bluuebunny/crossref_metadata_2025 huggingface dataset:
Interactive health communication applications for chronic disease: Patient and carer perspectives
Authors: Kerr C , Murray E , Stevenson F , Gore C , Nazareth I
Published: July 2005

Interactive health communication applications (IHCAs) may be particularly useful to patients and carers managing chronic disease. We have run eight focus groups with patients and two with carers involving a total of 40 participants. The focus groups were designed to seek patients’ and carers’ requirements of IHCAs and to identify the criteria they would use to assess them. Analysis revealed that many participants saw the value and potential of IHCAs. Even those with modest previous computer experience could use them with little tuition. The findings from this study have policy implications for the development of applications to maximize the potential benefit of IHCAs to patients and carers.
Patient and provider perspectives on home telecare: Preliminary results from a randomized controlled trial
Authors: Mair F S , Goldstein P , May C , Angus R , Shiels C , Hibbert D , O'connor J , Boland A , Roberts C , Haycox A , Capewell S
Published: July 2005

A randomized controlled trial of home telecare for the management of acute exacerbations of chronic obstructive pulmonary disease has been undertaken in the north-west of England. A videophone was used that communicates via the ordinary telephone network. The intervention period for each participant was two weeks. Participants in the telecare arm of the trial were asked to complete logbooks to record their experiences of each telecare encounter. A simple, self-completed, 10–item questionnaire was used that consisted of a Likert scale, ranging from 1 (totally disagree) to 5 (totally agree). Fourteen nurses completed 150 logbooks and 22 patients completed 145 logbooks. These results demonstrate significant differences in perception between patients and their health-care providers with regard to telecare encounters across all the domains addressed. Participating patients consistently demonstrated more positive views of the telecare encounters than their health-care providers.
Wearable devices for telemedicine applications
Authors: Scheffler M , Hirt E
Published: July 2005

Wearable medical devices can provide both continuous monitoring and ubiquitous treatment. Challenges in this area include the need for a low-power/power-saving design to extend battery life and to reduce the size of the battery itself. This is followed by size and weight restrictions to meet patient expectations of what is ‘wearable’, the biocompatibility of all outer housings and the final assembly concept. Two examples of wearable medical device are described: a wrist-wearable telemedicine monitor for heart patients (AMON) and a generic belt-integrated computing platform for home and hospital use (QBIC). The electrocardiogram (ECG), the blood oxygen saturation (SpO2) sensor and the blood pressure meter of the AMON device were tested with 29 subjects. The sensors were found to be functional, but as expected the data processing algorithms will need some fine-tuning. The prototype QBIC demonstrates a size reduction of 30–50% in relation to comparable devices.
Amino-Truncated β-Amyloid42 Peptides in Cerebrospinal Fluid and Prediction of Progression of Mild Cognitive Impairment
Authors: Vanderstichele Hugo , De Meyer Geert , Andreasen Niels , Kostanjevecki Vesna , Wallin Anders , Olsson Annika , Blennow Kaj , Vanmechelen Eugeen
Published: July 2005

Background: Early identification of patients with mild cognitive impairment (MCI) progressing to Alzheimer disease (MCI-AD) by use of biomarkers in cerebrospinal fluid (CSF) is an essential step toward improving clinical diagnosis and drug development. We evaluated whether different β-amyloid42 (Aβ42) peptides can add further information to the combined use of tau and Aβ1–42 for predicting risk of progression of MCI to AD.

Methods: We used xMAP® technology to simultaneously quantify different Aβ42 peptides modified at the amino terminus, tau, and phosphorylated tau (P-tau181P) in CSF. Aβ42 peptide concentrations were measured by use of immunoreactivity toward Aβ monoclonal antibodies [3D6 (Aβ42-3D6), WO2 (Aβ42-WO2), 6E10 (Aβ42-6E10), and 4G8 (Aβ42-4G8)]. The discriminant ability of the markers was evaluated by ROC curve analysis.

Results: The areas under the curves for the separation of MCI-AD from nonprogressing MCI (MCI-N) were significantly higher when we used Aβ42-3D6/Aβ42-WO2, Aβ42-3D6/Aβ42-6E10, or Aβ42-3D6/Aβ42-4G8 compared with Aβ42-3D6. In addition, differentiation of MCI-N from MCI-AD was improved by quantification of full-length Aβ1–42 (Aβ42-3D6) compared with Aβ42-WO2, Aβ42-6E10, or Aβ42-4G8. Several Aβ42 peptides truncated at the amino terminus (Aβ11–42 and Aβ8–42) were identified in CSF by surface-enhanced laser desorption/ionization time-of-flight technology.

Conclusion: The CSF markers tau, Aβ42 forms, and P-tau181P, when used as adjuncts to clinical diagnosis, have the potential to help identify AD pathology and could be a valuable asset for early AD diagnosis.
Optimized Real-Time Quantitative PCR Measurement of Male Fetal DNA in Maternal Plasma
Authors: Zimmermann Bernhard , El-Sheikhah Ahmad , Nicolaides Kypros , Holzgreve Wolfgang , Hahn Sinuhe
Published: July 2005

Background: Circulating fetal DNA (cfDNA) in maternal plasma has been measured to investigate its possible relationship with pregnancy-related disorders, including fetal trisomy 21 and preeclampsia. The circulating concentrations of single-copy fetal genes, however, are close to the detection limits of PCR methods.

