phosphorylation of the microtubule-associated protein Tau by SAPK4/p38δ at Thr50 promotes microtubule assembly
Authors: Feijoo Carmen , Campbell David G. , Jakes Ross , Goedert Michel , Cuenda Ana
Published: January 2005

Phosphorylation regulates both normal and pathological Tau functioning. This microtubule-associated protein plays a role in the organization and integrity of the neuronal cytoskeleton under normal conditions and becomes hyperphosphorylated and aggregated in a number of neurodegenerative diseases referred to as tauopathies. In this study, we identify and compare the residues in human Tau phosphorylated in vitro by all four p38 MAPK isoforms, and study the regulation of the phosphorylation of Thr50, under conditions where p38 MAPKs are active in cells. Through biochemical analysis, loss of function studies and analysis of endogenous and overexpressed Tau proteins, we show that SAPK4/p38δ is the major kinase phosphorylating Thr50 in Tau, when cells are exposed to osmotic stress. We also show that mutation of Thr50 to glutamic acid, which mimics phosphorylation, increases the ability of Tau to promote tubulin polymerisation in vitro and in vivo. Moreover, we show that Thr50 is phosphorylated in filamentous Tau from Alzheimer's disease brain. These findings suggest a role for Tau in the adaptative response of neurons to stress and indicate that SAPK4/p38δ and/or SAPK3/p38δ may contribute to the hyperphosphorylation of Tau in the human tauopathies.
Contribution of the forelimbs and hindlimbs of the horse to mechanical energy changes in jumping
Authors: Bobbert Maarten F. , Santamaría Susana
Published: January 2005

The purpose of the present study was to gain more insight into the contribution of the forelimbs and hindlimbs of the horse to energy changes during the push-off for a jump. For this purpose, we collected kinematic data at 240 Hz from 23 5-year-old Warmbloods (average mass: 595 kg) performing free jumps over a 1.15 m high fence. From these data, we calculated the changes in mechanical energy and the changes in limb length and joint angles. The force carried by the forelimbs and the amount of energy stored was estimated from the distance between elbow and hoof, assuming that this part of the leg behaved as a linear spring. During the forelimb push, the total energy first decreased by 3.2 J kg-1 and then increased again by 4.2 J kg-1 to the end of the forelimb push. At the end of the forelimb push, the kinetic energy due to horizontal velocity of the centre of mass was 1.6 J kg-1 less than at the start, while the effective energy(energy contributing to jump height) was 2.3 J kg-1 greater. It was investigated to what extent these changes could involve passive spring-like behaviour of the forelimbs. The amount of energy stored and re-utilized in the distal tendons during the forelimb push was estimated to be on average 0.4 J kg-1 in the trailing forelimb and 0.23 J kg-1 in the leading forelimb. This means that a considerable amount of energy was first dissipated and subsequently regenerated by muscles, with triceps brachii probably being the most important contributor. During the hindlimb push, the muscles of the leg were primarily producing energy. The total increase in energy was 2.5 J kg-1 and the peak power output amounted to 71 W kg-1.
Vocal tract filtering and sound radiation in a songbird
Authors: Nelson Brian S. , Beckers Gabriël J. L. , Suthers Roderick A.
Published: January 2005

Bird vocalizations resonate as they propagate through a relatively long trachea and radiate out from the oral cavity. Several studies have described the dynamics with which birds actively vary beak gape while singing and it has been hypothesized that birds vary beak gape as a mechanism for varying vocal tract resonances. Nevertheless, few studies have attempted to quantify the effects of beak gape on vocal tract resonances. We replaced eastern towhee, Pipilo erythrophthalmus L., syringes with a small speaker and obtained recordings of frequency sweeps while rotating each subject in a horizontal plane aligned with either the maxilla or mandible. We describe vocal tract resonances as well as how sound radiates as a function of beak gape. Results are inconsistent with the hypothesis that songbirds vary beak gape as a mechanism for `tracking' fundamental frequencies in vocalizations. Instead, decreases in beak gape seem to attenuate resonances that occur between ∼4 and 7.5 kHz. We propose that songbirds vary beak gape as a mechanism for excluding and/or concentrating energy within at least two distinct sound frequency channels.
Sodium-sensitive and -insensitive copper accumulation by isolated intestinal cells of rainbow troutOncorhynchus mykiss
Authors: Burke J. , Handy R. D.
Published: January 2005