Methods: We optimized a protocol for the real-time quantitative PCR amplification of the multicopy sequence DYS14 on the Y-chromosome. This was compared with an established real-time PCR assay for the single-copy SRY gene.

Results: By probit regression analysis, the measurements of male DNA by the DYS14 assay had a 10-fold lower detection limit (0.4 genome equivalents) than did measurements of SRY. For plasma samples from women in the first trimester of pregnancy, imprecision (CV) was 2%–22% when amplifying DYS14 compared with 26%–140% for SRY.

Conclusions: The low copy numbers of fetal DNA in plasma of women in the first trimester of pregnancy cannot be measured precisely when targeting single-copy sequences. Better results are obtained by amplifying a sequence that is present in multiple copies per male genome.
Direct Molecular Haplotyping of the IVS-8 Poly(TG) and PolyT Repeat Tracts in the Cystic Fibrosis Gene by Melting Curve Analysis of Hybridization Probes
Authors: Millson Alison , Pont-Kingdon Genevieve , Page Sam , Lyon Elaine
Published: July 2005

Background: Molecular haplotyping is a developing technology with great potential for use in clinical diagnostics. We describe a haplotyping method that uses PCR combined with hybridization probes.

Methods: We designed a LightCycler assay that uses fluorescence resonance energy transfer hybridization probes to haplotype the poly(TG) and polyT (TG-T) tract in the IVS-8 region of the CFTR gene. The reporter probe was designed as a perfect match to the TG12-5T allele.

Results: Analysis of 132 samples revealed 9 unique derivative melting temperatures (Tms); the lowest was 42.4 °C and the highest was 63.6 °C. The lowest Tms were in the TGn-9T group, the intermediate Tms in the TGn-7T group, and the highest Tms in the TGn-5T group. Haplotype frequencies were highest (39%) for TG11-7T and lowest (0.4%) for TG13-5T.

Conclusions: Different combinations of polymorphisms under the reporter hybridization probe had unique and characteristic Tms. This property enables genotyping as well as determination of the phase of multiple variants under the probe, a principle we demonstrated by haplotyping the TG-T repeat tract in the IVS-8 region of the CFTR gene.
Routine Isotope-Dilution Liquid Chromatography–Tandem Mass Spectrometry Assay for Simultaneous Measurement of the 25-Hydroxy Metabolites of Vitamins D2 and D3
Authors: Maunsell Zoë , Wright Dennis J , Rainbow Sandra J
Published: July 2005

Background: Measurement of 25-hydroxyvitamin D2 and D3 (25-OH D2 and D3) is essential for investigating vitamin D deficiency. Competitive binding techniques are unable to distinguish between the 2 metabolites and suffer from interference from other hydroxy metabolites of vitamin D.

Methods: We used isotope-dilution liquid chromatography–tandem mass spectrometry (ID-LC-MS/MS) for routine determination of 25-OH D2 and D3 with a stable-isotope–labeled internal standard (IS). Serum samples (100 μL) were denatured with methanol–propanol containing IS, vortex-mixed, extracted into hexane, and dried under nitrogen. The reconstituted extract was chromatographed on a BDS C8 HPLC column, and the metabolites and IS were detected by electrospray ionization MS/MS in multiple-reaction monitoring mode.

Results: 25-OH D2 and D3 and the IS nearly coeluted, whereas 1α-hydroxyvitamin D3 was separated; total run time was 8 min. The interassay CVs for 25-OH D2 were 9.5% and 8.4% at 52 and 76 nmol/L, respectively, and for 25-OH D3 were 5.1% and 5.6% at 55 and 87 nmol/L, respectively. The detection limit of the present method was <4 nmol/L for both metabolites. Method comparison with a commercial RIA measuring total 25-hydroxyvitamin D showed good correlation: y = 0.97x − 2.7 nmol/L (r = 0.91). The analytical system can assay 100 samples in 12.5 h.

Conclusions: This simple robust interference-free LC-MS/MS assay is suitable for routine measurement of the 25-hydroxy metabolites of vitamins D2 and D3 in human serum. The assay has been in use for 9 months and has been used to assay more than 6000 routine samples.
Relation Between Glare and Driving Performance
Authors: Theeuwes Jan , Alferdinck Johan W. A. M. , Perel Michael
Published: July 2005

The present study investigated the effects of discomfort glare on driving behavior. Participants (old and young; U. S. and Europeans) were exposed to a simulated low-beam light source mounted on the hood of an instrumented vehicle. Participants drove at night in actual traffic along a track consisting of urban, rural, and highway stretches. The results show that the relatively low glare source caused a significant drop in detecting simulated pedestrians along the roadside and made participants drive significantly slower on dark and winding roads. Older participants showed the largest drop in pedestrian detection performance and reduced their driving speed the most. The results indicate that the deBoer rating scale, the most commonly used rating scale for discomfort glare, is practically useless as a predictor of driving performance. Furthermore, the maximum U. S. headlamp intensity (1380 cd per headlamp) appears to be an acceptable upper limit.
Ecological Interface Design: Progress and Challenges
Authors: Vicente Kim J.
Published: July 2005

Ecological interface design (EID) is a theoretical framework for designing human-computer interfaces for complex sociotechnical systems. Its primary aim is to support knowledge workers in adapting to change and novelty. This literature review shows that in situations requiring problem solving, EID improves performance when compared with current design approaches in industry. EID has been applied to industry-scale problems in a broad variety of application domains (e.g., process control, aviation, computer network management, software engineering, medicine, command and control, and information retrieval) and has consistently led to the identification of new information requirements. An experimental evaluation of EID using a full-fidelity simulator with professional workers has yet to be conducted, although some are planned. Several significant challenges remain as obstacles to the confident use of EID in industry. Promising paths for addressing these outstanding issues are identified. Actual or potential applications of this research include improving the safety and productivity of complex sociotechnical systems.
The Perceived Utility of Human and Automated Aids in a Visual Detection Task
Authors: Dzindolet Mary T. , Pierce Linda G. , Beck Hall P. , Dawe Lloyd A.
Published: July 2005

Although increases in the use of automation have occurred across society, research has found that human operators often underutilize (disuse) and overly rely on (misuse) automated aids (R. Parasuraman & V. Riley, 1997). Nearly 275 Cameron University students participated in 1 of 3 experiments performed to examine the effects of perceived utility (M. T. Dzindolet, H. P. Beck, L. G. Pierce, & L. A. Dawe, 2001) on automation use in a visual detection task and to compare reliance on automated aids with reliance on humans. Results revealed a bias for human operators to rely on themselves. Although self-report data indicate a bias toward automated aids over human aids, performance data revealed that participants were more likely to disuse automated aids than to disuse human aids. This discrepancy was accounted for by assuming human operators have a "perfect automation" schema. Actual or potential applications of this research include the design of future automated decision aids and training procedures for operators relying on such aids.
Variable-Resolution Displays: A Theoretical, Practical, and Behavioral Evaluation
Authors: Parkhurst Derrick J. , Niebur Ernst
Published: July 2005

Variable-resolution display techniques present visual information in a display using more than one resolution. For example, gaze-contingent variable-resolution displays allocate computational resources for image generation preferentially to the area around the center of gaze, where visual sensitivity to detail is the greatest. Using such displays reduces the amount of computational resources required as compared with traditional uniform-resolution displays. The theoretical benefits, imple-mentational issues, and behavioral consequences of variable-resolution displays are reviewed. A mathematical analysis of computational efficiency for a two-region variable-resolution display is conducted. The results are discussed in relation to applications that are limited by computational resources, such as virtual reality, and applications that are limited by bandwidth, such as internet image transmission. The potential for variable-resolution display techniques as a viable future technology is discussed.
A Sociotechnical Method for Designing Work Systems
Authors: Waterson Patrick E. , Older Gray Melanie T. , Clegg Chris W.
Published: July 2005

The paper describes a new method for allocating work between and among humans and machines. The method consists of a series of stages, which cover how the overall work system should be organized and designed; how tasks within the work system should be allocated (human-human allocations); and how tasks involving the use of technology should be allocated (human-machine allocations). The method makes use of a series of decision criteria that allow end users to consider a range of factors relevant to function allocation, including aspects of job, organizational, and technological design. The method is described in detail using an example drawn from a workshop involving the redesign of a naval command and control (C2) subsystem. We also report preliminary details of the evaluation of the method, based on the views of participants at the workshop. A final section outlines the contribution of the work in terms of current theoretical developments within the domain of function allocation. The method has been applied to the domain of naval C2 systems; however, it is also designed for generic use within function allocation and sociotechnical work systems.
Age and Visual Impairment Decrease Driving Performance as Measured on a Closed-Road Circuit
Authors: Wood Joanne M.
Published: July 2005

In this study the effects of visual impairment and age on driving were investigated and related to visual function. Participants were 139 licensed drivers (young, middle-aged, and older participants with normal vision, and older participants with ocular disease). Driving performance was assessed during the daytime on a closed-road driving circuit. Visual performance was assessed using a vision testing battery. Age and visual impairment had a significant detrimental effect on recognition tasks (detection and recognition of signs and hazards), time to complete driving tasks (overall course time, reversing, and maneuvering), maneuvering ability, divided attention, and an overall driving performance index. All vision measures were significantly affected by group membership. A combination of motion sensitivity, useful field of view (UFOV), Pelli-Robson letter contrast sensitivity, and dynamic acuity could predict 50% of the variance in overall driving scores. These results indicate that older drivers with either normal vision or visual impairment had poorer driving performance compared with younger or middle-aged drivers with normal vision. The inclusion of tests such as motion sensitivity and the UFOV significantly improve the predictive power of vision tests for driving performance. Although such measures may not be practical for widespread screening, their application in selected cases should be considered.
Dimensions of Arousal: Wakefulness and Vigor
Authors: Dickman Scott J.
Published: July 2005

Factors such as shift work, sleep deprivation, and noise affect job performance in part because they affect individuals' levels of arousal. Recent work on arousal has identified two distinct forms of arousal that affect performance in very different ways. Tense arousal represents a continuum from calmness to anxiety, whereas energetic arousal reflects a continuum from tiredness to energy. The three studies reported here sought to determine the usefulness of breaking down energetic arousal still further, into dimensions of wakefulness and vigor. In the first study, a factor analysis of self-reported psychological state data determined that wakefulness and vigor did form separate factors. The second study found that the circadian rhythms of wakefulness and vigor differed; wakefulness increased over the day, whereas vigor peaked at noon. The third study examined the relationship between the two types of arousal and performance on a reading comprehension task. Although both wakefulness and vigor showed an association with performance, only vigor showed the inverted-U-shaped relationship embodied in the Yerkes-Dodson law. These data suggest that distinguishing between wakefulness and vigor will clarify how changes in arousal levels affect productivity. These results also suggest that the schedule for optimal performance of tasks depends on whether they are facilitated by either wakefulness or vigor.
Fixation Disparity: Binocular Vergence Accuracy for a Visual Display at Different Positions Relative to the Eyes
Authors: Jainta Stephanie , Jaschinski Wolfgang
Published: July 2005