The pathway for copper (Cu) uptake across the mucosal membrane into intestinal cells has not been elucidated in fish. Copper accumulation in freshly isolated intestinal cells from rainbow trout Oncorhynchus mykiss was measured after exposure to 0–800 μmol l–1 CuSO4 for 15 min. With external Cu concentration (Cuo) of 800 μmol l–1, the rate of Cu accumulation by cells was 1.88±0.52 nmol Cu mg–1cell protein h–1 compared to 0.05±0.01 nmol Cu mg–1 cell protein h–1 with no added Cuo (means ± s.e.m., N=6). Deduction of a rapid Cu accumulation measured on/in cells at time zero (about 12% of the total Cu uptake when Cuo was 800 μmol l–1)revealed a saturable uptake curve, which reached a plateau at 400 μmol l–1 Cuo (Km=216 μmol l–1 Cuo; Vmax=1.09 nmol Cu mg–1 cell protein h–1; 140 mmol l–1 NaCl throughout). Incubation of cells at 4°C did not prevent Cu accumulation. Lowering external [Na+] to 11 mmol l–1 (low Na+o) generally did not alter the rate of Cu accumulation into the cells over a 15 min period. Under low Na+o conditions Cu accumulation was exponential(non-saturable). Na+-insensitive Cu accumulation dominated (59% of total Cu accumulation) when Cuo was 400 μmol l–1 or less. At high Cuo (800 μmol l–1), removal of Na+ caused a 45% increase in Cu accumulation. Pre-incubation of cells with blocking agents of epithelial Na+ channel (ENaC) for 15 min (normal [NaCl] throughout) caused Cu accumulation rates to increase by 40-fold (100 μmol l–1phenamil), 21-fold (10 μmol l–1 CDPC) or 12-fold (2 mmol l–1 amiloride) when Cuo was 800 μmol l–1 compared to those in drug-free controls. Lowering the external chloride concentration [Cl–]o from 131.6 to 6.6 mmol l–1 (replaced by sodium gluconate) caused the rate of Cu accumulation to increase 11-fold when Cuo was 800μmol l–1. Application of 0.1 mmol l–1DIDS (normal Cl–o) caused a similar effect. Lowering external pH from 7.4 to pH 5.5 produced a 17-fold, saturable,increase in Cu accumulation rate, which was not explained by increased instantaneous Cu accumulation on/in cells at low pH. We conclude that Cu accumulation by intestinal cells is mainly Na+-insensitive and more characteristic of a pH- and K+-sensitive Ctr1-like pathway than Cu uptake through ENaCs.
The pupillary response of cephalopods
Authors: Douglas R. H. , Williamson R. , Wagner H.-J.
Published: January 2005

This paper provides the first detailed description of the time courses of light-evoked pupillary constriction for two species of cephalopods, Sepia officinalis (a cuttlefish) and Eledone cirrhosa (an octopus). The responses are much faster than hitherto reported, full contraction in Sepia taking less than 1 s, indicating it is among the most rapid pupillary responses in the animal kingdom. We also describe the dependence of the degree of pupil constriction on the level of ambient illumination and show considerable variability between animals. Furthermore, both Sepia and Eledone lack a consensual light-evoked pupil response. Pupil dilation following darkness in Sepia is shown to be very variable, often occurring within a second but at other times taking considerably longer. This may be the result of extensive light-independent variations in pupil diameter in low levels of illumination.