Some observers do not fixate accurately at the point of regard: Their vergence angle (between the visual axes of the two eyes) may correspond to points slightly nearer or farther away. This vergence error, or fixation disparity, was measured with nonius (vernier) lines at six positions of a visual display relative to the eyes. At viewing distances of 40, 60, and 100 cm, the display was located either at eye level or at a downward inclination of gaze direction of -25dG relative to horizontal. Viewing conditions resembled typical office work. Lowering the screen induced a near shift in mean vergence response of 0.6 min arc, irrespective of viewing distance; the closer the screen, the more distant was the vergence response relative to the target (by 2.5 min arc on average). The slope of this proximity-fixationdisparity curve is an individual parameter of the vergence system. Actual or potential applications of this research include recommendations for the comfortable viewing distance of visual displays.
LCD versus CRT Displays: A Comparison of Visual Search Performance for Colored Symbols
Authors: Hollands J. G. , Parker H. A. , McFadden S. , Boothby R.
Published: July 2005

Visual search performance for tactical symbols was examined with liquid-crystal (LCD) and cathode-ray tube (CRT) displays. Twenty-four adult participants (19 men, 5 women; mean age 41 years) searched for navy tactical display symbols on a map background. LCD and CRT displays of similar size and resolution (52 cm diagonal, 1280 x 1024 pixels) were used. Viewing angle (0° vs. 60° of azimuth), set size, target color (blue, red, or white), target presence, and search type (feature vs. conjunction) were also manipulated. Participants showed reduced sensitivity for red and blue symbols viewed 60° off axis with the LCD relative to on-axis LCD, or to the CRT on or off axis. Colored symbols viewed off axis on the LCD produced longer response times in feature search and lower search efficiency in conjunction search. The results argue against the use of current LCD technology when off-axis viewing is likely and color coding is used.
Oligodendrocyte Specification in Zebrafish Requires Notch-Regulated Cyclin-Dependent Kinase Inhibitor Function
Authors: Park Hae-Chul , Boyce Janene , Shin Jimann , Appel Bruce
Published: July 2005

Cyclin-dependent kinase inhibitors (Cdkis) influence both cell-cycle progression and differentiation of neural cells. However, the precise roles of Cdkis in coordinating formation of neurons and glia and the mechanisms that regulate expression of genes that encode Cdkis in the vertebrate CNS remain unknown. Here, we report that, in zebrafish, expression of the Cdki genecyclin-dependent kinase inhibitor 1c(cdkn1c), ap57homolog, is negatively regulated by Delta-Notch signaling and that Cdkn1c function is required for neural plate cells to stop dividing and differentiate as neurons on schedule, even in the absence of Notch signaling activity. Furthermore, Cdkn1c function is required for specification of oligodendrocytes from ventral spinal cord precursors. We propose that levels ofcdkn1cexpression are an important factor in regulating neural development: high levels of Cdkn1c promote cell-cycle exit and neuronal development, whereas, during late embryogenesis, neural cells that have low but functional levels of Cdkn1c, regulated by Notch activity, are specified for oligodendrocyte fate.
Neonatal and Adult Neurogenesis Provide Two Distinct Populations of Newborn Neurons to the Mouse Olfactory Bulb
Authors: Lemasson Morgane , Saghatelyan Armen , Olivo-Marin Jean-Christophe , Lledo Pierre-Marie
Published: July 2005

In mammals, the olfactory bulb (OB) constitutes one of two regions of the postnatal brain with continuous neurogenesis throughout life. Despite intense explorations of neuronal replacement in the adult OB, little is known about the mechanisms that operate at earlier postnatal stages. This question is particularly pertinent, because the majority of local interneurons are born in the neonate, when olfaction controls vital functions. Here, we analyzed the recruitment of newborn cells to the granule cell (GC) layer (GCL) and found that the postnatal mouse OB is supplied with two spatiotemporally distinct populations of newborn interneurons.

Early born [postnatal day 3 (P3) to P7] GCs constitute a threefold larger population compared with those generated later (P14-P60), and some of them are produced locally within the OB itself. Newborn interneurons generated at P3-P7 were predominantly targeted to the external edge of the GCL, whereas newly generated cells were positioned deeper in older mice. Additionally, although ∼50% of adult newborn cells were eliminated within a few weeks of reaching the OB, almost the entire population of early born GCs survived until adulthood. Importantly, early olfactory experience specifically modifies the number of newborn GCs in neonates but leaves unaltered the amount of neurons generated during adulthood. Together, these results demonstrate that early postnatal neurogenesis endows the neonate bulbar circuit with newborn GCs that differ morphologically and functionally from those produced in the adult.
Brain Oxytocin Correlates with Maternal Aggression: Link to Anxiety
Authors: Bosch Oliver J. , Meddle Simone L. , Beiderbeck Daniela I. , Douglas Alison J. , Neumann Inga D.
Published: July 2005

The oxytocinergic system is critically involved in the regulation of maternal behavior, which includes maternal aggression. Because aggression has been linked to anxiety, we investigated the maternal aggression and the role of brain oxytocin in lactating Wistar rats selectively bred for high anxiety-related behavior (HAB) or low anxiety-related behavior (LAB) during the 10 min maternal defense test. HAB dams displayed more maternal aggression against a virgin intruder compared with LAB dams, resulting in more defensive behavior and higher anxiety of HAB-defeated virgins. The different levels of aggression were accompanied by opposite oxytocin release patterns within the paraventricular nucleus (PVN; HAB, increase; LAB, decrease). Furthermore, oxytocin release was higher within the central nucleus of the amygdala (CeA) of HAB dams compared with LABs. A direct correlation between the offensive behavior displayed during the maternal defense test and local oxytocin release was found in both the PVN and CeA. Using retrodialysis, blockade of endogenous oxytocin action by infusion of an oxytocin receptor antagonist (des-Gly-NH2,d(CH2)5[Tyr(Me)2,Thr4]OVT) into the PVN or CeA reduced maternal aggression of HAB dams, whereas infusion of synthetic oxytocin into the PVN tended to increase aggression toward the intruder in LAB dams. There were no significant differences in oxytocin receptor mRNA expression or oxytocin receptor binding between lactating HAB and LAB dams. Therefore, differences in intracerebral release patterns of oxytocin, rather than differences at the level of oxytocin receptors, are critical for the regulation of maternal aggressive behavior.
Extended Habit Training Reduces Dopamine Mediation of Appetitive Response Expression
Authors: Choi Won Yung , Balsam Peter D. , Horvitz Jon C.
Published: July 2005

A wide range of behaviors is impaired after disruption of dopamine (DA) transmission, yet behaviors that are reflexive, automatic, or elicited by salient cues often remain intact. Responses triggered by strong external cues appear to be DA independent. Here, we examined the possibility that a single behavior may become DA independent as a result of extended training. Rats were trained to execute a head-entry response to a cue signaling food delivery. Vulnerability of the response to D1or D2receptor blockade was assessed on day 3, 7, or 17 of 28-trial-per-day training. During the early stages of training, the D1receptor antagonistR(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH 23390) increased response latencies; however, the same behavior was unaffected by SCH 23390 in animals tested during the later stages of training. Other aspects of behavior such as locomotion and head-entry responses during the uncued intertrial interval remained vulnerable to SCH 23390 throughout the experiment. This D1-mediated response was unaffected by the D2antagonist raclopride, even at a dose that strongly suppressed locomotion. The results provide strong evidence that a D1-dependent behavior becomes less dependent on DA with extended training. A number of fundamental neurobiological changes occur as behaviors become learned habits; at least for some responses, this change involves a shift from D1-mediated to D1-independent responding.
Age-Associated Alterations of Hippocampal Place Cells Are Subregion Specific
Authors: Wilson Iain A. , Ikonen Sami , Gallagher Michela , Eichenbaum Howard , Tanila Heikki
Published: July 2005

Aging is associated with spatial memory impairments and with deficient encoding of information by the hippocampus. In young adult rats, recent studies on the firing properties of hippocampal neurons have emphasized the importance of the CA3 subregion in the rapid encoding of new spatial information. Here, we compared the spatial firing patterns of CA1 and CA3 neurons in aged memory-impaired rats with those of young rats as they explored familiar and novel environments. We found that CA1 place cells in aged and young rats had similar firing characteristics in the familiar and novel environments. In contrast, aged CA3 place cells had higher firing rates in general and failed to change their firing rates and place fields as much as CA3 cells of young rats when the rats were introduced to a novel environment. Thus, aged CA3 cells failed to rapidly encode new spatial information compared with young CA3 cells. These data suggest an important and selective contribution of CA3 dysfunction to age-related memory impairment.
Lack of NMDA Receptor Subtype Selectivity for Hippocampal Long-Term Potentiation
Authors: Berberich Sven , Punnakkal Pradeep , Jensen Vidar , Pawlak Verena , Seeburg Peter H. , Hvalby Øivind , Köhr Georg
Published: July 2005

NMDA receptor (NMDAR) 2A (NR2A)- and NR2B-type NMDARs coexist in synapses of CA1 pyramidal cells. Recent studies using pharmacological blockade of NMDAR subtypes proposed that the NR2A type is responsible for inducing long-term potentiation (LTP), whereas the NR2B type induces long-term depression (LTD). This contrasts with the finding in genetically modified mice that NR2B-type NMDARs induce LTP when NR2A signaling is absent or impaired, although compensatory mechanisms might have contributed to this result. We therefore assessed the contribution of the two NMDAR subtypes to LTP in mouse hippocampal slices by different induction protocols and in the presence of NMDAR antagonists, including the NR2A-type blocker NVP-AAM077, for which an optimal concentration for subtype selectivity was determined on recombinant and native NMDARs. Partial blockade of NMDA EPSCs by 40%, either by preferentially antagonizing NR2A- or NR2B-type NMDARs or by the nonselective antagonistd-AP-5, did not impair LTP, demonstrating that hippocampal LTP induction can be generated by either NMDAR subtype.
Amyloid-β Peptide Inhibits Activation of the Nitric Oxide/cGMP/cAMP-Responsive Element-Binding Protein Pathway during Hippocampal Synaptic Plasticity
Authors: Puzzo Daniela , Vitolo Ottavio , Trinchese Fabrizio , Jacob Joel P. , Palmeri Agostino , Arancio Ottavio
Published: July 2005

Amyloid-β (Aβ), a peptide thought to play a crucial role in Alzheimer's disease (AD), has many targets that, in turn, activate different second-messenger cascades. Interestingly, Aβ has been found to markedly impair hippocampal long-term potentiation (LTP). To identify a new pathway that might be responsible for such impairment, we analyzed the role of the nitric oxide (NO)/soluble guanylyl cyclase (sGC)/cGMP/cGMP-dependent protein kinase (cGK)/cAMP-responsive element-binding protein (CREB) cascade because of its involvement in LTP. The use of the NO donor 2-(N,N-dethylamino)-diazenolate-2-oxide diethylammonium salt (DEA/NO), the sGC stimulator 3-(4-amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine, or the cGMP-analogs 8-bromo-cGMP and 8-(4-chlorophenylthio)-cGMP reversed the Aβ-induced impairment of CA1-LTP through cGK activation. Furthermore, these compounds reestablished the enhancement of CREB phosphorylation occurring during LTP in slices exposed to Aβ. We also found that Aβ blocks the increase in cGMP immunoreactivity occurring immediately after LTP and that DEA/NO counteracts the effect of Aβ. These results strongly suggest that, when modulating hippocampal synaptic plasticity, Aβ downregulates the NO/cGMP/cGK/CREB pathway; thus, enhancement of the NO/cGMP signaling may provide a novel approach to the treatment of AD and other neurodegenerative diseases with elevated production of Aβ.
lin-8, Which Antagonizes Caenorhabditis elegans Ras-Mediated Vulval Induction, Encodes a Novel Nuclear Protein That Interacts With the LIN-35 Rb Protein
Authors: Davison Ewa M , Harrison Melissa M , Walhout Albertha J M , Vidal Marc , Horvitz H Robert
Published: July 2005

Ras-mediated vulval development in C. elegans is inhibited by the functionally redundant sets of class A, B, and C synthetic Multivulva (synMuv) genes. Three of the class B synMuv genes encode an Rb/DP/E2F complex that, by analogy with its mammalian and Drosophila counterparts, has been proposed to silence genes required for vulval specification through chromatin modification and remodeling. Two class A synMuv genes, lin-15A and lin-56, encode novel nuclear proteins that appear to function as a complex. We show that a third class A synMuv gene, lin-8, is the defining member of a novel C. elegans gene family. The LIN-8 protein is nuclear and can interact physically with the product of the class B synMuv gene lin-35, the C. elegans homolog of mammalian Rb. LIN-8 likely acts with the synMuv A proteins LIN-15A and LIN-56 in the nucleus, possibly in a protein complex with the synMuv B protein LIN-35 Rb. Other LIN-8 family members may function in similar complexes in different cells or at different stages. The nuclear localization of LIN-15A, LIN-56, and LIN-8, as well as our observation of a direct physical interaction between class A and class B synMuv proteins, supports the hypothesis that the class A synMuv genes control vulval induction through the transcriptional regulation of gene expression.
Epistatic Pleiotropy and the Genetic Architecture of Covariation Within Early and Late-Developing Skull Trait Complexes in Mice
Authors: Wolf Jason B , Leamy Larry J , Routman Eric J , Cheverud James M
Published: July 2005

The role of epistasis as a source of trait variation is well established, but its role as a source of covariation among traits (i.e., as a source of “epistatic pleiotropy”) is rarely considered. In this study we examine the relative importance of epistatic pleiotropy in producing covariation within early and late-developing skull trait complexes in a population of mice derived from an intercross of the Large and Small inbred strains. Significant epistasis was found for several pairwise combinations of the 21 quantitative trait loci (QTL) affecting early developing traits and among the 20 QTL affecting late-developing traits. The majority of the epistatic effects were restricted to single traits but epistatic pleiotropy still contributed significantly to covariances. Because of their proportionally larger effects on variances than on covariances, epistatic effects tended to reduce within-group correlations of traits and reduce their overall degree of integration. The expected contributions of single-locus and two-locus epistatic pleiotropic QTL effects to the genetic covariance between traits were analyzed using a two-locus population genetic model. The model demonstrates that, for single-locus or epistatic pleiotropy to contribute to trait covariances in the study population, both traits must show the same pattern of single-locus or epistatic effects. As a result, a large number of the cases where loci show pleiotropic effects do not contribute to the covariance between traits in this population because the loci show a different pattern of effect on the different traits. In general, covariance patterns produced by single-locus and epistatic pleiotropy predicted by the model agreed well with actual values calculated from the QTL analysis. Nearly all single-locus and epistatic pleiotropic effects contributed positive components to covariances between traits, suggesting that genetic integration in the skull is achieved by a complex combination of pleiotropic effects.
The Evolution of Plastic Recombination
Authors: Agrawal Aneil F , Hadany Lilach , Otto Sarah P
Published: July 2005

Empirical data suggest that recombination rates may change in response to stress. To study the evolution of plastic recombination, we develop a modifier model using the same theoretical framework used to study conventional (nonplastic) modifiers, thus allowing direct comparison. We examine the evolution of plastic recombination in both haploid and diploid systems. In haploids, a plastic modifier spreads by forming associations with selectively favored alleles. Relative to nonplastic effects, selection on the plastic effects of a modifier is both much stronger and less sensitive to the specifics of the selection regime (e.g., epistasis). In contrast, the evolution of plastic recombination in diploids is much more restricted. Selection on plasticity requires the ability to detect DNA damage or cis-trans effects as may occur through maternal effects on fitness.
Genetic Analysis of Variation in Gene Expression inArabidopsis thaliana
Authors: Vuylsteke Marnik , van Eeuwijk Fred , Van Hummelen Paul , Kuiper Martin , Zabeau Marc
Published: July 2005

In Arabidopsis thaliana, significant efforts to determine the extent of genomic variation between phenotypically divergent accessions are under way, but virtually nothing is known about variation at the transcription level. We used microarrays to examine variation in transcript abundance among three inbred lines and two pairs of reciprocal F1 hybrids of the highly self-fertilizing species Arabidopsis. Composite additive genetic effects for gene expression were estimated from pairwise comparisons of the three accessions Columbia (Col), Landsberg erecta (Ler), and Cape Verde Islands (Cvi). For the pair Col and Ler, 27.0% of the 4876 genes exhibited additive genetic effects in their expression (α = 0.001) vs. 32.2 and 37.5% for Cvi with Ler and Col, respectively. Significant differential expression ranged from 32.45 down to 1.10 in fold change and typically differed by a factor of 1.56. Maternal or paternal transmission affected only a few genes, suggesting that the reciprocal effects observed in the two crosses analyzed were minimal. Dominance effects were estimated from the comparisons of hybrids with the corresponding midparent value. The percentage of genes showing dominance at the expression level in the F1 hybrids ranged from 6.4 to 21.1% (α = 0.001). Breakdown of these numbers of genes according to the magnitude of the dominance ratio revealed heterosis for expression for on average 9% of the genes. Further advances in the genetic analysis of gene expression variation may contribute to a better understanding of its role in affecting quantitative trait variation at the phenotypic level.
RNA Cleavage Linked With Ribosomal Action
Authors: Yamanishi Haruyo , Yonesaki Tetsuro
Published: July 2005

Ribonuclease LS in Escherichia coli is a potential antagonist of bacteriophage T4. When T4 dmd is mutated, this RNase efficiently cleaves T4 mRNAs and leads to the silencing of late genes, thus blocking T4 growth. We previously found that, when two consecutive ochre codons were placed in the open reading frame of T4 soc, RNase LS cleaved soc mRNA at a specific site downstream of the ochre codons. Here, we demonstrate that RNase LS cleaves soc RNA at the same site even when only a single ochre codon is present or is replaced with either an amber or an opal codon. On the other hand, disruption of the Shine-Dalgarno sequence, a ribosome-binding site required for the initiation of translation, eliminates the cleavage. These results strongly suggest that RNase LS cleaves in a manner dependent on translation termination. Consistent with this suggestion, the cleavage dependency on an amber codon was considerably reduced in the presence of amber-codon-suppressing tRNA. Instead, two other cleavages that depend on translation of the region containing the target sites occurred farther downstream. Additional analysis suggests that an interaction of the ribosome with a stop codon might affect the site of cleavage by RNase LS in an mRNA molecule. This effect of the ribosome could reflect remodeling of the high-order structure of the mRNA molecule.
Eu-heterochromatic Rearrangements Induce Replication of Heterochromatic Sequences Normally Underreplicated in Polytene Chromosomes of Drosophila melanogaster
Authors: Abramov Yuri A , Kogan Galina L , Tolchkov Eugenii V , Rasheva Vanya I , Lavrov Sergei A , Bonaccorsi Silvia , Kramerova Irina A , Gvozdev Vladimir A
Published: July 2005

In polytene chromosomes of D. melanogaster the heterochromatic pericentric regions are underreplicated (underrepresented). In this report, we analyze the effects of eu-heterochromatic rearrangements involving a cluster of the X-linked heterochromatic (Xh) Stellate repeats on the representation of these sequences in salivary gland polytene chromosomes. The discontinuous heterochromatic Stellate cluster contains specific restriction fragments that were mapped along the distal region of Xh. We found that transposition of a fragment of the Stellate cluster into euchromatin resulted in its replication in polytene chromosomes. Interestingly, only the Stellate repeats that remain within the pericentric Xh and are close to a new eu-heterochromatic boundary were replicated, strongly suggesting the existence of a spreading effect exerted by the adjacent euchromatin. Internal rearrangements of the distal Xh did not affect Stellate polytenization. We also demonstrated trans effects exerted by heterochromatic blocks on the replication of the rearranged heterochromatin; replication of transposed Stellate sequences was suppressed by a deletion of Xh and restored by addition of Y heterochromatin. This phenomenon is discussed in light of a possible role of heterochromatic proteins in the process of heterochromatin underrepresentation in polytene chromosomes.
Adaptation in Sexuals vs. Asexuals: Clonal Interference and the Fisher-Muller Model
Authors: Kim Yuseob , Orr H Allen
Published: July 2005

Fisher and Muller's theory that recombination speeds adaptation by eliminating competition among beneficial mutations has proved a popular explanation for the advantage of sex. Recent theoretical studies have attempted to quantify the speed of adaptation under the Fisher-Muller model, partly in an attempt to understand the role of “clonal interference” in microbial experimental evolution. We reexamine adaptation in sexuals vs. asexuals, using a model of DNA sequence evolution. In this model, a modest number of sites can mutate to beneficial alleles and the fitness effects of these mutations are unequal. We study (1) transition probabilities to different beneficial mutations; (2) waiting times to the first and the last substitutions of beneficial mutations; and (3) trajectories of mean fitness through time. We find that some of these statistics are surprisingly similar between sexuals and asexuals. These results highlight the importance of the choice of substitution model in assessing the Fisher-Muller advantage of sex.
Drosophila ATM and Mre11 Are Essential for the G2/M Checkpoint Induced by Low-Dose Irradiation
Authors: Bi Xiaolin , Gong Min , Srikanta Deepa , Rong Yikang S
Published: July 2005

Others have suggested recently that the conserved ATM checkpoint kinase is minimally involved in controlling the G2/M checkpoint in Drosophila that serves to prevent mitotic entry in the presence of DNA damage. Our data indicate that both ATM and its regulator Mre11 are important for the checkpoint and that their roles become essential when animals are challenged with a low dose of X rays or when they have compromised checkpoint function of the ATM-related ATR kinase.
The Extent of Linkage Disequilibrium Caused by Selection on G6PD in Humans
Authors: Saunders Matthew A , Slatkin Montgomery , Garner Chad , Hammer Michael F , Nachman Michael W
Published: July 2005

The gene coding for glucose-6-phosphate dehydrogenase (G6PD) is subject to positive selection by malaria in some human populations. The G6PD A− allele, which is common in sub-Saharan Africa, is associated with deficient enzyme activity and protection from severe malaria. To delimit the impact of selection on patterns of linkage disequilibrium (LD) and nucleotide diversity, we resequenced 5.1 kb at G6PD and ∼2–3 kb at each of eight loci in a 2.5-Mb region roughly centered on G6PD in a diverse sub-Saharan African panel of 51 unrelated men (including 20 G6PD A−, 11 G6PD A+, and 20 G6PD B chromosomes). The signature of selection is evident in the absence of genetic variation at G6PD and at three neighboring loci within 0.9 Mb from G6PD among all individuals bearing G6PD A− alleles. A genomic region of ∼1.6 Mb around G6PD was characterized by long-range LD associated with the A− alleles. These patterns of nucleotide variability and LD suggest that G6PD A− is younger than previous age estimates and has increased in frequency in sub-Saharan Africa due to strong selection (0.1 < s < 0.2). These results also show that selection can lead to nonrandom associations among SNPs over great physical and genetic distances, even in African populations.
Evaluating UV‐B Effects and EDU Protection in Soybean Leaves Using Fluorescence
Authors: Middleton Elizabeth M. , Kim Moon S. , Krizek Donald T. , Bajwa Ravinder K. S.
Published: July 2005

A growth‐chamber experiment was conducted to evaluate whether ethylenenediurea (EDU), a chemical shown to be protective against ozone pollution, could ameliorate foliar damage induced by ultraviolet‐B (UV‐B) radiation exposure in ‘Roanoke’ soybean (Glycine max L.), a UV‐B–sensitive cultivar, and whether these effects could be discriminated using fluorescence (F) observations. The experiment had four treatment groups: control; biologically effective UV‐B (18 kjm−2 day−1); EDU (500 μmol mol−1); and both UV‐B and EDU (UV/EDU). Measurements included photosynthetic pigments, F image system (FIS) images of adaxial surfaces in four spectral regions (blue, green, red and far‐red) and F emission spectra of the pigment extracts produced at two excitation wavelengths, 280 nm (280EX) and 380 nm (380EX). Several F ratios from 280EX, 380EX and the FIS images successfully separated the low UV vs high EDU group responses based on means alone, with intermediate values for controls and the combined UV/EDU groups. A UV‐B/blue emission ratio, F315/F420 (280EX), was correlated with chlorophyll content (μg cm−2)(R= 0.88, P < 0.001), as was a ratio of emissions at two UV‐A wavelengths: F330/F385 (280EX) (R= 0.87). These two 280EX ratios were also linearly correlated with emission ratios produced by 380EX, such as the far‐red/green ratio, F730/F525 (380EX) (R= 0.92, P < 0.001), and clearly distinguished the UV‐B and EDU groups separately, and which bracketed the similar intermediate responses of the UV/EDU and control groups. The FIS images additionally captured the following anatomical spatial patterns across the leaf surfaces: (1) emissions of UV‐B–irradiated leaves were more uniform but lower in intensity than those of other groups; and (2) emissions of EDU‐treated leaves exhibited the greatest variation in spatial patterns because veins had elevated blue F and leaf edges had enhanced red and far‐red F. This experiment supports the hypothesis that EDU substantially ameliorated UV‐B damage to foliage, a result that relied on the combined use of FIS images and emission spectra.
Rapid Detection of Aspergillus flavus Contamination in Peanut with Novel Delayed Luminescence Spectra
Authors: Chen WenLi , Xing Da , Chen WeiGui
Published: July 2005

Employing a luminescence spectrometer the usefulness of light‐induced delayed luminescence (DL) for the detection of aflatoxinB1 (AfB1) contamination in whole peanut was studied. Peanut was artificially contaminated with Aspergillus flavus (7.5 × 105conidia/mL) and incubated for 0–72 h. The DL and fluorescence spectra of contaminated peanut were obtained by a luminescence spectrometer. The correlation between the spectra and contamination levels was established. The DL and fluorescence intensity has a negative correlation with the AfB1 concentration. Our results suggested that the DL technique might be useful for the rapid and noninvasive evaluation of AfB1 contamination levels in whole peanut.